Handbook for Curing the Common Cold: The Zinc Lozenge Story

Handbook o Cu ing he Common Cold
The Zinc Lozenge S o y
Geo ge A. Eby
Copy igh Page
Published by:
Publica ions Di ision
Geo ge Eby Resea ch
Aus in, Texas U.S.A.
Copy igh (c) 1994 by Geo ge A. Eby
All igh s ese ed. Wi h he excep ion o ac ual igu es p esen ed, no pa o his publica ion may be ep oduced, s o ed in a e ie al sys em, o ansmi ed, in any o m
o by any means, elec onic, mechanical, pho ocopying, eco ding, o o he wise wi hou p io w i en pe mission om he au ho . Absolu ely no unau ho ized ep oduc ion
is allowed unde penal y o law.
As long as he sou ce is p ope ly c edi ed, he publishe gi es pe mission o all o ep oduce igu es wi hin his publica ion, as mos echnical igu es a e equa ed wi h
unado ned ac s and hey -- and mos o he echnical igu es and suppo da a ega dless o sou ce -- a e no copy igh able unde exis ing Uni ed S a es case law.
Copy igh (c) 1994 by Cha les A. Pas e nak - Fo ewo d
Copy igh (c) 1994 by Da id A. J. Ty ell - Fo ewo d
Copy igh (c) 1994 by Widad Al-Nakib - Fo ewo d
Copy igh s o a icles in Appendix:
Copy igh (c) 1993 Ame ican Socie y o Mic obiology, "Reduc ion in Du a ion o Common Colds by Zinc Glucona e Lozenges in a Double-Blind S udy." (used wi h
pe mission)
Copy igh (c) 1993 B i ish Socie y o An imic obial Chemo he apy, "P ophylaxis and T ea men o Rhino i us Colds wi h Zinc Glucona e Lozenges." (used wi h
pe mission)
Lib a y o Cong ess Ca alog Ca d Numbe : 93-090841
ISBN: 0-9638967-0-9
P in ed in Aus in, Texas, Uni ed S a es o Ame ica.
Fi s edi ion, i s p in ing: Feb ua y 14, 1994,
In e ne publica ion: Decembe 3, 2002
Dedica ed o my daug he ,
Ka en Lynn Eby
and
se endipi y
Table o Con en s
Chap e 1. In oduc ion - page 1
Magni ude o Heal h P oblem
E iologic Agen s
Seasonal Va ia ion in E iologic Agen s
New E idence o Rhino i uses as P incipal Cause o Colds
Immune Response o he Nose
O e iew o Common Cold T ea men s
In oduc ion o Zinc Glucona e Lozenges
S abili y Cons an s
Calcula ing A ailabili y o Zn2+ Ions
Conside a ion o Body Acid-Base Balance
Chap e 1. Re e ences
Chap e 2. In Vi o E ec s O Zn2+ Ions - page 9
An i i al E ec s o Zinc Ions
An ibac e ial and An i ungal Ac i i y
As ingency
Non-Speci ic Memb ane P o ec ion
Cy olysin
Complemen
Mas Cells
His amine o Kinins in Colds?
T-cell Lymphocy es
In e e on Induc ion
An i-In lamma o y Ac ion
Zinc, S ess, and Common Colds
O e iew o E ec s o Zn2+ Ions in Common Cold The apy
Chap e 2. Re e ences
Chap e 3. Zinc Lozenge Me hod o T ea ing Colds - page 25
Nasal Adminis a ion and Sys emic Abso p ion
O al Ca i y Abso p ion
Mou h-Nose Elec ic Ci cui
Fick's Fi s Law
Ionic Di usion
Zinc Ion A ailabili y (ZIA) Values
Ma hema ics O Common Cold Du a ion
Chap e 3. Re e ences
Chap e 4. E ec s o Zinc Lozenges on Du a ion o Common Colds page - 33
4.A. E ec s O Hyd a ed Zn2+ Ions on Du a ion o Common Colds
4.A.1. O iginal 1984 Eby S udy
Pa ien s
T ea men P o ocol
Resul s o 146-Pa ien S udy
Du a ion o Cold Symp oms
Se e i y o Cold Symp oms
Side E ec s and Complain s
D op-ou s and Signi icance
Zinc Ion A ailabili y
4.A.2. G ea B i ain Medical Resea ch Council Common Cold Uni 1987 S udy
Lozenge Composi ion
Resea ch Design
Resul s o P ophylac ic T ial
Resul s o The apeu ic T ial-Mean Clinical Sco es
Resul s o The apeu ic T ial-Mean Daily Nasal Sec e ion Weigh s
MRC Conclusions
Du a ion o Common Colds and ZIA Calcula ion
Zinc Ion A ailabili y
4.A.3. McNeil 11.5-Mg Zinc Glucona e Lozenge S udy
Resul s o S udy
Cause o Lozenge Bi e ness
Lozenge Fo mula ion
Zinc Ion A ailabili y
4A.4. Danish 4.5-Mg Zinc Glucona e Lozenge S udy
Resul s o S udy
Zinc Ion A ailabili y
4.B. E ec o S ong Zinc Complexes on Du a ion o Common Colds
4.B.1 Zinc O o a e Lozenges wi h Zinc Glucona e Nasal Sp ay S udy
Resul s o S udy
Zinc Ion A ailabili y
4.B.2. Zinc Aspa a e Lozenge S udy
Resul s o S udy
Zinc Ion A ailabili y
C. E ec s o S ong Complexes wi h Ligand in Excess on Du a ion o Common Colds
4.C.1. Ci ic Acid Fla o Masked Zinc Glucona e Lozenge S udy
Zn2+ Ion A ailabili y in he Zinc Glucona e and Ci ic Acid Sys em
Resul s o S udy
Zinc Ion A ailabili y
4.C.2. Aus alian 10 mg Zinc Ace a e E e escen Lozenge S udy
Resul s o S udy
Zinc Ion A ailabili y
4.C.3. Zinc Glucona e-Glycine Lozenge S udy
Zinc Specia ion in he Zinc-Glucona e-Glycine Sys em
E ec s o As ingency
Zinc Ion A ailabili y
D. Summa y and Commen s
Chap e 4. Re e ences
Chap e 5. Cen al Finding o Linea Rela ion be ween ZIA and E icacy - page 63
ZIA Fac o s
Compa a i e ZIA Values
P ojec ion o Nega i e ZIA Values
Tas e Scale and ZIA
Concession o Tas e Th ough Use o a Double Loading Dose
Zn2+ Ions and Zinc Compound Mola Concen a ion wi h ZIA Values
Chap e 5. Re e ences
Chap e 6. E ec s o Fla o -Masking on E icacy - page 71
S ong Chela ion o Zinc
Va ious Non-Chela ing Fla o Masks
Ane hole as Fla o Mask
Low ZIA Value o 5-G am Zinc Glucona e Lozenge
Sea ch o E icacy and Pleasan Tas e
Chap e 6. Re e ences
Chap e 7. Zinc Ace a e Lozenges, Successo o Zinc Glucona e Lozenges - page 77
Zinc Ace a e as Sou ce o Zn2+Ions
Fla o S abili y
7.A. Gene al Lozenge Conside a ions
F uc ose, Suc ose, and Dex ose as Pha maceu ical Ca ie s
Comme cial Di ec ly Comp essible Table Bases
Fla o s
Undesi able Ing edien s
P elimina y Examples o Fla o -S able, Pleasan -Tas ing Zinc Ace a e Lozenges
Table P esses
In oducing mMolT
Tas e Tes s, Zn2+ Ion Mola Concen a ion, and ZIA Values o P elimina y Zinc Ace a e Lozenges
Gene al Lozenge Design Conside a ions o Maximizing ZIA
7.B. S anda d Design Lozenges
Compa ison o Zinc Glucona e and Zinc Ace a e in Iden ical Table Bases
Medicinal Addi i es
7.C. Ad anced Design Lozenges
E ec o Comp essi e Fo ce on Lozenge Dissolu ion Ra e
E ec o Comp essi e Fo ce on ZIA
De e mina ion o Recommended Dosage S eng h
E ec o Fo ce Applied on Lozenge Thickness
D. Sou ces o Lozenge Componen s
E. O he Commen s
O he Fo mula ions
Elimina ing As ingency om Zinc Lozenges
Chap e 7. Re e ences
Chap e 8. Zinc Biochemis y - page 88
Zinc in Gene ics
Gene al Zinc Biochemis y
Zinc, HIV, and AIDS
GRAS S a us Assessmen
Recen Human Sa e y and Toxicologic Da a
Lack o Toxici y in Common Cold S udies
Possible Ad e se E ec in P egnancy
Indus ial Sa e y and Ma e ial Sa e y Da a Shee o Zinc Ace a e
Concluding Commen s on Toxici y
Chap e 8. Re e ences
Chap e 9. Conclusions and Recommenda ions - page 97
Recommended S anda d Zinc Ace a e Lozenge Fo mula ion
Recommended Ad anced Design Zinc Ace a e Lozenge Fo mula ion
Changes in Fo mula ion Allowable
Minimum E ec i e Dose
Manu ac u ing Va iables A ec ing ZIA
Impo ance o Placebo Ma ching
Di e ences in Lozenge Tas e Pe cep ion in Well and Ill Volun ee s
Placebo Lozenge Fo mula Conside a ions
Recommended Placebo Lozenge Fo mula
Recommended Clinical T ial P o ocols
Imp o ing Clinical Resul
Expec ed Clinical Resul s om Ad anced Design Lozenges
Full Ci cle
Expec ed Side E ec s and Con aindica ions
Use o Zinc Ace a e Lozenges o T ea Uppe Respi a o y Alle gy
Use o Zinc Ace a e Lozenges o T ea Mononucleosis
Concluding Rema ks
Chap e 9. Re e ences
Lis o Figu es
Figu e 1. Dis ibu ion o zinc ionic species in he Zn2+ and gluconic acid sys em
Figu e 2. E ec o di e en hal -li es on pe cen o pa ien s wi h symp oms on a ious days, showing weigh ed a e age du a ions
Figu e 3. Du a ion o common colds in ZIA 100 zinc glucona e- and placebo- ea ed g oups
Figu e 4. A e age o al se e i y o colds in ZIA 100 zinc glucona e- and placebo- ea ed g oups
Figu e 5. Daily clinical sco e o ZIA 43.9 zinc glucona e- and placebo- ea ed g oups
Figu e 6. Daily nasal sec e ion weigh s in g ams o ZIA 44 zinc glucona e- and placebo- ea ed g oups
Figu e 7. Du a ion o common colds using bi e ZIA 25 zinc glucona e and placebo
Figu e 8. E ec o e y low dosage ZIA 13.4 zinc glucona e and placebo
Figu e 9. E ec o ZIA 0 zinc o o a e and placebo lozenges and zinc glucona e nasal sp ay
Figu e 10. Es ima ed e ec o ZIA 0 zinc aspa a e and placebo lozenges
Figu e 11. Mole ac ion Zn2+ species e sus pH o solu ion wi h Zn2+ and excess ci ic acid (H3L)
Figu e 12. Mole ac ion o equimola zinc and ci ic acid a 10 mMol
Figu e 13. Es ima ed e ec o ZIA -12.5 zinc glucona e-ci a e and placebo lozenges
Figu e 14. Es ima ed e ec o ZIA -54 zinc ace a e- a a a e-ca bona e lozenges and placebo
Figu e 15. Le e om R. J. E. Williams showing p ocedu e and me hod o p oducing e e escence in zinc ace a e lozenges
Figu e 16. Es ima ed e ec o zinc glucona e-glycine and placebo on du a ion o colds
Figu e 17. E ec o p e ea men cold du a ion o zinc glucona e-glycine ea ed sub-g oups
Figu e 18. Concen a ion o Zn2+, and a ious zinc glycina e and zinc hyd oxide species in he zinc glucona e-glycina e sys em
Figu e 19. Rela ionship o zinc ion a ailabili y (ZIA) alues and educ ion in du a ion o common colds
Figu e 20. Concen a ion o Zn2+ ion in he zinc and ace a e sys em by pH
Figu e 21. E ec o comp essi e o ce upon dissolu ion imes
Figu e 22. E ec o comp essi e o ce upon ZIA alues
Figu e 23. E ec o zinc con en on ZIA and Zn2+ mMol concen a ion
Figu e 24. Rela ionship o lozenge zinc con en o sali a p oduc ion.
Figu e 25. Rela ionship o lozenge zinc con en o lozenge dissolu ion a e
Figu e 26. E ec o o ce applied o lozenge hickness
Figu e 27. Expec ed e ec o ZIA 100 and ZIA 400 lozenges
Lis o Tables
Table 1. Cha ac e is ics o 80 subjec s
Table 2. Numbe o pa ien s epo ing common cold symp oms a a ious imes
Table 3. A e age se e i y o 10 common cold symp oms a a ious imes
Table 4. Side e ec s and complain s
Table 5. 11.5-mg zinc lozenge o mula ion es ed by McNeil Consume P oduc s Company
Table 6. Examples o ci ic acid - sodium bica bona e in e e escen o mula ions om Moh le
Table 7. ZIA ac o s (zinc, ac ion Zn2+, dissolu ion imes, doses pe day and sali a gene a ed)
Table 8. S udy lozenges, ZIA alues, elec onic cha ge, and educ ion in du a ion o colds.
Table 9. Lozenge as e, sali a y pH, nea a e as e and o e nigh a e as e
Table 10. Zinc2+ ion and zinc compound sali a y mola concen a ion compa ed wi h ZIA alues
Table 11. Cha ac e is ics o p elimina y 23-mg zinc (zinc ace a e) 5-g am lozenges ha ing di e en di ec ly comp essible bases
Table 12. Medicinal ing edien s o inco po a ion in o common cold lozenge
Table 13. Ad anced design 15 mg zinc (zinc ace a e) lozenge cha ac e is ics (3.5 and 5.0 g am)
Table 14. A e age zinc con en , ZIA, Zn2+ ion concen a ion and sali a p oduc ion om zinc ace a e lozenges
Table 15. Sou ce and cos o zinc ace a e lozenge ing edien s
Table 16. Possible daily in ake o zinc in millig ams pe kilog am o body weigh
Fo ewa d by Cha les A. Pas e nak, PhD, MD
Today, zinc supplemen s a e ound on he heal h- ood shel es o pha macies and d ug s o es, alongside ginseng, yeas ex ac , and oil o win e g een. Bu le us no
o ge ha oday's al e na i e o homeopa hic medicine -- complemen a y is p obably a be e wo d -- is omo ow's o hodox medicine. The e a e plen y o examples o
illus a e his poin : om he use o digi alis o p e en hea a ack o quinine o p e en mala ia, o he echnique o accina ion o p e en in ec ious disease. The la e is
a pa icula ly s iking example. Th ee cen u ies ago he p ac ice o a iola ion (inhaling he pus om a small-pox ic im o p o ec onesel agains he onse o his
dis igu ing disease) was no so much an old wi es' ale as a young mis ess's ale: ha ing been used o cen u ies ea lie by he Chinese, i was p esc ibed o he
Ci cassian maidens who inhabi ed he sul an's se aglio in he O oman Empi e o p o ec hei luscious skins. Today, ollowing on om he success s o y o he small-pox
accine, billions o dolla s a e being spen by he mos espec ed esea ch es ablishmen s o he wo ld o de elop accines agains mala ia, in luenza, HIV, and a hos o
o he in ec ious agen s. I we had a accine agains hino i uses, we migh no need o igh he common cold wi h Zn2+ ions om zinc lozenges.
The ouble wi h zinc is ha , like i amin C, i is p esen in mos o ou die s in quan i ies su icien o p e en majo de iciency disease ( a e enough, anyway, in he case
o zinc). Why should we ake mo e? The answe lies in he way in which i amins and o he essen ial nu ien s such as i on, coppe , zinc, o iodine wo k: wi h he possible
excep ion o iodine, whose unc ion seems o be con ined o he hy oid gland, mos o he i amins and nu ien s play a ole in p ac ically e e y issue o he body. Fo
example, while he die a y in ake o i amin C o zinc by heal hy people o he Wes e n wo ld may be su icien o p e en scu y o he skin disease o Ac ode ma i is
en e opa hica, espec i ely, his does no mean ha a li le bi ex a may no be bene icial in igh ing a numbe o di e en in ec ious diseases. Fo no only do i amin C
and zinc unc ion in many di e en issues, bu he na u es o hose unc ions a e mani old. Zinc, o example, is equi ed o dozens o qui e di e en molecula
in e ac ions wi hin cells: i is easy o en isage ha a a pa icula die a y in ake mos o hese wo k no mally, bu one o wo a e below pa ; his would place he indi idual
a isk o he onse o disease. Mo eo e , he imposi ion o a pa icula s ess such as a i al in ec ion places addi ional demands on ce ain cells wi hin he body, and no
one should be su p ised ha a highe concen a ion han no mal o a c i ical nu ien such as zinc u ns ou o be bene icial.
Geo ge Eby is a cou ageous man. He is nei he scien is no physician, ye he has ba led wi h he medical es ablishmen and pha maceu ical companies o a decade o
pe suade hem o ake se iously his p oposal ega ding h oa lozenges eleasing Zn2+ ions as an e ec i e ea men o common colds. The e is oom in all walks o li e
o as u e and in elligen men like Geo ge Eby: he challenge om inqui ing and c i ical laymen is o en immensely bene icial o scien is s and physicians se in hei ways.
And who in he Uni ed S a es can doub he con ibu ions made by hei mos eminen layman -- P esiden Thomas Je e son? While Geo ge Eby's sugges ion 15 yea s
ago ha his hospi alized leukemic daugh e be gi en addi ional nu ien s ha included zinc may ha e no been as d ama ic as he decision 250 yea s ago o Lady Ma y
Wo ley Mon ague -- wi e o he B i ish En oy in Cons an inople -- o adminis e a small dose o li e small pox o he son o p o ec him agains subsequen exposu e,
Geo ge Eby may ne e heless ha e s umbled on o mo e han one no el o m o he apy using zinc. Read wha ollows and judge o you sel .
Cha les A. Pas e nak, Ph.D., D.Sc., Hon M.D.
P o esso o Biochemis y
Uni e si y o London a
S Geo ge's Hospi al Medical School
London (UK)
and
Di ec o o he Ox o d In e na ional
Biomedical Cen e
Fo ewo d by Da id AJ Ty ell, MD, Di ec o
Some yea s ago Geo ge Eby no ed ha using zinc glucona e lozenges appa en ly bene i ed his daugh e 's colds, so he o ganized a clinical ial o es he idea. The
esul s showed ha such ea men imp o ed he ou come. Al hough he ial did ha e some aul s, we conduc ed a u he es o his o mula ion in olun ee s gi en
expe imen al colds a he Common Cold Uni a Salisbu y. The esul s o he es seemed o show bene i i he lozenges we e gi en be o e o du ing he cold, ye simila
s udies a he excellen uni a he Uni e si y o Vi ginia ailed o con i m ou indings.
M . Eby has aken expe ad ice and in es iga ed he possibili y ha i isn' me ely he p esence o zinc in he lozenge which ma e s, bu he amoun and du a ion o he
Zn2+ ions eleased ha de e mines whe he he e is an e ec o no . He has combined his own s udies o he cha ac e is ics o he o mula ions used wi h he published
esul s o ials in a ype o me a-analysis. I is no possible o p esen he amoun o bene i in o mally he same e ms, bu he esul s do suppo his case ha he
di e ences migh be due o he elease cha ac e is ics o he Zn2+ ions.
O cou se his doesn' se le he p oblem. I has been sugges ed ha ou ials ailed o con ol adequa ely o he olun ee s guessing whe he hey had ac i e o placebo
lozenges, and so p oduced a spu ious posi i e esul . The e is also he p oblem ha he e is no e idence ha Zn2+ ions ac ually each he in ec ed mucous memb anes in
he nose; howe e , in a sense ha does no ma e as he e a e many examples o ac i e ea men s being disco e ed when he e was no e idence o how hey wo ked.
I is he e o e wo hwhile keeping he deba e open in spi e o he nega i e esul s in some ials and o he much less plausible claims o bene i s om zinc. This book
helps in ha deba e by b inging oge he summa ies o he biology o zinc, he esul s o he ials in common colds and he esul s o he analyses o he o mula ions
used. The ex s o o iginal pape s a e also he e o help he ca e ul eade .
I welcome his book. The bes esul o i s publica ion would be a leas one igo ous ial using zinc lozenges o mula ed wi h p ecisely he cha ac e is ics o hose used
and ecommended by M . Eby, and wi h igo ous moni o ing o he double-blind p ecau ions and he clinical cou se o he pa ien s.
Da id A. J. Ty ell, M.D.,
e i ed Di ec o Common Cold Uni
B i ish Medical Resea ch Council,
Salisbu y (UK)
and cu en ly wi h he:
B i ish Medical Resea ch Council
AIDS Di ec ed P og amme Public Heal h Labo a o y Se ice
Cen e o Applied Mic obiology and Resea ch
Po on Down, Salisbu y, UK
Fo ewo d by Widad Al-Nakib, MD
In 1994, he e con inues o be a deba e as o he e icacy o zinc in he p e en ion and/o ea men o he common cold. The ini ial s udies conduc ed by Eby e al (1984)
did sugges some e icacy al hough he ials we e no pe haps as igo ously con olled as hey should ha e been. We conduc ed double blind placebo-con olled s udies
a he MRC Common Cold Uni in Salisbu y and ound some bene i i he lozenges we e gi en jus be o e o a e he onse o colds. One o he main c i icisms o ou
ials was ha he e was no a su icien numbe o olun ee s in he second phase o he s udy which was he ea men wi h zinc lozenges. S udies in he USA and
Aus alia howe e , ailed o con i m hese indings. This book a emp s o e iew he ole o zinc lozenges in he p e en ion and ea men o he common cold and
summa izes he biology o zinc. I, like Da id Ty ell, he e o e welcome his book and hope ha i would con inue o deba e he subjec u he wi h he hope ha i may
encou age u he con olled ials.

Widad Al-Nakib, MA FRCPa h PhD
P incipal In es iga o , Common cold Uni
B i ish Medical Resea ch Council CCU
cu en ly a Ad anced Pa hology Se ices
London UK
P e ace
In an e o o p o ide a uni ying hypo hesis, his handbook analyzes all epo s o zinc lozenge o common cold esea ch epo ed since publica ion o my 1984 a icle in
An imic obial Agen s and Chemo he apy which documen ed a way o educing he a e age du a ion o common colds by se en days using zinc glucona e lozenges.
Common colds a e mos ly caused by hino i uses, and zinc glucona e is a good sou ce o Zn2+ ions which a e an i hino i al.
The s o y has been old a ound he wo ld o how in 1979 my leukemic 3-yea old daugh e , Ka en, s a ed a e olu ion. She had e used o swallow he 50-mg zinc
supplemen because she had a se e e common cold. Ins ead, she allowed he zinc glucona e able o dissol e slowly in he mou h du ing an a e noon nap, esul ing in
he e mina ion o he cold wi hin se e al hou s -- wi hou u he ea men o elapse. A e his se endipi ous disco e y, I ound simila esul s in o he amily membe s,
iends, and co-wo ke s.
Swallowed able s, nasal oin men s, nasal sp ays, and nose d ops we e also es ed. Nose d ops we e expec ed o wo k be e han lozenges; howe e , no educ ion in
du a ion o common colds was obse ed. The dicho omy was di icul o unde s and, as colds a e an in ec ion o he nose, no he mou h. In e ospec , hese indings a e
consis en wi h published li e a u e da ing om 1901 on zinc ea men o nasal ca a h ia he nasal ou e as a sho -li ed nasal deconges an .
Why? A biologically closed elec ic ci cui (BCEC) be ween he mou h and nose con ols local mo emen o me allic ions. O he many BCECs desc ibed in 1984 by Bjö n
E. W. No dens öm, he mou h-nose BCEC is he mos eadily obse able.
O e a wo-yea expe imen al pe iod om 1979 o 1981, I o malized wha I hough o be he bes p o ocol o using zinc glucona e lozenges. William W. Halcomb (a
gene al p ac ice physician and alle gis now in Mesa, A izona), Donald R. Da is (a nu i ion scien is who wo ked o Na ional Academy o Science membe Roge J.
Williams [deceased] a he Clay on Biochemical Ins i u e Founda ion a he Uni e si y o Texas a Aus in), and I conduc ed he o iginal double-blind s udy using slow-
dissol ing zinc glucona e able s -- as lozenges -- in he all o 1981 o ea wild common colds.
The esul s showed he expec ed e icacy. Zinc glucona e lozenges educed he a e age du a ion o common colds by se en days, wi h excep ionally s ong s a is ical
signi icance om he i s ew hou s, again wi hou elapse o colds. Ou a icle caused o he s o a emp o eplica e ou indings.
In 1984, he Medical-Scien i ic Di ec o o RBS Pha ma-Milan (now pa o Rôhne-Poulenc Pha ma, I alia, S. P. A.), Rinaldo Pelleg ini sough my eam's ad ice on how o
compound zinc glucona e lozenges. By ha ime, my eam had comple ed a no-e ec zinc o o a e (non-ionizable) lozenge o common colds s udy. On he basis o he
con lic ing zinc glucona e and zinc o o a e esul s, we ecommended a oidance o zinc chela o s in lozenges. The pleasan - as ing, uc ose-based RBS Pha ma lozenges
we e es ed on expe imen al colds by Da id A. J. Ty ell and co-wo ke s a he G ea B i ain Medical Resea ch Council (MRC) Common Cold Uni . Analysis o he da a
om he MRC s udy showed nasal sec e ions essen ially e u ned o no mal in he zinc- ea ed g oup by day 4, while colds in he placebo- ea ed g oup con inued.
Analysis o mean clinical sco es showed colds we e essen ially absen in six days wi h zinc ea men . Compa ed o he his o ic a e age o 10.8 days o un ea ed colds,
a educ ion o 4.8 days in common cold du a ion occu ed. Fo he i s ime, an in e na ionally ecognized common cold esea ch g oup e i ied a clinical ea men o
sho en common cold symp oms. The posi i e esul s we e discom i ing o he MRC scien is s, because he ope a i e mechanism emained elusi e.
The issue became con ounded when o he s udies came up wi h di e en indings om he Texas and MRC s udies. Some zinc glucona e lozenges had objec ionable
as e and long-las ing a e as e, se iously impai ing pa ien compliance. Zinc glucona e de eloped a epu a ion o being bi e , and lozenges needed la o -masking.
Ac ually, bi e ness esul s only when zinc glucona e is combined wi h dex ose. Zinc glucona e in uc ose -- as in he MRC lozenges -- as es pleasan when la o ed and
has a mild a e as e. The wide disag eemen be ween s udies caused esea che s o assume he posi i e indings o be aul y. In 1988, le e s o he edi o o
An imic obial Agen s and Chemo he apy sugges ed di e ences in s abili y cons an s as being esponsible o ailu es. The le e s p oduced bo h insigh ul, and misleading
in o ma ion.
In appa en de ense o ci ic acid la o -masked zinc glucona e lozenge wo k, one le e asse ed zinc glucona e-ci a e lozenges p oduced a sali a y pH o 2.3 (s omach
acid pH), con ending one hund ed pe cen o he zinc was eleased as Zn2+ ions.
Realizing he imp obabili y o a sali a y 2.3 pH om use o he zinc glucona e-ci a e lozenges and he imp obabili y o a ailabili y o Zn2+ ions a physiologic pH, Guy
Be hon, Di ec o o Resea ch a INSERM Uni 305 in Toulouse, F ance, en e ed he ay. One esponsibili y o INSERM Uni 305 is o de e mine he bioa ailabili y o
d ugs a physiological pH 7.4, he only ele an pH o an i i als and many o he chemo he apeu ic agen s. De e mina ion o bioa ailabili y is a complex and di icul e o
in ol ing solu ion chemis y. A e a close collabo a ion be ween Guy Be hon and mysel om 1988 o 1993, a epo was p oduced ho oughly examining bioa ailabili y
o Zn2+ ions om he con lic ing zinc lozenge a icles. The esul ing epo , -- The "Zinc Lozenge and Common Cold S o y" -- is published sepa a ely by Ma cel Dekke ,
Inc. in Handbook o Me al-Ligand In e ac ions in Biological Fluids, edi ed by Guy Be hon. We all owe Guy Be hon ou g a i ude. Had he no in e ened, he wo k would
ha e died, and I would ha e gone on o do some hing else, disillusioned and disappoin ed. Wo se, an e ec i e cu e o he common cold would ha e been bu ied and
p obably ne e esu ec ed.
P esen a ion o comp ehensi e solu ion chemis y da a is pa o he analysis o he a ious con lic ing epo s in his handbook. Guy Be hon's esea ch demons a ed
Zn2+ ions we e a ailable a physiologic pH om e icacious zinc glucona e lozenges. Mo e impo an ly, he clea ly and con incingly demons a ed Zn2+ ions we e no
a ailable a physiologic pH om non-e icacious lozenges.
Quan i ica ion o he amoun o Zn2+ ions capable o pene a ing o al mucous memb anes h ough lozenge use elies upon Zn ion sali a y concen a ion a pH 7.4 and
ime o con ac , ollowing Fick's laws o memb ane di usion. The zinc ion a ailabili y (ZIA) me hod o analysis discussed in Chap e 3 was de eloped in 1991 as an
applica ion o Fick's laws in a mou h-nose BCEC. ZIA alues a e de e mined by he a ailabili y o Zn2+ ions a pH 7.4 o e ime o abso p ion in o o al mucosal
memb anes.
Elec ical cha ge o zinc species is impo an as Zn2+ ions a e abso bed in o o al issues and ollow a eadily measu able mou h-nose BCEC. Neu al and nega i ely
cha ged species a e una ec ed o epelled, espec i ely, and ha e no known biologic ac i i y in ea ing colds.
Compa ing ZIA alues o he zinc lozenges o he esul an changes in du a ion o colds yields a linea eg ession ha ing a ( ho) alue o 0.96, p o iding econcilia ion o
all p e iously di e gen esul s and a sound s a is ical basis o a uni ying hypo hesis. Fo comple e de ails, see Chap e 5 and examine Figu e 19 en i led "Rela ionship o
zinc ion a ailabili y (ZIA) alues and educ ion in du a ion o common colds." Lozenges ha ing a posi i e ZIA eleased Zn2+ ions and we e bene icial. Lozenges eleasing
no Zn2+ ions p oduced no esul s, and lozenges ha ing nega i e ZIA alues usually wo sened colds.
The ZIA e sus cold du a ion ela ionship also demons a es a me hod o p edic ou come o u u e s udies wi h assu ance o esul s in clinical ials. Linea i y in ZIA --
e sus -- cold du a ion da a is he hea o his handbook and o ms he ounda ion o u u e esea ch.
Chap e 7 discusses zinc ace a e lozenges as he successo o zinc glucona e o use in common cold ea men . Zinc ace a e has essen ially no as e in dex ose o
uc ose a e icacious ZIA alues, and lozenges a e la o -s able when p ope ly o mula ed. Zinc ace a e lozenges elease 100 pe cen o hei zinc as Zn2+ ions a
physiologic pH 7.4. Full ioniza ion o zinc ace a e is a signi ican imp o emen o e zinc glucona e, as zinc glucona e eleases only 30 pe cen Zn2+ ions possible a pH
7.4. Chap e 7 de ails indings ela ing ZIA- o-lozenge dissolu ion a es, comp essi e o ces used in able manu ac u e, zinc dosage, lozenge weigh , and many o he
a iables. Chap e 7 also shows unexpec ed non-linea i y in ZIA alues as zinc ace a e con en is inc eased in lozenges.
Wi hou comp ehensi e solu ion chemis y and ZIA analyses, unde s anding di e ences be ween he zinc lozenges o common cold s udies is impossible, as was ound
by Y. J. Po e and L. L. Ha , who su eyed li e a u e desc ibing use o zinc lozenges o common colds in he May 1993, issue o The Annals o Pha maco he apy. Po e
and Ha we e gi en an impossible ask, as hey only had an idea o he complexi y o he chemis y in ol ed and did no ha e su icien in o ma ion (pa icula ly c i ical
unpublished lozenge design ma e ials om manu ac u e s) o a i e a a co ec conclusion.
I belie e go e nmen al and pha maceu ical company o icials, as well as he public, wan an inexpensi e and sa e cu e o common colds. Un o una ely, p esen socie y
has been augh o equa e common cold cu es o he elusi e oun ains o you h sough cen u ies ago. Wi hou his handbook, he li e a u e seems o suppo ha belie . I
since ely hope his handbook will s imula e medical esea che s wi hou es ed in e es s in o he common cold ea men s o conduc clinical ials o ZIA 50 o 200 zinc
ace a e lozenges o common colds. Be o e he public can bene i , esponsible public and p i a e heal h o icials mus ind he u h o hemsel es. Once he -- no cu e o
he common cold -- able is uni e sally e ealed as alse, pe haps go e nmen al and pha maceu ical company o icials will lis en o my zinc lozenge s o y and he public
will e en ually bene i .
Eng a ed in glis ening whi e ma ble abo e he en ance o he Uni e si y o Texas Main Building in Aus in, Texas, which houses comp ehensi e medical, li e science and
pha maceu ical lib a ies, a e he encou aging Biblical wo ds: "Ye shall know he u h and he u h shall make you ee."
Pe haps he ull u h abou zinc lozenges and common colds es ablished and p ese ed in his handbook will esul in new, ocused esea ch and submission o a New
D ug Applica ion o he Uni ed S a es Food and D ug Adminis a ion o zinc ace a e lozenges as cu e o common colds. I ha e done all I can. I mus place he u u e o
zinc ace a e lozenges as cu e o common colds in he hands o o he s. Le 's see wha will be done. Assuming a ailabili y o app op ia e inances and coope a ion by
common cold au ho i ies and egula o y agencies, we can igh ully expec zinc ace a e lozenges o win app o al o a Food and D ug Adminis a ion New D ug
Applica ion, esul ing in placemen o zinc ace a e lozenges as he cu e o he common cold on he ma ke wi hin he nex i e yea s.
signed Geo ge A.
Eby
Acknowledgmen s
I am deeply indeb ed o a la ge numbe o scien is s, medical esea che s, and o he s o whom I can only say hank you. The ollowing a e acknowledged o speci ic
pa icipa ion:
William W. Halcomb, now o Mesa, A izona, conduc ed ou 1984 clinical ial. Donald R. Da is and Mi chell E. Gidseg o Aus in, Texas, helped in s a is ical analyses,
w i ing he o iginal 1984 ex , and in many ui ul discussions.
B uce D. Ko an , o Du Pon Cen al Resea ch in Wilming on, Delawa e, wo ked wi h Zn2+ ions and hino i uses and p o ided help ul insigh .
Rinaldo Pelleg ini o Milan, I aly, Medical-Scien i ic Di ec o o RBS Pha ma-Milan, ook he ime o isi wi h us and lis en o ou wa nings abou me allic chela o s and
made he la o -masked zinc glucona e lozenges success ully demons a ed by he B i ish Medical Resea ch Council Common Cold Uni in Salisbu y, England (MRC).
Da id A. J. Ty ell and co-wo ke s a he MRC Common Cold Uni had he cou age o publish he clinical u h, e en hough hey could no de e mine he ope a i e
mechanism, and o his kind o ewo d ema ks.
Guy Be hon, Di ec o o Resea ch a INSERM Uni 305 in Toulouse, F ance, wen a ou o his way o help, and single-handedly sa ed his line o esea ch.
Cha les A. Pas e nak, a S . Geo ge's Hospi al Medical School, Uni e si y o London, ook he ime o isi wi h me and explain how Zn2+ ions could s abilize cell plasma
memb anes and pe haps be he means by which zinc lozenges sho en colds. I am also g a e ul o his kind o ewo d.
Bill Bannen o Gene al Nu i ion P oduc s in G een ille, Sou h Ca olina, disclosed he McNeil o mula ion.
Claude. B. Goswick o Texas A&M Uni e si y, College S a ion, Texas, e ealed he ac ual dosages used in he McNeil clinical ial.
Jack M. Gwal ney J ., o he Uni e si y o Vi ginia a Cha lo es ille, Vi ginia, p o ided ank and help ul commen s.
R. B uce Ma in, Uni e si y o Vi ginia a Cha lo es ille, Vi ginia, p o ided he o mula and zinc-ci ic acid specia ion da a applicable o he B is ol Mye s lozenges.
R. J. E. Williams o Faulding LTD, Adelaide, Sou h Aus alia, disclosed he o mula ion o he e e escen lozenges used by Robe M. Douglas. Robe M. Douglas, now
a he Aus alian Na ional Uni e si y, Na ional Cen e o Epidemiology and Popula ion Heal h in Canbe a, has shown con inued in e es .
M. L. McCu cheon o he Uni e si y o Minneso a a Dulu h, sen me an unpublished accoun o hei ailed zinc aspa a e s udy (0 ZIA), which helped show ha no hing
happens i he e a e no zinc ions. I a Hill o Resea ch Di ec ions in Locus , New Je sey, len suppo and echnical assis ance.
James W. McGini y, Salomon A. S a chancsky, Roland A. Bodmeie , and o he s a he D ug Dynamics Ins i u e, College o Pha macy, Uni e si y o Texas in Aus in, ga e
much and a ied assis ance.
Paul T. Zel ze , now a he De elopmen al Biology G oup a UCLA in Los Angeles s a ed me on his line o inqui y while he was my daugh e 's oncologis . Richa d M. Hol
o Child en's Hospi al o Aus in, Texas p o ided pedia ic se ices and pa icpa ed in many help ul con e sa ions. Michael Cas leman, au ho , o San F ancisco,
popula ized zinc lozenges o colds and has gi en me endless suppo .
Allison E. Rowland o Texas A&M Uni e si y, College S a ion, Texas, con ibu ed much-needed edi o ial se ices.
Mos o all, I e y much app ecia e he suppo p o ided o me by my amily. Thelma Lloyd Eby, my mo he (deceased), who inanced he beginning o his esea ch; Pa sy
Ann Eby, my belo ed wi e who gi es and gi es and gi es wi hou end; Ka en Lynn Eby, my belo ed daugh e , and he child who p omp ed he insigh as well as he need
o his line o inqui y a he ende age o h ee; and Colin Ma in Eby, my belo ed son, o his suppo and unde s anding.
signed Geo ge A.
Eby
The Elephan - Adap ed om a Famous Su i S o y
Once he e was a poo Pe sian illage whe e all we e blind. One day a s ange new c ea u e called an elephan appea ed a he illage wall. Since no one in he illage
had e e hea d o an elephan , he h ee wises o he blind illage s wen ou o disco e wha he new c ea u e was like. They all el he c ea u e. The i s blind sage el
he ail and said, "This c ea u e canno be an elephan , his is a ope!" The second blind sage el he leg and said, "No, his is a ee!" The hi d blind sage el he side
and said, "No, you ools, his is a wall!"
As he h ee sages a gued amongs hemsel es, a lesse blind man, no knowing any be e , moun ed he elephan and ode away.
Adap ed om a Famous Su i S o y
Chap e 1. In oduc ion
Execu i e summa y: Chap e 1 in oduces (a) he mul ibillion dolla annual magni ude o he common cold p oblem, (b) new e idence showing hino i uses as he cause
o 60 o 70 pe cen o colds, (c) he immune sys em's esponse o i uses as cause o common cold symp oms, (d) he uni e sal ailu e o exis ing comme cial
ea men s o educe common cold du a ion, (e) he bene icial e ec s o zinc glucona e lozenges con aining 23 mg zinc used e e y wo hou s while awake in educing
symp om se e i y and he a e age du a ion o common colds by se en days, ( ) applicable scien i ic and ma hema ical concep s, and (g) he solu ion chemis y
de e mina ion o a 30 pe cen hyd a ed Zn2+ ion elease om zinc glucona e a physiologic pH 7.4.
Handbook o Cu ing he Common Cold -- The Zinc Lozenge S o y is p o oca i ely i led. Some p o essionals may be inclined o ejec his idea wi hou eading pas he
i s line. I so, conside ha his handbook is a se ious scien i ic w i ing on how o sho en he du a ion o common colds using zinc lozenges. This handbook shows zinc
con en alone is insu icien o de e mine e icacy; a he , he zinc compound used, he o al esidence ime, and o he physical and chemical p ope ies o lozenges
de e mine lozenge e icacy.
Mos people do no belie e a cu e o he common cold will be de eloped un il well in o he 21s cen u y. I he eade is discom o ed by wha he eads, i is because he
handbook dispu es he "no cu e o he common cold" concep ion. Scien is s and physicians some imes become de ensi e, and e en apoplec ic, a he hough o a lowly
ino ganic c ea ed nea he beginning o ime in a dis an supe no a ha ing such no el e ec s. Fo laymen o lea n a simple, eadily manu ac u ed common cold cu e is
a ailable now, and o ind majo pha maceu ical companies ha e igno ed i can be a sou ce o conside able i i a ion as well. Pe haps hose companies ha e u ned away
only because hey ha e no unde s ood he complex issues and solu ion chemis y in ol ed.
A medical name o such ejec ion is he " oma o e ec ," acco ding o D s. James and Jean Goodwin w i ing in he Jou nal o he Ame ican Medical Associa ion.(1) The
Goodwins poin ou ha many highly e icacious he apies, pa icula ly e y simple and inexpensi e ones, a e ejec ed i hey a e no comple ely unde s ood. O en wha
ge s los in selec ing a he apy a e he only issues ha eally ma e : Does i help? Is i oxic? How much does i cos ?
This handbook opens a bold new wo ld wi h i s comp ehensi e ins uc ion o u he explo a ion and maximiza ion o unde s anding o he mechanisms o ac ion, o mula-
dependen e icacy, sa e y, and low cos o zinc ace a e lozenges. As wi h many o he ea men s, we may ne e be able o pinpoin he p ecise mechanism o ac ion. Wi h
a billion o mo e colds pe yea in he Uni ed S a es alone, a cu e is despe a ely needed -- whe he i is simple o complex -- so long as i is e ec i e, sa e, and
inexpensi e. A simple solu ion o many colds is now a ailable. I is no wha classically ained scien is s wan ed, bu i is a ailable o hose su icien ly secu e in hei own
aining o accep adical new concep s. The disco e y o zinc lozenge o common colds mus no , he e o e, become ano he " oma o e ec ."
Magni ude o Heal h P oblem
Acu e espi a o y illness accoun s o o e one-hal o all acu e disabling condi ions annually acco ding o na ional heal h su ey da a.(2) The common cold is he mos
common o iden i iable acu e espi a o y diso de s and accoun s o abou 20 pe cen o all condi ions and ailmen s and abou 40 pe cen o all espi a o y condi ions.(3)
This includes 110 million disabling colds pe yea , causing abou 300 million days o es ic ed ac i i y, abou 60 million los days o school, and abou 50 million los days
o wo k.(4) When conside ing mino , nondisabling espi a o y illnesses, common colds ep esen a s ill highe p opo ion o espi a o y diseases. They a e es ima ed o
occu a a es o wo o i e colds pe pe son pe yea . Abou 5 pe cen o he popula ion ha e a cold a any gi en ime. Common cold symp oms usually las om a ew
days o wo weeks, and one-hal a e o e in a week. O e one billion common colds occu in he Uni ed S a es each yea . Financial conside a ions o he common cold
a e s agge ing. Abou $5.5 billion pe yea a e spen on colds in he Uni ed S a es. Abou $3 billion a e spen on p o essional consul a ions wi h abou $1.5 billion on
emedies and abou $1 billion on analgesics, much o ha amoun o ea ing common colds.(5) Many acu e espi a o y diso de s a ec human beings, bu his handbook
conside s only he common cold, which is echnically conside ed o be a i al, usually hino i al, in ec ion o he supe icial columna cells o he nasal u bina e epi helium
and pe haps he nasopha ynx.
E iologic Agen s
Michael Cas leman's book "Cold Cu es"(5) accu a ely condenses much o wha is cu en ly known abou he e iology o common colds. His book is ci ed in hese sec ions
because o i s essen ial au hen ici y and eadabili y and because Handbook o Cu ing he Common Cold is no abou common colds pe se, bu hei ea men wi h zinc
lozenges. Indi iduals in e es ed in he i ology, immunology, and physiology o common colds should ead he au ho i a i e wo ks o o he s.
Common colds a e induced by o e 200 ypes o i uses, wi h o e 113 ypes o human hino i uses causing he majo i y. Colds a e also caused by co ona i uses,
in luenza i uses, he pes simplex i uses, espi a o y syncy ial i uses, coxsackie i uses, pa ain luenza i uses, adeno i uses, and echo i uses. Some colds a e caused
ei he by unknown agen s o i uses causing sys emic i aemia. Echo i uses, polio, measles, and some adeno i uses cause sys emic i aemia as well as common cold
symp oms. Mos o he i uses do no , and hey emain in nasal and nasopha yngeal mucosa whe e hey cause only common cold symp oms. Nasal d ainage and nasal
conges ion a e p ima y symp oms o common colds. Malaise, headache, e e , muscle pain, so e h oa , sc a chy h oa , cough, and hoa seness a e equen ly occu ing
seconda y symp oms.(5)
Seasonal Va ia ion in E iological Agen s
Seasonal a ia ions in cold-causing i uses ha e been no ed wi h di e ences in hos suscep ibili y.(5) Rhino i uses cause colds yea - ound, and ha e been implica ed in
abou 50 pe cen o all common colds occu ing in he sp ing, summe , and all, a leas un il ecen ly. The la ge numbe o hino i uses (o e 100 dis inc hino i uses)
and a ian s a ec ing child en and adul s make a accine essen ially impossible. F equency o hino i us in ec ion alls o wi h age. Pa ain luenza i uses ha e been
implica ed in 15 o 25 pe cen o all, win e , and sp ing colds, a ec ing mos ly in an s and child en. This amily o ou i uses causes se e e colds in in an s wi h
signi ican po en ial o complica ions, bu only mild colds in adul s. Va ious s ains o in luenza A and B a e implica ed in 10 o 20 pe cen o cold-like illnesses in la e all,
win e , and ea ly sp ing. In luenza causes pa icula ly se e e symp oms as well as many mo e cold-like illnesses du ing pe iodic wo ldwide epidemics. Co ona i uses, a
amily o 13 i uses ha ing a dis inc i e c owned appea ance unde he elec on mic oscope, cause 10 o 20 pe cen o uppe espi a o y in ec ions and a e mos ac i e in
win e and sp ing. Respi a o y syncy ial i uses (RSV) ha e been implica ed in abou 10 pe cen o colds. These i uses a e usually ound in all, win e , and sp ing colds.
They cause mild colds in adul s, bu a e he leading cause o pneumonia in in an s. Riba i in has been shown e ec i e in RSV pneumonia. Th ee ou o mo e han 40
adeno i uses cause abou 5 pe cen o win e colds. Mili a y ec ui s a e a he g ea es isk. Adeno i uses a e mos ac i e in all and win e . S ains o echo i uses and
coxsackie i uses, pa o he en e o i us g oup, cause 5 o 10 pe cen o colds. These en e o i uses a e ac i e om Ap il h ough Decembe wi h peak ac i i y in summe
and all. They a ec mos ly in an s, child en, and mili a y ec ui s wi h ypical cold symp oms and possibly dia hea. O he i uses cause up o 25 pe cen o colds yea -
ound. He pes simplex i uses can cause colds o long du a ion. Rhino i uses cause colds yea a ound, bu hey a e mos ac i e om Ap il h ough Oc obe , no du ing
he heigh o he annual cold and lu season.(5)
New E idence o Rhino i uses as P incipal Cause o Colds
B i ish esea che s using new echniques ha e e y ecen ly sugges ed hino i uses accoun o 60 o 70 pe cen o all common colds, no 30 o 50 pe cen as p e iously
epo ed. Sebas ian Johns on, o he Depa men o Mic obiology a he Uni e si y o Sou hamp on in England, ecen ly used polyme ase chain eac ion echniques o
de elop ul asensi i e es s o be e iden i y cold i uses in as hma ic child en. In 108 child en, age 9 o 11 yea s wi h as hma, 290 espi a o y complain s (common colds
and ches in ec ions) we e examined wi h he new esea ch me hods. Se en y-eigh pe cen o all complain s we e i ally ela ed, and o hem 60 o 70 pe cen we e
caused by hino i uses.(6)
Immune Response o he Nose
The nose is he body's i s line o de ense agains ai bo ne i uses.(5) The empe a u e and mois u e o he inne nose end o inhibi g ow h o some i uses. The nasal
u bina es by hei lap-like shape and copious blood supply assis in wa ming and mois ening ai . The in e io o he nose is lined wi h goble cells ha exc e e s icky
mucus. The nasal in e io also has cilia, iny p ojec ing hai s, ha ap inhaled i uses, pollen, medica ion, and dus pa icles. Cilia mo e hem down he h oa , p e en ing
con ac wi h unde lying cells in he nose and h oa . The cells lining he espi a o y ac also sec e e immunoglobulin A (IgA) helping o p e en in ec ions by combining
wi h he su aces o i uses and bac e ia o change hei shape in o one no allowing a achmen . Recen ly, in e cellula adhesion molecule 1 (ICAM-1) has been iden i ied
as he molecule ha a aches hino i uses o cells.(5)
Du ing a cold, i uses ha e managed o pene a e nasal mucus and in ade nasal and pe haps nasopha yngeal issues.(5) Vi uses en e cells and wi hin a ew hou s
seize con ol o cell gene ics and o ce cells o make housands o copies o in ading i uses. As cells become in ec ed, hey elease chemicals ini ia ing se e al
esponses om he body's immune sys em, including esponses om immune cells o he nasal mucosa. Wi hin an hou , p os aglandins a e eleased p oducing
in lamma ion and a ac ing in ec ion- igh ing whi e blood cells called neu ophils. These cells a emp o a ack in ading i uses wi hou damaging in ec ed cells.
Neu ophil ac i i y inc eases in lamma ion, and he in ec ed a ea becomes swollen and ed. Onse o a common cold is hus signaled wi h symp oms such as so e h oa ,
i chy eyes, a headache, o a gene alized ill eeling. Tissues and capilla ies dila e, and plasma, mo e neu ophils, and o he whi e blood cells lood he a ea. They cause
inc eased mucus p oduc ion, a aised empe a u e, a unny nose, sneezing, and coughing. Release o kinins, pe o in, pe haps his amine, and o he mas cell asoac i e
ing edien s inc ease capilla y pe meabili y and cause inc eased mucus p oduc ion by goble cells.(5)
I aised nasal empe a u e and neu ophil engul men a e insu icien o s op i al in asion, monocy es and lymphocy es pass hough capilla y walls and assis .(5) In he
p esence o in lamma ion and o he signs o in ec ion, monocy es ans o m hemsel es in o mac ophages ea ing as many as 100 i uses each. These cells elease
in e leukin- 1 causing he body's empe a u e o ise and ac i a e lymphocy es. Release o in e leukin-1 o ese empe a u e esul s in chills, which o en p ecede a e e .
B- and T-cell lymphocy es a e he main wa io s in de ense o he nose. B-cells p oduce immunoglobulins. These an ibodies plug cold- i us ecep o si es and p e en
i uses om s icking o nasal and nasopha yngeal cells. Some o hese cells become memo y cells helping o p e en ecu ence o in ec ion. T-cell lymphocy es when
summoned o he si e o in ec ion u n in o "kille cells" ha elease cy olysin (pe o in) which opens po es in cells. Kille cells a ack and kill i us-in ec ed cells. O he
"helpe /induce " T-cells s imula e B-cells o p oduce addi ional an ibody. Some T-cells become "supp esso " T-cells e mina ing an ibody p oduc ion and kille -cell ac i i ies
a e i uses ha e been con olled. T-cells also elease se e al o he in ec ion- managing chemicals, including mac ophage ac i a ion ac o , mac ophage inhibi ion ac o ,
in e leukin-1 and -2, and in e e on. In e e on p e en s cell dea h caused by i uses and p e en s i al eplica ion. Complemen p o eins lyse cells and coa i us pa icles
making i easie o mac ophages o ecognize and diges hem. Complemen aids kille cells in iden i ying in ec ed cells, which mus be des oyed. Common cold
symp oms a e no p oduced by i uses, bu by he immune sys em's many, pe haps o e eac i e, esponses o i al in ec ion.(5)
O e iew o Common Cold T ea men s
Th oughou eco ded his o y, common colds ha e been e ac o y o a emp s o sho en hei du a ion. Whe he ea ed o no , he hal -li e o common colds emained
abou 7 days wi h an a e age du a ion o abou 10 o 11 days. T ea men and ad ice include: Pliny he Younge 's i s cen u y ea men o "kissing he hai y muzzle o a
mouse," a oiding dampness and exposu e o cold empe a u es, a oiding sneezes o pe sons wi h colds, a oiding shaking hands, ea ing chicken soup, aking a ious
he bs, men hola ed lozenges, eucalyp ol lozenges, ho ehound lozenges, an ihis amines, nasal deconges an s, analgesics, cough sy ups, an i ussi es, inhaling wa m
mois ai , aking megadoses o Vi amin C, using in e e on nasal sp ays, "kille " issues soaked in iodine, ga gles, an icholine gics, humidi ie s, nega i e ai ions,
medi a ion, acupunc u e, elec onic ai il e s, a ious an i hino i al agen s, an ibio ics o p e en seconda y in ec ion, and, mos ecen ly, he use o zinc glucona e h oa
lozenges.
In oduc ion o Zinc Glucona e Lozenges
In 1984, zinc glucona e lozenges con aining 23 mg o zinc used e e y wo hou s while awake (a lozenge abou 9 imes pe day) we e i s epo ed by Eby and o he s a
he Uni e si y o Texas a Aus in o sho en he du a ion o common colds by an a e age o 7 days when compa ed o placebo. Resul s o he s udy we e ca ied by he
Associa ed P ess and became headlines in newspape s wo ld-wide. This s udy showed he hal -li e o common colds ea ed wi h zinc o ha e been 2.7 days, compa ed
o 7.5 days o placebo- ea ed pa ien s. S a is ical signi icance was high h oughou he s udy (P = 0.0005 on he se en h day o ea men ). Lozenges we e un la o ed,
o e - he- coun e able s ha ing no soluble ing edien s o he han zinc glucona e. As a mildly objec ionable chalky as e and a e as e we e epo ed by abou one-hal o
he pa ien s ecei ing zinc glucona e lozenges pa icipa ing in he s udy, he s a is ics we e also e alua ed excluding pa ien s exp essing commen s abou as e o
a e as e. Resul s we e ound o emain he same, wi h high s a is ical signi icance.(7)
This 1984 epo s imula ed ollow-up esea ch bo h in i o and in i o. The new in i o wo k in ol ed usage o chemically weake and di e en lozenges, and
con o e sy ensued. O ally abso bed hyd a ed Zn2+ ions anspo ed mechanically and h ough p e e en ial pa hways in biologically closed elec ic ci cui s be ween he
o al and nasal ca i ies a e belie ed o be esponsible o educ ion in du a ion. S udies wi h posi i e indings demons a e e ec s o lozenges eleasing adequa e Zn2+
ions while nega i e s udies do no .
The i s s abili y cons an o zinc glucona e is log K1=1.70, which means zinc glucona e is highly ionizable and allows eady elease o Zn2+ ions in o o al issues o
localized abso p ion. A maximum o 60 pe cen o zinc om zinc glucona e will be p esen in sali a as Zn2+ ions, bu only a maximum o 30 pe cen will be p esen a pH
7.4, he pH o o al issues, blood, and lymph. A pe cen age o Zn2+ ions is p ecipi a ed by sali a y p o eins and hyd oxide, while ac i e amoun s a e abso bed in o he o al
and o opha yngeal issues. Ha ing nume ous pha macologic p ope ies, abso bed Zn2+ ions p o ide a nea ly pe ec common cold ea men .
Follow-up in i o s udies we e ma ed by e o s o elimina e objec ionable as e in he zinc glucona e lozenges. No esea che a emp ed o eplica e esea ch using
lozenges iden ical o lozenges used by he Eby g oup. Mos e o s by pha maceu ical and nu i ional supplemen companies o p epa e la o ed, pleasan - as ing zinc
glucona e lozenges ailed. Those e o s esul ed in lozenges ha we e much weake in biologic ac i i y. Also, hose expe imen al lozenges usually as ed a mo e
objec ionable han he un la o ed lozenges used in he o iginal 1984 s udy. Because no o he g oup a emp ed o eplica e he o iginal s udy wi h iden ical lozenges, i
was no clea whe he he o iginal s udy was aul y o he "imp o ed" lozenges we e impo en because o Zn2+ ion una ailabili y o la o - masking di icul ies.
Be o e he disco e y o la o -s able, pleasan - as ing zinc ace a e lozenges, elimina ion o objec ionable as e was by s ong chela ion by zinc binde s such as ci ic acid,
a a ic acid, sodium bica bona e, glycine, aspa ic acid, o o ic acid, by addi ion o ane hole la o -mask, o by use o low-dosages o zinc.
A good excep ion was he 1987 B i ish Medical Resea ch Council Common Cold Uni zinc lozenge o common cold s udy.(8) Using lozenges chemically iden ical o he
o iginal Eby g oup lozenges, he MRC Common Cold Uni s udy showed g ea e e icacy in sho ening colds han any p e ious s udy e e conduc ed by he Common
Cold Uni .
Clinical ailu es o highly s able zinc complexes wi h excess chela o (essen ially nega i ely cha ged zinc species), highly s able zinc complexes (essen ially neu ally
cha ged zinc complexes), and hose lozenges con aining e y low zinc dosage ha e caused loss o c edibili y o all zinc lozenge composi ions as e ec i e common cold
ea men s, including hose highly ionizable zinc compounds eleasing la ge amoun s o ac i e Zn2+ ions. Wi hou means o la o -mask lozenges, i appea ed Zn2+ ion
migh no become a use ul ool in he igh agains common colds. C ea ion o la o -s able, pleasan - as ing zinc ace a e lozenges as discussed in Chap e 7 he ein,
p o ides a new way o s udy he e ec s o Zn2+ ion in sho ening common cold du a ion.
S abili y Cons an s
To s udy zinc and he common cold, one mus ealize Zn2+ ions in amoun s su icien o sho en common colds a e a ailable only om a ew highly soluble and highly
ionizable zinc compounds. Some zinc compounds a e soluble a o al issue pH bu do no elease Zn2+ ions as hey ha e been s ongly seques e ed by he ligand; o he
solubles elease Zn2+ ions as hey ha e been only weakly seques e ed. Fo seques a ion o me allic ions o occu , wo gene al condi ions mus be me : (a) ligand mus
ha e p ope s ea ic and elec onic con igu a ion in ela ion o me al ions being complexed, and (b) he su ounding milieu (pH, ionic s eng h, solubili y, e c.) also mus be
conduci e o complex o ma ion. The capabili y o a ligand o elease me al ions unde hese a ying condi ions is ound using solu ion chemis y.
Posi i ely cha ged, aqueous solu ion zinc ions (Zn2+ ions) om e y weakly complexed zinc compounds a e he only o m o zinc ha ing an i-common cold p ope ies
including an i i al ac ion, cell memb ane p o ec ion, an ihis aminic e ec , and in e e on-inducing p ope ies. Zn2+ ions and se e al s ongly chela ed zinc compounds ha e
T-cell lymphocy e and as ingency ac i i y. An i-common cold zinc complexes and hei ela i e an i i al s eng hs can be de e mined om he i s s abili y cons an
( o ma ion cons an , equilib ium cons an , o ecip ocal o dissocia ion cons an ) o complexes o zinc and ligands. The heo e ical impo ance o he a ailabili y o Zn2+
ions in ea ing common colds was demons a ed in 1989 by Me luzzi and co-wo ke s a Boeh inge Ingelheim Pha maceu icals while wo king on he ICAM-1 p ojec .
(9,10) These scien is s demons a ed he an i hino i al e ec o zinc o be di ec ly ela ed o he amoun o Zn2+ ions a ailable and comple ely un ela ed o he o al
amoun o zinc complex.
Calcula ing A ailabili y o Zn2+ Ions
36. Pola nick J, Bach ach HL. E ec o zinc and o he chemical agen s on oo -and-mou h disease i us eplica ion. An imic obial Agen s and Chemo he apy. 1978;13:
731-734.
37. Sanga DV, B yan J, Ha is TJ, e al. Remo al o he genome-linked p o ein o oo -and-mou h disease i us by abbi e iculocy e lysa e. Jou nal o Vi ology. 1981;39:
67-74.
38. Fi po EJ, Palma EL. Inhibi ion o oo -and-mou h disease i us and p ocapsid syn hesis by zinc ions. A chi es o Vi ology. 1979;61:175-181.
39. Nakai K, Lucas-Lena d J. P ocessing o mengo i us p ecu so polypep ides in he p esence o zinc ions and sul hyd yl compounds. Jou nal o Vi ology. 1976;18:918-
925.
40. Le inson W, Fa as A, Woodson B, e al. Inhibi ion o RNA-dependen DNA polyme ase o Rous sa coma i us by hiosemica bazones and se e al ca ions.
P oceedings o he Na ional Academy o Sciences, USA. 1973;70:164-168.
41. Clegg JCS, B zeski H, Kennedy SIT. RNA polyme ase componen s in Semliki Fo es i us-in ec ed cells: syn hesis om la ge p ecu so s. Jou nal Gene al Vi ology.
1976;32:413-430.
42. B acha M, Schlesinge MJ. Inhibi ion o Sindbis i us eplica ion by zinc ions. Vi ology. 1976;72: 272-277.
43. Eps ein J. SV40- ans o med human cells ail o g ow in zinc concen a ions which pe mi no mal human ib oblas p oli e a ion. Jou nal o Cellula Physiology. 1982;
110:17-22.
44. Hu JW, Sas y KS, Go don MP, e al. The ac ion o me al ions on obacco mosaic i us ibonucleic acid. Biochemis y. 1964;3:501-506.
45. Ka z E, Ma gali h E. Inhibi ion o accinia i us ma u a ion by zinc chlo ide. An imic obial Agen s and Chemo he apy. 1981;19:213-217.
46. Zasla sky V. Inhibi ion o accinia i us g ow h by zinc ions: e ec on ea ly RNA and hymidine kinase syn hesis. Jou nal o Vi ology. 1979;29: 405-408.
47. Diene TO, McKinley MP, P usine SB. Vi oids and p ions. P oceedings o he Na ional Academy o Sciences USA. 1982;79:5220-5224.
48. Bu zow JL, Eichho n GL. Di e en suscep ibili y o DNA and RNA o clea age by me al ions. Na u e. 1975;254: 358-359.
49. Zhang ZY, Rea don IM, Hui JO, e al. Zinc inhibi ion o enin and he p o ease om human immunode iciency i us ype 1. Biochemis y. 1991;30: 8717-8721.
50. Se gio W. Zinc sal s ha may be e ec i e agains he AIDS Vi us HIV. Medical Hypo heses. 1988; 26:251-253.
51. Ko an BD. S a egies o inhibi i al polyp o ein clea ages. In: S . Geo gie V, McGowan JJ, eds. AIDS: An i-HIV Agen s, The apies, and Vaccines. Annals o he New
Yo k Academy o Sciences. 1990;616:252-257.
52. Sou h, TL, Blake PR, Sowde RC III, e al. The nucleocapsid p o ein isola ed om HIV-1 pa icles binds zinc and o ms e o i al- ype zinc inge s. Biochemis y.
1990;29:7786-7789.
53. Gallaghe IHC, Cu ess TW. The e ec o ace elemen s on he g ow h and e men a ion by o al S ep ococci and Ac inomyces. A chi es o O al Biology.
1977;22:555-562.
54. Skjö land K, Gje mo P, Rölla G. E ec o some poly alen ca ions on plaque o ma ion in i o. Scandina ian Jou nal o Den al Resea ch. 1978; 86:103-107.
55. Oppe mann RV, Rölla G, Johansen JR, e al. Thiol g oups and educed acidogenici y o den al plaque in he p esence o me al ions in i o. Scandina ian Jou nal o
Den al Resea ch. 1980;88:389-396.
56. Oppe mann RV, Rölla G. E ec o some poly alen ca ions on he acidogenici y o den al plaque in i o. Ca ies Resea ch. 1980;14:422-427.
57. G eenbe g SB, Ha is D, Giles P, e al. Inhibi ion o Chlamydia achoma is g ow h in McCoy, HeLa, and human p os a e cells by zinc. An imic obial Agen s and
Chemo he apy. 1985;27:953-957.
58. Schlie e P, Johnson W, Galask RP. Bac e ial g ow h inhibi ion by amnio ic luid. VI. E idence o a zinc-pep ide an ibac e ial sys em. Ame ican Jou nal o Obs e ics
and Gynecology. 1976;125: 906-910.
59. Windholz M, Buda a i S, Blume i RF, e al, eds. The Me ck Index. Rahway NJ:Me ck & Company. 1983;1455-1458.
60. Ibid; 226.
61. Ibid; 1153.
62. Osol A. As ingen s and an ipe spi an s. In: Osol A. ed. Reming on's Pha maceu ical Sciences, 16 h Edi ion. Eas on:Mack Publishing Co. 1980;720-723.
63. Suga man B. Zinc and in ec ion. Re iews o In ec ious Diseases. 1983;5:137-147.
64. Bash o d CL, Alde GM, Menes ina G, e al. Memb ane damage by hemoly ic i uses, oxins, complemen , and o he cy o oxic agen s - a common mechanism
blocked by di alen ca ions. The Jou nal o Biological Chemis y. 1986;261: 9300-9308.
65. Bash o d CL, Menes ina G, Henka PA, e al. Cell memb ane damage by cy olysin. The Jou nal o Immunology. 1988;141:3965-3974.
66. Bash o d CL, Alde GM, G aham JM, e al. Ion modula ion o memb ane pe meabili y: E ec o ca ions on in ac cells and on cells and phospholipid bilaye s ea ed
wi h po e- o ming agen s. Jou nal o Memb ane Biology. 1988;103:79-94.
67. Pas e nak CA. Vi us, oxin, complemen : common ac ions and hei p e en ion by Ca2+ o Zn2+. Bio Essays. 1987; 6:14-19.
68. Lich enheld MC, Olsen KJ, Lu P, e al. S uc u e and unc ion o human pe o in. Na u e. 1988; 335:448-451.
69. Boyle MDP, Langone JJ, Bo sos T. S udies on he e minal s ages o immune hemolysis. IV. E ec o me al sal s. The Jou nal o Immunology. 1979; 122:1209-1213.
70. P asad AS. Zinc in humans. In: Risby TH, ed. Ul a ace Me al Analysis in Biological Sciences and En i onmen . Washing on D.C.:Ame ican Chemical Socie y; 1979.
71. Ba e JT. Tex book o Immunology. S . Louis:C. V. Mosby Co; 1978.
72. S uckho G, Heymann E. Ra pe i oneal mas cells elease dipep idyl pep idase II. Biochemis y Jou nal. 1986;236:215-219.
73. Dansche G, Obel J, Tho lacius-Ussing O. Elec on mic oscopic demons a ion o me als in a mas cells. A cy ochemical s udy based on an imp o ed sul ide sil e
me hod. His ochemis y. 1980;66: 293-300.
74. Selye H. The Mas Cell. Washing on DC: Bu e wo hs P ess; 1965;302.
75. U nas B, Abo g CH, Be gq is U. No ole o zinc in he s o age o his amine in a pe i oneal mas cells. Ac a Physiologica Scandina ica. 1975;93:401-408.
76. Ma one G, Lich ens ein LM. Inhibi ion o his amine elease om human basophils by zinc chlo ide. Fede a ion P oceedings. 1978;37:590.
77. Ma one G, Findlay SR, Lich ens ein LM. Modula ion o basophil his amine elease by zinc. Jou nal o Alle gy and Clinical Immunology. 1979;65:171.
78. Ma one G, Columbo M, de Paulis A, e al. Physiological concen a ions o zinc inhibi he elease o his amine om human basophils and lung mas cells. Agen s and
Ac ion. 1986;18:103-106.
79. Ch apil M. E ec o zinc on cells and biomemb anes. Medical Clinics o No h Ame ica. 1976; 60:799-812.

80. Mousli M, Gies J-P, Be and G. The Sensi i i y o Zn2+ disc imina es be ween ypical and a ypical mas cells. Agen s and Ac ions. 1990;30:102-105.
81. Ma ell AE, Smi h RM. C i ical S abili y Cons an s. New Yo k: Plenum P ess; 1991.
82. Be hon G, Kayali A. His amine as a ligand in blood plasma. Pa 5. Compu e simula ed dis ibu ion o me al his amine complexes in no mal blood plasma and
discussion o he implica ions o a possible ole o zinc and coppe in his amine ca abolism. Agen s and Ac ions. 1982;12:398-407.
83. Be hon G, Va samidis A, Blaquie e C, e al. His amine as a ligand in blood plasma. Pa 7. Mala e, malona e, malea e and a a e as adju an s o zinc o la o
his amine issue di usion h ough mixed-ligand coo dina ion. In i o es s on lymphocy e p oli e a ion. Agen s and Ac ions. 1987;22:231-247.
84. Be hon G, Ge monneau P. His amine as a ligand in blood plasma. Pa 6. Aspa a e and glu ama e as possible pa ne ligands o zinc and his amine o a o
his amine ca abolism. Agen s and Ac ions. 1982;12:619-629.
85. Pa II, Fo mulas. In: Me ck's 1901 Manual o he Ma e ia Medica. New Yo k:Me ck and Co. 1901;125.
86. Remedies o nasal ca a h. In: Me ck's Manual o he Ma e ia Medica. New Yo k:Me ck and Co. 1923;160.
87. F anklin P. T ea men o hay e e by in anasal zinc ioniza ion. The B i ish Medical Jou nal. June 27, 1931; 1115-1116.
88. Shields C. The ioniza ion ea men o hay e e . The P ac i ione . Janua y-June 1936;645-648.
89. Bailey LD, Shields C. T ea men o hay e e by in anasal zinc ioniza ion. The B i ish Medical Jou nal. Ap il 17, 1937;808.
90. Zinc bo a e deconges an . In: Howa d MA, ed. Mode n D ug Encyclopedia and The apeu ic Index. New Yo k:D ug Publica ions; 1956;1168.
91. Wei CD. In anasal ioniza ion in he ea men o asomo o nasal diso de s. The Jou nal o La yngology and O ology. 1967;81:1143-1149.
92. Cas leman M. Cold Cu es. New Yo k:Fawce Columbine;1987.
93. Eggles on PA, Hendley JO, Gwal ney JM J , e al. His amine in Nasal Sec e ions. In e na ional A chi es o Alle gy and Applied Immunology. 1978; 57:193-200.
94. Nacle io RM, P oud D, Lich ens ein LM, e al. Kinins a e gene a ed du ing expe imen al hino i us colds. Jou nal o In ec ious Diseases. 1988; 157:133-142.
95. Eggles on PA, Hendley JO, Gwal ney JM J . Media o s o immedia e hype sensi i i y in nasal sec e ions du ing na u al colds and hino i al in ec ion. Ac a O o-
La yngologia Supplemen . 1984; 413:25-35.
96. P oud D, Nacle io RM, Gwal ney JM, Hendley JO. Kinins a e gene a ed in nasal sec e ions du ing na u al hino i us colds. Jou nal o In ec ious Diseases.
1990;161:120-123.
97. Ga ey MJ, Gwal ney JM J , Sas e A, e al. In anasally and o ally adminis e ed an ihis amine ea men o expe imen al hino i us colds. Ame ican Re iew o
Respi a o y Disease. 1987;136: 556-560.
98. Ga ey MJ, Kaise DL, Hayden FG. Ine ec i eness o o al e enadine in na u al colds: e idence agains his amine as a media o o common cold symp oms. Pedia ic
In ec ious Disease Jou nal. 1988;7:223-228.
99. Nacle io RM, P oud D, Kagey-Sobo ka A, e al. Is his amine esponsible o he symp oms o hino i us colds? A look a he in lamma o y media o s ollowing in ec ion.
Pedia ic In ec ious Disease Jou nal. 1988;7:218-222.
100. Bo um P, G onbo g H, B o eld S, e al. Nasal eac i i y in hini is. Eu opean Jou nal o Respi a o y Diseases Supplemen . 1983;128 (P 1):65-71.
101. Ca e -Ba ne JK, C use LW, P oud D. Kinins a e gene a ed in nasal sec e ions du ing in luenza A in ec ions in e e s. Ame ican Re iew o Respi a o y Diseases.
1990;142:162-166.
102. Lemanske RF J , Dick EC, Swensen CA, e al. Rhino i us uppe espi a o y in ec ion inc eases ai way hype eac i i y and la e as hma ic eac ions. Jou nal o
Clinical In es iga ion. 1989;83:1-10.
103. Welli e RC, Wong DT, Sun M, e al. The de elopmen o espi a o y syncy ial i us-speci ic IgE and he elease o his amine in nasopha yngeal sec e ions a e
in ec ion. New England Jou nal o Medicine. 1981;305:841-846.
104. P asad AS. Zinc in Human Nu i ion. Boca Ra on, FL: CRC P ess; 1979;65.
105. Chand a RK, Au B. Single nu ien de iciency and cell-media ed immune esponses: Zinc. The Ame ican Jou nal o Clinical Nu i ion. 1980;33:736-738.
106. P asad AS. Disco e y and impo ance o zinc in human nu i ion. Fede a ion P oceedings. 1984; 43:2829-2834.
107. Beisel WR, Edelman R, Nauss K, e al. Single-nu ien e ec s on immunologic unc ions. Jou nal o he Ame ican Medical Associa ion. 1981;245: 53-58.
108. Phillips JL, Aza i P. Zinc ans e in: Enhancemen o nucleic acid in phy ohemagglu inin-s imula ed human lymphocy es. Cellula Immunology. 1974;10:31-37.
109. Da denne M, Pléau JM, Naba a B, e al. Con ibu ion o zinc and o he me als o he biological ac i i y o he se um hymic ac o . P oceedings o he Na ional
Academy o Sciences USA. 1982;79: 5370-5373.
110. Ba es J, McClain CJ. The e ec o se e e zinc de iciency on se um le els o albumin, ans e in, and p ealbumin in man. Ame ican Jou nal o Clinical Nu i ion.
1981;4: 1655-1660.
111. Beach RS, Ge shwin ME, Hu ley LS. Ges a ional zinc dep i a ion in mice: pe sis ence o immunode iciency o h ee gene a ions. Science. 1982;218 469-471.
112. Golden MHN, Jackson AA, Golden BE. E ec o zinc on hymus o ecen ly malnou ished child en. Lance . No embe 19, 1977;1057-1059.
113. Ducha eau J, Delepesse G, V ijens R, e al. Bene icial e ec s o o al zinc supplemen a ion on he immune esponse o old people. The Ame ican Jou nal o
Medicine. 1981;70:1001-1004.
114. Ducha eau J, Delespesse G, Ve eecke P. In luence o o al zinc supplemen a ion on he lymphocy e esponse omi ogens o no mal subjec s. The Ame ican Jou nal
o Clinical Nu i ion. 1981;34:88-93.
115. Ma he G, Blazsek I, Gil-Delgado MA, e al. The e ec o zinc on no mal and neoplas ic T-lymphocy e p oli e a ion. Medical Oncology & Tumo Pha maco he apy.
1985;2: 203-210.
116. Wazewska-Czyzewska M, Wesie ska-Gadek J, Legu ko L. Immunos imula o y e ec s o zinc in pa ien s wi h acu e lymphoblas ic leukemia. Folia Haema ology.
1978;105: 727-732.
117. Ca da AO, Babacan E, Gözdasoglu S, e al. Zinc and ane gy in pedia ic Hodgkin's disease in Tu key. Cance . 1987;59:305-309.
118. Rocklin RE, Habe ek-Da idson A. His amine ac i a es supp esso cells in i o using a cocul u e echnique. Jou nal o Clinical Immunology. 1981; 1:73-79.
119. Chand a RK. Excessi e in ake o zinc impai s immune esponses. Jou nal o he Ame ican Medical Associa ion. 1984;252:1443-1446.
120. Rea don CL, Lucas DO. Zn++ - and Hg++ - media ed induc ion o mi ogenesis, cell-media ed cy o oxici y, and in e e on p oduc ion in mu ine lymphocy es. In:
Pa ke JW, O'B ian RL, eds. P oceedings o he Fi een h Leukocy e Cul u e Con e ence. New Yo k:John Wiley and Sons, Inc. 1983; 449.
121. Rea don CL, Lucas DO. Hea y me al mi ogenesis: Zn++ and Hg++ induce cellula cy o oxici y and in e e on p oduc ion in mu ine T lymphocy es. Immunobiology.
1987; 175:455-469.
122. Salas M, Ki chne H. Induc ion o in e e on-g in human leukocy e cul u es s imula ed by Zn2+. Clinical Immunology and Immunopa hology. 1987;45:139-142.
123. Gaine JH. E ec s on in e e on o hea y me al excess and zinc de iciency. Ame ican Jou nal o Ve e ina y Resea ch. 1977;38:863-867.
124. No is D. Zinc and cu aneous in lamma ion. A chi es o De ma ology. 1985;121:985-989.
125. Ch apil M, S anko a L, Weldy P, e al. The ole o zinc in he unc ion o some in lamma o y cells. In: Zinc Me abolism: Cu en Aspec s in Heal h and Disease. New
Yo k: Alan R. Liss, Inc; 1977;103-122.
126. Subcommi ee on Zinc, Commi ee on Medical and Biological E ec s o En i onmen al Pollu an s, Di ision o Medical Sciences, Assembly o Li e Sciences Na ional
Resea ch Council. Zinc. Bal imo e:Uni e si y Pa k P ess; 1979; 235.
127. Beisel WR, Peka ek RS, Wannemake RW J . Homeos a ic mechanisms a ec ing plasma zinc le els in acu e s ess. In: P asad AS, Obe leas D eds. T ace Elemen s
in Human Heal h and Disease. New Yo k:Academic P ess; 1976;97.
128. Ma inez-Cai o S, Coello P, Al a ez T, e al. PMN cell phagocy ic unc ion in malnou ished pa ien s wi h zinc up ake. A chi os de In es iga ion Medica. 1980;11:227-
238.
129. Kelley RW, Abel MH. Coppe and zinc inhibi he me abolism o p os aglandin by he human u e us. Biology o Rep oduc ion. 1983;28:883-889.
130. Cohen S, Ty ell DAJ, Smi h AP. Psychological s ess and suscep ibili y o he common cold. New England Jou nal o Medicine. 1991;325:606-612.
Chap e 3. Zinc Lozenge Me hod o T ea ing Colds
Execu i e Summa y Chap e 3 discusses he a ionale o applica ion o hyd a ed Zn2+ ions o he o al ca i y, a he han he nose. The biologically closed elec ic ci cui
(BCEC) be ween he in e io o he mou h and he in e io o he nose is desc ibed. The mou h-nose BCEC anspo s Zn2+ ions one-way only; om he mou h in o i ally
in ec ed issues o he nose, and explains why zinc applied di ec ly o nasal issues is ine ec i e. Once wi hin in ec ed nasal issues, Zn2+ ions p oduce bene icial e ec s
ha sho en common colds. The zinc ion a ailabili y (ZIA) concep is in oduced. ZIA is c ucial o unde s anding he a ia ions in esul s epo ed in he clinical ials
desc ibed in Chap e 4. Zinc lozenge e icacy depends o ally upon lozenge ZIA, which in u n depends upon he concen a ion o hyd a ed Zn2+ ions in sali a o e he
ime o lozenge dissolu ion and ea men s pe day. The ZIA concep is an applica ion o Fick's laws o pe meabili y as hey a e ex ended o include low o cha ged
pa icles in bioelec ic ields.
Zn2+ ions a e highly an i hino i al bo h di ec ly and h ough s imula ion o in e e on p oduc ion. Zn2+ ions p o ec cell memb anes in i o as e ec i ely as in e e on. I a
way o in oduce and keep Zn2+ ions in he icini y o supe icial columna cells o he nasal u bina e epi helium ( he cells hough o be in ec ed by hino i uses in
common colds) could be ound, hen Zn2+ ions could inhibi hino i al eplica ion and p o ec cells om hino i al a ack in i o. I may seem less di ec o implausible o
apply zinc o o al issues and no nasal issues, bu adminis a ion o he nose is known no o educe he du a ion o common colds. Zn2+ ions applied o he o al and
o opha yngeal mucous memb anes appea o be eadily abso bed in o he o al memb anes whe e Zn2+ ions mig a e in o nasal issues by di usion, osmosis, and
elec opho e ic o ce. Sali a is well known o be con inually abso bed in o o al and o opha yngeal issues.
Nasal Adminis a ion and Sys emic Abso p ion
Fo eign subs ances in oduced in anasally a e apidly clea ed by mucous sec e ions and equi e equen adminis a ion (e e y 10 o 15 minu es)(1) o keep subs ances
in he nose on op o nasal mucus, cilia and mucous memb anes, bu no wi hin nasal issues. Nasal mucus is cons an ly being exc e ed, lowing ou wa d om issues and
ca ying i uses, an igens, dus , and medica ions in o he h oa by ac ion o he cilia. Zn2+ ion di usion in o hese in ec ed issues by nasal adminis a ion agains he low
o mucus and mou h-nose elec ical ci cui is di icul i no impossible. Zinc nasal sp ay does no esul in clinical educ ion in du a ion o common colds, e en when 10
mMol zinc glucona e nasal sp ay is adminis e ed e e y 15 o 30 minu es, al hough zinc does p o ide a empo a y deconges an e ec .(2) Simila ly, zinc sul a e nasal
sp ays ha e been shown by De ek B yce-Smi h a he Uni e si y o Reading in G ea B i ain o ha e a mild nasal deconges an e ec wi h no e ec on he du a ion o
common colds.(3) Conside able e idence (discussed in Chap e 2) om be o e 1900 o abou 1960 shows ha zinc compounds applied o he nos ils we e weak nasal
deconges an s unassocia ed wi h educ ion in common cold du a ion.
Addi ionally, o al doses o zinc do no p oduce su icien ly high concen a ion in he nasal issues o a ec common cold du a ion, unless he o al doses a e ex emely
la ge (se e al g ams), and hese la ge doses may be somewha oxic o blood- o ming issues and o he o gans.
O al Ca i y Abso p ion
A much mo e e ec i e me hod o in oducing Zn2+ ions in o nasal issues has been de eloped using zinc h oa lozenges. This use esul s om a se endipi ous
obse a ion in 1979 o a nea -ins an aneous elie om a cold a e use o a 50-mg zinc as zinc glucona e lozenge in a leukemic 3-yea -old child.(4) The o al ca i y -- and
o opha yngeal issues gene ally -- being pa o he diges i e sys em abso b, a he han epel, nu ien s and o he soluble subs ances emaining in con ac wi h hem.
Abso p ion h ough hese mucous memb anes has been likened o abso p ion by o he diges i e sys em issues and pa icula ly o in es inal issues, while nasal issues
appea o be mo e akin o cilia ed, in olu ed skin. Gene al abso p ion o d ugs kep in he mou h consis s o a p ocess o dissolu ion, ollowed by anspo o dissol ed
d ug and o he soluble ing edien s ac oss mucosal memb anes in o issues and usually in o gene al ci cula ion.(5)
D ugs mus a e se se e al biologic memb anes be o e eaching he si e o ac ion. In he o al ca i y he e a e wo egions, buccal and sublingual, whe e he memb anes
a e e y hin and ha e a copious blood supply.(6) Sublingual adminis a ion o Zn2+ ion en ails he placemen o he lozenge unde he ongue o i s ul ima e abso p ion
in o he sys emic ci cula ion and is no eally p ac ical because o he la ge size o he lozenges. Buccal adminis a ion o Zn2+ ion is o dina ily accomplished by placing he
lozenge be ween he cheek and gums. D ugs, including Zn2+ ions gi en by sublingual and buccal adminis a ion en e he ci cula ion di ec ly and a e ca ied o o al, acial,
nasal, and body issues be o e passage h ough he li e 6 whe e Zn2+ ions may be seques e ed by leukocy e endogeneous media o (LEM) ac ion.(7,8) Venous d ainage
om he o al ca i y goes di ec ly o he hea .(6) Es ima es o in i o a ailabili y o cha ged species om s a ic in i o obse a ions, such as 11 pe cen Zn2+ ions in
sali a(9 and 2 o 8 pe cen Zn2+ ions in se um,(10) may o may no be applicable in i o because o nume ous ac o s including pH, empe a u e, and elec omo i e o ces
ac ing on cha ged pa icles. In common cold he apy wi h zinc lozenges, o al-nasal po en ial di e ence accele a es abso p ion o Zn2+ ions om sali a, ioniza ion o Zn2+,
and mo ili y o Zn2+ ions.
Wi h highly soluble subs ances such as ionizable zinc compounds, he a e o pe mea ion ac oss biologic memb anes, no dissolu ion, is he a e-de e mining s ep. The
a e o pe mea ion is dependen upon size, ela i e aqueous and lipid solubili ies, and ionic s eng h.(5,6) Like mos biologic memb anes, o al mucosal memb anes a e
la gely lipoidal in cha ac e . Hence, good lipid solubili y o a d ug is an impo an ac o in assessmen o i s abso p ion po en ial. Many d ugs a e ei he weakly acid o
weakly alkaline compounds, and in solu ion, depending on pH alue, exis as ionized o un-ionized species. Un-ionized neu al species a e mo e lipid-soluble and hence
mo e eadily abso bed in he absence o an elec omo i e o ce (EMF). Cha ged species depend almos o ally upon concen a ion applied, ime applied, and cha ges o
memb anes and ionized solu e and a e abso bed h ough passi e ans e aided o epelled by elec omo i e o ces.(5,11,12) Endo helial cells hemsel es a e pe meable
o lipophilic subs ances bu no o hyd ophilic subs ances.(5,11)
A published Zn2+ ion oil/wa e pa i ion coe icien has no been ound bu is expec ed o be ex emely low o ze o. Sali a y glycop o eins coa ing o al mucosa a e known
o ca y nega i e cha ges and a e an impo an binding si e o ca ionic subs ances, such as Zn2+, in he mou h.(5) The la e , including Zn2+ ions, pass h ough capilla y
walls h ough in e epi helial spaces, called s oma a, po es o leaky junc ions and a e a ac ed o elec onega i e o al mucous memb anes.(11) Once Zn2+ ions en e he
o al mucous memb ane, hey appea o ollow p e e en ial pa hways in biologically closed elec ic ci cui s leading o he nose whe e hey exe bene icial e ec s, and/o
Zn2+ ions may be mechanically anspo ed. The e o e, he main ac o s in de e mining he amoun o Zn2+ ions ans e ing h ough o al mucosal memb anes a e sali a y
concen a ion o Zn2+ ions, and he ime o al and o opha yngeal mucosal memb anes a e exposed o Zn2+ ions, as well as elec ical e ec s, which a e p esumably abou
he same in all people.
The a e, ou e, mo emen , binding, and concen a ion o soluble zinc, including Zn2+ ions, once abso bed in o o al and nasal issues using his me hod ha e no been
de e mined. Wi h opical ea men by zinc glucona e o ace a e lozenges, an inc ease in Zn2+ ion se um concen a ion in o al, h oa , and nasal issues appea s bo h
possible and p obable. Capilla y memb ane po es a e known o be sealed by Zn2+ ions aiding in he anspo o Zn2+ ions o e long dis ances.(11) Howe e , Zn2+ ions
om zinc glucona e h oa lozenges do no appea in nasal mucus a e use o one lozenge in amoun s di e en om placebo du ing he i s ew hou s a e
adminis a ion in well, non-alle gic pa ien s as de e mined h ough use o u nace analysis a omic abso p ion spec opho ome y.(13) Such esul s a e no unexpec ed, as
no e idence exis s o goble cells selec i ely aking up Zn2+ ions o mi o lymph o plasma zinc con en so quickly.
Anecdo al obse a ion o weak local issue sensa ions while using zinc glucona e lozenges sugges s a way o ack mo emen o zinc in o issues. Some pa ien s say he
zinc seems o mig a e: upwa d in o he nose, eyes, and ea s whe e d ying ac ions on issues can be obse ed; hen in o acial issues, and emples whe e i can be el ;
hen downwa d in o he h oa , pha ynx, esophagus, and s omach. A d ying e ec o Zn2+ ions in he h oa and on ocal co ds o singe s ha ing espi a o y alle gies who
use zinc glucona e lozenges esul s in imp o ed abili y o sing, showing mo emen o zinc o i s d ying e ec s in o he la ynx and achea.
Al hough he means by which zinc mo es in o hese issues emains obscu e (pe haps di usion, osmosis, and elec opho esis), lympha ic ci cula ion mo e han enous
ci cula ion o Zn2+ ions ou o hese issues is deduced. Fo example, i zinc lozenges a e used h oughou he day and a bed ime, hen zinc concen a ion in nasal and
nasopha yngeal issues may become high, and mo emen o zinc ou o hese issues s ops when lymph mo emen s ops. Consequen ly, Zn2+ ions emain in con ac wi h
i ally in ec ed issues o e nigh wi hou lympha ic d ainage. Colds a e mos o en obse ed o disappea du ing nigh ime sleep, which is a ime when lympha ic
ci cula ion is a es ed. Upon a ising, he mou h and nose a e o en unusually d y. O al d ying ollows he use o highly ionizable zinc compounds (no igh ly bound zinc)
and may be explained by an i hino i al, an ihis aminic e ec s, cell memb ane s abiliza ion, an i-cy olysin (pe o in) e ec s, as ingency, and o he an i-in lamma o y
p ope ies associa ed wi h Zn2+ ions.
Because he con en o zinc in plasma (mos ly igh ly complexed wi h albumin, ans e in, and o he blood p o eins) is abou 1 mg/ml and in mos issues i anges om 11
o 150 mg/g, ob iously an ac i e o acili a ed up ake exis s, bu li le is known o he na u e o he up ake mechanisms o a ious cells.(14)
Mou h-Nose Elec ic ci cui
Acco ding o B. E. No dens öm o he Ka olinska Ins i u e in S ockholm, ample e idence exis s o ci cula o y ci cui s wi h he abili y o mo e elec ically cha ged me allic
ions long dis ances.(11) Using a digi al ol me e , he p esen au ho has measu ed a 90 o 120 milli ol po en ial di e ence be ween he o al ca i y and he in e io o he
nose, wi h he mou h ac ing anodic. A mou h-nose cu en may also be in e ed using an ohm-me e . Re e sing mou h and nose leads changes eadings usually by abou
10,000 ohms (10,000 ohms one way and 20,000 ohms he o he way). Resis ance luc ua es by 100 o 300 ohms wi h he espi a o y hy hm. Simila measu emen s while
dissol ing zinc ace a e lozenges and a a ious imes up o an hou a e dissolu ion showed he same esul s. I con i med by o he s, hese obse a ions may be he mos
eadily obse able examples o biologically closed elec ic ci cui s (BCEC) in human beings.
A su plus o nega i e cha ge always cha ac e izes he su ace o cells as well as mos i uses, al hough some issues ha e g ea e elec onega i i y han o he s. The
sou ce o elec ons in he mou h may be om loss o p o ons om mucop o eins passed om o al issues in o sali a o he po en ial-inducing, ba e y-like, ac ion o he
ongue. No dens öm has shown muscles, such as he ongue, and inju ed o in ec ed issues o gene a e po en ials o he magni ude no ed by Eby in he mou h-nose
ci cui .(11)
Posi i ely cha ged Zn2+ ions appea o mig a e along p e e en ial pa hways be ween he mou h and nasal issues as well as in o o he non-o al local issues and enous
and lympha ic d ainage pa hways. Pe haps some ac ion o Zn2+ ions mig a es he long dis ance (aided by Zn2+ ion-induced capilla y memb ane po e closu e) om he
o al ca i y in o nasal issues ia p e e en ial pa hways in BCEC, and some mig a es by mechanical anspo . In anasal Zn2+ ions should p o ide an an i hino i al e ec ,
induce in e e on p oduc ion, and d y nasal issues. These indings sugges passi e abso p ion (mechanical anspo , di usion, il a ion, and osmosis) o Zn2+ ions om
mou h in o he nose o be aided by elec opho esis.
Along wi h he s ong epelling e ec s o nasal mucus and cilia on o eign subs ances in oduced o he nose as no ed by Aoki1 and many o he s, he ol age di e en ial
epels in anasally in oduced Zn2+ ions om mucosal su aces, u he explaining ine icacy om 10 mMol zinc glucona e nasal sp ays (see Chap e 4.B.1.).
Fick's Fi s Law
Linea i y in pha maceu ical dose- esponsi eness is usually a ibu ed o passi e di usion o neu ally cha ged lipophilic subs ances ac oss biologic memb anes acco ding
o Fick's i s law and o mechanical anspo by he a e ial, enous, and lympha ic sys ems. Toxici y om in acellula accumula ion o zinc om lipophilic o s ongly
bound complexes o neu ally cha ged zinc(15,16) may be qui e eal, sugges ing only non- oxic, as ingen , 100 pe cen hyd a ed Zn2+ ions should be p o ided om zinc
lozenges.
Passi e di usion happens when d ug molecules exis in high concen a ion on one side o a memb ane and lowe concen a ion on he o he side. Di usion occu s in an
e o o equalize d ug concen a ion on bo h sides o he memb ane in hose cases whe e he a e o anspo is p opo ional o he concen a ion g adien ac oss he
memb ane. When he olume o luids is ixed, he mo emen o d ug ac oss a memb ane can be desc ibed in e ms o Fick's laws.
Fick's i s law s a es he a e o di usion o anspo ac oss a memb ane is di ec ly p opo ional o he su ace a ea o he memb ane and o he concen a ion g adien
and is in e sely p opo ional o he hickness o he memb ane.(6) The gene al exp ession o Fick's i s law o di usion is dm/d = -DAdc/dx whe e m is he quan i y o
d ug o solu e di using in ime , dm/d is he a e o di usion, D is he di usion cons an , A is he c oss-sec ional a ea o he memb ane, dc is he change in concen a ion,
and dx is he hickness o he memb ane.(6) A change in any o hese a iables will al e he a e o anspo o d ug in o he blood o e a gi en ime.
D ugs a e apidly abso bed h ough hin memb anes such as he o al mucosa. In he assessmen o abso p ion po en ial o d ugs, a ious expe imen s using biologic
memb anes ha e been conduc ed o demons a e Fick's i s law. Expe imen s a e ca ied ou a di e en mucosal concen a ions o d ugs o de e mine he esponse o
ea men .
Cons ancy o amoun ans e ed pe uni ime pe uni concen a ion o e a wide ange o mucosal solu ion concen a ions indica es passi e ans e o d ug and
compliance wi h Fick's i s law.(5,6) Passi e ans e e e s o a ee di usion ac oss a memb ane composed o channels o a ious sizes wi hou biologic ac i i y o
elec ochemical p ocesses being in ol ed.(5,6)
As he concen a ion g adien ac oss he ba ie is inc eased, he lux ac oss he ba ie inc eases in di ec p opo ion.(5,6) By a ying he amoun o d ug gi en in i o in
a gi en ime d ug concen a ion can be a ied. D ug abso p ion is asce ained by blood and u ina y analysis o by esponse o ea men .(5,6)
A linea ela ionship be ween di e en amoun s o d ug gi en in a gi en pe iod and he deg ee o imp o emen sugges s abso p ion unde Fick's i s law applies in i o.
In common cold he apy wi h Zn2+ ions, ec opho e ic e ec s al e Zn2+ ion mo ili y and abso p ion unde Fick's laws, which inc eases abso p ion o e uncha ged
subs ances. Fick's laws include elec omo i e o ces ac ing on elec ically cha ged pa icles.(11,12) Hyd a ed Zn2+ ions mo e ac oss memb anes and h ough li ing
issues unde Fick's i s and second laws.(11) Hyd ophilic subs ances, including Zn2+ ions, pass be ween cells h ough in e epi helial spaces called s oma a, po es o
leaky junc ions; in he case o me allic ions, hey also ollow p e e en ial pa hways in BCEC.(11)
Posi i ely cha ged me allic ions a e anspo ed in cha ged clus e s eac ing wi h elec onega i e cell memb anes a sho dis ances o a long dis ances when capilla y
cell memb anes a e closed by high concen a ions o Zn2+ ions.(11) Nega i ely cha ged complexes a e epelled om cell su aces and i uses which a e always
elec onega i e.(11) In con as , neu ally cha ged complexes a e no aided o epelled by elec ic ields and hei mo emen depends only upon di usion and mechanical
anspo .(11)
Ionic Di usion
S a ing wi h he au ho i a i e wo ks o Lehninge ,(17) Bock is and D azic,(18) Newman,(19) Nobel(20) and o he s, in he ield o ene gy exchanges in chemical eac ions,
No dens öm de eloped he concep o biochemical eac ions in BCEC o include ionic di usion. Ionic di usion in BCEC occu s acco ding o Fick's i s law which can
also be w i en as -Q = D (dc/dx) in which Q, in mole pe m2 , is he quan i y o ions a e sing a uni a ea o sol en pe uni ime. The ac o D is he di usion coe icien ,
which exp esses (in 1/ m2 uni s) he p opo ional abili y o an ion o di use a dis ance dx in a sol en a a concen a ion di e ence dc. In a non-s eady s a e his concep
can o en be exp essed as x = cons an imes he squa e oo o D , whe e D = di usion cons an (in 1/m2 ) and = ime (seconds).(11)
In No dens öm's eloquen wo ds, in he ollowing equa ion ep esen ing a nons a ic condi ion, he amoun o ma e ial Q passing a uni a ea A pe second o e dis ance
dx leads o QA - (Q + dQ/dx x dx) A = dc/d x Adx showing he in low o ma e ial Q h ough he a ea A, minus he a e o Q hough he a ea A o e he dis ance dx, equals
he concen a ion change pe uni ime hough he dis ance dx h ough he same a ea A. This equa ion can be simpli ied o he con inui y equa ion -dQ/dx = dc/d .
Subs i u ing Fick's i s law in o he con inui y equa ion esul s in Fick's second law dc/dx = D(d2c / dx2), which in a h ee-dimensional dis ibu ion, gi es dc/d = D(d2c / dx2
+ d2c / dy2 + d2c / z2). This equa ion desc ibes he unc ion o local adminis a ion o an ionic d ug, such as Zn2+ ions, du ing applica ion o expe imen al di ec cu en o
wi hin a BCEC in li ing issue.(11)
Figu e 2. E ec o di e en hal
li es on colds
A e age du a ion o colds by hal -li es
In common cold ea men wi h zinc lozenges, ionic mo ili y and o al di usion calcula ions can be used in heo y. Howe e , o p ac ical use in compa ing he e icacy o
di e en zinc lozenge o mula ions agains he du a ion o common colds, Fick's laws can be g ea ly simpli ied by assuming cons ancy be ween pa ien s o he c oss-
sec ional a ea o he o al mucosal memb ane, i s hickness, acial h ee-dimensional geome y, BCEC con igu a ion, mou h-nose EMF (and di ec ion), as well as many
o he a iables excluding all bu he numbe o doses, he lozenge dissolu ion ime, he elec onic cha ge o he zinc species and he ini ial zinc concen a ion. Pe haps he
la ges e o in oduced by hese assump ions esul s om he di e ing cha ac e is ics o small child en and adul s. By in oducing ime, a es a e con e ed in o o als.
Zinc Ion A ailabili y (ZIA) Values
The no ion o zinc ion a ailabili y (ZIA) used he e is de i ed om Fick's i s and second laws o di usion, bu ZIA does no measu e he amoun o Zn2+ ion abso bed
ac oss biologic memb anes. By calcula ing ZIA alues o he a ious s udies, he inding o linea i y in esponse o ea men (see Figu e 19 in Chap e 5) sugges s ZIA o
be a ela i e de e minan o he amoun abso bed in compliance wi h Fick's laws o memb ane di usion. The e o e, ZIA is de ined as he po en ial o daily abso p ion o
Zn2+ ions in o o al and o opha yngeal mucosal memb anes a pH 7.4 be ween lozenges ha ing se e al di e en cha ac e is ics, o ZIA = KZiT, whe e K = 0.7697, and Zi =
ini ial concen a ion o Zn2+ ions, and T = ime.
Fo calcula ion o daily ZIA o compa a i e pu poses be ween lozenge o mula ions, he daily ZIA alue equals he cons an 0.7697, imes lozenge zinc dosage (mg),
imes ac ion as Zn2+ ion a pH 7.4 (ini ial ac ion be o e p ecipi a ion o Zn2+ ions by sali a y p o eins and abso p ion in o o al mucosal memb anes), imes o al
dissolu ion ime (minu es) o lozenges, imes lozenges used pe day, di ided by olume (ml) o sali a gene a ed (nume ically equal o o al sali a gene a ed minus
lozenge weigh in g ams co ec ed o lozenge speci ic g a i y) du ing each o al dissolu ion. Some o he ac s can be de e mined only by s udying he in a-o al
dissolu ion/expec o a ions o zinc-laden sali a, o zinc-laden sali a. Linea , o a leas uni o m, lozenge dissolu ion a es occu in all lozenges es ed (see Chap e 7).
To u he illus a e, he ZIA alue o he o iginal 1984 Eby lozenges is 100. The 660 mg lozenges con aining 23 mg zinc glucona e ini ially eleased 30 pe cen Zn2+ ion a
pH 7.4 (see Figu e 1 in Chap e 1). The cons an K is 0.7697. Lozenges dissol ed in 30 minu es. Lozenges we e used 9 imes a day. Lozenges gene a ed 15 ml zinc-
laden sali a pe applica ion. When mul iplied oge he , hey equal +129.92K. To se he ZIA o 100 o he Eby lozenges as a s anda d; K, he e o e, equals 0.7697 ml /
minu es x mg x doses/day.
The ZIA o mula and concep a e used h oughou he emainde o his handbook o compa e c i ical pe o mance c i e ia o di e en zinc lozenge o mula ions.
Lozenges wi h equal ZIA alues, wi hin a easonable ange cen e ed on he abo e example, heo e ically will ha e equal e icacy agains colds, al hough ini ial Zn2+ ion
concen a ions should be mo e han 5 mMol.
In he e en mo e s ong zinc chela o is p esen han needed o bind all Zn2+ ions and o o he wise p oduce a ZIA alue o ze o, he ZIA alue is conside ed o be
nega i e.
Ma hema ics o Common Cold Du a ion
Re iew o common cold s udies shows esul s o ha e been exp essed in a ious e ms, wi h mos o hem showing he e ec o ea men on symp om se e i y.
Techniques include mean clinical sco es, symp om clinical sco es, o al nasal mucus weigh s, o al numbe o acial issues used, and o he subjec i e measu es o
wellness.
Mo e ecen ly, hal -li es o common colds and weigh ed a e age du a ions o common colds we e shown o be app op ia e means o common cold analysis when he a e
o decay is exponen ial.(4) Acco ding o Gwal ney, one-hal o un ea ed hino i us colds a e o e in one week, h ee- ou hs a e o e in wo weeks, while se en-eigh hs
las h ee weeks o less, and so o h.(21) The e o e, he hal -li e (H) o un ea ed colds is 7 days. Wi h each passing week, one-hal o emaining colds disappea .
Figu e 2. E ec o di e en hal -li es on pe cen o pa ien s wi h symp oms on a ious days, showing weigh ed a e age du a ions
(a ows).
The e ec o a hypo he ical zinc and placebo ea men ha ing di e en hal -li es on pe cen age o pa ien s du ing i s week o
ea men and p ojec ed alues beyond he week o ea men a e shown in Figu e 2. Conside he si ua ion whe e 50 pe cen o
pa ien s a e well by day 2.2 wi h zinc ea men and by day 7 wi h placebo; 75 pe cen a e well by day 4.4 wi h zinc ea men , and
by day 14 wi h placebo; 86.5 pe cen a e well by day 6.6 wi h zinc ea men , and by day 21 wi h placebo. Using hal -li e heo y, he
expec ed numbe o pa ien s eco e ed can be p ojec ed beyond du a ion o s udies. Es ima es a e he week o ea men a e
p edica ed upon hal -li e o colds con inuing o decay a same a e as du ing he week o ea men .
Rela ed o he hal -li e o common colds is he a e age du a ion. Al hough a e age du a ion is no he same as hal -li e, hey a e
equen ly con used wi h each o he . The a e age du a ion is equal o he numbe o days colds pe sis , whe e he sum o days is
aken o e he collec ion o pa ien s, di ided by o al numbe o pa ien s. The a e age du a ion is ma hema ically ela ed o hal -li e
(H) o common colds. Fo common colds decaying a a se exponen ial a e, a e age du a ion o common colds is p o ided by he
ma hema ical exp ession whe e N is ini ial numbe o pa ien s, and H is hal -li e o colds obse ed in s udy g oup.
The exp ession simpli ies o H/ln 2, and ln 2 equals 0.6931. The e o e, once he hal li e (H) is
de e mined and he decay a e is ound o be exponen ial, he a e age du a ion can be di ec ly
de e mined. Fo example, zinc- ea ed colds ha ing a hal li e o 2.2 days ha e an a e age du a ion o
3.2 days, and placebo- ea ed colds wi h a hal -li e o 7 days ha e an a e age du a ion o 10 days.
A ows in Figu e 2 show weigh ed a e age du a ion. Di e ences in weigh ed a e age du a ion be ween
ea ed and un ea ed colds di ec ly ollow. This me hod is no eliable o colds no decaying a an
exponen ial a e.
O he me hods o de e mining a e age du a ion mus be used o non-exponen ially decaying colds, which would in ol e obse ing he du a ion o each cold, an a duous
ask o placebo- ea ed colds. In he case o nonexponen ially decaying colds, hal -li e analysis and compa ison o decay a es (plo ed as he numbe o colds emaining
on each day o he s udy) a e p obably su icien .
The abo e me hod o de e mining hal -li e and es ima ing a e age du a ions o exponen ially decaying common colds should be adop ed as he a o ed means o
measu e e ec s o zinc lozenges on sho ening he du a ion o common colds. Hal -li e and a e age du a ion analyses may be used o supplemen all o he me hods o
measu ing e ec s o ea men s including mean clinical sco es, o al nasal mucus weigh s, and numbe o acial issues used. Each o he epo s in Chap e 4 ha e been
e-analyzed using published ac s and ac ual de ails om lozenge manu ac u e s, and hal -li e and a e age educ ions (o inc eases) in du a ion ha e been calcula ed
using all he a ailable in o ma ion.
Chap e 3 Re e ences
1. Aoki FY. Dis ibu ion and emo al o human se um albumin - Techne ium 99m ins illed in anasally. B i ish Jou nal o Clinical Pha macology. 1976;3:869-878.
2. Eby GA, Da is DR, Halcomb WW. E ec o zinc o o a e lozenges wi h zinc glucona e nasal sp ay in common cold ea men - a double blind s udy. Unpublished da a,
1984.
3. B yce-Smi h D. Sp ay p epa a ions o espi a o y ac in ec ions. Eu opean Pa en Applica ion 381522, Augus 8, 1990.
4. Eby GA, Da is DR, Halcomb WW. Reduc ion in du a ion o common cold symp oms by zinc glucona e lozenges in a double blind s udy. An imic obial Agen s and
Chemo he apy. 1984;25: 20-24.
5. Wadke DA, Se ajuddin ATM, Jacobson H. P e o mula ion es ing. In: Liebe man HA, Lachman L, Schwa z JB, eds. Pha maceu ical Dosage Fo ms: Table s Volume 1.
New Yo k: Ma cel Dekke , Inc.; 1989.
6. McGini y JW, S a chansky SA, Ma in A. Bioa ailabili y in able echnology. In: Liebe man HA, Lachman L, Schwa z JB, eds. Pha maceu ical Dosage Fo ms: Table s
Volume 2. New Yo k: Ma cel Dekke , Inc; 1989.
7. Subcommi ee on Zinc, Commi ee on Medical and Biological E ec s o En i onmen al Pollu an s, Di ision o Medical Sciences, Assembly o Li e Sciences, Na ional
Resea ch Council. Zinc. Bal imo e:Uni e si y Pa k P ess; 1979;305.
8. Beisel WR, Peka ek RS, Wannemake RW J . Homeos a ic mechanisms a ec ing plasma zinc le els in acu e s ess. In: P asad AS, Obe leas D eds. T ace Elemen s in
Human Heal h and Disease. New Yo k: Academic P ess; 1976;87-102.
9. Hu o d SR, Smi h GL, Williams DR, e al. Me al ions and hei in e ac ions wi h biological luids: specia ion o ace me als in sali a. Re . Pos . Quim. 1985;27:423-424.
10. P asad AS, Obe leas D. Binding o zinc o amino acids and se um p o eins in i o. Jou nal o Labo a o y and Clinical Medicine. 1970;76:416-425.
11. No dens öm BE. Biologically Closed Elec ic Ci cui s. Clinical, Expe imen al and Theo e ical E idence o an Addi ional Ci cula o y Sys em. S ockholm:No dic Medical
Publica ions; 1983; 112-172.
12. Gup a D, Ho PS. Some o mal aspec s o di usion. In: Gup a D, Ho PS, eds. Di usion Phenomena in Thin Films and Mic oelec onic Ma e ials. Pa k Ridge, NJ:Noyes
Publica ions. 1988;2.
13. Gwal ney JM J . Uni e si y o Vi ginia School o Medicine, Cha lo es ille, VA. Unpublished da a, 1984.
14. Jackson MJ. Physiology o Zinc: Gene al Aspec s. In: Mills CF, ed. Zinc in Human Biology. New Yo k: Sp inge -Ve lag; 1989.
15. Me luzzi VJ, Cip iano D, McNeil D, e al. E alua ion o zinc complexes on he eplica ion o hino i us 2 in i o. Resea ch Communica ions in Chemical Pa hology and
Pha macology. 1989;66: 425-440.
16. Geis FC, Ba eman, JA, Hayden FG. In i o ac i i y o zinc sal s agains human hino i uses. An imic obial Agen s and Chemo he apy. 1987;31: 622-624.
17. Lehninge AL. Biochemis y. 2nd ed. New Yo k: Wo h Publishing, Inc.; 1975.
18. Bock is O'M, D azic D. Elec o-Chemical Science. London:Taylo & F ancis; 1972.
19. Newman J. Elec ochemical Sys ems. Englewood Cli s, NJ:P en ice-Hall; 1973.
20. Nobel PS. In oduc ion o Biophysical Plan Physiology. San F ancisco:W.H. F eeman & Co.; 1974;92.
21. Gwal ney JM J . Rhino i us. In: Mandell GL, Douglas RG J , Benne JE, eds. P inciples and P ac ices o In ec ious Diseases. New Yo k:John Wiley & Sons; 1979;
1124-1134
Chap e 4. E ec s o Zinc Lozenges on Du a ion o Common Colds
Execu i e summa y Chap e 4 desc ibes h ee possible e ec s o zinc lozenges upon common colds. Lozenges con aining e y weak complexes o zinc elease
posi i ely cha ged zinc (hyd a ed Zn2+ ions) a pH 7.4, esul ing in posi i e ZIA alues. As he concen a ion o Zn2+ ions and he ime o e which hey a e applied a e
inc eased, du a ion o colds and se e i y o cold symp oms a e p opo iona ely educed. Use o lozenges ha ing a ZIA alue o 25 educed he a e age du a ion o colds
by 1.6 days. Use o lozenges ha ing a ZIA alue o 44 educed he mean clinical sco e and a e age du a ion and nasal sec e ion weigh s o colds by 4.8 days. Use o
lozenges ha ing a ZIA alue o 100 educed he du a ion and se e i y o common colds by 7 days.
Lozenges con aining s ongly complexed zinc elease neu ally cha ged zinc complexes (ZnL0) a pH 7.4, esul ing in a ZIA alue o ze o. Lozenges ha ing ze o ZIA
alues ha e no e ec upon ei he symp om se e i y o du a ion o common colds.
Lozenges con aining s ongly complexed zinc wi h s ong ligands in mola excess elease nega i ely cha ged zinc complexes (ZnLNN-) a pH 7.4, esul ing in nega i e
ZIA alues. Lozenges ha ing nega i e ZIA alues inc ease bo h he se e i y and du a ion o common colds.
Di e gence in esul s be ween clinical ials o he eigh dis inc ly di e en p op ie a y zinc lozenges e iewed is comple ely econciled when zinc ion a ailabili y (ZIA)
alues a e conside ed.
Lack o knowledge o he a ailabili y o Zn2+ ions by bo h he au ho s o he ollowing s udies and he independen manu ac u e s o lozenges used in he au ho s' s udies
has se iously impeded clinical esea ch in ol ing lozenges eleasing Zn2+ ions as ea men and cu e o he common cold. Some clinical esea che s, no knowing he
lozenges supplied by manu ac u e s con ibu ed ew o no Zn2+ ions, came o belie e "zinc didn' wo k."
The pu pose o he ollowing e iews o he clinical s udies is o b ing o ligh he amoun o Zn2+ ions a ailable om s udy lozenges (ZIA alues o ea men s) and o
compa e hose alues wi h he educ ion in du a ion in common colds.
Using his app oach, i becomes ob ious ha o al Zn2+ ions -- and no o al zinc compounds -- a e e ec i e in educing he du a ion o common colds. I will also be
shown he amoun o educ ion in du a ion is di ec ly ela ed o he amoun o Zn2+ ions a ailable as calcula ed using ZIA alues, e lec ing Fick's laws. Sali a y Zn2+ ion
concen a ions h oughou he ollowing e iews a e gi en a pH 7.4, unless o he wise indica ed, and should be in e p e ed as ini ial concen a ions o maximums, as
some Zn2+ ions bind wi h sali a y p o eins and some a e abso bed in o issues.
Each o he ollowing epo s was analyzed using published da a, lozenge samples om he s udies, manu ac u e s' o mulas o he lozenges used in he s udies, and
eplica ed lozenges based upon he manu ac u e 's desc ip ions o de e mine ZIA, hal -li es, and changes in du a ion. All da a a e suppo ed by he o iginal sou ces.
Con i ma ion o he lozenge ing edien s and manu ac u ing p ocedu es can be ob ained om he o iginal ci ed sou ces.
E e y possible e o was made o epo he indings o he esea che s accu a ely, o disco e exac ly how lozenges we e made, o disco e how lozenges we e ac ually
used, and o disco e he ing edien s and hei amoun s p esen in he lozenges.
E e y possible e o was expended o assess accu a ely he di e ences in he epo ed esul s caused by a ia ion in he p ocedu es and ac ual chemis y o he
lozenges used in clinical ials.
4.A. E ec s o Hyd a ed Zn2+ Ions on Du a ion o Common Colds
Se e al published epo s, which will be ully desc ibed la e in his chap e , show he bene icial e ec s o posi i ely cha ged hyd a ed Zn2+ ions on common cold se e i y
and du a ion. Analysis o he epo s shows zinc glucona e lozenges con aining no o he zinc-complexing agen s educe he se e i y and du a ion o common colds in a
dose-dependen manne . The ac ion o zinc ini ially eleased om zinc glucona e a 30 mMol as Zn2+ ion is abou 30 pe cen a pH 7.4 in he absence o any o he
chela o (see Figu e 1 in Chap e 1). The i s s udy used unswee ened zinc glucona e able s as lozenges. Table s s imula ed p oduc ion o e y li le sali a and las ed
abou 30 minu es. Lozenges p oduced a high ZIA alue and educed colds by 7 days. The second s udy used uc ose-based zinc glucona e lozenges. Swee ness
s imula ed p oduc ion o mo e sali a. Lozenges dissol ed mo e quickly, had a ZIA alue sligh ly less han hal he alue o he i s s udy lozenges, and p opo iona ely
educed colds by 4.8 days. The hi d and ou h s udies used low-dosage lozenges, had lowe ZIA alues, and we e less e ec i e on common colds.
Chap e 4. A.1. - O iginal 1984 Eby S udy
Du ing he all cold season o 1981, Geo ge A. Eby, Donald R. Da is, and William W. Halcomb es ed 660-mg zinc glucona e able s used as h oa lozenges con aining
23 mg zinc (1.5 RDA) and no o he zinc chela o s o soluble ing edien s. The Eby g oup ound he zinc glucona e lozenges e ec i e in sho ening he a e age du a ion o
na u al common colds by 7 days in a double-blind clinical ial.(1) The wo expe imen al g oups in he s udy esponded comple ely di e en ly, and he e ec s o he
lozenges we e clea om he beginning. In he zinc- ea ed g oup 22 pe cen we e well wi hin 1 day, e sus none in he placebo- ea ed g oup (P = 0.008, by exac
binomial). The hal -li e (H) o zinc- ea ed colds was 2.7 days compa ed o 7.5 days o placebo- ea ed o un ea ed na u al colds. This is o say, each 2.7 days, he
numbe o pa ien s emaining ill was educed by one-hal wi h zinc ea men ; his esul occu ed a 7.5 days o placebo ea men . A e age du a ion (H/ln 2) o zinc-

ea ed colds was, he e o e, 3.9 days, while placebo- ea ed colds a e aged 10.8 days. On day 7, 86 pe cen o 37 zinc- ea ed pa ien s we e asymp oma ic compa ed
wi h only 46 pe cen o 28 placebo- ea ed pa ien s (P = 0.0005). The en i e a icle is p esen ed he e.
The only ing edien s in he 660-mg able s we e 175 mg zinc glucona e (23 mg zinc), dicalcium phospha e, mic oc ys alline cellulose, sodium s a ch glycola e,
magnesium s ea a e, and FD & C yellow numbe 5 and blue numbe 1 (aluminum lake) colo ing. Wi h excep ion o he lake colo s, all ing edien s we e essen ially
nonsoluble and non eac i e wi h zinc glucona e. S abili y cons an compu a ions e ealed abou 60 pe cen o zinc was p esen as Zn2+ ion a sali a y pH 5 o 5.5, and 30
pe cen o zinc was p esen as Zn2+ ion a physiologic pH 7.4 (see Figu e 1 in Chap e 1). Al hough lake colo s p obably chela ed some zinc, he amoun appea s o ha e
been insigni ican . The exac quan i ies o each ing edien excep zinc glucona e a e unknown, bu one could heo ize ha amoun s used we e calcula ed o esul in a
slow dissolu ion a e. Table s equi ed abou 30 minu es o dissol e in he mou h.
Because lozenges we e small, bland, ha d able s ha dissol ed slowly, lozenges s imula ed p oduc ion o e y li le (15 ml) in a-o al dissolu ion/expec o a ions o zinc-
laden sali a. Sali a y Zn2+ ion concen a ion was 7.4 mMol o less a pH 7.4. The pH o zinc-laden sali a was 5.5. The pH o simila concen a ions o zinc glucona e in
de-ionized wa e was 6.4. Lozenges p oduced mode a ely s ong as ingency in he mou h and conside able amoun s o nonpalpable sali a y p o ein p ecipi a e.
Lozenges we e used e e y wo hou s while awake and o aled 9 doses/day. Lozenges had a ZIA alue o 100.
No pa ien complained o bi e ness. Placebo lozenges con ained calcium lac a e as placebo, bu we e o he wise iden ical o zinc glucona e lozenges in espec o
ing edien s, size, shape, colo , odo , and ex u e. The p ima y as e in bo h zinc glucona e and placebo lozenges was o dicalcium phospha e. Bo h had a d y, chalky,
medicinal la o . Nei he zinc glucona e lozenges no placebo lozenges we e pe cei ed by he pa ien s o in es iga o s as ha ing an objec ionable, bi e as e ypical o
zinc glucona e p epa ed wi h soluble swee ene s such as suc ose o dex ose.
Nei he he zinc glucona e able s no placebo able s we e designed o o al dissolu ion, and he e o e no swee ene s o la o s we e p esen .
Pa ien s
All pa ien s we e ec ui ed du ing he all using local adio and ele ision ad e isemen s. People wi h ea ly onse common colds we e in i ed o join a clinical s udy
in ended o de e mine i zinc glucona e lozenges could sho en du a ion o common colds. All pa ien s we e bo h sel diagnosed and diagnosed by he physician (William
W. Halcomb, a gene al p ac ice physician and alle gis ) o ha e uncomplica ed common colds.
Pe sons p esen ing wi h an alle gy we e no admi ed o his s udy. Likewise, p egnan women and pe sons on immunosupp essi e d ugs we e no admi ed. Pe sons wi h
known se ious heal h diso de s we e also excluded.
In o med consen was ob ained in w i ing a e explana ion o he s udy. Pa ien s illed ou a p in ed heal h ques ionnai e and we e ins uc ed in he s udy p o ocol.
Pa ien s chose a andomly coded bo le con aining ei he 75 zinc glucona e o 75 placebo lozenges in a double-blind manne .
The ollowing ea men ins uc ions a e he exac ins uc ions gi en in he o iginal 1984 clinical ial, and hese ins uc ions should be ollowed in all u u e clinical ials.
T ea men P o ocol
A he i s o ice isi , pa ien s we e ins uc ed o dissol e able s slowly as lozenges. Loading dose was wo able s (46 mg zinc), aken one a e ano he . The double-
s eng h loading dose was conside ed impo an o apid eco e y om symp oms, and e e yone was ins uc ed o be ce ain he double dose was aken. Emphasis was
placed upon slowly dissol ing lozenges in a manne in ended o maximize he amoun o zinc ha could be abso bed in o mucosal memb anes o he mou h and h oa .
Adul s and you hs o e 60 pounds we e o dissol e one able e e y wo hou s while awake a e he loading dose. Child en unde 60 pounds we e o dissol e 1/2 able
e e y wo hou s while awake. All we e ins uc ed o con inue ea men e e y wo hou s while awake un il 6 hou s a e he end o he las common cold symp om. All we e
ins uc ed o a oid s ess and include one o wo ea men s du ing he i s day a e cessa ion o symp oms as insu ance agains elapse.
Expe ience wi h many common colds using zinc glucona e lozenge ea men du ing he 4 yea s immedia ely p eceding he s udy also showed esul s could be imp o ed
i ce ain o he s eps we e ollowed. Pa ien s we e old esul s migh be imp o ed i pa ien s (a) slep a e he i s ea men and a e o he ea men s when possible, (b)
used a lozenge a bed ime (especially impo an as lymph ci cula ion s ops du ing sleep holding Zn2+ ions in issues o e nigh ), (c) ook lozenges a e meals and liquids
(no be o e o on an emp y s omach o a oid nausea), (d) a oided mou hwashes o alcohol, (e) a oided aspi in, an ihis amines, deconges an s, o o he cold emedies,
and (g) a oided smoking.
Pa ien s we e ins uc ed o ea soda c acke s i nausea occu ed. Mo e ecen esea ch con i ms hese echniques o imp o e esul s, pe haps by helping o p e en
emo al o zinc om o al issues as well as by p e en ing immunosupp ession o complexa ion o Zn2+ ions by o he d ugs.
Each pa ien was gi en a " ea men esponse o m" in which hey we e o eco d se e i y o en common cold symp oms each day o 7 days a he same ime o day as
hei ini ial o ice isi . Symp oms s udied we e headache, e e , muscle pain, sneezing, nasal d ainage, nasal obs uc ion, so e h oa , sc a chy h oa , cough,
hoa seness, and o he . Common cold symp oms we e sco ed as being ei he se e e (3 poin s), mode a e (2 poin s), mino (1 poin ), o absen (0 poin s). Space was
p o ided o eco d side e ec s and o he commen s abou ea men .
Chi-squa e and - es s a is ical es s we e used excep as no ed. P alues below 0.05 we e conside ed signi ican .
Resul s o 146-Pa ien S udy
Resul s o he s udy o hose pa ien s ha ing been ill o only 3 days be o e en ollmen ha e been published.(1) The pape was c i icized on se e al coun s. One c i icism
was only six y- i e pa ien s ou o 146 pa ien s who en olled we e epo ed. This omission sugges ed bias, e en hough he main esul s o all epo able pa ien s we e
men ioned in he epo as: "A e he 7-day expe imen , 90 pe cen o he zinc- ea ed pa ien s epo ed no cold symp oms, compa ed wi h only 49 pe cen o he placebo-
ea ed pa ien s (P << 0.0001)."
Table 1. Cha ac e is ics o 80 pa ien s
____________________________________________________________________________
Zinc- ea ed Placebo- ea ed
___________________________________________________________________________
To al pa ien s 41 39
Male/ emale 20/21 22/17
Age ange 11-63 14-67
Mean age + s.e.m. 34 + 2.0 37.5 + 2.3
Smoke s 9 9
His o y o alle gy 15 14
His o y o o e 4 colds/yea 7 8
P e ea men use o zinc supplemen s 4 5
P e ea men use o i amin C 13 17
Mean p e-en ollmen du a ion
o colds + s.e.m. (days) 2.2 + 0.2 2.6 + 0.3
Mean ini ial numbe o
symp oms + s.e.m. 5.4 + 0.3 6.3 + 0.4
Mean ini ial o al se e i y
sco e poin s + s.e.m. 9.5 + 0.7 10.3 + 0.7
___________________________________________________________________________
The epo was limi ed ou o conce n by he au ho s and jou nal edi o s o possible supe imposed alle gies and bac e ial in ec ions in colds o longe du a ion. Also, a
main goal o he esea ch was o s udy he e ec s o zinc glucona e lozenges on colds o sho p e- ea men du a ion, no long du a ion. Sho p e- ea men du a ion
be e assessed possible impac o Zn2+ ions on hino i uses which a e belie ed o eplica e immedia ely be o e onse o common cold symp oms and du ing he i s day
o wo o symp oms. To encou age unbiased epo ing o p e- ea men du a ion o common colds, all pa ien s we e accep ed in o he s udy ega dless o how long hei
colds had las ed be o e ini ia ion o ea men .
The second and main c i icism was he possibili y o unblinding because o o al side e ec s and as e di e ences be ween zinc and placebo. To answe unblinding
c i icisms, subg oups o zinc- ea ed pa ien s o e ing commen s o complain s abou as e, a e as e, and o al side e ec s we e compa ed wi h hose no o e ing
complain s. The e we e no di e ences in esponse o zinc ea men be ween he wo subg oups. Tas e p oblems associa ed wi h zinc glucona e in suc ose, dex ose, and
suga -alcohols a e absen om zinc glucona e able s ha ing no o he soluble ing edien s.
O 146 olun ee s o iginally en olled in he s udy, colds had las ed 10 days o less in 83 o he zinc- ea ed pa ien s, and in 63 o he placebo- ea ed pa ien s. O hese,
108 e u ned esponse epo s (64 zinc, 44 placebo) o which 80 con ained su icien da a o ull analysis (41 zinc, 39 placebo). Cha ac e is ics o hese 80 pa ien s a e
shown in Table 1 along wi h in o ma ion abou hei colds. Analysis o hese cha ac e is ics and a numbe o o he s indica ed andomiza ion p ocedu e o ha e been
success ul in p oducing simila g oups. Th ee measu es o deg ee o illness indica ed he placebo g oup o ha e had sligh ly mo e in ense colds han he zinc g oup. One
o hese measu es app oached s a is ical signi icance (ini ial numbe o symp oms epo ed, = 1.8, wo- ailed P = 0.08), bu his di e ence does no appea o ha e
a ec ed esul s.
Du a ion o Cold Symp oms
Table 2 shows numbe s o pa ien s who epo ed a ious common cold symp oms a di e en imes. Each o he mos common symp oms (nasal d ainage, nasal
obs uc ion, so e h oa , sc a chy h oa and headache) was ini ially epo ed by 60 o 80 pe cen o pa ien s, while he leas common symp om ( e e ) was ini ially
epo ed by abou 30 pe cen o he pa ien s. These obse a ions a e gene ally compa able o esul s o Gwal ney(2) o hino i us colds. Table 2 also con ains ou cen al
indings on pa ien s who epo ed p esence o any one o mo e o 10 common cold symp oms a a ious imes.
Table 2. Numbe s o pa ien s epo ing common cold symp oms a a ious imes.
______________________________________________________________________
Symp om T ea men Hou Hou Hou Day Day Day Day Day Day Day
G oup 0 6 12 1 2 3 4 5 6 7
______________________________________________________________________
Headache Zinc 27 17 12 9 5 4 0 0 1 1
Headache Placebo 23 19 17 13 7 6 5 3 3 5
Fe e Zinc 13 11 8 7 5 2 0 0 1 0
Fe e Placebo 12 10 10 8 6 5 5 4 2 3
Muscle pain Zinc 20 16 13 10 5 3 0 0 0 1
Muscle pain Placebo 17 15 14 12 8 5 5 5 4 4
Sneezing Zinc 21 14 12 9 7 6 2 0 2 1
Sneezing Placebo 27 20 19 17 13 9 8 7 7 7
Nasal
d ainage Zinc 31 26 24 23 20 17 8 4 4 4
Nasal
d ainage Placebo 32 30 32 32 28 25 23 20 19 15
Nasal obs -
uc ion Zinc 24 23 20 18 16 11 6 3 3 3
Nasal obs -
uc ion Placebo 32 30 29 30 27 22 17 16 15 11
So e h oa Zinc 27 22 17 15 9 5 1 1 0 0
So e h oa Placebo 23 21 19 16 13 10 7 6 5 4
Sc a chy
h oa Zinc 22 17 12 13 9 5 1 2 0 0
Sc a chy
h oa Placebo 29 27 26 25 18 14 14 11 11 10
Cough Zinc 18 16 l3 12 10 9 5 4 4 3
Cough Placebo 24 23 23 22 20 16 16 11 11 11
Hoa seness Zinc 19 15 13 15 9 6 1 1 1 1
Hoa seness Placebo 25 20 18 20 14 9 10 6 5 5
______________________________________________________________________
Any symp om Zinc 41 37 35 31 24 18 10 8 5 4
Any symp om Placebo 39 39 39 39 37 32 29 27 26 20
______________________________________________________________________
Du a ion o common colds was de ined as p esence o any one o mo e o hese en symp oms. P esence o any one o mo e common cold symp om is he main esul o
he s udy, and is also shown in Figu e 3.
The wo expe imen al g oups clea ly esponded di e en ly, and he e ec s o zinc we e appa en om he beginning. In he zinc g oup, sizable numbe s o pa ien s
became comple ely asymp oma ic a he quickly -- 15 pe cen wi hin 12 hou s and 25 pe cen by 24 hou s -- whe eas no placebo- ea ed pa ien was symp om- ee wi hin
24 hou s (P < 0.02 a 12 hou s, P < 0.001 a 24 hou s, by exac binomial calcula ions).
The plo o he zinc g oup is oughly an exponen ial decay wi h a hal -li e o abou 2.2 days; his is o say, hal o he emaining symp oma ic pa ien s became symp om
ee abou e e y 2.2 days. In con as , hal o he placebo g oup equi ed 7 days o become asymp oma ic, in ag eemen wi h gene ally accep ed du a ions o common
colds. In ou zinc- ea ed popula ion, 90 pe cen we e asymp oma ic by day 7 compa ed wi h 51 pe cen o he placebo- ea ed popula ion (P << 0.0001).
The expe imen was oo sho o measu e ully a e age du a ion o cold symp oms, especially in he placebo g oup. E en i all symp oms emaining on day 7 had ended
by day 8 o bo h g oups (ex emely unlikely), he e ec o zinc lozenges on a e age du a ion would ha e been s a is ically highly signi ican (a e age du a ion would be
3.0 days in he zinc g oup and 5.9 days in he placebo g oup, P<< 0.0001). Imp o ed es ima es o a e age du a ion o hese colds can, in his case, be based on a e age
du a ion o an exponen ial decay cu e (hal -li e/ln 2) and on hal -li es. This me hod o ex apola ion leads o a e age du a ions o 3.2 days and 10 days and o an
es ima ed 7-day educ ion in he a e age du a ion a ibu able o zinc glucona e lozenges.
Examina ion o he en indi idual symp oms epo ed in Table 2 shows each o ha e clea ed mo e apidly in he zinc g oup han in he placebo g oup. In some cases
hese di e ences a e independen ly s a is ically signi ican a e jus 1 day (P<0.05 by exac binomial calcula ion o nasal d ainage, and cough). Mos pe sis en
symp oms (nasal d ainage, nasal obs uc ion, and cough) had hal -li es o abou 5 o 7 days in he placebo g oup, bu only abou 3 days in he zinc g oup. All o he
symp oms, including se e al pain- ela ed symp oms (muscle pain, so e h oa ,sc a chy h oa , e e , headache), sneezing, and hoa seness seemed o disappea
comple ely by he ou h day in nea ly all zinc- ea ed pa ien s. In placebo- ea ed pa ien s, hese symp oms did no imp o e a e he hi d day du ing he week o he
s udy. Only wo pa ien s epo ed ecu ence o any symp oms a e becoming symp om ee. Bo h we e in he zinc g oup. In one pa ien one mild symp om ecu ed 1 day
a e s opping ea men , bu i disappea ed again a e 5 mo e lozenges. This pa ien con essed he had aken only abou hal o he ecommended dosage h oughou he
expe imen . The o he pa ien was asymp oma ic on day 2 bu had a ull-blown cold wi h six symp oms on day 3. She esumed ea men and was asymp oma ic again by
day 4 and he ea e . Al hough p o ision o lis ing o he symp oms was made, only one pe son (in he zinc g oup) indica ed ano he symp om: acu e sinusi is which
clea ed in 3 days.
Figu e 3. Du a ion o common colds in ZIA 100 zinc glucona e- and placebo- ea ed g oups.
The possible e ec on esul s o he di e ence be ween he wo g oups in hei ini ial numbe o symp oms was e alua ed. Se e al me hods showed he e was no
app eciable e ec . The e was essen ially no co ela ion be ween ini ial symp oms and du a ion o colds in ei he g oup ( = 0.1 zinc, -0.1 placebo). Likewise an analysis o
co a iance showed negligible in e ac ion o hese a iables. As a inal es , he e ec o empo a ily excluding om analysis 20 pe cen o placebo pa ien s ha ing he
mos ini ial symp oms and 20 pe cen o he zinc pa ien s wi h ewes ini ial symp oms ( he eby mo e han emo ing ini ial di e ence be ween g oups) was calcula ed.
The e was s ill no change in hal -li es and s a is ical ends p e iously gi en.
Ra es o eco e y in a ious subg oups o pa ien s we e s udied. The da a sugges zinc may ha e bene i ed women mo e han men, pe haps because o size and weigh
di e ences o di e ences in o al mucosal memb ane hicknesses, and non-smoke s mo e han smoke s (by 1-2 days a e age du a ion, P = 0.05 o 0.2 a se e al di e en
imes). Da a simila ly sugges ed in bo h he zinc- and placebo- ea ed g oups younge pa ien s eco e ed mo e quickly han olde pa ien s (by 2-3 days a e age du a ion),
and pa ien s who epo ed aking i amin C supplemen s be o e he s udy eco e ed mo e quickly han hose who did no (by 1 day a e age du a ion). These possible
Figu e showing apid decline in numbe o pe sons wi h
colds gi en zinc compa ed o people gi en placebo
ela ionships a e unce ain and equi e u he s udy. No o he cha ac e is ic was ound o impac eco e y in
subg oups, including he p esence o absence o complain s abou as e o side e ec s.
Diligen e o s o de ec di e ences in esponses o ea men be ween zinc- ea ed pa ien s who eco ded a
complain abou o al side e ec s and zinc- ea ed pa ien s who did no we e pe o med. Plo s o du a ion o
cold da a o bo h subg oups we e iden ical, s ongly sugges ing as e was no a ac o in esponses o zinc-
ea ed pa ien s.
In p elimina y ield ials in nume ous pa icipan s be o e he o mal clinical s udy, we equen ly obse ed ha
when zinc ea men was s a ed wi hin 2 hou s o onse o cold symp oms, he appa en colds usually would
be abo ed wi hin 1 o 4 hou s.
The p esen s udy could no adequa ely es his obse a ion because only wo zinc- ea ed pa ien s' colds had
las ed 6 hou s o less be o e en ollmen . Al hough one pa ien became asymp oma ic wi hin 6 hou s, he o he
pa ien 's cold las ed 5 days.
Se e i y o Cold Symp oms
Table 3 shows a e age se e i y sco es a a ious imes o each o he 10 symp oms s udied. Fo all
symp oms, se e i y sco es ell conside ably as e in he zinc g oup han in he placebo g oup. Table 3 also
shows a e age se e i y sco es o all symp oms combined, and hese a e p esen ed in Figu e 4. Mos
pe sis en symp oms (nasal d ainage, nasal obs uc ion and cough) we e educed in se e i y in he zinc g oup
by abou 30 o 40 pe cen du ing he i s day, by abou 60 pe cen by he ou h day, and by abou 66 o 83 pe cen by he se en h day. All o he symp oms, including
pain- ela ed symp oms (muscle pain, so e h oa , sc a chy h oa , e e , and headache), sneezing, and hoa seness appea ed o disappea comple ely by he ou h day in
nea ly all zinc- ea ed pa ien s. In he placebo- ea ed pa ien s, no symp om imp o ed signi ican ly a e he ou h day. Se e i y o zinc- ea ed colds was one-hal o
placebo- ea ed colds on day 2.5. Se e i y o colds in he zinc- ea ed g oup was less han 12 pe cen o he se e i y o common colds in he placebo- ea ed g oup on he
se en h day.
Table 3. A e age se e i y o 10 common cold symp oms a a ious imes*
____________________________________________________________________________
Symp om T ea ed Hou Hou Hou Day Day Day Day Day Day Day
G oup N 0 6 12 1 2 3 4 5 6 7
____________________________________________________________________________
Headache Z 27 1.70 0.93 0.59 0.41 0.26 0.19 0.00 0.00 0.04 0.04
Headache P 23 1.48 1.22 1.09 1.00 0.48 0.39 0.35 0.26 0.26 0.39
Fe e Z 13 1.46 1.23 0.92 0.77 0.46 0.15 0.00 0.00 0.08 0.00
Fe e P 12 1.42 1.17 1.17 0.92 0.67 0.58 0.58 0.50 0.33 0.42
Muscle pain Z 20 1.65 1.35 0.90 0.60 0.30 0.20 0.00 0.00 0.00 0.05
Muscle pain P 17 1.41 1.18 1.18 0.94 0.65 0.47 0.47 0.47 0.41 0.41
Sneezing Z 21 1.43 0.90 0.67 0.62 0.48 0.43 0.14 0.00 0.14 0.05
Sneezing P 27 1.52 1.07 1.00 1.04 0.81 0.59 0.56 0.52 0.56 0.56
Nasal
d ainage Z 31 1.87 1.23 1.10 1.10 0.97 0.77 0.45 0.23 0.23 0.16
Nasal
d ainage P 32 1.94 1.56 1.59 1.66 1.47 1.28 1.13 1.00 0.97 0.84
Nasal
obs uc Z 24 1.83 1.50 1.29 1.13 0.92 0.67 0.38 0.25 0.25 0.17
Nasal
obs uc P 32 1.84 1.53 1.59 1.66 l.44 1.09 0.91 0.91 0.88 0.75
So e h oa Z 27 1.78 1.33 1.11 0.89 0.56 0.30 0.07 0.04 0.00 0.00
So e h oa P 23 1.70 1.30 1.22 l.22 0.91 0.61 0.43 0.39 0.30 0.26
Sc a chy
h oa Z 22 1.73 1.27 0.86 0.91 0.68 0.36 0.09 0.14 0.00 0.00
Sc a chy
h oa P 29 1.66 1.24 1.28 1.21 0.90 0.69 0.69 0.62 0.59 0.52
Cough Z 18 2.06 1.39 1.11 0.94 0.83 0.61 0.39 0.28 0.28 0.22
Cough P 24 1.75 1.46 1.54 1.38 1.29 1.08 1.00 0.75 0.75 0.71
Hoa seness Z 19 1.84 1.16 0.89 0.95 0.58 0.37 0.05 0.05 0.05 0.05
Hoa seness P 25 1.40 1.16 1.04 1.04 0.68 0.56 0.52 0.44, 0.44 0.44
____________________________________________________________________________________________________________
All symp. Z 41 9.46 6.63 5.15 4.54 3.34 2.29 0.93 0.56 0.59 0.41
All symp. P 39 10.33 8.21 8.10 7.85 6.21 4.90 4.39 3.95 3.69 3.51
____________________________________________________________________________________________________________
*G oup sums o se e i y sco es in poin s di ided by numbe o pa ien s N ha ing symp om a s a o ea men (se e e = 3 poin s, mode a e = 2 poin s, mino = 1 poin ,
absen = 0 poin s).
An ini ial ab up dec ease in epo ed se e i y occu ed in bo h g oups a hou 1 (no shown), pe haps pa ly because o changed ci cums ances and expec a ions
ollowing en ollmen in he s udy. Then he wo g oups di e ge con incingly a 12 hou s and he ea e (P<0.01 o 0.001 h ough day 7). Whe eas he zinc g oup eco ded
a 50 pe cen d op in se e i y sco es in less han 1 day, he placebo g oup equi ed 3 days o he same educ ion. In he zinc g oup, o al se e i y sco es con inued o all
apidly and nea ly exponen ially om hou 6 h ough day 7, wi h a hal -li e o 1.5 days, compa ed o a hal -li e o 5 days in he placebo g oup a e hou 6.
Se e i y in zinc- ea ed colds di e ged om se e i y o placebo- ea ed colds in he i s day o ea men (Figu e 4). They d opped o abou 60 pe cen o placebo by day
1, and emained a abou 20 pe cen o he se e i y o placebo- ea ed colds om day 4 h ough day 7. S anda d e o o mean (s.e.m.) did no exceed one poin o
placebo- ea ed colds a any ime. The s.e.m. did no exceed one poin o zinc- ea ed colds du ing he i s 3 days and did no exceed one-hal poin om day 4 h ough
day 7. In i o, zinc has e ec s on p os aglandin me abolism.(3) Those e ec s may a ibu e o a eeling o well being and educ ion in pain- ela ed symp oms (muscle
pain, so e h oa , sc a chy h oa , e e , and headache) in common cold ea men .
Side E ec s and Complain s
Space was p o ided on he esponse o m o epo side e ec s and o he commen s. Pa ien s we e old nausea, omi ing, and dia hea we e possible side e ec s. La ge
doses o zinc (350 mg zinc) ha e been used as an eme ic. Table 4 shows all epo ed complain s, including epo s om pa ien s who d opped ou . Abou 38 pe cen mo e
o he zinc g oup han he placebo g oup epo ed some objec ion o ea men , p ima ily unpala able as e, i i a ion o mou h issues, and dis o ion o sense o as e.
Nausea in a ew pa ien s was p obably a ibu able o zinc, bu his is no es ablished by he p esen da a (P = 0.3). Mos o he complain s we e mild and conside ed an
accep able pa o ea men .
Figu e 4. A e age o al se e i y o colds in ZIA 100 zinc glucona e and placebo- ea ed g oups.
On he o he hand, mos o he d opou s om he zinc g oup esul ed om o al side e ec s including able g i iness. Reac ion o zinc glucona e able s was qui e a ied.
A ew pa ien s had s ong eac ions o hei as e while he majo i y o pa ien s had no commen , accep ing he bland, chalky as e as a easonable and accep able pa o
ea men . Some o al side e ec s a e now p ima ily a ibu ed o he nonsoluble o mula ion o lozenges. Unpala able as e was a esul o zinc glucona e and dicalcium
phospha e. I i a ion o mou h, ongue, and h oa may also be caused by ab asi e non-soluble able excipien s. Th ee- ou hs o all complain s we e om women. Mos
Figu e showing apid decline in se e i y o
colds o pe sons gi en zinc compa ed o people
gi en placebo
side e ec s we e accep ed as a no mal pa o he apy by pa ien s, and we e conside ed a ade-o o a quick
eco e y. A comple e lis ing o side e ec s and complain s is ound in Table 4.
Table 4. Side e ec s and complain s
_________________________________________________________________________
Zinc- ea ed Placebo- ea ed
_________________________________________________________________________
To al numbe o pa ien s
(includes d opou s) 61 (100%) 44 (100%)
Numbe o pa ien s epo ing
side e ec s and/o complain s 33 (54%) 7 (16%)
F equency o side e ec s
and/o complain s:
Unpala able as e 10 (16%) 2 (5%)
I i a ion o mou h, ongue
o h oa 9 (15%) 1 (2%)
Nausea o s omach dis ess 9 (15%) 4 (9%)
Dis o ion o sense o as e 7 (11%) 1 (2%)
T ansien mou h so es 3 (5%) 1 (2%)
Vomi ing 2 (3%) 0 (0%)
Dia hea 1 (2%) 1 (2%)
________________________________________________________________________
Bene icial side e ec s epo ed by se e al pa ien s and la e e i ied wi h clinical and ield expe ience(4) includes elimina ion o p e en ion o dysmeno hea and bloa ing,
and elimina ion and p e en ion o angina pec o is. C amping and bloa ing we e con olled in o e 90 pe cen o women using 30-mg zinc doses 1 o 3 imes pe day as
needed wi h meals se e al days each mon h. Women o en commen ed hey hough hey would miss hei pe iod. Elimina ion o symp oms may e lec he s ong e ec
o Zn2+ ions on p os aglandin me aboli es in he u e us.(3) Comple e con ol o angina pec o is wi h 60-mg zinc able s 3 imes a day occu s in one-hal o pa ien s in
clinical p ac ice,(4) which is in ag eemen wi h long- e m zinc, lead, and cadmium en i onmen al pollu ion s udies epo ed in Poland in ol ing housands o people wi h
angina and ischemia o e o (P < 0.001).(5) Co ona y isk ac o s sugges ed by Chand a wi h much la ge (300 mg zinc/day) doses(6) appea e e sed a hese lowe
doses (see Chap e 8).
D op-ou s and Thei Signi icance
Among 64 pa ien s in he zinc- ea ed g oup who e u ned esponse epo s, 20 (31 pe cen ) a e conside ed d opou s because hey s opped ea men and/o s opped
eco ding symp oms be o e cessa ion o symp oms. Th ee o he epo s we e ejec ed because o lack o usable da a o because no a ion by pa ien s ha lozenges we e
swallowed a he han dissol ed. Mos zinc d op-ou s (14 pa ien s) occu ed wi hin 24 hou s o s a ing ea men ; 13 esul ed om objec ions o ea men , 8 om side
e ec s, and 5 om as e. Th ee blamed lack o bene i . A he ime o d opping ou , 13 zinc- ea ed pa ien s had imp o ed, wo we e wo se, and i e we e unchanged o
change was unknown based on se e i y sco es.
D op-ou s in he placebo g oup we e a he di e en . Among 44 epo s om placebo- ea ed pa ien s, 15 (34 pe cen ) d opped ou (10 p ema u ely s opped ea men
and i e s opped eco ding symp oms). Se en s opped wi hin 24 hou s o s a ing ea men , and only one no ed objec ion o he ea men as eason. Ten placebo- ea ed
pa ien s blamed lack o bene i . A he ime o s opping, h ee placebo- ea ed pa ien s' se e i y sco es we e imp o ed, six we e wo se, and six we e unchanged. Ten
pa ien s who s opped ea men bu who eco ded adequa e symp om da a we e included in he placebo g oup analysis, because hei s opping placebo " ea men " could
no bene i hei colds and because hei omission migh dis o sampling o he g oup.
The signi ican numbe o pa ien s who d opped ou makes unce ain how p ecisely esul s ep esen he en i e popula ion, bu hese d op-ou s do no a ec he
undamen al inding. Assuming all d op-ou s would ha e ecei ed no bene i (i.e., as placebo pa ien s), he e s ill would ha e been a signi ican bene i a e 7 days: o
zinc- ea ed pa ien s, 16 o 64 asymp oma ic e sus placebo- ea ed pa ien s 23 o 44 asymp oma ic (P < 0.005). A simila , addi ional conside a ion o hose pa ien s who
did no e u n epo s s ill demons a es a signi ican bene i o zinc lozenge ea men o e placebo (P < 0.02). Only i we assume all zinc- ea ed d op-ou s emained ill
h ough day 7 (a ho izon al esponse line), and placebo d op-ou s healed a he same a e as o he placebo ecipien s (hal li e = 7.5 days) do he di e ences become
signi ican . In his ex emely un ealis ic case o an acu e, sel -limi ing illness, 16 o 48 (33.3 pe cen ) zinc ecipien s would s ill be ill as compa ed wi h 17 o 33 (51.5
pe cen ) placebo ecipien s. (Chi squa e = 2.68, P > 0.10.)
Zinc Ion A ailabili y
The able s equi ed abou 20 minu es o dissol e in lowing wa e ba h es s and abou 30 minu es o dissol e in he mou h. This di e ence esul s om he di e ences in
dynamics be ween he wo me hods. Fo example, pa ien s o en pigeon-hole lozenges in hei cheeks wi h li le dissolu ion occu ing. Because lozenges we e small,
bland, ha d able s ha dissol ed slowly, li le zinc-laden sali a was gene a ed (15 ml) esul ing in a high Zn2+ ion mola concen a ion (7.4 mMol) which was 74 imes
an i hino i al concen a ion acco ding o Ko an and co-wo ke s(7) and 148 imes an i hino i al concen a ion acco ding o Me luzzi and co-wo ke s(8) and Geis and co-
wo ke s.(9)
Table s had a ZIA alue o 100 and educed he a e age du a ion o all common cold symp oms by 7 days. ZIA 100 lozenges may p oduce an i hino i al e ec s, judging
om he e y apid ini ial esponse om hese lozenges no seen in any s udy wi h lowe ZIA alues.
Chap e 4.A.2. G ea B i ain Medical Resea ch Council Common Cold Uni 1987 S udy
The B i ish Medical Resea ch Council (MRC) Common Cold Uni in Salisbu y, England, es ed zinc glucona e lozenges (23 mg zinc) agains placebo in double-blinded
human hino i us (HRV)-2 p ophylaxis and he apeu ic e icacy clinical ials.(10) The en i e a icle is p esen ed he e.
In he p ophylaxis s udy, zinc educed he o al mean clinical sco e om 8.2 in he placebo g oup o 5.7. This educ ion was s a is ically signi ican on he second day a e
i us challenge wi h HRV-2.
In he he apeu ic s udy, he mean clinical sco e o zinc- ea ed pa ien s was consis en ly lowe han o placebo- ea ed pa ien s a e day 1, educing mean clinical sco e
o e he 6-day s udy om 41 in he placebo- ea ed g oup o 27.2 in he zinc- ea ed g oup. On each day o he s udy a e day 1, mean nasal sec e ion weigh s om zinc-
ea ed pa ien s we e less han hal hose o placebo- ea ed pa ien s. On day 4 and a e wa d, nasal sec e ion weigh s in he zinc- ea ed g oup we e nea ly an o de o
magni ude lowe han in he placebo- ea ed g oup. Resul s we e s a is ically signi ican by se e al measu emen s a imes du ing he s udy.
The as ingen lozenges we e used e e y wo hou s while awake, o aling 9 doses/day. Lozenges we e soluble, pleasan - as ing, 1-g am, we -g anula ed uc ose-
Me hocel( )-based comp essed able s. No dis inguishable di e ence in as e o appea ance be ween zinc and placebo lozenges was obse ed. The zinc glucona e
lozenges p oduced 22 g ams o zinc-laden sali a and dissol ed in 19 minu es. Sali a y Zn2+ ion concen a ion was 5 mMol o less a pH 7.4. Sali a y pH was 5.4.
Reduc ion in du a ion was based upon he e u n o no mal o symp oms in all zinc- ea ed pa ien s on day 6 compa ed wi h he 10.8-day his o ic a e age du a ion o
colds. Thus, ea men educed a e age du a ion o colds by 4.8 days. Zinc lozenges had a ZIA alue o 44.
The zinc glucona e lozenges es ed we e made by RBS Pha ma o Milan, I aly, (now pa o Rôhne-Poulenc Pha ma, I alia, S.P.A.). P o esso Rinaldo Pelleg ini, Medical-
Scien i ic Di ec o o RBS Pha ma was he only esea che o isi wi h he o iginal Texas g oup and ollow ad ice conce ning omi ing zinc chela o s om he lozenge
o mula ion. RBS Pha ma compounded zinc glucona e in uc ose (a suga ), he only swee able base ha does no become bi e in solid s a e eac ions wi h zinc
glucona e.
Lozenge Composi ion
Es ima ed e ec o zinc glucona e-
glycine (10 mole) e sus placebo
E ec o p e ea men o cold du a ion
Chap e 4.C.3. - Zinc Glucona e-Glycine (1:10-mole) Lozenge S udy
In a 1992 double-blind, clinical s udy in ol ing 87 pa ien s by God ey and co-wo ke s a Da mou h College, zinc glucona e wi h glycine in 10 mola excess as la o -
mask in 4.5 g am suc ose-co n sy up ha d boiled candy lozenges and iden ically as ingen and la o ed annic acid placebos we e bo h epo ed o ha e la e e icacy
agains na u al common colds.(42)
Howe e , he epo ed educ ions in "a e age du a ion o colds" appea in ac uali y educ ions in hal -li es. The e o e, he hal -li e o zinc glucona e-glycine (ZGG)- ea ed
colds, no he a e age du a ion (see Figu e 2 and explana ion in Chap e 3), was 1.27 days sho e (4.86 days) han placebo- ea ed colds (6.13 days) ( = 2.01, P < 0.05)
in pa ien s ha ing colds o an a e age o 1.34 days be o e s a ing ea men . O dina ily, he hal -li e o un ea ed o placebo- ea ed colds is conside ed o be 7 days.
A e he ou h day o ea men , pa ien s using ZGG became symp om- ee somewha as e han olun ee s using placebo. Resul s we e epo ed o be signi ican ly
di e en by day 6 (P = 0.05).
The mos equen symp om in bo h g oups a e 7 days o ea men was nasal d ainage and nasal conges ion. Abou 13 pe cen o he ZGG- ea ed g oup and abou 34
pe cen o he placebo- ea ed g oup s ill had nasal symp oms a e 7 days o ea men . F om he hal -li e da a abo e and Figu e 1 o God ey and co-wo ke s, i is
possible o es ima e he o e -all e ec o ZGG e sus placebo on common colds in he whole s udy g oup (see Figu e 16).
Resul s seemed be e wi h ini ia ion o ea men o colds s a ing wi hin 24 hou s o he onse o he i s symp om (see Figu e 17). Se e i y o symp oms emaining on
he se en h day o he sub-g oup o ZGG- ea ed pa ien s ha ing been ill o less han 1 day be o e s a ing ea men was also less han o he ZGG- ea ed sub-g oup
ha ing been ill o 2 days p io o s a ing ea men .
Figu e 16. Es ima ed e ec o zinc glucona e-glycine and placebo on du a ion o colds.
The conclusion by God ey and co-wo ke s ha ZGG lozenge ea men sho ened he a e age du a ion o cold by 43 pe cen
appea s e oneous. Thei e o esul s om misin e p e ing hal -li es o colds (usually 7 days), as he "a e age du a ions" o
colds (usually abou 10 o 11 days), which is an en i ely di e en ma e . An accu a e assessmen o he e ec o ZGG
lozenges on colds mus ake hese majo ma hema ical and concep ual di e ences in o accoun .
Figu e 17. E ec o p e ea men cold du a ion o zinc glucona e-glycine
ea ed sub-g oups. (cou esy o Jou nal o In e na ional Medical Resea ch).
I he assessmen o God ey and co-wo ke s ha colds i s ea ed on hei i s
day ha e a " o al a e age du a ion" (in ac uali y a hal -li e) o 5.3 days, he hal -
li e mus be compa ed wi h he his o ical 7 day hal -li e o colds, no he 9.2 day
a e age du a ion igu e used in he God ey and co-wo ke s epo . The e o e,
he educ ion in hal -li e was only 1.7 days. I he hal -li e is di ided by he na u al log o 2 o gi e he a e age educ ion in
du a ion o exponen ially decaying colds, he esul is 2.5 days. Howe e , his me hod o analysis is inaccu a e o hese non-
exponen ial decay cu es.
The mos accu a e conclusions a e one-hal o he ZGG- ea ed colds ended 1.2 o 1.7 days be o e no mal, and ZGG- ea ed
pa ien s a ed be e wi h essen ially all colds being absen a e se en days o ea men wi h ZGG when ea men was
s a ed on he i s day o hei colds.
Zinc glucona e-glycine lozenges con ained 23.7 mg zinc and 10 mola equi alen s o glycine ela i e o zinc. A e age zinc-laden sali a y olume was 26.3 ml.(43)
Lozenges we e used e e y 2 hou s while awake. To al zinc concen a ion was 14 mMol. Lozenges dissol ed in 15 minu es.
Zinc Specia ion in he Zinc Glucona e-Glycine Sys em
The s abili y cons an s o zinc glycina e complexes a e ela i ely high; o example, log K1 = 4.8 a 37°C.(44) Wi h a 10-mole excess o glycine a he published sali a y
pH o 5.0, a ailable Zn2+ ion concen a ion is 20 pe cen , bu i alls apidly o ze o a pH 6.4; and only neu ally and nega i ely cha ged zinc glycina e and hyd oxide
species exis a physiological pH 7.4 and abo e as shown in Figu e 18.
NOTE: Lea n abou he meaning o "s abili y cons an s" he e.
Figu e 18. Concen a ion o Zn2+, posi i ely cha ged zinc glucona e (ZnL+), and a ious zinc glycina e and zinc
hyd oxide species in he zinc glucona e - glycina e sys em. Zinc and glucona e a e p esen a 30 mMol and
glycine is p esen a 300 mMol concen a ion. Dis ibu ion o zinc ionic species is cou esy o Guy Be hon,
INSERM U 305, CNRS, Toulouse, F ance, 1992.
Glycine eplaces glucona e in solid s a e eac ions du ing hea ed p emixing o zinc glucona e and glycine
powde s and a ele a ed candy-making empe a u e, as well as in solu ions. Acco ding o Be hon, only neu ally
and nega i ely cha ged zinc glycina e species and excess glycine exis in solu ion a pH 7.4. Ye , Za embo and
co-wo ke s belie e zinc was 90 o 93 pe cen Zn2+ ion a pH 5.08 because o a p e iously unknown "ca aly ic
ac ion o sali a."(42,43) Howe e , zinc glucona e wi h only 60 pe cen Zn2+ ion con en (see Figu e 1) added o
ha d-boiled candy s ock a candy-making empe a u e and pH 5 se e ely ca amelizes and quickly becomes
o ensi ely malodo ous wi hou added glycine o o he s ong chela o such as ci ic acid o acacia.
E ec s o As ingency
Because Zn2+ ions, ZGG, and annic acid a e each as ingen in sali a, la e-occu ing e icacy no iced in he zinc glucona e-glycine epo o ZGG lozenges is mos likely
a ibu able o as ingency. The ac ion appea s no om an i hino i al ac ion o Zn2+ ions a physiologic pH 7.4, as no Zn2+ ions a e a ailable acco ding o Be hon (see
Figu e 18).
Any possible Zn2+ ion ac ion on hino i uses should occu du ing he i s ew days o a cold when hino i uses a e p esen , ye no educ ion in du a ion o colds was
no ed in his s udy du ing hose ea ly days. In ac , he equencies o nasal symp oms we e he leas a ec ed by ZGG lozenges. E ec s on indi idual symp oms du ing
he ea ly phase also we e likely o ha e been caused by as ingency, and no Zn2+ ions. La e ac i i y in a cold -- when i uses a e essen ially absen -- sugges s he e ec
on du a ion is mos likely caused by local as ingency, a d ying ac ion. This ac ion mos likely would no include signi ican p e en ion o elease o his amine om mas
cells conside ing molecula s abili ies.
The sugges ion by God ey and co-wo ke s ha he placebo was ac i e seems implausible, and may no be suppo ed by ac s since he hal -li e o placebo- ea ed colds
was 6.13 days which is essen ially he same as he his o ical hal -li e o un ea ed common colds a 7 days, pa icula ly when one adds he p e- ea men day.
Zinc Ion A ailabili y
In his anomaly om he ZIA - day educ ion end, ZIA is unques ionably nega i e om lack o Zn2+ ions, he p esence o neu ally (85%) and nega i ely (15%) cha ged
zinc glycine species, and glycine in excess a pH 7.4. Howe e , no ZIA da a-poin can be de e mined as he esul s do no all in o he quad an used o es ima e ZIA
alues o o he lozenges ha ing nega i e ZIA alues. This anomaly esul s in a ho izon al line o he le o he o igin a a posi i e 1.27 days.
Chap e 4.D. - Summa y and Commen s

I zinc lozenges a e o be use ul as a me hod o educe he du a ion and se e i y o colds, su icien Zn2+ ions mus be a ailable o do he job. None o he ollow-up
s udies used he same o mula ion as he o iginal Eby, Da is, and Halcomb s udy, and none achie ed esul s nea ly as good. To ob ain he desi ed quick esul s, he
lozenge ZIA alue should be a leas 100. This means ha sali a y Zn2+ ion concen a ion should be 7.4 mMol, applica ion o Zn2+ ions om lozenges should occu o e a
30-minu e pe iod, and lozenges should be aken 9 imes pe day.
Inc eased usage a e o s onge lozenges sho en colds in clinical p ac ice e en mo e han epo ed in published s udies. Ea ly use o ZIA 100 lozenges, pe haps wi hin a
ew minu es o a ew hou s o he i s obse ed common cold symp om, mos o en abo s incipien colds. A e a ew lozenges, no u he ea men is usually equi ed.
Wha is mos su p ising abou he published esea ch e iewed he e is he nea o al lack o ideli y by o he esea che s o he o iginal disco e y o o each o he . The
i s ene o scien i ic esea ch is exac duplica ion o expe imen s by o he s o de e mine he alidi y o he o iginal esea ch.
Appa en ly, o he han he in e iew wi h Pelleg ini conce ning he de elopmen o he lozenges used in he Medical Resea ch Council Common Cold Uni ial led by
Da id A. J. Ty ell (Al-Nakib e al. epo ), no a emp appea s o ha e been made o eplica e he solu ion chemis y o he o iginal Eby e al. zinc glucona e lozenges.
In each case, esea ch appea s o ha e been led o inhibi ed by comme cial, no scien i ic, in e es s. Make s o each o he comme cial composi ions es ed we e
appa en ly unin e es ed in he disco e y unless hey could quickly "make zinc lozenges as e like candy."
Had esea che s known ha uc ose was he only swee ca bohyd a e able base sui able o use wi h zinc glucona e, he disappoin men wi h la o -masking could ha e
been a oided, and zinc glucona e would no ha e de eloped i s epu a ion o being objec ionable in as e o ine icacious. Coun less expe imen s by he p esen au ho
showed uc ose o be he only sui able able base o zinc glucona e.
Un o una ely, he I alian company ha sponso ed he MRC zinc glucona e lozenge esea ch was pu chased by a company unin e es ed in he o e - he-coun e common
cold ma ke . Those I alian lozenges we e he i s ully la o -masked zinc glucona e lozenges and hey could ha e p o ided conside able elie o common cold su e s
had hey been comme cialized.
O he igh ly bound zinc compounds and zinc compounds ha elease no Zn2+ ions a pH 7.4 canno sho en colds. Howe e , hey do no leng hen colds ei he . Nea ly all
o e - he-coun e zinc lozenges a ailable in he e ail ade a e o his ype. Cu en ly, lozenges ad e ised o con ain zinc glucona e and zinc oxide a e abou 99.99% zinc
oxide o elimina e objec ionable as e and a e as e om zinc glucona e eac ions wi h dex ose able base.
One may ques ion he alidi y o nega i e ZIA alue es ima es, bu he ac emains ha lozenges eleasing nega i ely cha ged zinc species (ZnLN-) inc eased he du a ion
o common colds in a dose- esponse manne ela i e o placebo.
One bes explana ion o he inc ease in du a ion is elimina ion o endogenous (na i e) Zn2+ ions om o al and nasal issues by ZnLN-. Zn2+ ions a e highly concen a ed (4
o 20 mMol) in mas cell and basophil g anules. Conside able Zn2+ ions a e eleased du ing deg anula ion o hese cells du ing in lamma ion. Clea ly, ZnLN- eleased om
hese lozenges binds endogenous Zn2+ ions p esen in o al and nasal issues and luids as he e a e ew o he posi i ely cha ged biochemicals o bind. I elease o Zn2+
ions om mas cells du ing in lamma ion has he unc ion o inhibi ing i al eplica ion, s imula ing T-cells, s abilizing cell memb anes, egula ing mas cell homeos asis,
ca abolizing his amine, and s imula ing in e e on p oduc ion du ing common colds as hey do in i o (See Chap e 2), hen one could expec ha common colds would
be leng hened by neu alizing endogenous Zn2+ ions wi h ZnLN- o ende hem biologically una ailable a physiologic pH.
Why he 1992 zinc glucona e-glycine o mula ion was epo ed o be e ec i e wi h i s nega i e ZIA alue and glycine excess is unce ain. Pe haps he i i a ing acid e ec
was mo e han o se by as ingency o Zn2+ ions a pH 5.0. Nega i ely cha ged zinc species we e no he p edominan species a pH 7.4, as he g ea majo i y (85%) was
p esen as neu ally cha ged zinc glycina e. In he opinion o he p esen au ho , impo an e o s ound by Be hon and he p esen au ho cas doub upon he alidi y o
he ZGG s udy.
Au ho s o se e al s udies discussed in his chap e may disag ee wi h conclusions exp essed by he p esen au ho conce ning physiologic a ailabili y o Zn2+ ions in
hei s udies. The p esen au ho would ha e bene i ed -- and would ha e been pleased -- had hose o he au ho s been co ec in hei asse ions o ull bioa ailabili y o
Zn2+ ions and equi alence o he o iginal Eby s udy.
Conclusions p esen ed abou hei claims a e opinions o he p esen au ho based upon e idence and indings by neu al expe s in a ious ields including solu ion
chemis y, physiology, medicine, d ug manu ac u ing, and pha macology.
Chap e 4 Re e ences
1. Eby GA, Da is DR, Halcomb WW. Reduc ion in du a ion o common colds by zinc glucona e lozenges in a double blind s udy. An imic obial Agen s and Chemo he apy.
1984;25:20-24.
2. Gwal ney JM J . Rhino i us. In: Mandell GL, Douglas RG J , Benne JE, eds. P inciples and P ac ices o In ec ious Diseases. New Yo k:John Wiley and Sons; 1979:
1124-1134.
3. Kelly RW, Abel MH. Coppe and zinc inhibi he me abolism o p os aglandin by he human u e us. Biology o Rep oduc ion. 1983;28:883-889.
4. Halcomb WW. Mesa, A izona. Pe sonal communica ion, 1992.
5. Giec L, Wnuk-Wojna AM, T usz-Gluza M, e al. Epide- miologic e alua ion o he co ona y isk in physical wo ke s on non e ous me alwo ks. Pa II. Co ona y hea
disease. P zegl Lek. 1980;37: 507-510. (English ansla ion a ailable)
6. Chand a RK. Excessi e in ake o zinc impai s immune esponses. Jou nal o he Ame ican Medical Associa ion. 1984;252:1443-1446.
7. Ko an BD, Kau e JC, Bu e wo h BE. Zinc ions inhibi eplica ion o hino i uses. Na u e. 1974; 248:588-590.
8. Me luzzi VJ, Cip iano D, McNeil D, e al. E alua ion o zinc complexes on he eplica ion o hino i us 2 in i o. Resea ch Communica ions in Chemical Pa hology and
Pha macology. 1989;66: 425-440.
9. Geis FC, Ba eman, JA, Hayden FG. In i o ac i i y o zinc sal s agains human hino i uses. An imic obial Agen s and Chemo he apy. 1987;31: 622-624.
10. Al-Nakib W, Higgins PG, Ba ow I. P ophylaxis and ea men o hino i us colds wi h zinc glucona e lozenges. Jou nal o An imic obial Chemo he apy. 1987;20: 893-
901.
11. Ty ell DAJ. MRC AIDS Di ec ed P og amme, Public Heal h Labo a o y Se ice, Cen e o Applied Mic obiology and Resea ch, Po on Down, Salisbu y, SP4 0JG,
England. Pe sonal communica ion, 1993.
12. Smi h DS, Helzne EC, Nu all CE J , e al. Failu e o zinc glucona e in ea men o acu e uppe espi a o y ac in ec ions. An imic obial Agen s and Chemo he apy.
1989;33:646-648.
13. B iggs, Finch P, Ma ulewicz MC, e al. Complexes o coppe (II), calcium, and o he me al ions wi h ca bohyd a es: Thin-laye ligand-exchange ch oma og aphy and
de e mina ion o ela i e s abili ies o complexes. Ca bohyd a e Resea ch. 1981;97:181-188.
14. Bannan B. Gene al Nu i ion P oduc s, G een ille, SC. Unpublished da a, 1989.
15. Weismann K, Jakobsen JP, Weismann JE, e al. Zinc glucona e o common cold. Danish Medical Bulle in. 1990;37:279-281.
16. S ö KB. Ahlgens In e na ional, H ido e, Denma k. Pe sonal communica ion, 1992.
17. Eby GA, Da is DR, Halcomb WW. E ec o zinc o o a e lozenges wi h zinc glucona e nasal sp ay in common cold ea men - a double-blind s udy. Unpublished,
1984.
18. Ha isch G and K e schme M. Some aspec s o a non-linea e ec o zinc ions on he his amine elease om a pe i oneal mas cells. Resea ch Communica ions in
Chemical and Pa hological Pha macology. 1987;55:39-48.
19. Tucci ER, Ke CH, Li NC. Linea ee ene gy ela ionships o p o on dissocia ion and me al complexa ion o py imidine acids. Jou nal o Ino ganic Nuclea Chemis y,
1967;29:1657.
20. Aoki FY. Dis ibu ion and emo al o human se um albumin- echne ium 99m ins illed in anasally. B i ish Jou nal o Clinical Pha macology. 1976;3:869-878.
21. Cas leman M. Cold Cu es. New Yo k:Fawce Columbine;1987:ch 19.
22. McCu cheon ML, Ande son JL and Co on GE. Uni e si y o Minneso a a Dulu h. Unpublished da a, 1987.
23. Schennum B. Quan um Inc., Eugene, O egon. Unpublished da a, 1989.
24. Be hon G, Ge monneau P. His amine as a ligand in blood plasma. Pa 6. Aspa a e and glu ama e as possible pa ne ligands o zinc and his amine o a o
his amine ca abolism. Agen s and Ac ions. 982;12: 619-629.
25. Ma in RB. pH as a a iable in ee zinc ion concen a ion om zinc-con aining lozenges (le e ). An imic obial Agen s and Chemo he apy. 1988;32: 608-609.
26. Fa BM, Conne EM, Be s RF. Two andomized con olled ials o zinc glucona e lozenge he apy o expe imen ally induced hino i us colds. An imic obial Agen s
and Chemo he apy. 1987;31:1183-1187.
27. Ko an BD. E. I. du Pon de Nemou s Co., Wilming on, DE. Pe sonal communica ion, 1992.
28. Hill I, Locus NJ; Eby GA, Aus in TX. Unpublished da a, 1989.
29. Be hon G, May PM, Williams DR. Compu e simula ion o me al-ion equilib ia in bio luids. Pa 2. Fo ma ion cons an s o zinc(II)-ci a e- cys eina e bina y and e na y
complexes and imp o ed models o low-molecula -weigh zinc species in blood plasma. Jou nal Chemical Socie y, Dal on. 1978;1433-1438.
30. Ma ell AE, Smi h RM. C i ical S abili y Cons an s. New Yo k: Plenum P ess; 1991: ols 1-6.
31. Sillùn LG, Ma ell AE. S abili y Cons an s o Me al-Ion Complexes. Special Publica ion No. 17. London:Bu ling on House; 1964.
32. Fu ia TE. Seques an s in ood. In: Fu ia TE, ed. CRC Handbook o Food Addi i es. 2nd ed. Wes Palm Beach:CRC P ess; 1972.
33. Adle S, F aley DS. Acid-base egula ion, cellula and whole body. In: A ie AI, DeF onzo RA, eds. Fluid, Elec oly e, and Acid-Base Diso de s. New Yo k:Chu chhill
Li ings one. 1985;1:227.
34. Guy on AC. Regula ion o acid-base balance. In: Tex book o Medical Physiology. New Yo k:W. B. Saunde s Co. 1986:439.
35. No dens öm BE. Biologically Closed Elec ic Ci cui s. Clinical, Expe imen al and Theo e ical E idence o an Addi ional Ci cula o y Sys em. S ockholm:No dic Medical
Publica ions; 1983.
36. Fa BM, Gwal ney JM. Zinc glucona e o he common cold: An e alua ion o placebo ma ching. Jou nal o Ch onic Diseases. 1987;40: 875-879.
37. Douglas RM, Miles HB, Moo e BW. Failu e o e e escen zinc ace a e lozenges o al e he cou se o uppe espi a o y ac in ec ions in Aus alian adul s.
An imic obial Agen s and Chemo he apy. 1987;31:1263- 1265.
38. Williams RJE. F. H. Faulding & Company, Adelaide, Sou h Aus alia, Pe sonal communica ion, 1987.
39. Moh le R. E e escen able s. In: Liebe man HA, Lachman L, Schwa z JB. eds. Pha maceu ical Dosage Fo ms: Table s. New Yo k:Ma cel Dekke , Inc.; 1989:1.
40. Hach B, Be hon G. Me al ion-FTS nonapep ide in e ac ions. A quan i a i e s udy o zinc(II)-non-apep ide complexes ( hymulin) unde physiological condi ions and
assessmen o hei biological signi icance. Ino ganica Chimica Ac a. 1987;136: 165-171.
41 Be hon G, Va samidis A, Blaquie e C, e al. His amine as a ligand in blood plasma. Pa 7. Mala e, malona e, malea e and a a e as adju an s o zinc o la o
his amine issue di usion h ough mixed-ligand coo dina ion. In i o es s on lymphocy e p oli e a ion. Agen s and Ac ions. 1987;22:231-247.
42. God ey JC, Conan Sloane B, Smi h DS. Zinc Glucona e and he Common Cold. The Jou nal o In e na ional Medical Resea ch. 1992;20:234.
43. Za embo JE, God ey JC, God ey NJ. Zinc(II) in Sali a: De e mina ion o concen a ions p oduced by di e en o mula ions o zinc glucona e lozenges con aining
common excipien s. Jou nal o Pha maceu ic Sciences. 1992; 81:128-130.
44. Alemda oglu T, Be hon G. T ace me al equi emen s in o al pa en e al nu i ion II. Po en iome ic s udy o he me al-ion equilib ia in he zinc-his idine, zinc-glycine,
zinc-cys eine-his inidine, zinc-glycine- his idine and zinc-glycine-cys eine sys ems unde physiological condi ions. Jou nal o Elec oanaly ical Chemis y and In e acial
Elec ochemis y. 1981;128:49-62.
Chap e 5. Cen al Finding o Linea Rela ion be ween ZIA and E icacy
Execu i e summa y Chap e 5 p esen s he cen al inding o linea ela ionship be ween zinc ion a ailabili y (ZIA) alues and educ ions in he du a ion o common
colds. Linea i y is an impo an disco e y made possible only om igo ous analyses o he physical and chemical p ope ies o he eigh dis inc ly di e en p op ie a y
lozenges s udied. C i ical ZIA ac o s, ZIA alues, and compa a i e as e es s o lozenges a e p esen ed. Da a show a ela ionship be ween ZIA and e icacy bu no
ela ion be ween ZIA and o he ac o s.
Hyd a ed Zn2+ ions a pH 7.4 ha e been shown o ha e a b oad ange o e ec s in igh ing common colds. In i o, zinc glucona e lozenges wi h high daily ZIA alues ha e
apidly educed cold du a ion and se e i y; lozenges wi h mode a e ZIA alues show only la e e icacy agains du a ion; and, wi h a mino excep ion, lozenges wi h low,
ze o, and nega i e daily ZIA alues ailed in clinical s udies.
Clea ly, di e en esul s ha e occu ed (as men ioned in Chap e 4), and a me hod o econcile di e ences is needed. By o ganizing he da a using ZIA alues and
changes in common cold du a ion, a linea ela ionship be ween ZIA and educ ions in du a ion in colds esul s. A su p ising inc ease in du a ion usually occu s using
lozenges yielding nega i ely cha ged zinc species.
Table 7. ZIA Fac o s (zinc, ac ion Zn2+, dissolu ion imes, doses/day, and sali a gene a ed)
S udy Lozenge Amoun o F ac ion Dissolu ion Doses Sali a Lozenge
zinc (mg) Zn2+ Time (min) /day (g ams) (g ams)
________________________________________________________________________
Eby zinc glucona e
in nonsoluble
able 23.0 0.30 30 9 15.0 0.66
MRC zinc glucona e
in uc ose
able 23.0 0.30 19 9 22.0 1.00
McNeil zinc glucona e
in mixed able 11.5 0.30 15 10 17.5 1.56
Danish 4.5 mg zinc
glucona e in
mal i ol lozenge 4.5 0.30 15 12 17.0 3.00
Zinc o o a e
lozenge 37.0 0.00 40 6 18.0 3.00
Zinc aspa a e
lozenge 24.0 0.00 14 9 18.0 3.00
Zinc glucona e
and ci ic acid 23.0 0.00 15 9 35.0 4.50
Zinc ace a e
wi h a a ic,acid
& sodium bica b-
ona e in manni ol 10.0 0.00 10 9 44.0 3.00
Zinc glucona e-
glycine (10 mole) 23.7 0.00 15 9 26.3 4.50
_____________________________________________________________________
ZIA Fac o s
Da a collec ed du ing analysis o lozenge pe o mance and daily ZIA calcula ions include mg zinc, ac ion o zinc as hyd a ed Zn2+ ions, leng h o ime o dissol e
lozenges in minu es, numbe o doses/day, and sali a olume p oduced by zinc lozenges (nume ically equi alen o weigh o sali a minus lozenge weigh ). Da a a e
summa ized in Table 7.
Da a we e ob ained by lozenge dissolu ion/expec o a ion expe imen a ion using lozenges based upon desc ip ions o he lozenges in he o iginal clinical epo s o upon
lozenge o mula ions and da a supplied by he o iginal au ho s o lozenge manu ac u e s. E e y possible e o was made o use he exac lozenges used by he ialis s
o eplica ions exac ly duplica ing he chemical and physical p ope ies o he lozenges.
Compa a i e ZIA Values
Compa ison o zinc ion a ailabili y (ZIA) alues o clinical s udies shows close ela ionship o ac ual clinical esul s. The inding o easonable linea i y o hose
ela ionships ep esen s he cen al inding o his epo . Fo scien i ic objec i i y, esul s om expe imen al zinc lozenge ea men s o common colds in he a ious
published s udies mus be compa ed in an iden ical manne h ough ZIA educ ion o inc ease in common cold du a ion. ZIA is he concen a ion o Zn2+ ions applied o
he o al mucosa o e ime, which equals: [0.7697 imes mg zinc, imes ac ion as Zn2+ ion, imes ime o dissol e (minu es), imes numbe o doses pe day], di ided by
[ o al mg sali a minus mg lozenge weigh as app oxima ion o sali a olume in ml]. The cons an 0.7697 se s he Eby and co-wo ke e e ence alue o 100 o ease in
compa ison. (See Chap e 3, Zinc Ion A ailabili y Values, o mo e in o ma ion on ZIA alues and hei calcula ion.)
Table 8. S udy lozenges, ZIA alues, elec onic cha ge, and educ ion in du a ion o colds.
_________________________________________________________________________
S udy Lozenges ZIA alues Cha ges E icacy
_________________________________________________________________________
Eby (23 mg zinc)
zinc glucona e in
nonsoluble able s 100 2+,1+,0 7-day educ ion in
du a ion o colds
MRCC (23 mg zinc)
zinc glucona e in
uc ose able s 44 2+,1+,0 4.8-day educ ion in du a ion o colds
McNeil (11.5 mg zinc)
zinc glucona e in
mixed base 25 2+,1+,0 1.6-day educ ion in
du a ion o colds
Danish 4.5 mg zinc
glucona e in mal i ol 13.4 2+,1+,0 none
Zinc o o a e lozenges 0 0 none
Zinc aspa a e lozenge 0 0 none
Zinc glucona e and
1.33 mole ci ic acid -11 * 0, N- 1-day inc ease in
du a ion o colds
& wo sened symp oms
Zinc ace a e wi h e y
la ge mola excesses
o a a ic acid and
sodium bica bona e
in manni ol lozenge -55 * 0, N- 4.4-day inc ease in
du a ion o colds
& wo sened symp oms
Zinc glucona e-glycine
in ha d candy lozenge
(10 mole glycine 1992) Unknown 0, N- 1.3 day educ ion in
(nega i e) du a ion o colds
____________________________________________________________________________
* Nega i e ZIA alues we e de e mined by p ojec ion.
Table 8 da a (excluding nega i e alues) we e analyzed o de e mine co ela ion be ween zinc ion a ailabili y (ZIA) and change in du a ion o common colds in hese
s udies. Spea man's ank di e ence co ela ion me hod was used. Spea man's is mos use ul wi h samples o small size.(1) The s a is ic was ( ho) = 0.96. The es o
he hypo hesis ha he popula ion co ela ion is ze o is signi ican beyond 0.02 le el in a 2- ailed es . F om a s a is ician's pe spec i e, "one is wa an ed in ejec ing he
null hypo hesis ha he e is no ela ionship be ween ZIA alues and educ ion in du a ion in common colds." Addi ional da a using lozenges abo e ZIA alue 70 would be
help ul in con i ming and ex ending hese obse a ions.
By compa ing daily ZIA alues and educ ion in du a ion o common colds, a linea ela ionship can be es ablished be ween hese (Figu e 19), and linea i y is he cen al
inding o his epo . Reasonable linea i y h ough he ange shows ha he e is a good ela ionship be ween ZIA alues and educ ion in du a ion o common colds in
hese s udies. This linea i y can be used o p edic he e icacy o clinically un es ed zinc lozenges based upon ZIA alues o expe imen al lozenges ha ing zinc
complexed wi h e y weak ligands and no added zinc chela o s. Linea i y shows ha seemingly di e gen esul s o s udies by Eby, Douglas, Fa , Smi h, and o he s a e
econciled by conside ing zinc ioniza ion a ailabili y (ZIA).
F om he epo s analyzed, ZIA and Zn2+ ion, bu no zinc compounds, a e co ela ed wi h he educ ion in du a ion o common colds. Co ela ion is consis en wi h he
indings o Me luzzi and co-wo ke s o in i o ac i i y o zinc agains hino i uses.(2) Reduc ion in du a ion is also co ela ed wi h Zn2+ ion-laden sali a concen a ion, bu
i is no a eliable indica o o u u e lozenge e icacy, as du a ion o o al con ac by Zn2+ ions mus be conside ed. One can also a gue ha e icacy is linea ly co ela ed
only wi h he concen a ion o zinc glucona e, because only zinc glucona e-de i ed Zn2+ ions ha e shown e icacy in published s udies epo ed o da e. Howe e ,
un epo ed expe imen al e idence wi h zinc ace a e lozenges in many subjec s clea ly demons a es he impo ance o a ailabili y o Zn2+ ions in sho ening colds.
Lozenges ha ing a posi i e ZIA alue educe he du a ion o common
colds in a dose- esponse manne . ZIA 25 lozenges educe du a ion o
colds by abou 1-1/2 day, while lozenges ha ing a ZIA alue o 44 educe
he du a ion o colds by 4.8 days, and lozenges ha ing a ZIA alue o 100
educe he du a ion o colds by 7 days. Lozenges con aining igh ly bound
zinc complexes ha e a ze o ZIA and do no change he du a ion o colds.
Lozenges eleasing nega i ely cha ged zinc species a physiologic pH
inc ease he du a ion o common colds in a dose- esponse manne .
Figu e 19. Rela ionship o zinc ion a ailabili y (ZIA) alues and educ ion in du a ion o common colds in days (y = 0.077x - 0.16).
The highly e icacious lozenges es ed by Eby and colleagues in 1984 had a ZIA alue mo e han wice as high as he nex highes lozenge (MRC), and much highe han
he o he lozenges. Absence o a signi ican e ec om Zn2+ ions on he a e and amoun o i uses exc e ed by olun ee in he s udy by Al-Nakib and co-wo ke s a he
Medical Resea ch Council Common Cold Uni ,(3) does no mean an i hino i al e ec is absen using lozenges wi h highe , mo e e icacious ZIA alues and highe Zn2+
ion sali a y concen a ions. A ZIA alue o 50 and a 5 mMol sali a y Zn2+ ion concen a ion appea o be h esholds o signi ican ea ly Zn2+ ion e ec s on he se e i y and
du a ion o colds. One migh expec an i hino i al ac i i y, in e e on induc ion, his amine mi iga ion, and cell memb ane s abiliza ion and d ying e ec s o occu a
su icien ly high ZIA, pe haps a abou ZIA 100 and 7.4 mMol Zn2+ ion concen a ion, whe e a much s onge clinical e ec was obse ed.
Linea i y is a ibu ed o di usion o hyd a ed Zn2+ ions ac oss biologic memb anes and h ough issues acco ding o Fick's i s and second laws wi h elec opho e ic
e ec s. These obse a ions a e he mos eadily obse able examples o biologically closed elec ic ci cui s, as i s p oposed by No dens öm.(4)
Along wi h he s ong epelling e ec s o nasal mucus and cilia on o eign subs ances in oduced o he nose, as no ed by Aoki(5) and many o he s, he di e en ial epels
in anasally in oduced Zn2+ ions om mucosal su aces, u he explaining lack o e icacy om zinc nasal sp ays.
The impo ance o he amoun o zinc a ailable, he ac ion as Zn2+ ion, lozenge dissolu ion imes, sali a gene a ion, and dosages pe day can all be unde s ood as
equally impo an in his sys em, as no ac o was emphasized o e ano he . Wi hin ce ain limi s, he sys em demons a es an impo an ool needed o design success ul
common cold lozenges. Dissolu ion imes and sali a p oduc ion a e as impo an as amoun o Zn2+ ions eleased and appea o be impo an a eas o de elopmen al
e o s, while inc easing he numbe o lozenges used pe day is a simple me hod o inc easing e icacy.
E en hough he sys em shows linea i y h oughou he ange s udied, he ac ual cu e is p obably pa abolic wi h an upwa d slope om nega i e ZIA alues h ough abou
ZIA 500. A some poin be ween abou ZIA 500 and pe haps ZIA 1000, he cu e may le el o . A some poin o e 1000, he cu e may de elop a downwa d slope
demons a ing mas cell deg anula ion and gene al issue inju y caused by oxic concen a ion o Zn2+ ions as desc ibed by in i o and oxici y s udies.
P ojec ion o Nega i e ZIA Values
Nega i e ZIA alues o 2 o he 3 zinc lozenges ha ing excess s ong zinc chela o s we e es ima ed by s aigh -line p ojec ion o he non-nega i e alues using he
equa ion ound in he legend o Figu e 19. The zinc glucona e-glycine da a-poin , ac ually a ho izon al line a +1.27 days, would be loca ed in he uppe -le quad an o
Figu e 19, bu i was omi ed as i would ha e caused con usion and i was meaningless in o ma ion. No nega i e alue was used in de e mining o he cu e.
Leng hened colds we e associa ed wi h se e al lozenge o mula ions ha ing nega i e ZIA alues -- ha is -- lozenges eleasing nega i ely (and neu ally) cha ged zinc
species a pH 7.4.
One may ques ion he alidi y o nega i e ZIA alue es ima es, bu he ac emains ha lozenges eleasing nega i ely cha ged zinc species (ZnLN-) inc eased he
du a ion o common colds in a dose- esponse manne ela i e o placebo.
As discussed in Chap e 2, Zn2+ ions a e highly concen a ed (4 o 20 mMol) in mas cell and basophil g anules. Zinc2+ ions a e eleased du ing deg anula ion o hese
cells du ing in lamma ion. ZnLN- eleased om hese lozenges binds na i e Zn2+ ions p esen in o al and nasal issues and luids. I elease o Zn2+ ions om hese cells
du ing in lamma ion has he unc ion o inhibi ing i al eplica ion, s imula ing T-cells, s abilizing cell memb anes, egula ing mas cell homeos asis, ca abolizing his amine,
and s imula ing in e e on p oduc ion du ing common colds as hey do in i o, hen one mus assume ha common colds would be leng hened by neu alizing na i e Zn2+
ions wi h ZnLN- o ende hem biologically una ailable a physiologic pH -- hus making colds wo se.
Tas e Scale and ZIA
Lozenge as e is a c ucial c i e ion o comme cializa ion o zinc lozenges. Each o he s udies ollowing Eby and co-wo ke s used lozenges selec ed o pleasan as es.
Zinc glucona e lozenges known no o ha e a pleasan as e we e no conside ed o es ing. E en hough he McNeil-sponso ed lozenges had a bi e as e a he ime o
he s udy, i is sa e o assume McNeil and Gene al Nu i ion ep esen a i es did no know zinc glucona e in combina ion wi h dex ose molecule would become d ead ully
bi e a e aging, o i hey did, hey had no idea how o co ec he la o -masking p oblem.
Had he eigh s udies been a ed on a as e scale, ela ionships conce ning ZIA alues and as e could ha e been be e de eloped. Volun ee s ha e ca e ully as e- es ed
each o he lozenges (o nea ly exac chemical copies) used in he eigh clinical s udies and o e he ollowing subjec i e, ela i e anking o zinc lozenge as e
accep abili y. Al hough as e p e e ences a e highly subjec i e, di e ences no ed we e ob ious. On a scale o 0 o 10 (wi h 0 being d ead ully bi e , 5 being accep able bu
no pa icula ly pleasan , and 10 being as pleasan as candy o no as e sensa ion o he han as ingency), he lozenges a e a ed in Table 9 below.
Tas e accep abili y is dependen upon he zinc complex, o he lozenge ing edien s and hei eac ions wi h zinc, bu as e accep abili y is no dependen upon ZIA.
The 1984 lozenges es ed by Eby and co-wo ke s had no only he as e o zinc glucona e bu also he as e o dicalcium phospha e, and bo h ac i e and placebo
lozenges p ima ily as ed chalky. Lozenges used by he MRC elied upon s ong, swee I alian la o s and uc ose o p ese e bo h as e and p omo e e icacy h ough
absolu e compliance. Wi hou o he soluble ing edien s, as e was s able and easonably pleasan . The McNeil lozenges we e so bi e om complexa ion o zinc
glucona e wi h dex ose ha clinical ailu e and lack o compliance esul ed. The Aus alian lozenges elied upon g ea ly educed dosage and chela ion by a a ic acid
and sodium bica bona e o elimina e as ingency, also elimina ing e icacy o he modi ied zinc ace a e lozenges. The as e associa ed wi h hei lozenges was o la o ed
a a ic acid.
Table 9. Lozenge as e, sali a y pH, nea a e as e and o e nigh a e as e.
_____________________________________________________________________
S udy lozenges ZIA Sali a y Lozenge Nea O e nigh
alues pH as e a e as e* a e as e
________________________________________________________________________
Eby zinc glucona e
(23 mg zinc)
able s 100 5.5 5 6 8
MRC zinc glucona e
(23 mg zinc)
uc ose lozenge 44 5.4 9 7 8
McNeil zinc glucona e
(11.5 mg zinc) 3-g
mixed swee ene s
lozenge 25 6.4 0 3 5
Danish zinc glucona e
(4.5 mg zinc)
mal i ol lozenges 13.4 6.4 7 8 9
Zinc o o a e
(37 mg zinc)
3.6-g lozenges 0.0 7 6 8 10
Zinc aspa a e
(24 mg zinc) lozenge 0.0 7 8 10 10
B is ol-Mye s zinc
glucona e (23 mg zinc)
and ex amola ci ic
acid ha d candy
(suc ose/co n sy up)
lozenges -11 4.3 8 10 10
Aus alian zinc ace a e
(10 mg zinc) e e escen
lozenges wi h a a ic acid,
sodium bica bona e in
manni ol -55 4.1 7 8 9
God ey zinc
glucona e-glycine Unknown 5.0 9 9 10
(nega i e)
_______________________________________________________________________
* Nea a e as e is a e as e obse ed du ing he i s 2 hou s a e comple ion o lozenge.
The B is ol-Mye s lozenges elied upon chela ion by ci ic acid and o ange la o oils o elimina e objec ionable as e wi h a esul ing loss o e icacy. Insoluble zinc o o a e
in lozenges was essen ially as eless bu lozenges we e o ally ab asi e. Zinc aspa a e lozenges we e na u ally pleasan - as ing, we e highly chela ed, eleased no Zn2+
ions, and had no e icacy. God ey designed zinc glucona e-glycine (10 mole) lozenges ha we e pleasan - as ing bu yielded no Zn2+ ions a physiologic pH 7.4. Al hough
God ey's lozenges we e pseudo-as ingen , such is he esul o some Zn2+ ion being a ailable a sali a y pH 5.0 bu no a he highe physiologic pH capable o a ec ing
a educ ion in common cold du a ion. All pH es s we e conduc ed wi h bo h Nes e and Co ning pH me e s calib a ed wi h esh Ricca pH 4, 7, and 10 e e ence bu e
solu ions. Na u al sali a y pH a ies be ween pH 6.2 and 7.2, wi h pH 6.2 o 6.5 being obse ed in hese es s.
Concession o Tas e Th ough Use o a Double Loading Dose
Be o e he Eby 1984 clinical ial, he au ho de e mined ha he minimum dosage should be abou 50 mg zinc om zinc glucona e e e y 2 hou s, no he 23-mg dosage
used in he ial. Howe e , lozenge ha shness sugges ed some pa ien s would ejec ea men , and he dosage was comp omised o 23 mg doses e e y 2 hou s. The ull
dosage (46 mg zinc) was e ained as a loading dose because conside able anecdo al e idence was a ailable o he au ho ha he i s dose aken was impo an o
achie e ex emely apid ea men esponses when aken su icien ly ea ly in a cold.
T ea men esponses mo e apid han documen ed occu equen ly in ield use. Fas e esponses a e possible using la ge doses o mo e equen dosing wi h zinc
glucona e o zinc ace a e. Ex emely apid esponses occu i ea men is s a ed upon announcemen by a h oa o nose ickle o an incipien cold.
No o he esea che s inco po a ed a loading dose in o hei p o ocols. The ZIA alue o he loading dose desc ibed by Eby and co-wo ke s was he e o e 4.6 imes highe
han he ZIA alue om he i s lozenge used in he MRC ial, eigh imes he McNeil lozenge alue, and so o h.
Zn2+ Ions and Zinc Compound Mola Concen a ion wi h ZIA Values
Al hough ZIA alues a e he bes indica o s o success ul lozenges, Zn2+ ion concen a ions a e no ewo hy as concen a ions a e impo an componen s o ZIA alues
(see Table 10). Clea dis inc ions can be de ec ed in sali a y Zn2+ ion concen a ion and zinc compound concen a ion. The mos e ec i e lozenges p oduced he highes
ZIA alues and sali a y Zn2+ ion concen a ions, while he la ges concen a ion o zinc in sali a was ound wi h he ine ec i e zinc o o a e lozenges. Fo compa ison,
no mal zinc se um concen a ion is 0.015 + 0.006 mMol; and minimum an i hino i al- and in e e on-inducing concen a ions o Zn2+ ions a e 0.05 mMol acco ding o
Me luzzi2 and Geis and colleagues,(6) o 0.10 mMol acco ding o Ko an and co-wo ke s.(7) Zinc glucona e eleases 30 pe cen o i s zinc as Zn2+ ion a physiologic pH
7.4.
Table 10. Zn2+ ion and zinc compound sali a y mola concen a ion compa ed wi h ZIA alues.
___________________________________________________________________________
S udy Lozenge ZIA Zn2+ mMol Zinc
Value a pH 7.4 mMol
___________________________________________________________________________
Eby 23 zinc glucona e in
nonsoluble able s 100.0 7.4 24.7
MRC 23 zinc glucona e in
uc ose able s 44 5.0 16.8
McNeil 11.5 mg zinc
glucona e lozenges 25 3.3 11.1
Danish 4.5 mg zinc glucona e
lozenges 13.4 1.5 5.0
Zinc o o a e lozenge 0.0 0.0 31.0
Zinc aspa a e lozenge 0.0 0.0 20.0
Zinc glucona e-ci a e lozenges -11 0.0 10.0
Zinc ace a e- a a a e
-ca bona e lozenges -55 0.0 3.0
Zinc glucona e-glycine lozenges Nega i e 0.0 13.9
(unknown)
_______________________________________________________________________
In 1989, Vincen J. Me luzzi, and co-wo ke s showed an i hino i al e ec s o zinc in HeLa cells we e di ec ly ela ed o he amoun o Zn2+ ion a ailable and un ela ed o
he o al amoun o zinc complex a ailable.(2)
Simila ly, he p esen au ho has shown he educ ion in du a ion o common colds o depend upon ZIA, which depends upon Zn2+ ion concen a ion and ime o con ac
wi h o al mucosal memb anes, -- no he amoun o zinc compound.
Sali a y Zn2+ ion concen a ion is an o e simpli ied and misleading indica o o e icacy. High sali a y Zn2+ ion concen a ions may ha e a low ZIA alue i lozenges
dissol e oo quickly. The ime ha Zn2+ ion is applied (as ime o dissol e lozenges) and numbe o doses pe day a e impo an a iables in de e mining ZIA alues o
expe imen al lozenges.

Good examples o he limi ed ela ionship in ZIA alues be ween chemically simila 23-mg zinc as zinc ace a e lozenges may be seen in Chap e 7, Table 11.
Chap e 5. Re e ences
1. Guil o d JP, F uch e B. Fundamen al S a is ics in Psychology and Educa ion. 6 h edi ion. New Yo k:McG aw-Hill; 1978
2. Me luzzi VJ, Cip iano D, McNeil D, e al. E alua ion o zinc complexes on he eplica ion o hino i us 2 in i o. Resea ch Communica ions in Chemical Pa hology and
Pha macology. 1989;66: 425-440.
3. Al-Nakib W, Higgins PG, Ba ow I, e al. P ophylaxis and ea men o hino i us colds wi h zinc glucona e lozenges. Jou nal o An imic obial Chemo he apy. 1987;20:
893-901.
4. No dens öm BE. Biologically Closed Elec ic Ci cui s, Clinical, Expe imen al and Theo e ical E idence o an Addi ional Ci cula o y Sys em. S ockholm:No dic Medical
Publica ions; 1983.
5. Aoki FY. Dis ibu ion and emo al o human se um albumin- echne ium 99m ins illed in anasally. B i ish Jou nal o Clinical Pha macology. 1976;3:869-878.
6. Geis FC, Ba eman, JA, Hayden FG. In i o ac i i y o zinc sal s agains human hino i uses. An imic obial Agen s and Chemo he apy. 1987; 31:622-624.
7. Ko an BD, Kau e JC, Bu e wo h BE. Zinc ions inhibi eplica ion o hino i uses. Na u e. 1974; 248:588-590.
Chap e 6. - E ec s o Fla o -Masking on E icacy
Execu i e Summa y Chap e 6 desc ibes la o masking echniques o zinc glucona e lozenges. One me hod, chela ion by s ong ligands such as 30% ex amola ci ic
acid, o 10- old ex amola glycine elimina es Zn2+ ions a physiologic pH and des oys e icacy. Addi ion o s ong chela o s o zinc glucona e lozenges was e oneously
belie ed o be necessa y by o he s, because dex ose and all ca bohyd a es based upon dex ose eac wi h zinc glucona e in solid s a e eac ions esul ing in bi e ness
upon lozenge aging. F uc ose, he isome o dex ose, does no ad e sely eac wi h zinc glucona e and is he only sui able swee ene o use in la o masked zinc
glucona e lozenges. Ei he la o masked zinc glucona e lozenges, o zinc glucona e lozenges ha ing posi i e ZIA alues a e each possible sepa a ely, bu no oge he
(unless he able base is uc ose wi h no o he soluble ca bohyd a es). Zinc glucona e lozenges ha ing a ZIA alue g ea e han 50 a e no possible wi hou undesi able
inc eases in zinc con en .
Two basic me hods o la o -masking zinc lozenges exis . The i s me hod in ol es s ong chela ion o zinc in zinc glucona e o ano he compound o zinc. S ong
chela ion always esul s in loss o e icacy in common cold ea men . The second me hod, he only one o allow e icacy agains he du a ion o common colds, in ol es
no addi ional chela ion. Examples include zinc glucona e wi h a non- eac i e able base wi h o wi hou a la o -masking agen (s ong la o oil) o subs i u ion o zinc
ace a e o zinc glucona e as zinc ace a e na u ally equi es no la o mask.
When zinc glucona e is as ed in i s pu e o m, o when comp essed in o able s con aining no o he soluble ing edien s o when compounded wi h uc ose and
Me hocel( ), zinc glucona e has a mildly objec ionable, bland, chalky as e and a e as e. The a e as e can las 24 hou s. In solu ions o zinc glucona e, he main zinc
species ound a physiologic pH is zinc glucona e-hyd oxide (see Figu e 1). Zinc glucona e-hyd oxide is a neu al zinc compound ha can en e cells causing
objec ionable as e, a e as e, and issue inju y. Conside able imp o emen in lozenge as e -- wi hou an objec ionable a e as e -- is ob iously necessa y o de elop a
comme cially success ul p oduc . Zinc glucona e lozenges can ha e high ZIA alues, o lozenges can be pleasan ly la o ed, bu bo h cha ac e is ics a e no possible
simul aneously in lozenges con aining 23 mg zinc o less o easons desc ibed below.
Fo p ac ical pu poses, use o zinc ace a e sol es he as e/ZIA incompa ibili y p oblem ound in zinc glucona e lozenges. When compounded in o 5-g am suga lozenges,
zinc ace a e lozenges can ha e high ZIA alues, a e la o -s able, and ha e pleasan as es wi h no added la o mask.
S ong Chela ion o zinc
Managemen o me allic ions in ood has ecei ed conside able a en ion by he ood indus y. Me allic ions o i on, coppe , and zinc p esen in some ood p oduc s, e en
in minuscule amoun s, can cause ad e se e ec s on ood la o and in eg i y. I hose me allic ions a e allowed o emain in ood p oduc s, e en in e y low
concen a ions, me allic ions can g ea ly educe shel li e o a s, oils, and o he oods subjec o spoiling and oxida ion.
F om a ood manu ac u ing pe spec i e, howe e , me allic chela o s se e o s abilize o enhance nume ous p ope ies iden i ied wi h wholesome ood, including la o ,
colo , and ex u e.(1) Addi ion o mos ood chela o s does no impai abso p ion o zinc om oods passing h ough he in es inal ac because s omach acid dissocia es
zinc om he ligand. Se e al e o s we e made by companies o ind a chela ing la o mask o zinc glucona e.
Ci ic acid in he B is ol Mye s zinc glucona e lozenges (see Chap e 4.C.1) and a a ic acid in he Aus alian zinc ace a e lozenges (see Chap e 4.C.2) a e wo ood
acidi ie s ha ha e been di ec ly used o chela e zinc lozenges o imp o e hei la o . Sodium bica bona e in he Aus alian lozenges p o ided a sou ce o ca bonic acid
in solu ion o eac wi h zinc glucona e o o m nonsoluble, nonionizable zinc ca bona e. Chela o s, by de ini ion, educe o elimina e Zn2+ ions in solu ions a physiologic
pH.
Highly chela ed compounds o zinc, including zinc o o a e (see Chap e 4.B.1) and zinc aspa a e (see Chap e 4.B.2), ha e been shown o be wi hou any e ec on he
du a ion o common colds. Zinc aspa a e, zinc oxide, and zinc amino acid chela e lozenges -- all highly chela ed and ine ec i e agains colds -- a e he zinc lozenges
mos likely o be encoun e ed in heal h ood s o es.
Glycine and o he swee amino acids we e p oposed by Za embo, God ey and co-wo ke s o be e ec i e la o masks o zinc glucona e and o he ionizable zinc
compounds (see Chap e 4.C.3). Con a y o claims o 93 pe cen Zn2+ ions being eleased in o sali a om hese lozenges, glycine (10 mole) eleases no Zn2+ ions a pH
7.4 acco ding o Be hon. Ha d candy zinc glucona e lozenges compounded wi h glycine slowly change colo om a ligh an o b igh o angish-b own du ing ambien
summe s o age condi ions, sugges ing a Maila d eac ion occu s be ween suga s and glycine.
Glycine has been escinded om he FDA lis o Gene ally Rega ded As Sa e (GRAS) ing edien s (21 CFR §170.50) and has been p ohibi ed as an addi i e o oods
including candy lozenges and cough d ops since 1971. Glycine is only allowed in p esc ip ion d ugs unde a U.S. Food and D ug Adminis a ion New D ug Applica ion.(2)
Howe e , glycine is pe mi ed as a ood addi i e o imp o e he biologic quali y o he o al p o ein in a ood con aining na u ally occu ing, p ima ily in ac p o ein bu is no
o be allowed in excess o 3.5 pe cen o he o al p o ein.(3) 1998 Addendum: The U.S. Cong ess passed a law in 1995 dec eeing all amino acids sa e.
Zinc glucona e lozenges we e desc ibed in a echnical bulle in published by Akzo Chemie Company o The Ne he lands da ed Janua y 22, 1986.(4) Ten millig ams o zinc
(77 mg zinc glucona e) we e inco po a ed in 3.5 g am candy lozenges. The lozenge ille was so bi ol wi h 2 pe cen gum a abic (acacia). Zinc glucona e was added a
121 deg ees C. o so bi ol and gum a abic. The mix u e was ba ch cooked o 144 deg ees C., and cooled o 77 deg ees C. o add peppe min oil. The mix u e was
deposi ed in molds, and held o e nigh a 39 deg ees C. The esul an p oduc was c ys al clea , had no as e o zinc glucona e, and had no as ingency. Gum a abic
(acacia) has a high molecula weigh (240,000 o 580,000), is ex emely soluble in wa e a wice i s weigh , and is acidic o li mus.(5) Gum a abic consis s o (-)-
a abinose, (+)-galac ose, (-)- hamnose, (+)-glycu onic acid, annins and o he chemicals. Gum a abic is incompa ible wi h mos me allic sal s, including sal s o zinc, lead,
bo on, and i on. Combina ion esul s in p ecipi a ion o jelli ica ion.(5)
Zinc glucona e hea ed in so bi ol wi hou gum a abic apidly ca bonizes and de elops a oul, bu n odo p oducing lozenges ha ing no esea ch o comme cial u ili y. The
s a us o so bi ol as a zinc chela o is s a ed by B iggs and co-wo ke s(6) o be only 4 imes highe han dex ose (K1 = 0.04), bu so bi ol may be a much s onge zinc
chela o acco ding o Za embo and co-wo ke s.(7) Zinc chela ed o igh complexes wi h gum a abic in hese lozenges would ha e no e icacy agains common colds.
Encapsula ion o zinc glucona e powde , wi h he i s laye being hyd ophilic and second laye being hyd ophobic, educes bi e ness, as ingency, d yness, and
oughness o zinc glucona e by abou one- hi d when inco po a ed in o lozenges acco ding o a pa en assigned o Wa ne Lambe Company.(8) Hyd ocolloid ma e ials
including pec ins, algina es, cellulose and i s de i a i es, gela in, gums, mucilages, and mix u es a e used. Some hyd ocolloids a e zinc chela o s, and hey eac wi h zinc
glucona e o elimina e Zn2+ ions, as well as o educe and elimina e bi e ness and as ingency. Inco po a ion o ea ed zinc glucona e g anules in non- uc ose
comp essed lozenges esul s in damage o g anule memb anes wi h esul an delayed-onse bi e ness.
Al hough no echnically chela ion, mic oencapsula ion o zinc glucona e wi h nonsoluble cellulose memb anes was demons a ed by Eu and Ame ica, Inc., Vandalia,
Ohio, in 1985 wi h he idea o inco po a ing zinc glucona e in o chewing gum. The p oduc e ec i ely la o -masked zinc glucona e by p e en ing elease o zinc
glucona e in o sali a, esul ing in essen ially all zinc being swallowed and he eby ende ing p oduc s incapable o p oducing an e ec agains common colds.
Sou h A ican esea che s complexed zinc glucona e wi h EDTA, a powe ul zinc chela o , esul ing in no e icacy agains du a ion o common colds when used as a nasal
sp ay. Sp ays also caused conside able pain.
Va ious Non-Chela ing Fla o Masks
Zinc glucona e in he McNeil Consume P oduc s lozenges con aining suc ose, uc ose, manni ol and so bi ol (see Chap e 4.A.3) became e y bi e o e a mon h,
demons a ing he p oblem in main aining a la o -s able p oduc . Failu e o he McNeil lozenges can be di ec ly a ibu ed o poo pa ien compliance as a esul o
lozenge bi e ness. All swee ca bohyd a es excep uc ose eac wi h zinc glucona e o impa bi e ness.
F om 1986 o 1992 he p esen au ho conduc ed expe imen s o mask zinc glucona e la o . The main h us o he esea ch was o de elop echniques no chela ing
zinc, while educing bi e ness. Gene ally, he an ido e o bi e ness is swee ness. Nume ous a emp s we e made o ind swee ene s ha would educe bi e ness. Many
zinc compounds we e es ed in many di e en bases. A e o e 1000 ailu es es ing a ious zinc glucona e lozenge composi ions, b ie ly no ed below, he au ho
de eloped wo non-chela ing me hods o la o -masking zinc lozenges.
Lozenge o mula ions we e es ed using zinc glucona e and o he zinc compounds in ei he ha d boiled candy o di ec ly comp essed lozenges. All zinc glucona e
lozenges and nea ly all o he zinc compounds es ed (excep zinc ace a e), ega dless o manu ac u ing echnique, made wi h bases con aining dex ose, suc ose,
manni ol, so bi ol, xyli ol, mal ose, mal odex ins, lac ose, o he swee able bases, and a ious combina ions became e y bi e wi hin a ew days o a ew mon hs.
The addi ion o 50 mg sodium, calcium, o acid saccha in o zinc glucona e in lozenges elimina ed bi e ness and a e as e om bo h zinc glucona e and o he zinc
compounds al hough saccha in complexes wi h Zn2+ ions. Lozenges became much oo swee esul ing in an o e ly bi e saccha in as e and a e as e. E icacy agains
common colds may ha e been impai ed by inco po a ion o saccha in. Lozenges we e unp edic able in hei la o . Using iden ical lozenges, some as e es e s
complained lozenges we e oo swee , while o he s complained o ex eme bi e ness. Pe cep ion o lozenge as e a ied oo widely wi h saccha in as a la o mask o be
o alue o comme cial de elopmen . Saccha in may also be objec ionable as a po en ial ca cinogen o pa ien s. The e o e, inco po a ion o saccha in may p eclude he
ulles u iliza ion o zinc lozenges. Inco po a ion o saccha in also caused se e e headaches in se e al as e es e s. Headaches did no occu in hose as e es e s when
saccha in was no used in lozenges.
Complexa ion o zinc in 1986 wi h saccha in by Syn heco Inc., Gas onia, No h Ca olina, o he p esen au ho esul ed in an ex emely swee composi ion using less
han 30 mg zinc saccha ina e in a 5-g am lozenge. I zinc dosage was inc eased o he apeu ic le els, la o became ex emely bi e . No o mal es s agains common
colds we e conduc ed wi h zinc saccha ina e because o ex eme bi e ness.
Addi ion o Magnaswee (mono-ammonium glycy hizina e), a la o enhance , inc eased he bi e ness and as ingency o zinc glucona e lozenges. Again, no es s
agains common colds we e conduc ed because o ex eme bi e ness.
Addi ion o o he supe -swee ene s including acesul ame K, aspa ame, and a ious lico ice ex ac s did no p oduce no iceable bene i o swee ness a chemically
insigni ican doses; and mos a e s ong zinc chela o s. Addi ion o phenyl ace aldehyde diisobu ylace al, a la o mask used in ex emely small amoun s, had no
bene icial e ec and ended o inc ease he bi e ness o zinc glucona e lozenges.
Ca bowax 8000 (polye hylene glycol molecula weigh 8000), o PEG, coa ing o zinc glucona e g anules using luid bed agglome a ion was pe o med by I. F. P., Inc. o
Hay ield, Minneso a, in 1989 and 1990 o he au ho . Coa ings we e in weigh - a ios o 10 pe cen , 50 pe cen , 100 pe cen , and 200 pe cen o zinc glucona e. Di ec ly
comp essed lozenges o agglome a ed suc ose (Suga ab( ) by he Edwa d Mendell Company in Ca mel, New Yo k) inco po a ing PEG-coa ed zinc glucona e we e
es ed o la o s abili y. A e a ew weeks, lozenges con aining 25 pe cen and 50 pe cen coa ings became bi e . A e 1 o 4 mon hs, lozenges con aining highe
amoun s o coa ing became bi e . Comp ession up u es PEG memb anes, allowing chemical eac ions be ween zinc glucona e and o he lozenge ing edien s. A gummy,
solid esidue in sali a esul ed om o al dissolu ion o lozenges.
Ca bowax ea men o uc ose p oduced lozenges con aining zinc glucona e ha did no become bi e upon aging, a leas o he i s 6 mon hs.
Ca bowax 8000 coa ing o g ound c ys alline uc ose (K ys a 300 by A. E. S aley Manu ac u ing Company, Deca u , Illinois) was possible only a low empe a u e and
only when PEG was dilu ed wi h wa e . The esul an agglome a ed uc ose p oduc con ained 9 o 12 pe cen PEG. Fi e g am, 7/8 inch diame e lozenges we e
p oduced wi h di ec comp ession. Lozenge quali y was high wi h a ha dness o o e 15 kg and 20 o 30 minu e dissolu ion. Addi ionally, un g ound K ys a 300 c ys als
we e coa ed wi h PEG 8000, and g ound K ys a 300 c ys als we e agglome a ed wi h PEG 8000 o use as able bases. Lozenges had a b eak s eng h o 12 o 25 kg,
espec i ely, when comp essed o 9 ons applied p essu e. Lozenges dissol ed in 20 o 25 minu es and p oduced 30 ml o sali a.
Zinc glucona e in PEG- ea ed uc ose was supe io in as e o o he zinc glucona e p oduc s. The mild as e and a e as e o pu e zinc glucona e emained, equi ing
modes la o -masking. Se e al zinc glucona e, uc ose, and PEG composi ions became an o ligh b own in se e e aging and he mal es s, sugges ing slow
deg ada ion o lozenges.
RBS Pha ma zinc glucona e lozenges es ed by he Medical Resea ch Council (see Chap e 4.A.2) we e ou s anding examples o la o -s able zinc glucona e lozenges.
RBS Pha ma lozenges had a 44 ZIA alue, nea ly he highes ZIA alue possible o la o -masked zinc glucona e. The one-g am lozenges we e made o uc ose, zinc
glucona e, and Me hocel( ) and we e swee ly la o ed. E en a e s o age o i e yea s, no ex a bi e ness occu ed, e en hough he la o oil was hen absen .
Howe e , he gene ally objec ionable bland, chalky zinc glucona e as e and 24-hou a e as e emained. The e is a 1- o-3 o de o magni ude educ ion in bi e ness
be ween zinc glucona e lozenges made wi h uc ose and zinc glucona e lozenges made wi h any o he swee able base a e equi alen lozenge aging.
As only mode a e amoun s (abou 30 pe cen ) o zinc glucona e a e a ailable as Zn2+ ions a pH 7.4, a daily ZIA o 100 using 23 mg zinc as zinc glucona e 9 imes pe
day is possible only om lozenges p oducing li le sali a and emaining in he mou h o an ex ended ime (see Chap e 4.A.1).
The maximum ZIA alue o 23-mg zinc la o -masked zinc glucona e lozenges ha ing a we g anula ed uc ose and Me hocel( ) base is abou ZIA 50 when used each 2
hou s. Consequen ly, o ob ain a ZIA 100 esponse wi h la o -masked zinc glucona e lozenges, pa ien s would necessa ily ea hemsel es once e e y hou while
awake. Al e na ely, lozenges wi h highe zinc glucona e dosages can be de eloped. Un o una ely, addi ion o Me hocel( ) causes an unpleasan slimy eeling in he mou h
because o he high iscosi y o he Me hocel( )-sali a mix, esul ing in a p oduc o ques ionable comme cial alue. Lozenges con aining zinc glucona e in a base o
c ys alline uc ose wi h Me hocel( ) binde do no become bi e ega dless o ime. Howe e , addi ion o as li le as 1 pe cen suc ose o o he swee ca bohyd a e is
su icien o cause onse o delayed bi e ness.
Clea ly, he only sui able able base o zinc glucona e is uc ose, which is non-comp essible in c ys alline o m. Howe e , zinc glucona e lozenges could be
manu ac u ed using mic o-powde ed uc ose (powde ed K ys a ( )). Powde ed K ys a ( ) con ains 2% silica gel as a mois u e abso ben and low enhance . Powde ed
K ys a ( ) was easily comp essed on a hand p ess o o m ex emely ha d lozenges ha ing a e y slow dissolu ion a e wi hou inc eased bi e ness o e ime. Lozenges
we e e y hyg oscopic. Di ec comp ession o lozenges using powde ed uc ose is no comme cially possible, because o he ex eme ligh ness and lu iness o he
composi ion, and he ex eme amoun o dus gene a ed by he p ocess.
Slugging (p ecomp ession o powde , ollowed wi h milling o ob ain comp essible g anules) he powde ed uc ose, e g inding he pelle s, and using he g ound
composi ion o mix wi h zinc glucona e and o he able ing edien s appea s easible and pe haps desi able. Addi ion o nonsoluble wax o uc ose may p oduce a iable
able base o zinc glucona e lozenges.
Table ing cha ac e is ics o uc ose and so bi ol using poly inylpy olidone (PVP) in isop opanol as a binde ha e been desc ibed(9) and migh be sui able o his
applica ion, bu hey ha e no been es ed by he au ho .
Ane hole as Fla o Mask
When he lozenge base is uc ose, zinc glucona e lozenges can be e ec i ely la o -masked wi h ane hole o elimina e unpala able as e and a e as e. Ane hole, a
highly s able bu a oma ic la o oil, is he main cons i uen o he essen ial oils o anise, s a -anise, and ennel. Ane hole is almos o ally insoluble in wa e and canno
chela e Zn2+ ions.
Ane hole is ound in be e ages, oods, candy, and pha maceu icals as a la o - and odo -masking agen . Ane hole is also used as a seda i e, s imulan , and expec o an
in cough mix u es and lozenges. The as e-masking e ec o ane hole on zinc compounds is s ong, long-las ing, and unique. Such pa ame e s allow sus ained
applica ion o zinc glucona e in he o m o a lozenge o he o al and o opha yngeal mucosa wi h no bi e as e o a e as e. Wi h he amoun o high-quali y ane hole
p ope ly balanced wi h zinc glucona e in a uc ose lozenge, ane hole can mask as e and a e as e o zinc glucona e o o e 24 hou s. Ane hole canno , howe e , mask
he bi e as e occu ing when zinc glucona e is combined wi h suc ose, dex ose, manni ol, so bi ol, lac ose, mal ose, xyli ol, o a ious combina ions.
Fla o -masked zinc glucona e lozenges can be p epa ed by adding 12-16 mg o high pu i y ane hole (A izole Ane hole Ex a, by A izona Chemical Company, Panama
Ci y, Flo ida) pla ed on o silica gel (Siloid 244FP, by Da idson Chemical, Bal imo e, Ma yland), wi h 175 mg zinc glucona e (23 mg zinc) o a 5-g am able o pu e uc ose
inco po a ing PEG 8000 o Me hocel( ) as a binde .
S abili y o ane hole la o -mask in uc ose was accep able o e a 4-mon h es pe iod, unless lozenge con aine emained unsealed. I le unsealed, ane hole quickly
e apo a es, and he lozenge as e e en ually becomes bland and chalky bu no o ensi e o bi e in as e. Sp ay d ied la o s o la o oil inco po a ed wi hin be a-
cyclodex ins we e no la o -s able, as dex ose wi hin hose composi ions eac ed wi h zinc glucona e causing bi e ness.
The main disad an ages o ane hole as a zinc glucona e la o mask a e ex eme a oma ici y and a dis inc i e, anes he ic-like as e in he amoun s used. E apo a i e loss
o only 2 o 3 mg ane hole is su icien o loss o la o mask. Al hough o he la o s can be added, such as eucalyp ol and men hol, he p ima y as e is ane hole and is
disliked by many as e- es e s.
In he inal analysis, ane hole la o -masking o zinc glucona e in uc ose lozenges does no p oduce a p oduc accep able in as e o e e yone, e en hough echnically
sound, modes ly e icacious lozenges a e possible.
Low ZIA Value o 5-G am Zinc Glucona e Lozenge
The mos ala ming inding abou ane hole la o -masked zinc glucona e lozenges is hei low ZIA alue. Fi e-g am uc ose and PEG lozenges con aining 23 mg zinc om
zinc glucona e comp essed o 9 ons, dissol e in he mou h in 21 minu es, and p oduce 30 ml sali a, esul ing in a daily ZIA 34 alue when a lozenge is used e e y 2
hou s while awake (9 /d). A pleasan as e could be ob ained wi h ane hole la o -masked, 5-g am uc ose-based lozenges, o e icacy could be ob ained wi h a slow-
dissol ing, un la o ed, nonsoluble able (see chap e 4.A.1). A zinc glucona e lozenge wi h bo h high e icacy and la o appea s impossible using di ec comp ession
echniques.
The we g anula ion echnique used by RBS Pha ma o p oduce he slow-dissol ing zinc glucona e lozenges es ed by he MRC Common Cold Uni may be he bes
echnique o p oducing bo h e icacy and la o . The RBS Pha ma lozenges p oduced a ZIA alue o 44 p ima ily because lozenges s imula ed only wo- hi ds he sali a
p oduced by 5-g am uc ose-based lozenges.
Sea ch o E icacy and Pleasan Tas e
Many o he zinc compounds we e examined o u ili y in zinc lozenges. Modes amoun s o zinc sul a e, zinc oxide, zinc picolina e, zinc asco ba e, and zinc amino acid
chela es showed li le o no u ili y agains he du a ion o se e i y o common colds.
Se e al in e es ing lipophilic compounds we e ound o be highly cy o oxic by Me luzzi and colleagues,(10) and we e no es ed by he au ho . Chela ed zinc compounds
eleasing neu al zinc complexes, including zinc glucona e ( eleases mainly zinc glucona e-hyd oxide a physiologic pH 7.4; see Figu e 1), may p oduce mild cy o oxici y.
The objec ionable 24-hou a e as e o zinc glucona e may be e idence o mild cy o oxici y h ough in a cellula abso p ion o zinc glucona e-hyd oxide.
Only zinc compounds eleasing 100 pe cen o hei zinc as Zn2+ ions a sali a y pH h ough physiologic pH 7.4 a e cu en ly iewed as ha ing adequa e sa e y po en ial
o use in zinc lozenges. O gene ally ega ded as sa e (GRAS) compounds, only zinc chlo ide and zinc ace a e ha e such p ope ies.
E alua ion o many zinc compounds ha ing a i s s abili y cons an o less han o equal o log K1 = 2.0, and pa icula ly zinc compounds ha ing a i s s abili y cons an
less han o equal o log K1 = 1.0 (zinc chlo ide, p opiona e, bu y a e, benzoa e, o ma e, ace a e and o he s),(1) we e conside ed, and nume ous o he expe imen s we e
conduc ed o e se e al yea s.
Pe haps he zinc compound mos likely iewed by zinc esea che s o be bene icial in zinc lozenges is zinc chlo ide. Zinc chlo ide has a e y low i s s abili y cons an
(log K1 = 0),(1) bu zinc chlo ide immedia ely complexes wi h ca bohyd a es such as dex ose and suc ose in si u o o m b own discolo a ions on whi e lozenges. Zinc
chlo ide and all lozenges made wi h i a e ex emely hyg oscopic. Zinc chlo ide also has an objec ionable, caus ic as e, ende ing i less han desi able o inco po a ion
in zinc lozenges.
Al hough many o mula ions using hese highly uns able zinc compounds appea ed use ul o sho en common colds, he sea ch ul ima ely led o zinc ace a e, an
ex emely pungen , sha ply la o ed, s able, non-hyg oscopic zinc compound which in concen a ed solu ions as es like inega . Pa en ly su p ising and unique, when
zinc ace a e is compounded in o swee , ca bohyd a e-based lozenges o almos any composi ion, lozenges ha e pleasan as es o he no mal pala e and a e la o -
s able o yea s.
Chap e 6 Re e ences
1. Fu ia TE. Seques an s in ood. In Fu ia TE ed., CRC Handbook o Food Addi i es. 2nd ed. Wes Palm Beach, Fl:CRC P ess; 1972:271-294.
2. Pa ag aph 170.50 Glycine (aminoace ic acid) in ood o human consump ion. Code o Fede al Regula ions Ti le 21: Food and D ug Adminis a ion, Depa men o
Heal h and Human Se ices, Pa s 170-199, e ised Ap il 1, 1990, O ice o he Fede al Regis e Na ional A chi es and Reco ds Adminis a ion:Washing on DC.
3. Ibid.; § 172.320 Amino acids.
4. Bekendam G. Technical Bulle in: Zinc glucona e lozenges. Akzo Chemie, De en e , The Ne he lands. Janua y 22, 1985.
5. Acacia. Windholz M, Buda a i S, Blume i RF, e al, eds. The Me ck Index. Rahway NJ:Me ck & Company. 1983.
6. B iggs J, Finch P, Ma ulewicz MC, e al. Complexes o coppe (II), calcium, and o he me al ions wi h ca bohyd a es: Thin-laye igand- exchange ch oma og aphy and
de e mina ion o ela i e s abili ies o complexes. Ca bohyd a e Resea ch. 1981;97:181-188.
7. Za embo JE, God ey JC, God ey NJ. Zinc(II) in sali a: de e mina ion o concen a ions p oduced by di e en o mula ions o zinc glucona e lozenges con aining
common excipien s. Jou nal o Pha maceu ical Sciences. 1992;81:128-130.
8. U.S. Pa en 5,059,419, da ed Oc obe 22, 1991.
9. Osbe ge T. Table ing cha ac e is ics o pu e c ys alline uc ose. Pha maceu ical Technology. June 1979.
10. Me luzzi VJ, Cip iano D, McNeil D, e al. E alua ion o zinc complexes on he eplica ion o hino i us 2 in i o. Resea ch Communica ions in Chemical Pa hology and
Pha macology. 1989;66: 425-440.
Chap e 7. Zinc Ace a e Lozenges as Successo o Zinc Glucona e lozenges
Execu i e Summa y Chap e 7 desc ibes zinc ace a e lozenges as he successo o zinc glucona e lozenges. Zinc ace a e is an ou s anding sou ce o hyd a ed Zn2+
ions, as 100 pe cen o zinc in zinc ace a e solu ions is a ailable as Zn2+ ion a physiologic pH 7.4. Zinc ace a e lozenges a e pleasan as ing, and la o s able o
yea s. The able base can be any ca bohyd a e swee ene such as uc ose, suc ose, dex ose, o o he di ec ly comp essible, swee ca bohyd a e pha maceu ical
ca ie s. None complexes wi h zinc ace a e o cause bi e ness in comp essed able s.
Zn2+ om zinc ace a e is p esen a 100%
Zinc ace a e lozenges ha ing ZIA alues o up o 280 using 25 mg o zinc can be eadily manu ac u ed. Zinc ace a e lozenges ha ing a ZIA alue o 100 when used 9
imes pe day can sho en he du a ion o hino i us common colds by an a e age o 7 days. Lozenges can ha e any la o , al hough p e e ence is gi en o peppe min .
Pha maceu ical cha ac e is ics o s anda d and ad anced design lozenges, including Zn2+ ion sali a y concen a ions, ZIA alues by dosage s eng h, ZIA alues and
dissolu ion a es by comp essi e o ces applied, and lozenge as e es esul s a e shown.
As o Oc obe 2007, he only zinc lozenges manu ac u ed o hese highes s anda ds a e ZinxLozenges.
Zinc ace a e lozenge composi ions a e unique, as hese lozenges ha e g ea po en ial o e icacy wi hou oxici y o objec ionable as e o a e as e o he no mal pala e.
As zinc ace a e lozenges elease only Zn2+ ions and no neu ally cha ged zinc species capable o en e ing cells, lozenges a e comple ely non- oxic. Zinc ace a e lozenges
do no ha e unpleasan as es o a e as es ypical o zinc glucona e o o he highly ionizable zinc compounds. Pleasan - as ing, la o -s able 5- o 25-mg zinc (zinc
ace a e) lozenges can be p epa ed using suc ose, uc ose, o dex ose able bases wi hou bi e ness. When s o ed in sealed con aine s, hey a e la o -s able o many
yea s. S anda d design and ad anced design lozenges, hei ZIA alues, and o he cha ac e is ics a e p esen ed in his chap e .
Zinc Ace a e as Sou ce o Zn2+ Ions
Al hough zinc glucona e is he bes known sou ce o Zn2+ ions in lozenges o ea ing common colds, zinc ace a e me i s special a en ion. Zinc ace a e has chemical
p ope ies p e e able o e zinc glucona e o use in zinc lozenges. Fo example, zinc ace a e dihyd a e is 29.7 pe cen zinc and anhyd ous zinc ace a e is 35.5 pe cen
zinc, compa ed wi h 13.14 pe cen zinc in zinc glucona e. Only 77.23 mg zinc ace a e is needed o p o ide 23 mg zinc, compa ed wi h 175 mg o zinc glucona e. O e
400 g ams o zinc ace a e will dissol e in a li e o wa e compa ed wi h 100 g ams/li e o zinc glucona e. Zinc ace a e has a conside ably lowe s abili y cons an han
zinc glucona e (log K1= 1.03 s. 1.70) unde iden ical labo a o y condi ions.(1) Zinc ace a e eleases 100 pe cen Zn2+ ions as no easonable complexa ion occu s
be ween zinc and ace a e in solu ions up o 20 mMol, a any pH be ween 2.8 and 7 and, a o io i, a abo e (Figu e 20).(2) Zinc ace a e is 3.33 imes as ionizable as zinc
glucona e a issue pH 7.4. Zinc ace a e was used in i o by Ko an and co-wo ke s a Du Pon o inhibi eplica ion o hino i uses.(3) Zn2+ ion, om zinc ace a e, is as
an i hino i al and as p o ec i e o mono-laye cells in i o as in e e on.
Figu e 20. Concen a ion o Zn2+ ion in he zinc and ace a e sys em by pH. Zinc and ace a e a e p esen a 10
mMol. Ace a e p o ona ion cu es in he p esence and absence o zinc we e ound o be exac ly supe -imposable.
Rega dless o pH, Zn2+ ion concen a ion (log K1=1.0) is essen ially 100%, wi h some zinc ace a e+ o a low
s abili y cons an (log K1=1.7) possibly o ming a highe pH. F om da a by Hach and Be hon.(2) and pe sonal
communica ion Augus 2, 1999.
I is ully capable o s abilizing cell memb anes and closing po es in cells induced by cy oly ic agen s. The
inc eased a ailabili y o Zn2+ ions a pH 7.4 allows Zn2+ ion concen a ion o be su icien ly high o p oduce high
ZIA alues e en when used in suga lozenges p oducing la ge amoun s o sali a. The apeu ic doses may be
as ingen bu need no be o ally i i a ing. When 5 o 23 mg o zinc om zinc ace a e is compounded in o 5-g am
suga -based lozenges, lozenges ha e ZIA alues om abou 30 o 200 and a e la o -s able and ha e pleasan
as es.
Fla o S abili y
Along wi h a much la ge amoun o a ailable Zn2+ ion, la o s abili y is ano he ex emely impo an p ope y o zinc ace a e as demons a ed o e mul i-yea high
empe a u e, summe s o age condi ions. Fo example, zinc ace a e di ec ly comp essed lozenges, in a base o c ys alline uc ose and agglome a ed suc ose (Mendell's
Suga ab( )) and also con aining 14 mg sodium saccha in and peppe min oil e ained a pleasan swee as e and had no objec ionable a e as e a e a 3-yea s o age
pe iod in ambien condi ions cycling om 120 deg ees F. in summe o 30 deg ees F. in win e . Simila indings we e p oduced using a able base o pu e uc ose
agglome a ed wi h polye hylene glycol 8000, al hough a colo change occu ed. In nume ous o he expe imen s, zinc ace a e comp essed lozenges wi h a ious
ca bohyd a e bases did no become bi e upon aging o he mal cycling o e a 3-yea pe iod.
When a pha maceu ically accep able ca ie is swee , lozenge as e is good. Zinc ace a e lozenges do no become bi e upon aging in he p esence o uc ose, suc ose,
o dex ose. Fla o s abili y is independen o mois u e con en : whe he lozenges a e mois o he ouch o d y, la o is no a ec ed ega dless o ime. Fla o -s abili y is
an ou s anding p ope y o zinc ace a e lozenges. Mo eo e , no discolo a ion o packaged lozenges has been no ed du ing s o age, sugges ing high chemical s abili y.
Accep abili y o zinc ace a e in zinc lozenges was comple ely unexpec ed, because undilu ed zinc ace a e has a d ead ully ile as e comple ely o ensi e by any s anda d
and much wo se han he as e o undilu ed zinc glucona e. The ace ic acid complex o zinc migh be expec ed o smell and as e like inega . C ys als do smell like
inega , bu lozenge composi ions a e comple ely de oid o any inega smell o as e. Zinc ace a e composi ions ne e ha e he long-las ing and o ensi e a e as es
ypical o zinc glucona e composi ions.
Also comple ely unexpec ed was he opposi e e ec o ane hol in zinc ace a e lozenges.
Chap e 7.A. Gene al Lozenge Conside a ions
Va ious ca bohyd a e able bases, la o s, undesi able ing edien s, and p elimina y la o - es ing expe imen s a e discussed as backg ound o selec ion o "s anda d
design" and "ad anced design" zinc ace a e lozenges. Signi ican di e ences in la o , ZIA alues, and sali a y concen a ions o Zn2+ ion esul ing om changing only he
able base a e discussed as basis o selec ing wo basic designs.
F uc ose, Suc ose, and Dex ose as Pha maceu ical Ca ie s
F uc ose is he swee es o he na u al suga s and is 1.73 imes swee e han suc ose. F uc ose is a componen o suc ose, a disaccha ide, and is an isome o dex ose,
he o he componen o suc ose. Dex ose is 0.74 imes as swee as suc ose. The s abili y cons an o dex ose o zinc is log K1 = 0.01.(1) Simila exceedingly low alues
a e ound o o he ca bohyd a es and zinc, and simila low s abili y is also expec ed o suc ose and uc ose. Mos nu ien s seem o dec ease abso p ion o zinc, bu
suc ose may inc ease abso p ion acco ding o animal s udies.(4)
Su p isingly and unexpec edly, uc ose does no isibly eac , change colo , o o m bi e compounds wi h zinc ace a e a highe ambien empe a u es, as his
monosaccha ide is a polyhyd oxy ke one and is usually conside ed highly eac i e. F uc ose is hyg oscopic, and ela i e humidi y should be less han 55 pe cen du ing
p oduc ion o a oid mois u e accumula ion.
By con as , dex ose, a polyhyd oxy aldhyde is no mally conside ed o be an ine monosaccha ide. Dex ose eac s wi h zinc glucona e and o he zinc compounds o e
ime o o m e y bi e complexes, bu dex ose does no eac wi h zinc ace a e o cause bi e ness. Because bo h ace ic acid and gluconic acid a e closely ela ed
monoca boxylic acids, i is s ange hey eac so di e en ly.
Comme cial Di ec ly Comp essible Table Bases
Use o pha maceu ical able bases and o he pha maceu ical able ing ma e ials sui able o make zinc ace a e lozenges a e well desc ibed in Pha maceu ical Dosages
Fo ms, Volumes 1, 2 and 3.(5) Table o mula ion(6) is well co e ed as a e chewable able s.(7) Each has applica ion o o mula ing zinc lozenges. The chap e on di ec ly
comp essed able s also has special signi icance, as p ope ies o able ing ing edien s a e discussed in de ail.(8)
Mendell's Suga ab( ) is a whi e, ee- lowing s o age-s able, ine able base o agglome a ed suga con aining 90 o 93 pe cen agglome a ed suc ose wi h he balance
being in e suga . Suga ab( ) has a swee ness alue o 1, iden ical o suc ose. When blended wi h he ac i e ing edien plus a sui able lub ican and comp essed,
Suga ab( ) p oduces mode a ely ha d, non iable able s. Suga ab( ) has good low cha ac e is ics, good comp essibili y, la o -masking, low hyg oscopici y, chemical
s abili y, noncloying swee ness, a wide ange o compa ibili ies, smoo h disin eg a ion, and pleasan a e as e. Suga ab( ) is a whi e g anula powde ha ing an a e age
pa icle size o 296 mic ons.(9) E en hough Suga ab( ) is swee e han Emdex( ) and equi alen in swee ness o Swee ex( ), zinc ace a e lozenges made wi h
Suga ab( ) ha e a sha p la o and a e as e.
Mendell's Swee ex( ) is a di ec ly comp essible chewable able base wi h a swee ness alue o 1, equi alen in swee ness o Suga ab( ) and suc ose. Swee ex( ) does
no con ain suc ose. Swee ex( ) is a blend o 70 pe cen Emdex( ) and 30 pe cen K ys a ( ) 300 c ys alline uc ose (A. E. S aley, Deca u , IL). Swee ex( ) has a
demons a ed binding capaci y o up o 50 pe cen ac i e ing edien s wi h no signi ican loss o comp essibili y. Swee ex is claimed by he manu ac u e o be ideally
sui ed o he di ec comp ession o chewable able s since i possesses quali ies o cool mou h- eel and is na u ally swee wi hou he inco po a ion o a i icial swee ening
a Zn2+ wis -- which came i s , he chicken o he egg? A ole o zinc in he managemen o HIV and AIDS is discussed. Zinc, zinc glucona e, and zinc ace a e a e
Gene ally Recognized as Sa e (GRAS) subs ances. No e idence o oxici y o sho e m adminis a ion o he apeu ic dosages o zinc has been ound.
The comple e biochemis y o zinc is a ou side he scope o his handbook. This su ey is gene ally es ic ed o i ems o majo in e es , and i ems o impo ance in
common cold esea ch, such as oxicology. Many implica ions and e ec s o zinc nu i ion and de iciency in human medicine a e o signi ican clinical in e es bu a e
omi ed o only b ie ly men ioned. The eade should conside a e iew o he many discussions by o he sou ces ega ding zinc in human nu i ion, biochemis y and
medicine.
Zinc in Gene ics
Zinc is an essen ial elemen in he nu i ion o human beings, animals, and plan s. Zinc is equi ed in he gene ic make-up o e e y cell and is an absolu e equi emen o
all biologic ep oduc ion. Zinc is needed in all DNA and RNA syn heses and is equi ed a e e y s ep o he cell cycle. DNA is abou 5000 imes less suscep ible o
damage by Zn2+ ion han is RNA, sugges ing i s ole in he p edominan e olu iona y selec ion o DNA, a he han RNA, as he bea e o he p ima y gene ic in o ma ion.
(1)
In p ebio ic chemis y on Ea h billions o yea s ago, zinc mos likely was he i s e ec i e nonenzyma ic polyme ase. Zinc emains an essen ial componen o all DNA
and RNA polyme ases examined oday.(2) Wi h a poly C empla e, Zn2+ alone can ca alyze he assembly o an ac i a ed GMP de i a i e (guanosine 5'-
phosphoimidazolide) in o poly G chains 30 o 40 esidues in he na u al 3'-5' linkage.(2) Al hough o he me als a e ca aly ic, Zn2+ ion p oduces g ea e ideli y.
Zinc's unc ion as a nonenzyma ic polyme ase sugges s an ino ganic answe o he age-old ques ion, "Which came i s he chicken o he egg?"
"Zinc inge s" a e inge -like p o usions ex ending om ansc ip ion ac o s o gene- egula ing p o eins and as ening o he wide, majo g oo e o a DNA molecule.(3)
Since he disco e y o zinc inge s in 1985, o e 200 p o eins, many o which a e ansc ip ion ac o s, ha e been ound o inco po a e zinc inge s. Zinc inge s ely o ally
upon Zn2+ ions o hei o m and unc ion. Zinc inge s ha e been iden i ied in species as di e se as yeas o human beings. Abou 1 pe cen o he DNA in human cells
speci y zinc inge s. As ew as 2 and as many as 37 zinc inge s occu on gene- egula ing p o eins. Zinc inge s a e belie ed o enable enzymes o ansc ibe a second
gene ic segmen om DNA in o RNA se ing as a empla e o syn hesis o a speci ic p o ein such as a s ing o amino acids o RNA i sel . The inge -like p ojec ions a e
pe ec ly sui ed o DNA ecogni ion by means o hei h ee-dimensional shape. F om an e olu iona y s andpoin , ances al genes speci ying a small p o ein o 30 o so
amino acids would easily pick up zinc om he en i onmen and would old wi hou assis ance in o a s able con o ma ion whe e hey would ha e he abili y o bind o DNA
and RNA.
Gene al Zinc Biochemis y
Abou 2 g ams o zinc is dis ibu ed h oughou he body (a e age 10 o 200 mmg/g am) o an adul human being.(4) Abso p ion o die a y zinc occu s o e he duodenal
and jejunal egions o he gas oin es inal ac . Ac i e anspo o zinc in o po al blood is media ed by me allo hionein. Zinc compe es wi h o he me als o abso p ion,
and abso p ion is belie ed g ea ly e a ded by inges ion o ibe and phy a es.(4,5)
Plasma zinc is complexed o o ganic ligands. Zinc-albumin complexes accoun o abou 50 pe cen o he zinc, and he me al is eadily exchangeable h oughou he
pe iphe al ci cula ion. Abou 7 o 8 pe cen is loosely bound o amino acid cons i uen s in plasma. The emaining 40+ pe cen age o plasma zinc is la gely bound o
mac oglobulins and una ailable o nu i ional pu poses. Se um and plasma zinc concen a ions in adul s ange om 80 o 150 mmg/dL, al hough ci cadian diu nal
luc ua ions occu in concen a ion.(4) Ci cadian diu nal a ia ion peaks a 9:30 AM and eaches a low a 8 PM wi h di e ences o 19 mmg/dL.(6) Ra he han an
en e ohepa ic ci cula ion, zinc expe iences a simila en e opanc ea ic ecycling.(4)
Zinc is an in eg al componen o abou 200 me alloenzymes, including ca bonic anhyd ase, alcohol dehyd ogenase, ca boxypep idase, glu amic dehyd ogenase, lac ic
dehyd ogenase, and alkaline phospha ase as well as ho mones, such as hymulin, es os e one, p olac in, and soma omedin.(4)
Zinc de iciency symp oms a e nonspeci ic, pe haps in pa because o hei need in so many enzymes and hei c i ical oles in bo h p o ein syn hesis and molecula
gene ics. Many enzymes may become non unc ional in he absence o zinc, e en hough he p esence o he enzyme emains undis u bed. The in eg i y o cell
memb anes, including he in eg i y o ed and whi e blood cells, depends upon loosely bound ionic zinc. Mo eo e , zinc de iciency is a cause o 33 pe cen o all ol ac o y
diso de s. In many espec s, he o al pic u e o zinc de iciency is eminiscen o essen ial amino acid de ici s.(4)
Zinc de iciency s un s g ow h and causes se ious me abolic dis u bances. Inadequa e in ake in people and animals esul s in se ious immunode iciency, inc eased
numbe s o in ec ions, inc eased se e i y o in ec ions, s un ed g ow h, and delayed sexual ma u a ion. As de ici s become wo sened, skin and o i icial lesions de elop
only o be subjec ed o an unchallenged bac e ial in asion, ye lesions do no moun a signi ican in lamma o y esponse.(4) The e o e, se e e zinc de iciency p oduces a
pa en ly ob ious immunode iciency in he cell-media ed (T-cell) immune sys em. Ad anced de iciency culmina es in dia hea, se e e was ing, and ul ima ely dea h. This
scena io is ypical o a leas 12 animal species including man.(4)
Zinc, HIV and AIDS
Zinc de iciency symp oms a e simila o hose o pa ien s su e ing om AIDS. Siegal and co-wo ke s i s desc ibed AIDS pa ien s wi h concu en he pes simplex
in ec ion in 1981. One imp ession o he disease o Siegal and co-wo ke s was immunosupp ession induced by zinc de iciency.(7) Zinc se um le els we e no mal.
No malcy could ha e been b ough abou by he pa ien s' ad anced s a e o ca abolism as pa ien s we e all ano ec ic and cachec ic. Addi ional zinc was adminis e ed o
hese i s ou AIDs pa ien s o eco d wi h no e ec . The amoun o zinc gi en was no s a ed bu was p obably abou 15 mg/day, he ecommended daily allowance
(RDA).
Unless zinc was gi en a e y high doses o 10 days o longe o es a he hymus in he manne o Golden and colleagues (abou 150 mg/day, o abou 1 mg pe
pound o body weigh ),(8) li le could be expec ed. This amoun o zinc is en imes he RDA and is essen ially iden ical o he dosages used o ea colds. Libano e and
co-wo ke s ound signi ican ly lowe (P < 0.001) zinc in se um in AIDS pa ien s. Zinc dec eased wi h he wo sening o he clinical and immunological pic u e (CD4 helpe
induce cells), sugges ing adminis a ion o zinc o he au ho s.(9)
Weine sugges ed adminis a ion o zinc o homosexual AIDS pa ien s.(10) Low se um zinc, equen ly ound in male homosexuals,(10) IV d ug abuse s, and o he
malnou ished pe sons will signi ican ly impai T-cell unc ion. Impai men would p e en comple e elimina ion o i us a e ini ial T-cell esponse o a any ime du ing
in ec ion. Demise o T-cells and immunosu iciency, and inc eases in se e i y o HIV in ec ion, and ul ima ely AIDS would esul . Adminis a ion o 1 mg zinc pe pound
body weigh pe day used by Golden and colleagues,(8) o 100 mg zinc pe day used by Ducha eau and colleagues(11,12) gi en on a p ophylac ic basis o a e he ime
o con ac ing HIV in ec ion should es o e o imp o e hymic unc ion, double T-cell unc ion, inc ease T-cell coun , help s abilize plasma cell memb anes, and ha e a
chance o elimina ing HIV in ec ion o p e en ing HIV in ec ion om p og essing o AIDS. (See Chap e 2 o u he in o ma ion on he e ec s o zinc in s imula ing T-cell
lymphocy e unc ion, including educ ion o supp esso T-cells, and enhancemen o in e e on p oduc ion.)
J. M. Co in epo ed ha he long, clinically la en phase ha cha ac e izes human immunode iciency i us (HIV) in ec ion o humans is no a pe iod o i al inac i i y, bu
an ac i e p ocess in which cells a e being in ec ed and dying a a high a e and in la ge numbe s (billions pe day).(13) These esul s led him o a simple s eady-s a e
model in which in ec ion, cell dea h, and cell eplacemen a e in balance, and imply ha he unique ea u e o HIV is he ex ao dina ily la ge numbe o eplica ion cycles
o bo h T-cell lymphocy es and i uses ha occu du ing in ec ion o a single indi idual. Conside ing he ex odina y dynamics o T-cell g ow h and eplacemen ,
adminis a ion o zinc in he dosages sugges ed seems manda o y o p o ide su icien zinc o allow unin e up ed T-cell g ow h, and mo e pa icula ly ans o ma ion o T-
cell lymphocy es o he ac i a ed s a e.
Unless all HIV a e success ully elimina ed by ac i a ed T-cells, coinciden al se e e, un ea ed bac e ial in ec ions a e HIV in ec ion could esul in a LEM eac ion by he
li e empo a ily wi hd awing zinc om he blood and T-cells,(13,14) pe haps esul ing in empo a y loss o T-cell con ol o HIV, esul ing in HIV ein ec ion, as would be
he case wi h any he apeu ic agen used in he ea men o HIV.
In HIV in ec ion, zinc se um concen a ions should be main ained nea he uppe limi o he no mal ange (150 mmg zinc/dL), bu no abo e he no mal ange.
Immunosupp ession and o he hemopoie ic side e ec s om wice no mal o g ea e zinc se um concen a ion may esul (see below and speci ically e e ences 32, and
34), pa icula ly i se um concen a ions o coppe , i on, and manganese all below hei no mal anges. Con e sely, no ice he amilial hype zincemia discussion below.
Expe imen al zinc ea men was es ed o immunos imula o y e ec s in an HIV-in ec ed 180-pound man. T-cell unc ion change [ he esul an o T-cell coun change
( om 90 o 120) and he ac ion o T-cells ac i a ed change ( om 7 o 10 pe cen )], doubled wi hin he i s 30 days. As he pa ien le he s udy, ollow-up was no
possible. Dosage es ed was 3 o 5 able s daily wi h each able con aining 30 mg zinc, 2 mg i on, 2 mg manganese, and 0.3 mg coppe .(15)
GRAS S a us Assessmen

Ce ain zinc sal s a e ood subs ances and a e Gene ally Recognized As Sa e (GRAS). In 1973, he Li e Sciences Resea ch O ice e-e alua ed heal h aspec s o
supplemen ing ood wi h ce ain GRAS zinc sal s ha we e commonly used as ood ing edien s.(16) Thei assessmen was based upon in o ma ion summa izing
wo ldwide scien i ic li e a u e ga he ed by he Food and D ug Adminis a ion om 1920 o 1970, supplemen ed by li e a u e sea ches o Toxline and Medline a ailable as
o No embe 1973, and summa ized in he ollowing pa ag aphs. The Selec Commi ee on GRAS Subs ances concluded:
"The e is no e idence in he a ailable in o ma ion on zinc sul a e, zinc oxide, zinc ace a e, zinc ca bona e, and zinc chlo ide ha demons a es, o sugges s easonable
g ound o suspec , a haza d o he public when hey a e used a le els ha a e now cu en in he manne now p ac iced. Howe e , wi hou addi ional da a, i is no
possible o de e mine whe he a signi ican inc ease in consump ion would cons i u e a die a y haza d."(16)
The Selec Commi ee ound daily in ake o zinc in he o al die a ied conside ably wi h age. The obse ed daily in ake o elemen al zinc pe kilog am o body weigh is
ound in Table (16). A e e iewing he a ailable da a, he Selec Commi ee commen ed ha because o he cen al ole o zinc as ei he an ac i a o o ce ain enzymes
o as a coenzyme in many me abolic eac ions, ela i ely la ge excesses o zinc sal s in he die can lead o me abolic dys unc ion. In pa icula , in e ac ion o zinc wi h
se e al o he mine al nu ien s, no ably i on, coppe , manganese and calcium, sugges s majo modi ica ion o zinc nu i ional balance migh lead o signi ican me abolic
dis u bances. In conside a ion o he po en ial o me abolic dis u bance by oxic doses o zinc, and cu en ly wide nu i ional use o zinc sul a e and zinc oxide in in an
o mulas, he commi ee sugges ed expanding knowledge o in e ac ions o zinc sal s in associa ion wi h die a y le els o o he essen ial mine al nu ien s.
The commi ee sugges ed es ablishing maximum limi s o le els o zinc sal s in oods, pa icula ly in o mulas o in an s, since his segmen o he popula ion now
consumes he highes le el o zinc sal s when calcula ed on a daily o body weigh basis.
Table 16. Possible daily in ake o zinc in millig ams pe kilog am o body weigh
___________________________________________________________________________
Age g oup Possible daily in ake in millig ams / kilog am body weigh
A e age in ake Maximum in ake
___________________________________________________________________________
0-5 mon hs 5.59 10.25
6-11 mon hs 0.72 3.41
12-23 mon hs 0.17 0.19
2-65 yea s < 0.01 < 0.01
___________________________________________________________________________
The p esen au ho sugges s lowe ing in an zinc in ake may be e oneous. Lowe ing zinc con en excessi ely in in an oods may con ibu e o in an immunosupp ession,
p og ession o HIV in in ec ed in an s o AIDS, and impai ed g ow h. Human colos um has been measu ed o con ain 825 mmg/dL on he i s day o lac a ion, alling o
507 mmg/dL on he i h day o lac a ion, emaining a o e 200 mmg/dL un il abou he hi d mon h o lac a ion, emaining a o e 200 mmg/dL un il abou he hi d mon h
o lac a ion, and a 70 mmg/dL o nea ly he en i e i s yea o li e.(17) Zinc om colos um ac i a es in an cell-media ed immuni y as well as s imula es cell g ow h. Cell
media ed immuni y mus emain supp essed in he e us and u e us o p e en hos -g a diso de s. Human amnio ic luid con ains an an ibac e ial amoun o zinc 4.4
imes se um concen a ion.(18)
The Selec Commi ee ound o ally inges ed zinc o be abso bed la gely om he duodenum. The deg ee o abso p ion is subs an ially a ec ed by nu i i e s a us wi h
espec o zinc, die a y phy a e, calcium, and phospho us. Usually abou 8 o 10 pe cen o zinc inges ed by a s, ca s, and dogs is abso bed, and he es is exc e ed in
eces. Re en ion may be highe in bone and skin han in o he issues, bu he elemen is p esen and needed in e e y cell. The a e age biologic hal -li e o zinc in he
adul man is 154 days. As happens wi h o he me als, zinc sal inges ed in oxic amoun s cause a a ie y o me abolic changes.
Toxic doses o zinc inhibi in es inal alkaline phospha ase, xan hine oxidase, li e ca alase, cy och ome oxidase, and succinic dehyd ogenase; also, oxic doses modi y
exc e ion o ni ogen, phospho us, and sul u . Fo example, eeding zinc oxide as 1 pe cen o he die o a s esul ed in inc eased u ina y exc e ion o ni ogen, while
phospho us and sul u exc e ion was educed. Fecal exc e ion was also inc eased, esul ing in dec eased ne e en ion. U ina y exc e ion o bo h u ic acid and c ea ine
was inc eased.(16)
The mos impo an ad e se e ec o eeding oxic doses o zinc appea s o be a speci ic mic ocy ic hypoch omic anemia, p obably ela ed o changes in i on and coppe
u iliza ion. Fo example, dec eases in i on s o age p o eins we e obse ed when a s we e ed a die con aining 0.4 pe cen zinc as zinc oxide. In o he s udies, die s
con aining 0.75 pe cen zinc esul ed in dec eased ed cell li e spans and inc eased i on exc e ion. Feeding an excess o zinc oxide (0.6 pe cen as zinc) o a s esul ed
in a dec ease in bo h i on and coppe le els o all issues, explaining mos o he enzyme changes. This e ec o zinc excess on i on and coppe me abolism appea s o
be he esul o in e e ence wi h i on and coppe u iliza ion a he cellula le el and he inc eased exc e ion o coppe . E idence o his in e ac ion is obse ed in s udies
o i on and coppe supplemen a ion. Supplemen a ion o hese me als can e e se anemia caused by excess zinc eeding. A simila in e ac ion has been ound wi h
calcium and manganese. Inc easing die a y calcium inc eased loss o zinc in a s and esul ed in dec eased abso p ion and dec easing u no e . In o he s udies, high
calcium and phospho us in akes appea ed o inc ease zinc equi emen in a s. By con as , eeding an excess (0.75 pe cen zinc as zinc ca bona e) in die s o young a s
o one week esul ed in a ma ked dec ease in bone calcium and phospho us.(16)
In he a , a le hal dose in 50 pe cen o cases (LD50) has been epo ed o be 1374 mg pe kg o bo h zinc sul a e hep ahyd a e and o zinc ace a e hep ahyd a e bu 750
mg pe kg o zinc chlo ide. Values o simila magni ude ha e been epo ed o mice and abbi s. One human a ali y has been epo ed. A woman's dea h was a ibu ed
o zinc sul a e poisoning ollowing acciden al consump ion o abou 30 g ams o he sal . This in ake amoun ed o abou 500 mg pe kilog am o body weigh , a dosage
simila o dosages ound o be o en le hal in animal s udies. Many sho - e m es s wi h high le els o zinc sal s ed o di e en animal species ha e shown no ad e se
e ec s a le els below 100 mg o he sal pe kilog am pe day, bu cu iously, ex ensi e s udies indica e ha eeding zinc oxide o zinc sul a e a le els g ea ly in excess o
500 mg o he sal pe kilog am ha e no consis en ly ad e se e ec s. The na u e o he compound appea s o play a signi ican ole in oxici y. Limi ed s udies o zinc
sul a e in ake ha e been conduc ed in human beings. The e was no e idence o oxici y a le els o up o 660 mg pe day o he hep ahyd a e (abou 10 mg o he sal pe
kg pe day) o up o 3 mon hs.(16)
Long- e m dosages in a s ha e been ca ied ou wi h zinc chlo ide, oxide, ca bona e, and sul a e. These s udies, ex ending o one yea and o e h ee gene a ions,
showed no e ec a le els up o 0.25 pe cen o die . In o he in es iga ions, zinc sul a e ed a die a y le els o abou 100 ppm o a s and dogs was epo ed o cause
hema ologic changes including mic ocy osis, coupled wi h polych omasia in some animals and hype ch omomasis in o he s; in addi ion, mo e apid u no e o ed blood
cells was obse ed.(16)
No e idence o ca cinogenici y o se e al zinc sal s was no ed in a s udies o e h ee gene a ions no in eeding a s zinc oxide (equi alen o 34.4 mg o zinc daily o
29 weeks), o zinc ca bona e (equi alen o 1 pe cen zinc in die ) o 39 weeks. No signi ican ca cinogenic di e ences be ween zinc- ea ed mice (5,000 ppm zinc as
zinc sul a e) and con ol g oups we e obse ed. These indings, he comp ehensi e c i ical analyses o he li e a u e by expe ienced in es iga o s, and ecen e iews by
wo labo a o ies specializing in expe imen al ca cinogenesis make i e iden han zinc sal s aken o ally should no be conside ed a ca cinogenic haza d.(16)
Animal ep oduc ion s udies pe o med h ough se e al gene a ions ha e disclosed no e idence o any ad e se e ec on e ili y, ges a ion, and heal h o e us om
eeding die s o up o 0.25 pe cen zinc chlo ide, zinc oxide, zinc ca bona e, o zinc sul a e o a s. In addi ion, speci ic s udies o e ec s o excess die a y zinc ed as
oxide, mala e, ace a e, ci a e, o sul a e on chemical composi ion and enzyma ic ac i i ies o ma e nal and e al issues ha e shown no ad e se e ec s. Te a ologic es s
on h ee species o animals we e nega i e: daily o al adminis a ion o up o 30 mg zinc sul a e pe kg o body weigh in mice (day 6 h ough day 15 o ges a ion), up o
42.5 mg pe kg in a s (day 6 h ough day 15 o ges a ion), and up o 88 mg pe kg in hams e s (day 6 h ough day 10 o ges a ion) had no clea ly disce nible e ec on
nida ion o on ma e nal o e al su i al. The numbe o abno mali ies obse ed ei he in so o skele al issues o he es g oups did no di e om he numbe occu ing
spon aneously in sham- ea ed con ols.(16)
Cu en ly se e al zinc compounds a e lis ed as GRAS by he Food and D ug Adminis a ion (FDA), bu zinc ace a e is no lis ed, al hough bo h zinc and ace ic acid a e
lis ed.(19) Zinc ace a e was a GRAS subs ance be o e e-e alua ion by he Selec Commi ee on GRAS subs ances in 1973, and was again ound o be GRAS by he
Selec Commi ee in 1973.(16) Zinc ace a e was no included in he GRAS lis by he FDA in CFR 21 because no ood use has been iden i ied o i be o e de elopmen o
zinc ace a e lozenges, and i was no being used in oods. Zinc ace a e may no be cu en ly used in oods because (a) zinc ace a e has an ex emely sha p and o ensi e
as e when no dilu ed wi h suga s, and (b) zinc ace a e is ex emely eac i e wi h mos ood ing edien s. An o icial USP XXI monog aph o zinc ace a e exis s.(20)
Heico Chemicals, Inc. o Delawa e Gap, Pennsyl ania, appea s o be he only U.S. company o e ing la ge olume sales o zinc ace a e dihyd a e U.S.P. sui able o use
in zinc ace a e lozenges. Zinc ace a e dihyd a e U.S.P. cu en ly is used (a) as a componen in zinc-eugenol den al cemen o accele a e se ing, (b) as a componen o an
eye lo ion and eye d ops in he ea men o conjunc i i is, (c) occasionally as an as ingen , (d) as a s yp ic, and (e) as an eme ic o bo h human and animal usage. Heico
has no d ug mas e ile on zinc ace a e dihyd a e U.S.P. Heico's zinc ace a e dihyd a e U.S.P. p oduc is cu en ly used by only one eselle in he amoun o one on pe
yea .
Recen Human Sa e y and Toxicologic Da a
In 1979, P asad ound zinc as being ela i ely non oxic in compa ison wi h o he ace me als.(21) Many o he oxic e ec s a ibu ed o zinc in he pas a e ac ually
a ibu able o con aminan s such as lead, cadmium, o a senic. Zinc is noncumula i e, and he p opo ion abso bed is hough o be in e sely ela ed o he amoun
inges ed. Vomi ing, a p o ec i e phenomenon, occu s a e inges ion o la ge quan i ies o zinc. Two g ams o zinc sul a e ha e been ecommended as an eme ic. Th ee
ypes o acu e oxic eac ions o zinc ha e been epo ed in human beings. The i s ype is "zinc ume e e " cha ac e ized by pulmona y mani es a ions, e e , chills, and
gas oen e i is obse ed in indus ial wo ke s who a e ch onically exposed o ho zinc oxide umes. In he second ype, oxici y was obse ed in a 16-yea -old boy who
slowly inges ed 12 g ams o me allic zinc dus o e a pe iod o 2 days. This condi ion was cha ac e ized by d owsiness, le ha gy, and inc eased se um lipase and amylase
le els wi hou addi ional sequela. The hi d ype o acu e zinc oxici y was obse ed in pa ien s wi h enal ailu e ollowing hemodialysis using wa e s o ed in a zinc-
gal anized ank. These pa ien s su e ed om nausea, omi ing, e e , and anemia.
The symp oms o zinc oxici y in human beings include dehyd a ion, elec oly e imbalance, abdominal pain, nausea, omi ing, le ha gy, dizziness, and lack o muscula
coo dina ion. Acu e enal ailu e will occu wi hin hou s o inges ing la ge amoun s o zinc chlo ide. Dea h is epo ed o ha e occu ed a e inges ion o 45 g ams o zinc
sul a e. This dose is conside ed massi e, conside ing he daily equi emen o zinc o man is in he ange o 15 o 30 mg/day. The compe i ion be ween zinc and coppe
o in es inal abso p ion and p o ein-binding si es is well known, and he e is a high p obabili y ha coppe de iciency will be induced in pa ien s ecei ing daily high
amoun s o zinc o a leas a mon h.(21)
In 1979 he Na ional Resea ch Council sub-commi ee on zinc ound i no o be highly oxic. Zinc oxicosis occu only when high dose le els o e whelm he homeos a ic
mechanisms con olling zinc up ake and exc e ion. Repo s o zinc ole ance as well as oxicosis in human beings a e spa se, bu exis ing e idence sugges s ha 500 o
1,000 millig ams o mo e o zinc may be inges ed on a daily basis wi hou ou wa dly obse able ad e se e ec s. Ten o mo e g ams o he me al aken as a single o al
dose may p oduce gas oin es inal dis ess, including nausea, omi ing, and dia hea. The commi ee also ound inges ion o la ge doses o zinc o educe bene icially
oxic s o es o cadmium.(22)
By 1988, Cunnane's e iew had li le mo e o o e on he oxici y o zinc, al hough he was mo e es ained han he Na ional Resea ch Council. Cunnane sugges ed ha
zinc was no comple ely non oxic, e en in he apeu ic dose ange (50 o 300 mg/day) on a long- e m basis. F equen ly, doses o zinc in excess o 50 mg causes
gas oin es inal side e ec s, including nausea. Zinc has biphasic and iphasic e ec s on many pa hways and on he immune sys em, pa icula ly T-cell lymphocy e
unc ion as will be discussed la e in his sec ion. Zinc's supp ession o coppe , i on and manganese u iliza ion may also be an impo an de imen in he long un wi hou
hei concu en adminis a ion. Adminis a ion o zinc may bene icially deple e s o es o i on esul ing in a educed inciden o angina pec o is and ischemia. Zinc is well
known o compe e wi h hese me als o gu abso p ion si es and blood anspo p o eins. Long- e m doses o zinc equi ed o deple e coppe a e epo ed o a y om
150 o 5,000 mg/day.(23)
Pha maceu ical adminis a ion and uses, ad e se e ec s, abso p ion, and he a e o zinc and zinc compounds including zinc ace a e we e e iewed in Ma indale The
Ex a Pha macopoeia in 1989.(24) No signi ican indica ions o oxici y o ad e se e ec s we e epo ed om he apeu ic doses o zinc, al hough nume ous
pha macologic uses o zinc, including zinc glucona e lozenge ea men o common colds, we e epo ed. P obable le hal o al doses o soluble zinc sal s including zinc
ace a e we e epo ed be ween 50 mg pe kg body weigh (be ween one easpoon and one ounce o an adul ) and 5 g ams pe kg body weigh (be ween 1 ounce and
one pin o an adul ).
In Clinical Toxici y o Comme cial P oduc s, Gosselin epo ed he oxici y a ing o soluble zinc sal s was 3 o 4, o mode a ely oxic o e y oxic.(25) Be e es ima es
place p obable le hal dose o a human being a 500 mg pe kg, which is close o a LD50 dose o 750 mg pe kg o zinc ace a e. Fo a 175 pound man, his would mean
consuming be ween 40 and 60 g ams o zinc ace a e, which is abou 3 o 5 heaping ablespoons.
Nume ous o he o iginal and e iew a icles ound no oxici y a le els used o ea common colds, pa icula ly when used only o 7 days o less.(26-31)
The inding o e e sible, ad e se immune sys em e ec s and dec eased plasma high-densi y lipop o ein-choles e ol by Chand a when zinc se um le els we e inc eased
o double no mal zinc se um le els(32) needs econcilia ion wi h e idence showing some amilies ha e ch onic zinc se um concen a ions 3 o 5 imes no mal. He i able
hype zincemia seemed o occu wi hou ob ious ha m, and amily membe s wi h high zinc se um con en li ed no mal li es.(33)
E en in a case o ex eme abuse o zinc glucona e (10- o 20- old he ecommended 23-mg zinc dosage o common colds) aken e e y 2 hou s o 4 mon hs, he
p incipal clinical indings consis ed o anemia, neu openia, e y high alkaline phospha ase, a se um zinc concen a ion 10 imes highe han no mal (an i i al), and
coppe and manganese concen a ions one- en h no mal. These indings we e e e sed wi h no appa en ha m a e wi hd awal o zinc and adminis a ion o ace
amoun s o coppe and manganese. Also, he pa ien was no ill du ing he ime o appa en oxic o e dose o zinc glucona e.(34) This obse a ion is in e es ing as i
documen s an an i i al zinc se um le el nea ly 10 imes no mal, showing ha ela i ely no mal cell li e and human li e a an i i al se um zinc concen a ions is possible.
Wi h lowe amoun s o o al zinc supplemen a ion, (15, 50 and 100 mg zinc pe day), F eeland-G a es obse ed no consis en changes in ei he plasma choles e ol o
high-densi y lipop o ein-choles e ol bu did obse e a signi ican nega i e co ela ion be ween die a y coppe and plasma choles e ol.(26)
Consequen ly, e ec s o ele a ed zinc se um concen a ion on choles e ol obse ed by Chand a a e ac ually caused by educ ions in coppe se um concen a ions
induced by ele a ed zinc, a he han being caused di ec ly by ele a ed zinc.
Lack o Toxici y in Common Cold S udies
F om he pe spec i e o ea men o common colds wi h zinc lozenges o 7 days, signi ican bene i s o T-cell immune sys em occu ed in Chand a's pa ien s du ing he
i s 2 weeks while zinc se um le els emained in he uppe no mal ange.(32)
As demons a ed by Fa and o he s, zinc se um le el and o he indica o s did no lea e no mal anges du ing adminis a ion o 23 mg zinc om zinc glucona e
adminis e ed e e y 2 hou s o 7 days.(35) No signi ican di e ences in i al signs be ween pa ien s ecei ing zinc and pa ien s ecei ing placebo occu ed. Clinical
labo a o y es s, including comple e blood coun , di e en ial leukocy e coun , me abolic p o ile, u inalysis, and le els o coppe and zinc in se um showed no signi ican
di e ences be ween he wo g oups excep o an inc eased mean le el o zinc in se um o 105 e sus 88 mmg zinc/dL (P < 0.001, = 4.40). No mal le els o zinc in
se um a e 70 o 150 mmg/dL in he e e ence labo a o y.(35)
In he English s udy, Al-nakib and colleagues ound a mino a ia ion in concen a ion o zinc in plasma o olun ee s, al hough no alues we e ou side e e ence limi s.
(36) All olun ee s ecei ing zinc showed a ma ked inc ease in u ina y zinc exc e ion.(36)
Zinc ace a e (150 mg elemen al zinc pe day) has been sponso ed as an o phan d ug o long- e m ea men o Wilson's disease.(37)
Possible Ad e se E ec in P egnancy
As none o he clinical ials o zinc lozenges o common colds included p egnan women, cau ion in p egnancy may be wa an ed as wi h any ea men du ing
p egnancy.
Kuma epo ed in an uncon olled ial e ec s o supplemen ing 100 mg zinc sul a e daily du ing he hi d imes e o p egnancy o subjec s on die s p o iding 6 mg
zinc/day ( o al 31 mg zinc/day). O he ou subjec s ea ed by Kuma , h ee p ema u e bi hs and one s illbi h occu ed, compa ed o 20 o 30 pe cen conside ed no mal
o women in unde de eloped coun ies including India.(38) Undesi able changes in he e us ha e been associa ed wi h in ake o e y low o excessi e amoun s o zinc,
magnesium, and manganese.(39)
Hambidge and associa es epo ed no change in ma e nal se um s a us o o he p oblems om supplemen ed die s p o iding 22 mg zinc pe day in a s udy o 10 middle-
income Uni ed S a es women.(40) Zinc in pe ina al nu i ional supplemen s is ei he absen o mos o en p esen in 25-mg dosages.(41)
Indus ial Sa e y and Ma e ial Sa e y Da a Shee o Zinc Ace a e
La ge non-pha maceu ical acu e and ch onic dosages and concen a ions o a numbe o zinc compound powde s used in indus y, including zinc chlo ide, zinc sul a e,
zinc ace a e, zinc oxide, and zinc glucona e, a e conside ed oxic o ex emely oxic and pain ul o issues o he uppe and lowe espi a o y sys em. In su icien
concen a ions, he powde s can inc ease his amine elease om mas cells,(42) causing in lamma ion and edema. In he special case o zinc chlo ide, dea h can occu
p ima ily om he ex emely caus ic e ec s o chlo ide on espi a o y issues. Zinc ume e e , an acu e disabili y, can occu when zinc umes a e inhaled om me al
hea ed o a empe a u e abo e i s mel ing poin . This disease is mos commonly associa ed wi h inhala ion o ecen ly o med zinc oxide umes. Mode a e exposu e o
zinc oxide dus does no cause zinc ume e e o he ex en ound wi h eshly o med zinc umes, appa en ly because o he agg ega ion o ume pa icles. Zinc oxide
dus has been said o elie e as hma when b ie ly inhaled.
OSHA equi es Ma e ial Sa e y Da a Shee s (MSDS)(43,44) o chemicals used in indus y. MSDS summa ize impo an ma e ial sa e y da a o he manu ac u e 's
p oduc . MSDS epo s by Heico Chemicals, Delawa e Wa e Gap, Pennsyl ania, a manu ac u e o zinc ace a e dihyd a e USP, and by J. T. Bake , Phillipsbu g, New
Je sey, a manu ac u e o eagen -g ade zinc ace a e dihyd a e, show zinc ace a e o be a sligh heal h and lammabili y haza d and a mode a e con ac haza d. Zinc
ace a e's chemical o mula is Zn.(CH3CO2)2.2H2O. Molecula weigh o he dihyd a e is 219.49, and 183.47 o anhyd ous. CAS numbe s a e 5970-45-6 o dihyd a e and
557-34-6 o anhyd ous. The mel ing poin is 237 C. Solubili y is app eciable a 1 g/2.3 ml wa e , and 1.6 ml boiling wa e . One g am dissol es in 30 ml alcohol o abou 1
ml o boiling alcohol. Speci ic g a i y is 1.735. The pH o zinc ace a e is 6.3. Zinc ace a e's oil/wa e pa i ion coe icien was no a ailable, bu is expec ed o be ze o. Zinc
ace a e dihyd a e is a whi e c ys al, and he anhyd ous o m is amo phous. Bo h ha e a ain ace ic acid odo . Vapo densi y is 6.3 (ai = 1).
Zinc ace a e is no ola ile and essen ially does no e apo a e. The dihyd a e may be dehyd a ed a 105 C. Zinc ace a e is no combus ible and is no a i e haza d,
al hough excessi e hea ing may elease ace ic acid umes. Zinc ace a e is a s able chemical when unhea ed, and haza dous polyme iza ion does no occu a any
empe a u e. Zinc ace a e is incompa ible wi h alkalies and s ong oxidizing agen s and will chemically eac wi h many o ganic and ino ganic subs ances. Zinc ace a e
decomposes upon se e e hea ing o zinc oxide, ca bon monoxide, and ca bon dioxide. In bo h acu e and ch onic indus ial o e exposu es, zinc ace a e is an eye i i an
and espi a o y haza d.
O e exposu e causes eye edness and i i a ion. Con inuous inhala ion o dus , concen a ed mis s, o ae osols may cause i i a ion o uppe espi a o y ac , igh ness
and pain in ches , and coughing. Inges ion causes nausea, omi ing, gas oin es inal i i a ion, and bu ns o he mou h and h oa . Inhala ion o concen a ed mis s
agg a a es espi a o y diso de s such as emphysema and as hma. Zinc ace a e is no ca cinogenic, and e a ologic es s on h ee species o animals we e nega i e. O al
a LD50 is 2460 mg/kg. D y zinc ace a e is no abso bed h ough he skin, bu ho , concen a ed solu ions can cause se e e skin i i a ion o bu ns. No ch onic e ec s o
o e exposu e ha e been iden i ied.
Bulk zinc ace a e is conside ed a haza dous, bu no ex emely haza dous indus ial chemical and is egula ed by se e al go e nmen al agencies. No special indus ial
p o ec i e equipmen is needed o he han good en ila ion, sa e y goggles, clo hing, and glo es. Fi s aid o o al inges ion, i he pe son is conscious, is o gi e la ge
amoun s o wa e and induce omi ing. I inhaled, he pe son is o mo e o esh ai . I he ic im is no b ea hing, a i icial espi a ion is indica ed. In case o eye o skin
i i a ion, he a ea should be washed wi h wa e .
Concluding Commen s on Toxici y
Lipophilic zinc complexes easily pene a e he cell plasma memb ane and we e ound o be cy o oxic in di ec ela ionship o hei lipophilici y by Me luzzi and colleagues,
(45) and one migh wonde i in e e ence wi h zinc inge s is one cause o such oxici y. Con e sely, some symp oms o disease, such as delayed sexual ma u i y, ising
om insu icien die a y zinc can now be a ibu ed o he inabili y o es ogen and and ogen ecep o s o old p ope ly in he absence o zinc.(3)
Al hough he use o Zn2+-ion eleasing zinc lozenges causes a localized ex acellula ise in Zn2+ ions a he concen a ions used, hey dec ease he pe meabili y o he
cell plasma memb ane o exclude addi ional Zn2+ ion abso p ion in o he in e io o cells. I zinc accumula ed in cells om zinc lozenge ea men , zinc would be cy o oxic.
Consequen ly, only zinc compounds eleasing 100 pe cen o hei zinc a pH 7.4 as Zn2+ ions, such as zinc ace a e, a e belie ed comple ely ee o zinc cy o oxici y.
O he zinc compounds eleasing neu al cell memb ane-pene a ing zinc complexes may esul in some deg ee o cy o oxici y, mani es ed in a a ie y o ways om o al
i i a ion o ou igh oxici y.
Zinc, in he o m o zinc glucona e o zinc ace a e lozenges, used a doses o 23 mg zinc o less, 9 imes pe day o 1 week, does no aise zinc se um le els and has a
eco d o sa e y wi h no un epo ed side e ec s known o exis since hei use began in 1979.
Chap e 8. Re e ences
1. Bu zow JL, Eichho n GL. Di e en suscep ibili y o DNA and RNA o clea age by me al ions. Na u e (London). 1975;254:358-359.
2. Ko nbe g A. O igin o DNA on Ea h. In: 1982 Supplemen o DNA Replica ion. San F ancisco: W. H. F eeman Co.; 1982:S224.
3. Rhodes D, Klug A. Zinc Finge s. Scien i ic Ame ican. 993;268: 56-65.
4. Zapsalis C and Beck RA. Food Chemis y and Nu i ional Biochemis y. New Yo k:John Wiley & Sons; 1985:1006-1009.
5. Obe leas D, Ha land BF. Nu i ional agen s which a ec me abolic zinc s a us. In: Zinc Me abolism: Cu en Aspec s in Heal h and Disease. New Yo k:Alan R. Liss, Inc.;
1977:11-24.
6. Ma kowi z ME, Rosen JF, Miz uchi M. Ci cadian a ia ions in se um zinc (Zn) concen a ions: co ela ion wi h blood ionized calcium, se um o al calcium and phospha e
in humans. Ame ican Jou nal o Clinical Nu i ion. 1985; 41:689-696.
7. Siegal FP, Lopez C, Hamme GS, e al. Se e e acqui ed immunode iciency in male homosexuals, mani es ed by ch onic pe ianal ulce a i e he pes simplex lesions.
The New England Jou nal o Medicine. 1981;305:1439-1444.
8. Golden MHN, Jackson AA, Golden BE. E ec o zinc on hymus o ecen ly malnou ished child en. The Lance . No . 19, 1977:1057-1059.
9. Libano e M, Bicocchi R, Raise E, e al. Zinc and lymphocy e subse s in pa ien s wi h HIV in ec ion. Mine a Medica (I aly). 1987;78:1805-1812.
10. Weine RG. AIDS and Zinc De iciency. Jou nal o he Ame ican Medical Associa ion. 1984;252:1409-1410.
11. Ducha eau J, Delepesse G, V ijens R, e al. Bene icial e ec s o o al zinc supplemen a ion on he immune esponse o old people. The Ame ican Jou nal o Medicine.
1981;70:1001-1004.
12. Ducha eau J, Delespesse G, Ve eecke P. In luence o o al zinc supplemen a ion on he lymphocy e esponse o mi ogens o no mal subjec s. The Ame ican Jou nal o
Clinical Nu i ion. 1981;34:88-93.
13. Subcommi ee on Zinc, Commi ee on Medical and Biological E ec s o En i onmen al Pollu an s, Di ision o Medical Sciences, Assembly o Li e Sciences Na ional
Resea ch Council. Zinc. Bal imo e:Uni e si y Pa k P ess; 1979;235.
14. Beisel WR, Peka ek RS, Wannemake RW J . Homeos a ic mechanisms a ec ing plasma zinc le els in acu e s ess. In: P asad AS, Obe leas D eds. T ace Elemen s
in Human Heal h and Disease. New Yo k:Academic P ess; 1976;97.
15. Wea e CA, Aus in, Texas. Manusc ip in p og ess.
16. Selec Commi ee on GRAS Subs ances. E alua ion o he Heal h Aspec s o Ce ain Zinc Sal s as Food Ing edien s, (SCOGS-21). Be hesda, MD: Li e Sciences
Resea ch O ice, Fede a ion o Ame ican Socie ies o Expe imen al Biology. 1973.
17. Shaw JCL. T ace elemen s in he e us and young in an . Ame ican Jou nal o Diseases o Child en. 1979;133:1260-1268.
18. P asad AS. Zinc in Human Nu i ion. Boca Ra on, FL:CRC P ess. 1979:24.
19. Pa 182-Subs ances Gene ally Recognized as Sa e, and Pa 184-Di ec Food Subs ances A i med as Gene ally Rega ded as Sa e. Code o Fede al Regula ions
Ti le 21:Food and D ug Adminis a ion, Depa men o Heal h and Human Se ices, Pa s 170-199, e ised Ap il 1, 1990, Washing on DC:O ice o he Fede al Regis e
Na ional A chi es and Reco ds Adminis a ion; 1990.
20. Zinc Ace a e. The Uni ed S a es Pha macopoeia, Twen y-Second Re ision and Na ional Fo mula y XVII, Rock ille, MD:Uni ed S a es Pha macopoeia Con en ion.
1990:1462.
21. P asad AS. Zinc in Human Nu i ion. Boca Ra on, FL: CRC P ess; 1979:66-68.
22. Subcommi ee on Zinc, Commi ee on Medical and Biological E ec s o En i onmen al Pollu an s, Di ision o Medical Sciences, Assembly o Li e Sciences Na ional
Resea ch Council. Zinc. Bal imo e, MD:Uni e si y Pa k P ess; 1979:305.
23. Cunnane SC. Zinc: Clinical and Biochemical Signi icance. Boca Ra on, FL: CRC P ess;1988:65-66.
24. Zinc. In Reynolds JEF, Pa i K, Pa sons AV, e al. eds. Ma indale, The Ex a Pha macopoeia, Twen y-Nin h Edi ion. London:The Pha maceu ical P ess; 1989.
25. Gosselin RE, Smi h RP, Hodge HC, e al. Clinical Toxicology o Comme cial P oduc s. Fi h ed. Bal imo e:Williams & Wilkins; 1984:II-143.
26. Fox MRS. Zinc excess. In Miles CF. Zinc in Human Biology. New Yo k:Sp inge -Ve lag; 1989.
27. P asad AS. T ace Elemen s and I on in Human Me abolism. New Yo k:Plenum Medical Book Company; 1978:328-329.
28. Unde wood EJ. T ace Elemen s in Human and Animal Nu i ion. 4 h ed. New Yo k:Academic P ess; 1977:230-232.
29. Lan zsch HJ, Schenkel H. E ec o speci ic nu ien oxici ies in animals and man: Zinc. In Rechcigl, J . Ed. CRC Handbook Se ies in Nu i ion and Food. Wes Palm
Beach, FL:CRC P ess, Inc., 1978.
30. Abdel-Mageed AB, Oehme FW. A e iew o he biochemical oles, oxici y and in e ac ions o zinc, coppe and I on: I. Zinc. Ve e ina y and Human Toxicology. 1990;
32:34-39.
31. Fosmi e GJ. Zinc Toxici y. Ame ican Jou nal o Clinical Nu i ion. 1990;51:225-227.
32. Chand a RK. Excessi e in ake o zinc impai s immune esponses. Jou nal o he Ame ican medical Associa ion. 1984;252:1443-1446.
33. Smi h JC J . He i able hype zincemia in humans. In B ewe GJ, P asad AS, eds. Zinc Me abolism: Cu en Aspec s in Heal h and Disease. New Yo k: Alan R. Liss,
1977.
34. P ei e CC, Papaioannou R, Sohle A. E ec o ch onic zinc in oxica ion on coppe le els, blood o ma ion and polyamines. O homolecula Psychia y. 1980;9:79-89.
35. Fa BM, Conne EM, Be s RF, e al. Two andomized con olled ials o zinc glucona e lozenge he apy o expe imen ally induced hino i us colds. An imic obial
Agen s and Chemo he apy. 987;31: 1183-1187.
36. Al-Nakib W, Higgins PG, Ba ow I, e al. P ophylaxis and ea men o hino i us colds wi h zinc glucona e lozenges. Jou nal o An imic obial Chemo he apy. 1987;20:
893-901.
37. Zinc Ace a e. In: USP D ug In o ma ion o he Heal h P o essional, V. O phan D ugs and Biological Lis ing. Rock ille, MD:The Uni ed S a es Pha macopoeial
Con en ion, Inc; 1992;2:58-59.
38. Kuma S. E ec o zinc supplemen a ion on a s du ing p egnancy. Nu i ion Repo s In e na ional. 1976;13:33-36.
39. K ause MV, Mahan LK. Food, Nu i ion and Die The apy. Philadelphia:W. B. Saunde s Co.; 1979: 283.
40. Hambidge KM, K ebs NF, Jacobs MA e al. Zinc nu i ional s a us du ing p egnancy: a longi udinal s udy. Ame ican Jou nal o Clinical Nu i ion. 1983;37:429-442.
41. Physicians' Desk Re e ence. 47 h ed. Mon ale, NJ: Medical Economics Da a; 1993.
42. Ha isch G, K e schme M. Some aspec s o a non-linea e ec o zinc ions on he his amine elease om a pe i oneal mas cells. Resea ch Communica ions in
Chemical and Pa hological Pha macology. 1987;55:39-48.
43. Ma e ial Sa e y Da a Shee o Zinc Ace a e Dihyd a e. Heico Chemical, Delawa e Wa e Gap, NJ. 1993.
44. Zinc Ace a e Dihyd a e. J.T. Bake , Phillipsbu g, NJ. 1990.
45. Me luzzi VJ, Cip iano D, McNeil D, e al. E alua ion o zinc complexes on he eplica ion o hino i us 2 in i o. Resea ch Communica ions in Chemical Pa hology and
Pha macology. 1989;66: 425-440.
Chap e 9. Conclusions and Recommenda ions
Execu i e Summa y Chap e 9 d aws conclusions and makes ecommenda ions. Hyd a ed Zn2+ ions ha e po en an i hino i al e ec s, powe ul cell memb ane
p o ec i e ac ions, ins an aneous cell po e-closing abili ies, s ong in e e on-inducing p ope ies, ou s anding d ying e ec s on sec e o y cells in nasal issues, and
e ec i e an i-in lamma o y ac ion. Zn2+ ions ha e been shown highly use ul in sho ening he du a ion o common colds when used in speci ic lozenge ea men
p o ocols. A se ious di e ence o opinion conce ning e icacy o zinc lozenges es ed om 1984 h ough 1992 exis ed.
The uni ying ZIA me hod o analysis p esen ed in his handbook p o ides comple e econcilia ion. All eigh clinical zinc lozenge o common cold s udies e iewed a e
equally alid, bu each s udy po ays only a small ace o he o e -all pic u e. Each o he s udies ep esen ed esponses om lozenges ha ing g ea ly di e en ZIA
alues, as a esul o g ea ly di e ing chemical composi ions. Se en day educ ions in a e age du a ion o common colds is possible and highly likely using lozenges
wi h a ZIA 100 alue.
Recommenda ions o esea ch on zinc ace a e lozenge o mula ions, placebo ma ching, and common cold ea men p o ocols a e also gi en. Me hods ound help ul o
imp o e clinical esul s a e gi en.
Rela ed uses o zinc ace a e lozenges in alle gy and mononucleosis, possible side e ec s, and con aindica ions a e discussed.
E idence exis s ha clea ly shows zinc glucona e lozenges o be e ec i e in educing du a ion o common colds; he only ques ion is by how much, which depends upon
ZIA alues. Zinc glucona e mixed wi h all known swee ene s, excep uc ose, is no la o -s able and always becomes e y bi e wi hin a ew days o a ew mon hs
wi hou s ong chela ing addi i es. Low ZIA alues om ully la o -masked zinc glucona e lozenges p eclude i s use in comme cial p oduc s. I zinc lozenges a e o
become success ul in educing du a ion o common colds, pleasan - as ing lozenges ha ing a high ZIA alue mus be de eloped.
Zinc ace a e is ex emely soluble and is 3.33 imes as ionizable as zinc glucona e. Equi alen amoun s o zinc om zinc ace a e p oduce highe ZIA alues and be e
esul s agains common colds han zinc glucona e. Zinc ace a e does no need la o -masking when i is mixed wi h suc ose, dex ose, o uc ose. Combina ions a e
la o -s able and ha e a pleasan as e and a e as e. Because p oduc ion o ully la o -masked zinc glucona e lozenges ha ing a ZIA alue o e 50 is p ac ically
impossible wi hou inc easing zinc con en o lozenges, zinc glucona e is no longe conside ed iable o use in zinc lozenges as ea men o common colds. Because o
supe io p ope ies, zinc ace a e is he successo o zinc glucona e in lozenges o be used o ea ing o cu ing he common cold.
Two basic zinc ace a e lozenge o mula ions a e ecommended o use in ea ing o cu ing common colds: he s anda d design and he ad anced design. The s anda d
design elies upon saccha in o p o ide added swee ness o dex ose able base. The ad anced design elies upon uc ose o p o ide he necessa y added swee ness.
Bo h o hese designs a e ully de eloped in Chap e 7.
Recommended S anda d Zinc Ace a e Lozenge Fo mula ion
S anda d zinc ace a e lozenges o ea men o he common cold a e 7/8 inch in diame e , ha e s anda d con ex aces, weigh 5 g ams and a e comp essed o he poin
(abou 6 o 10 ons) whe e u he comp ession does no esul in inc eases in a e age o al dissolu ion ime.
S anda d design lozenges should con ain as he ac i e ing edien 10 o 20 mg o zinc om zinc ace a e dihyd a e USP wi hin a able base comp ised o Mendell's
Emdex( ) agglome a ed dex ose. The lub ican should be 125 mg glyce yl monos ea a e. Lozenges a e pleasan as ing and la o -s able, al hough insu icien ly swee o
mos pala es. When necessa y, saccha in (1 o 10 mg), and peppe min oil (0.5 o 5 mg) may be added, al hough such addi i es chemically and physically a ec ZIA
alues. The zinc lozenges should ha e a ZIA alue o abou 150, dependen on o he a iables, p ima ily useage and dissolu ion a es. Such lozenges heo e ically will
sho en common colds by mo e han 7 days on a e age. Howe e , he addi ion o saccha in may be undesi able by many.
Recommended Ad anced Design Zinc Ace a e Lozenge Fo mula ion
The ad anced design lozenges should ha e a ZIA alue om 75 o 185. Ad anced design lozenges a e 5.0-g am lozenge ha ing a diame e o 7/8 inch and s anda d
con ex aces. Lozenges elease 15 o 23 mg Zn ion om zinc ace a e and p o ide 5.4 o 10 mMolT Zn2+ ion concen a ion.
Smalle 3/4 inch lozenges may be de eloped o o e come he objec ion by some use s conce ning he la ge size o he 7/8 inch diame e , 5-g am s anda d lozenge.
P esen expe ience indica es he possibili y o a 4-g am lozenge, bu lozenges lack su icien swee ness wi hou addi ion o saccha in o peppe min unless zinc dosages
a e simila ly educed. P esen expe ience shows mos people p e e he 5-g am lozenges wi hou added swee ene s o added la o s.
Ad anced design lozenges a e made wi h zinc ace a e dihyd a e USP, Mendell's Swee ex( ) (70 pe cen Emdex( ) agglome a ed dex ose and 30 pe cen c ys alline
uc ose), and glyce yl monos ea a e lub ican wi hou any o he addi i es such as saccha in o la o s. They a e mo e pleasan as ing and mo e la o -s able wi hou
ex a swee ene s o la o s.
Changes in Fo mula ions Allowable
To es ablish accu a e pe o mance baselines, no changes o addi ions o o he subs ances should be allowed un il he e a e su icien expe imen al lozenge s udies o
cause gene al accep ance o he indings.
Al hough 3/4-inch ad anced design lozenges a e conside ed easonably small, e en smalle lozenges migh be possible using non-palpable, di ec comp ession dex ose
o lac ose, swee ened wi h sodium saccha in. The i s s abili y cons an o zinc and lac ose is log K1 = 0.(1) Consequen ly, no easonable complexa ion be ween zinc and
lac ose is possible. Saccha in will complex wi h zinc. Al hough complexa ion is belie ed o be sligh , s abili y s udies mus be conduc ed be o e any use o chemically
signi ican saccha in.
Minimum E ec i e Dose
The concep o minimum e ec i e dose does no apply a dosage s eng hs below ZIA 100, as e icacy alls linea ly wi h declining ZIA alues. A some alue subs an ially
o e ZIA 100, a minimum e ec i e dose may be ound. Exceeding he minimum e ec i e dose would cause no u he clinical imp o emen and would be accompanied by
inc eased and unnecessa y o al side e ec s.
Manu ac u ing Va iables A ec ing ZIA
As shown in Chap e 7, many a iables can a ec ZIA alues o zinc lozenges. Lozenges equi e good quali y con ol p ocedu es du ing he manu ac u ing p ocess.
A e age ZIA alues a y be ween ba ches o lozenges when ce ain a iables a e al e ed. A e age ZIA alues mus be es ablished o each lozenge ba ch a ying in
e ms o (a) zinc compound used, esul ing in a di e en amoun o Zn2+ ion p esen a pH 7.4; (b) comp essi e o ces used in manu ac u e (may esul in di e en
a e age o al dissolu ion imes); (c) inconsis en hoppe illing (always esul s in di e en lozenge weigh s and comp essi e o ces applied); (d) changes in able p esses
(may esul in di e en a e age o al dissolu ion imes); (e) a ia ions in amoun , ype, o b and o lozenge ing edien s used, including able base, lub ican , d ying agen
o la o oils, la o oils, and mois u e; ( ) changes in able punches and dies ( esul ing able shape changes); and (g) changes in lozenge swee ness o la o ing (migh
inc ease o dec ease sali a p oduc ion o lozenge dissolu ion a es).
Impo ance o Placebo Ma ching
The subjec o placebo-blinding has ecei ed much a en ion in common cold esea ch as esea che s ely upon he s a emen s o pa ien s conce ning well-being in he
e alua ion o se e al clinical esul s.
Rejec ion o Vi amin C claims o sho ened colds esul ed om he ease by which pa ien s we e able o dis inguish he di e ence be ween Vi amin C and placebo
because o he well known as e o Vi amin C.(2) Au ho s including Linus Pauling,(3) Shul and co-wo ke s,(4) and Eby and co-wo ke s (see Chap e 4.A.1) ound pa ien s
aking Vi amin C had milde o sho e colds. Because o he amilia i y o i s as e, he p oblem o placebo-blinding is conside ed o be se ious in Vi amin C o common
cold esea ch.
Fa and Gwal ney(5) hypo hesized he esul s o Eby and co-wo ke s,(6) and by associa ion he esul s o he Al-Nakib and co-wo ke s,(7) o ha e been aul y because o
placebo unblinding. Thei hypo hesis was based upon as ing a single ma ked able o zinc glucona e and a single ma ked able o placebo by he same esea che s.(5)
The e we e some di e ences in as e.(5)
The con en ion by Fa and Gwal ney o placebo-unblinding in he s udy by Eby and co-wo ke s was no suppo ed by e idence, ei he in e nal o ex e nal o he o iginal
ials because (a) no pa ien in he o iginal s udy by Eby and co-wo ke knew he as e o zinc glucona e (o placebo); (b) he e was no s a is ically signi ican di e ence in
esponse be ween pa ien s commen ing on as e and pa ien s no commen ing in his s udy; (c) zinc and placebo lozenges we e indis inguishable in as e and appea ance
in he s udy by Al-Nakib and co-wo ke s; and (d) di e ences in esul s o all s udies o zinc lozenge o common colds a e en i ely accoun ed o by di e ences in ZIA
alues.
E en hough he pa ien s in he Al-Nakib s udy we e in qua an ine and we e cons an ly obse ed and e en hough he au ho s no ed ha he as e and appea ance o he
zinc glucona e and placebo lozenges used we e indis inguishable, some Uni ed S a es common cold esea che s did no accep he English esul s because clea ,
unambiguous, ho ough, s a is ical e idence was no published by Al-Nakib and co-wo ke s p o ing unequi ocally he absence o as e bias. The a ionale, hough
unsubs an ia ed o zinc lozenges, is ha e en i pa ien s a e obse ed con inuously by nu ses and/o physicians each day o he s udy, pa ien s ecei ing a mo e
disag eeable dosage may no no ice hei colds as much as hose on less ag eeable medica ion, hus hey migh bias s udy esul s.
Whe he his con en ion o as e-bias is ealis ic o no is i ele an in he Uni ed S a es. I no s a is ical e idence exis s showing he zinc- and placebo- ea ed pa ien s a e
equally likely o belie e hey a e ecei ing an ac i e o placebo, hen esul s o he s udy will no be accep ed.
An independen clinical ial o de e mine i pa ien s alsely epo e idence o clinical well-being because o zinc and placebo lozenge as e di e ences has no been
pe o med. These se ious and un ounded allega ions o e o s in placebo-blinding o zinc lozenges emain unp o ed and in need o econside a ion.
In iew o he igid, and pe haps un- ealis ic, expec a ions o pe ec placebo blinding, all u u e zinc lozenges o common cold s udies mus adhe e o he high s anda ds
es ablished by Fa and Gwal ney in hei a icle en i led "Zinc Glucona e: An E alua ion o Placebo Ma ching".(5) In hei s udy Fa and Gwal ney conduc ed as e es s
wi h se e al pilo s udies using 20 pa ien s, ollowed by wo ull ials wi h se e al hund ed pa ien s each. False esul s we e epo ed o ha e i s occu ed wi h small
g oups o people using lesse amoun o he bi e placebo, dena onium benzoa e. By using la ge amoun s o dena onium benzoa e, bo h zinc glucona e-ci a e- ea ed
and placebo- ea ed g oups we e equally con inced hey we e ei he ecei ing zinc, ecei ing placebo, o we e unce ain.
In he second and mo e accu a e es , he op ion "don' know" was emo ed, and pa ien s we e equi ed o decide be ween ei he "ac i e" o "placebo" esul ing in a
andom dis ibu ion o esponses. Tas e bias was no a conside a ion using he mo e bi e placebo in he zinc glucona e-ci a e lozenge ial. A equency dis ibu ion o
side e ec s om he lozenges showed he highe doses o dena onium benzoa e p oduced o al and sys emic side e ec s essen ially iden ical o side e ec s om zinc
glucona e-ci a e lozenges.
This is no o say zinc ace a e and placebo lozenges mus ha e iden ical as es. The zinc and placebo lozenges es ed by Fa and Gwal ney had clea ly dis inguishable
di e ences in la o , bu pa ien s had no way o de e mining which ea men hey we e ecei ing.
Di e ences in Tas e Pe cep ion in Well and Ill Volun ee s
Placebo ma ching e o s can esul when la o panel membe s who a e well and unin ec ed wi h hino i us o mally as e es zinc ace a e and placebo lozenges. The
as e pe cep ion o zinc ace a e lozenges du ing colds is signi ican ly di e en han while well. The pe cep ion o as ingency and "s eng h" o he lozenges is much lowe
du ing colds, allowing la ge dosages o be ole a ed when ill han when well. Consequen ly, ma ched placebos du ing well- olun ee condi ions may be unma ched du ing
hino i al in ec ion o olun ee s. The di ec ional endency owa d e o canno be known be o e es ing he e ec o hino i al illness upon he as e pe cep ion o he
placebo. Howe e , as e pe cep ion end is owa ds imp o emen in pe cep ion o swee ness du ing ea men o colds wi h zinc ace a e and glucona e lozenges, and
pe haps wi h placebos. Whe he his sugges s placebos should be mo e o less bi e o well olun ee s is unknown.
Ano he sou ce o placebo ma ching e o would occu when ill pa ien s a e asked abou hei ea men on days a e he s a o ea men o hei hino i us in ec ion. As
di e ences in esponse o ea men be ween zinc ace a e and placebo ea men a e g ea , asking i olun ee s ecei ed ac i e o placebo on he las day o he ial, o
example, would p oduce ob iously di e en esul s be ween he ac i e and placebo g oups.

Placebo Lozenge Fo mula Conside a ions
I esea che s ca e ully e alua e hei olun ee s wi h quan i iable, objec i e, daily clinical da a ( i al i e , nasal mucous weigh s, nasal ai low a es, empe a u e, nasal
and h oa in lamma ion, coughing a e, le ha gy, sleep equi emen , numbe o pain elie able s aken, and o he physician-obse ed signs and symp oms o common
colds), one would ob ain he mos accu a e esul s wi h placebo lozenges ha ing exac ly he same ing edien s as he ac i e lozenges -- wi hou zinc ace a e, o cou se.
The obse a ion o such quan i iable da a would seem o o e ide he necessi y o a pe ec ly ma ched placebo, bu such is no ue unde Uni ed S a es assump ions.
Addi ion o 0.25 o 1.00 mg o suc ose oc aace a e o 0.00125 o 0.005 mg dena onium benzoa e o p o ide a medicinal bi e ness will help con ince pa ien s hey ha e
an ac i e lozenge o p oduce he equi alen assessmen o ac i e- and placebo- ea men equi ed by Gwal ney wi hou ha m o he placebo esul s. Howe e , zinc
ace a e lozenges a e no bi e , and such addi ion is unwa an ed unless he bi e subs ance is also added o he ac i e zinc ace a e lozenges.
Some olun ee s, such as medical, biology and chemis y s uden s, would know "ace a e" in zinc ace a e is ela ed o ace ic acid. They migh expec he as e o inega ;
howe e , he e is no inega as e o odo associa ed wi h o al use o zinc ace a e lozenges. Only by ubbing we lozenges be ween he inge s does a ain odo o
inega on he inge ips occu . I ace ic acid is added o he placebo, he addi ion should no exceed 0.5 mg ace ic acid pe 5-g am lozenge.
To gi e iden ical blood pic u es be ween ac i e and placebo g oups, he placebo may con ain a highly chela ed zinc compound such as zinc ci a e. Zinc ci a e is known
o be neu ally cha ged a pH 7.4 (see Figu e 12 in Chap e 4), and clinically ine ec i e agains common colds. Howe e , his addi ion is no necessa y o p ese e a
easonable double blind aspec o a clinical ial.
Addi ion o excess s ong zinc chela o (1.33 mole ci ic acid) o zinc glucona e in placebo lozenges is highly ecommended, as wo sened esul s may be ound, esul ing
in elimina ion o he a gumen by Gwal ney(5) ha "zinc don' wo k, because placebos we en' ma ched".
T ue as ingen s in placebos a e discou aged, as as ingen s migh imp o e placebo esul s o se e al h oa symp oms h oughou he s udy and sho en hal -li es o
placebo- ea ed colds by a day. As e idence o his e ec , bene icial as ingen e ec s migh ha e occu ed in he God ey and co-wo ke 1992 ial wi h as ingen
placebo lozenges (see Chap e 4.C.3). Osol p o ides a discussion o as ingen s and pseudo-as ingen s.(8) He epo s mos as ingen s a e sal s o zinc, aluminum,
manganese, i on, and bismu h, o annins and polyphenolic compounds, wi h mos being bi e as ing.
O he subs ances such as acids, alcohols, phenols, o o he ela ed p o ein-p ecipi a ing subs ances a e no gene ally conside ed ue as ingen s as hey may pene a e
cell memb anes, while ue as ingen s, such as Zn2+ ions, do no .
Recommended Placebo Lozenge Fo mula
Pseudo-as ingen lozenges iden ical in as e and as ingen -like o al eeling can be made using he zinc glucona e plus 1.33 mole ci ic acid o mula o Fa and
Gwal ney(5) in o he wise iden ial lozenges. They a e cha ac e ized by sali a p oduc ion, sali a y p o ein p ecipi a ion, mou h- eel cha ac e is ics, o al dissolu ion imes,
blood and u ine pa ame e s essen ially iden ical o zinc ace a e lozenges. Howe e , placebos may be sligh ly mo e a , o bi e -swee in la o , and ci ic acid addi i e
may cause mino o al mou h- eel side-e ec s (pseudoas ingency). An independen clinical ial using he ac i e lozenges o Fa and Gwal ney as he placebo lozenges
in a double-blind, placebo-con olled clinical ial o ZIA 100 zinc ace a e lozenges would decisi ely close he doo o Gwal ney's a guemen s ha "zinc don' wo k".
Fo mal as e es s a e he manne o Fa and Gwal ney(5) in ill pa ien s should show one o mo e a ia ion o hese gene al o mula ions will p oduce no as e bias in
clinical ials.
Recommended Clinical T ial P o ocols
Wi h use o zinc ace a e lozenges, he "e e y 2 hou s while awake" p o ocol as desc ibed in he 1984 Eby s udy is necessa y o e ain ZIA alues, and is also he bes all-
a ound ea men p o ocol. Lozenges should be o ei he he s anda d o ad anced design. Pa ien s should be augh o allow slow lozenge dissolu ion o occu o
maximize abso p ion o Zn2+ ions in o mucosal memb anes o he mou h and h oa . The loading dose should be wo lozenges, one-a e -ano he , no wo-a -once. Adul s
and you hs o e 30 pounds should dissol e one lozenge e e y wo hou s while awake a e he loading dose. Child en unde 30 pounds may dissol e 1/2 lozenge e e y 2
hou s while awake, al hough i appea s unlikely o o e dose a small child wi h ull dosages (See Chap e 8, Table 16). Pa ien s should be ins uc ed o ea soda c acke s
o o he ood i nausea occu s while using zinc lozenges.
Pa ien s should be ins uc ed o con inue ea men e e y 4 o 6 wake ul hou s o a day a e he end o he las common cold symp om o help p e en elapse. Pa ien s
should no be equi ed o con inue ull ea men a e cessa ion o symp oms, because headaches may occu om con inued ea men in well pa ien s. Howe e , pa ien s
should also be ins uc ed o a oid s ess and include one o wo ea men s du ing he second day a e cessa ion o symp oms as u he insu ance agains elapse.
The ZIA alue o lozenges should be asce ained o each pa ien a he s a o each clinical ial o esea ch pu poses di ec ed owa d e i ying he ZIA/ educ ion-in-
du a ion heo y.
All clinical ials should be done in mul icen e ials whe e in es iga o s a each cen e do no know o he in es iga o s wo king on he p ojec . Double checking o all
pa ien da a shee s and double e i ica ion o all esul s (pe haps by pos - ial in e iews o pa ien s) by he ial sponso should be s anda d ope a ing p ocedu e. Some
esea che s, especially esea che s specializing in common colds, may ejec hei own posi i e indings as unbelie able.
Clinical ials may use wild colds om pa ien s ha ing had symp oms o no mo e han 3 days, o colds may be a i icially induced using human hino i uses and o he
common cold-causing i uses as desi ed. Pa ien s wi h HIV in ec ion, AIDs, acu e lymphocy ic leukemia, pedia ic Hodgkin's disease, and o he lymphocy e diseases may
be ea ed in s udies add essed speci ically a ea ing colds in such ill pa ien s wi h expec a ion o clinical imp o emen .
Clinical labo a o y es s may include comple e blood coun , di e en ial leukocy e coun , me abolic p o ile, u inalysis, le els o coppe and zinc in se um, u ine, and eces,
blood p essu e, and a omic abso p ion s udies.
All zinc se um es s should be conduc ed conside ing he s ong ci cadian hy hm o zinc. Peak le els occu a abou 9:30 AM and lowes alues occu a abou 8:00 PM,
wi h peak- ough di e ences o 19 mmg/dL.(9) These di e ences may be mo e han he di e ences ound be ween zinc and placebo ea men . Ac ual zinc abso p ion
migh be assessed using 69mZn wi h i s hal -li e o 13.9 hou s and a gamma ene gy o 439 Ke .(10)
Imp o ing Clinical Resul s
Expe ience wi h many common colds using zinc glucona e lozenge ea men du ing he 4 yea s immedia ely p eceding he 1984 s udy showed esul s could be imp o ed
i ce ain addi ional s eps we e ollowed. Pa ien s using he "e e y 2 hou " p o ocol should be ins uc ed esul s may be imp o ed i hey (a) sleep a e i s ea men and
o he ea men s when possible; (b) ea a bed ime (especially impo an as lymph low ceases du ing sleep esul ing in Zn2+ being held in issues esul ing in highe ZIA
alues); (c) ea a e meals and d ink (no be o e o a oid washing away o al Zn2+ ions); (d) a oid mou hwashes and alcohol; (e) a oid aspi in; ( ) a oid an ihis amines,
deconges an s, and o he cold emedies; and (g) a oid smoking. Yea s o expe ience clea ly shows sleeping a e use o lozenges is he mos aluable o hese s eps.
An addi ional s ep impo an in p e en ing lowe ai way in ol emen om hea sensi i e i uses such as hino i uses is applica ion o hea o he uppe back using a
hea ing pad. This s ep can be used e ec i ely du ing sleep, pa icula ly when pa ien s lie on hei backs wi h an app op ia e hea ing pad unde hei shoulde s.
ZIA alues o 432 can be ob ained by using ZIA 108 lozenges (18 mg zinc in 5-g am ad anced design lozenges) once each 30 minu es con inuously h oughou he
wake ul day. This p ocedu e is use ul when he pa ien s ongly desi es o be comple ely symp om- ee wi hin 24 o 48 hou s. This is a maximum- o ce e o , a ely used
o mo e han he i s day, because o he po en ial o o al issue i i a ion.
Expec ed Clinical Resul s om Ad anced Design Lozenges
Resul s om ield use lead he p esen au ho o belie e nea ly all colds can be e mina ed wi hin a day o wo (see Figu e 27). The hal -li e o colds ea ed wi h ZIA 108
ad anced design lozenges is expec ed o be 2 days, e sus 7.6 days o placebo o no ea men . Abou 15 pe cen o pa ien s can be expec ed o become asymp oma ic
wi hin 12 hou s, and 25 pe cen can be expec ed o become asymp oma ic wi hin 24 hou s.
Used e e y hal -hou o mo e han a ZIA 400 e ec , esul s can be imp o ed, pe haps wi h he majo i y o pa ien s becoming well wi hin 24 hou s. Because clinical
e idence o lozenges used o p oduce a ZIA 400 e ec is cu en ly lacking, one can only specula e on he ac ual s a is ical ou come. I hese alues a e p ojec ed om
Figu e 19 (see Chap e 5), ea men heo e ically p oduces 7- and 42-day a e age educ ions in du a ion. One may appea o be a nonsensical s a is ic because i is so
a beyond he 10.8 day a e age du a ion o un ea ed common colds.
Figu e 27. Expec ed e ec o ZIA 100 and 400 lozenges.
Bo h ea men s a e expec ed o cu e common colds. Pe haps he "42 day" a e age educ ion can bes be
in e p e ed as meaning a much g ea e ac ion will be well on he i s day han by no mal ea men . Al e na i ely,
ZIA 400 ea men may be in e p e ed as being excessi e, especially i used o mo e han 1 day. Al hough he
amoun o zinc aken on day 1 using he quad uple dosage is highe han he amoun using he ZIA 108 p o ocol,
he o al amoun o zinc aken o e he 7-day s udy pe iod is likely o be less han i zinc is aken using he ZIA 108
p o ocol.
Relapses can be p e en ed by aking a ew lozenges on he second and hi d day and by a oiding s ess on he
i s ew days a e eco e y.
Te mina ion o colds wi hin hou s epea edly occu s in ield usage o ZIA 100 lozenges when lozenges a e used
mo e o en han no mal a he ea lies sign o an impending cold. Rapid e mina ion o colds sugges s cell
memb ane s abiliza ion and pe haps an i hino i al e ec s a e ope a i e. In e e on induc ion does no appea
possible du ing he i s day, as 24 hou s we e necessa y o i s induc ion in labo a o y s udies. Howe e , in e e on
induc ion by he second day along wi h an i hino i al e ec s may keep colds om e u ning.
The mos likely explana ion o nea -ins an aneous esponse is memb ane s abiliza ion by Zn2+ ions and cell
memb ane po e closu e by Zn2+ ions, as sugges ed by Pas e nak.(11) Po e closu e applies o in lamma ion and mucus-p oducing cells such as mas and goble cells, and
issues d y apidly. Because po e closing occu s ins an aneously and is usually pe manen , clinical obse a ions may e lec in i o Zn2+ ion po e-closing ac i i y. Once
colds a e e mina ed, colds do no elapse as a gene al ule, co esponding well wi h in i o po e closu e esul s.
Reduc ion in acial edema om zinc ace a e lozenge ea men o colds is o en qui e isible, and coincides wi h pa ien imp o emen .
Vi al in ec ions gene ally depend upon cell-media ed immuni y o comple e esolu ion, and he e is no eason o belie e such would no be ue in common cold he apy
wi h lozenges eleasing Zn2+ ions.
Howe e , he zinc lozenge e ec wo ks equally well in T-cell immunosupp ession induced by chemo he apeu ic agen s in he ea men o childhood acu e lymphocy ic
leukemia. Zn2+ ions, pe haps h ough cell memb ane s abiliza ion, migh subs i u e o se e al oles usually played by T-cell lymphocy es. The po en ial bene i s o HIV
and AIDS pa ien s a e ob ious -- and impo an .
Full Ci cle
Re isi ing he o iginal inciden leading o his line o esea ch is me i ed. Conside he case o he 3-yea -old gi l su e ing om acu e lymphocy ic leukemia who e ained a
c ushed 50 mg zinc (zinc glucona e) able in he mou h while she napped o 2 hou s and awoke o ind he cold was gone wi hou elapse.
The es ima ed ZIA alue o he single ea men is 461. The dosage was 50 mg zinc glucona e yielding 30 pe cen o i s zinc as Zn2+ ion. The dosage was abso bed o e
he 120-minu es nap pe iod o one dose in a single day. Sali a p oduc ion is es ima ed a 10 g ams.
Sali a may ha e been less as he child had unde gone 500 ad c anial adia ion o wo weeks be o e he cold, which damaged he pa o id glands esul ing in a d y
mou h.
Reconside ing Fick's law and mucosal memb ane hicknesses, one migh suspec a 25-pound child would ha e hinne o al mucosal memb anes, pe haps less han one-
hal adul hickness, doubling he a e o abso p ion. Conside ing a d y mou h and hinne o al mucosal memb anes sugges s aising he ZIA calcula ion o an es ima ed
ZIA alue o o e 1000.
Conside ing he zinc dosage o body weigh a io, a 50-mg zinc dose in a 25-pound child is equi alen o a 300- o 400-mg zinc dose in an adul . These o al zinc doses
a e no oxic in small child en and a e app oached by nu sing in an s (see Chap e 8, Table 16).
A e conside ing he e idence in e ms o ZIA, doub ha a single lozenge could e mina e he child's cold in he manne desc ibed is mo e easily dispa ched. In ac uali y,
he o iginal inding now seems no only easonable bu expec ed. As lymph ci cula ion s ops du ing sleep, e en ion o Zn2+ ion in in ec ed issues is highes hen.
Consequen ly, bene i in e ms o mo e apid eco e y om sleeping a e use o lozenges and a bed ime use o a lozenge a e explained. O en pa ien s awake a e a
nigh 's sleep wi h only esidual nasal conges ion and s u iness. When conges ion is clea ed by blowing he nose, common cold symp oms o en do no e u n.
Expec ed Side E ec s and Con aindica ions
The side e ec s om ad anced design ZIA 92 o 138 lozenges a e expec ed o be essen ially non-exis en . No o al side e ec s, o he han mild o al d ying, a e expec ed
om he g ea majo i y o pa ien s. A ew pa ien s may expe ience an occasional mild a e as e ha does no occu consis en ly and is caused by unknown ac o s,
pe haps ela ed o he pa ien s' cu en zinc s a us.
Side e ec s om conside ably highe ZIA alue lozenges can occu . A e as e- es ing nea ly 1000 la o -masked o mula ions o zinc glucona e, zinc ace a e, and o he
zinc compound lozenges o e 6 yea s and e iewing many clinical and ield es s in hund eds o pa ien s wi h common colds since 1979, ou side e ec ha e been
de e mined o be expec ed when lozenges wi h high ZIA alues a e used.
Fi s , headaches can occu om o e -use o ZIA 160 o 200 lozenges in he absence o common cold symp oms du ing la o es ing. The headaches espond well o
ibup o en (600 o 800 mg doses). Why ZIA 160 o 200 lozenges cause headaches in pa ien s wi hou common cold symp oms bu e mina es headaches in pa ien s wi h
common colds is unknown, bu p obably ela es o highe e en ion o Zn2+ ions in issues o pa ien s wi hou common cold symp oms. Cell memb ane pe meabili y o
acial, o al, and nasal issues may be much highe in pa ien s wi h common colds (obse e hei edema ous aces), and Zn2+ ions may be apidly washed ou o hose
issues. In pa ien s wi hou colds, memb ane pe meabili y is lowe and Zn2+ ions may accumula e o high le els, pe haps ad e sely a ec ing p os aglandin syn hesis o i s
me abolism. This ac i i y can make la o - es ing wo k ime-consuming ( o a oid headaches) and can cause as e es e s o gi e wa nings abou headaches no
applicable o ill pa ien s. The p opensi y o de elop headaches inc eases wi h ZIA alues o he lozenges and equency o use.
Headaches can also occu wi h con inuous use o s anda d design ZIA 150 lozenges o a ZIA 600 e ec in he absence o a common cold. Headaches may be caused by
saccha in o a combina ion o saccha in and la o s. Se e al as e- es e s no iced headaches esul ing om use o s anda d design lozenges con aining saccha in,
al hough hey did no de elop headaches using o he wise iden ical lozenges wi hou saccha in.
None o he clinical ials o zinc lozenges showed zinc o cause headaches in pa ien s wi h common colds. Howe e , close examina ion o Tables 2 and 3 in Chap e 4
show headache symp oms ell o ze o in he zinc- ea ed g oup on days 4 and 5 bu ose sligh ly in days 6 and 7. Whe he hese obse a ions a e caused by pa ien s
con inuing zinc ea men a e cessa ion o common cold symp oms o hey a e andom headaches is unknown. Rega dless, headaches may occu i pa ien s use zinc
lozenges oo long a e cessa ion o symp oms.
Second, nausea is a andomly occu ing side e ec o zinc lozenges obse ed mos ly in women. On occasion e en small doses o zinc, whe he used as a lozenge o as
a die a y supplemen , cause some women o become nausea ed, occasionally o he poin o omi ing (see Table 4 in Chap e 4). This phenomenon is no an exclusi e
p ope y o zinc ace a e lozenges bu a p ope y o o ally adminis e ed zinc. Pa ien s should always be ad ised o use lozenges a e ea ing and d inking o a oid nausea,
i hey a e conce ned abou nausea. Ea ing soda c acke s -- and ood gene ally -- helps elie e nausea, and should be ecommended o pa ien s su e ing om lozenge-
induced nausea. In hose a e pa ien s knowing hey will omi i hey inges zinc, ea men o colds wi h zinc should be a oided o pe o med cau iously. Pa ien s p one
o omi ing should be wa ned no o d i e a mo o ehicle o pe o m dange ous asks while using zinc ace a e lozenges.
Thi d, o al i i a ion om con inuous o excessi e use o s ong zinc ace a e lozenges may occu bu no nea ly o he ex en esul ing om use o zinc glucona e lozenges.
Tongue and cheek issues seem mos a ec ed, and hose issues can become empo a ily so e. Howe e , in no case has o al i i a ion been oo se e e o discon inue
ea men using ZIA 100 lozenges, e en con inuously o a ZIA 400 e ec . Howe e , ZIA 150 lozenges used con inuously (ZIA 600) may cause o al i i a ion o a deg ee
p omp ing some pa ien s o wi hhold occasional ea men s du ing he 1-day ea men cou se.
Pa ien s ha e allen asleep wi h zinc glucona e lozenges in hei mou hs esul ing in a painless, aised whi e spo in he cheek issue. The whi e spo has no been no iced
wi h zinc ace a e lozenges, e en when pa ien s ha e allen asleep wi h a zinc ace a e lozenge in he mou h. Se e e issue i i a ion and he aised whi e spo a e mos
likely caused by cell memb ane pe mea ion o zinc glucona e-hyd oxide a pH 7.4 (see Figu e 1, Chap e 1), and no om Zn2+ ions om zinc ace a e. Spo s om zinc
glucona e lozenges subsided wi hin a day wi hou esidual issue ha m.
Fou h, empo a y al e a ion o ood as e is a common occu ence and is gene ally conside ed a nuisance a he han a side e ec . Occasionally, he al e a ion o as e
ex ends o he as e o zinc lozenges. Occasionally, a pa ien migh ind zinc ace a e lozenges o be sligh ly bi e , me allic, o somewha unpleasan , while he same
pa ien no mally has no complain abou zinc ace a e lozenges. D inking o ea ing usually esul s in imp o ed as e sensa ion wi hin a ew minu es.
One, and only one, olun ee epo ed a zinc ace a e lozenge o ha e a d ead ul as e, e en while o he olun ee s we e inding he as e o iden ical lozenges om he
same ba ch o be pleasan o good. Using di e en lozenge ba ches p oduced he same pe plexing esul s. All ood had begun o ha e a e y objec ionable as e o his
olun ee . The d ead ul as e o zinc ace a e lozenges may ha e been zinc induced-hypogusia, o may ha e been coinciden al hypogusia. I he obse a ion was zinc-
induced hypogusia, such would be qui e s ange, as many cases o hypogusia a e caused by zinc de iciency, no zinc excess. In his olun ee , as e abe a ion was also
associa ed wi h a den al sensi i i y and clinical dep ession. The ela ionship be ween hese and objec ionable lozenge as e is unknown and did no occu in any o he
pa ien wi h den al sensi i i y. The olun ee 's as e p oblem disappea ed upon desensi iza ion o he pa ien 's ee h wi h comme cial po assium ni a e-based den al
desensi ize s and cessa ion o dep ession. Zinc de iciency has been obse ed in clinical dep ession and may be he cause o dep ession- ela ed as e abno mali ies.
Use o Zinc Ace a e Lozenges o T ea Uppe Respi a o y Alle gy
Zinc applied o he nasal na es ei he wi h o wi hou elec ical s imula ion has a his o y o use da ing back o he 19 h cen u y (see Chap e 2). Clea ly, Zn2+ ions inhibi
he elease o his amine om mas cells. The use o zinc ace a e lozenges o con ol nasal alle gy empo a ily is new and e ec i e. A single ZIA 100 o 150 lozenge used
ea ly in he mo ning o en e mina es o g ea ly educes symp oms o se e al hou s o a day. Repea ed use as needed appea s bene icial and seems o cause no ha m.
Zinc Ace a e Lozenges and Mononucleosis
Con inuous use o ZIA 50 zinc ace a e lozenges ( esul ing in a ZIA 200 e ec ) while awake as ea men o se e e onsilli is caused by Eps ein Ba i us as
mononucleosis in a 17-yea old gi l p oduced apid (a) educ ion in o al and nasopha yngeal in lamma ion; (b) elimina ion o bila e al shaggy g ay onsilla exuda e; (c)
elimina ion o e e ; (d) imp o emen in pa ien 's eeling o well-being; (e) elimina ion o sup ao bi al edema; ( ) elimina ion o malaise, and a igue; (g) e u n o no mal
ocaliza ion; (h) elimina ion o ano exia; and (i) a ophy o ex emely swollen onsils o less han no mal size. All bene i s occu ed wi hin 1 o 3 days o ea men ini ia ion.
A e he i s lozenge, he pa ien esolu ely and con inuously used zinc ace a e lozenge ea men , e using codeine, ibup o en, and lidocaine. Co icos e iods o se e e
ai way obs uc ion we e no gi en in p e e ence o he bene icial e ec s epo ed om zinc ace a e lozenges. An ibio ic o concu en s ep h oa was con inued o he
no mal cou se. Splenomegaly, lymphadenophy, hepa omegaly and o he complica ions did no occu . No side e ec s o ea men no ecu ence o diseases occu ed.
The pa ien was able o e u n o school on he ou h day a e diagnosis (which occu ed on he 4 h day o illness) and was su icien ly well o esume a hle ic ac i i ies
on he ou een h day a e diagnosis. This anecdo e should s imula e o he s o in es iga e he an i i al p ope ies o Zn2+ ion agains Eps ein Ba i us and o conduc
clinical ials o he e ec s o zinc ace a e lozenges in ea men o mononucleosis.
As zinc ace a e eleases Zn2+ ions which a e an i i al o se e al he pes simplex i uses (see Chap e 2), Zn2+ ions also may be an i i al o he Eps ein Ba i us, ano he
membe o he he pes amily. Howe e a ho ough li e a u e sea ch e ealed no e idence o an i-Eps ein-Ba ac i i y by Zn2+ ions.
I Zn2+ ions a e an i i al o Eps ein-Ba i uses, zinc ace a e lozenge ea men o mononucleosis migh p e en Bu ki 's lymphoma. Bu ki 's lymphoma is associa ed wi h
Eps ein-Ba i us in A ica, Tu key, and o he loca ions whe e die a y zinc is o en inadequa e, bu a ely in coun ies such as he Uni ed S a es whe e zinc nu i ion is
no mally adequa e. As Bu ki 's lymphoma is a se ious and di icul - o- ea disease, immedia e in es iga ion o he e ec s o zinc ace a e lozenges in p e en ing Bu ki 's
lymphoma h ough ea men o mononucleosis is wa an ed.
Concluding Rema ks
The epo s o di e gen esul s o a ious zinc lozenges o common colds a e analyzed in his handbook. Each indi idual epo has been shown o illus a e a ace o
he o e -all e ec s o zinc lozenges. No single epo ep esen s he uni e se o possible e ec s in ea ing colds by all o he zinc lozenges. Lozenges eleasing Zn2+ ions
p o ide dose- and ime-dependen posi i e esul s, and lozenges eleasing neu al o nega i ely cha ged zinc species do no . The dis inc ion mus be d awn be ween
lozenges p o iding Zn2+ ions and lozenges no p o iding Zn2+ ions. These di e ences a e c ucial o he disco e y and mus no be o e looked o discoun ed. The
ela ionship be ween e icacy, as measu ed in educ ion in du a ion o common colds, is di ec ly ela ed o zinc ion a ailabili y (ZIA), which depends upon he a ailabili y o
Zn2+ ions and he ime ions a e applied o he o al mucosa.
All clinical s udies co ela e well wi h each o he when he s udies a e conside ed om he pe spec i e o zinc ion a ailabili y (ZIA). In he o iginal 1984 s udy, and
sepa a ely in he Al-Nakib and co-wo ke s udy, no pa ien complained o lozenge bi e ness, as lozenges con ained no soluble swee ene s complexing wi h zinc o o m
bi e ness.
Di e ences in ZIA a e a much la ge dis inguishing ea u e be ween success ul ials and unsuccess ul ials han he placebo-unblinding hypo hesis p esen ed by
Gwal ney and Fa . Consequen ly, he e is no e idence o suppo esul s-impai ing placebo-unblinding e ec s in he esul s o he o iginal 1984 s udy, o he one by Al-
Nakib and co-wo ke s.
A e conside able s udy, he p esen au ho sugges s 16 o 23-mg o zinc om zinc ace a e dihyd a e in ad anced design 5 g am comp essed lozenge (ZIA 100 o 185) is
he p ope dosage ange o ea ing common colds. In well pe sons, he highe dosage may seem oo as ingen and oo s ong. Howe e , in pa ien s ill will a common
cold he 23-mg zinc dosage seems much lowe , pe haps because he o al, acial and nasal issues a e so much mo e pe meable. This di e ence in as e pe cep ion
inco ec ly caused o he common cold esea che s as e- es ing he o iginal 1984 zinc glucona e lozenges while hey we e well o allege placebo-unblinding in he o iginal
1984 Eby and co-wo ke double-blind, clinical s udy.
In e ospec , some eade s may p e e a igu e g aphically showing he ac ion o zinc p esen as solu ion Zn2+ ions a physiologic pH o he se e al zinc compounds
s udied. C i ical ac ions o zinc as Zn2+ ions shown below a e om o iginal sou ce da a as p esen ed h oughou his handbook.
Figu e 28. F ac ion o zinc as Zn2+ ions a pH 7.4 as unc ion o i s s abili y cons an .
The alue o K1, he i s s abili y cons an , is g ea ly di e en o each zinc compound. The amoun o Zn2+ ion
a pH 7.4 d ops p ecipi ously o zinc compounds ha ing s abili y cons an s g ea e han log K1 = 1. The
p ecipi ous d op esul s om he s abili y cons an being a pa o di iso o he equa ion used o de e mine he
concen a ion o Zn2+ ions. See Calcula ing A ailabili y o Zn2+ ions in Chap e 1 o de ails. Wi h a hypo he ical
zinc compound ha ing a i s s abili y cons an o log K1 = 2, ea men o common colds would equi e nine
160-mg doses o zinc (mode a ely oxic dosage) daily o p o ide he same amoun o zinc ions as 9 doses daily
o zinc ace a e ha ing 16 mg zinc each. Simila ly, nine 16,000 mg doses o zinc om zinc aspa a e (nea
LD50 dosage) would be needed Fo sake o cla i y, s abili y cons an s below ze o a e no shown, bu hey can
exis . Common cold ea men equi es zinc ions, no o al zinc compound. Fo sa e y, e icacy, and pala abili y
easons, zinc compounds ha ing a i s s abili y cons an o e 100 (log K1 o e 2) a e unusable in common
cold lozenges.
Low mou h-nose BCEC esis ances sugges limi ed immuni y o uppe espi a o y ac in ec ions. Exceedingly
low esis ance appea s associa ed wi h ch onic nasal d ainage and/o alle gies. Ex emely high esis ance
alues appea associa ed wi h s ong esis ance o nasal in ec ions and alle gy. Hypo hesized ela ionships
be ween espi a o y disease suscep ibili y and elec ical esis ance emain unp o en and may wa an u he
in es iga ion. Ve i ica ion may demons a e an a p io i means o de e mine a pa ien 's suscep ibili y o hose
common cold i uses o which an ibody is low o absen , and o whom alle gic desensi iza ion migh no
bene i , bu supplemen al o al o opical zinc (using zinc ace a e lozenges) migh be o bene i .
This handbook's end is no he end o he s o y o using zinc lozenges o common colds, bu a he he s a ing poin o a Uni ed S a es Food and D ug Adminis a ion
New D ug Applica ion (NDA) so comme cializa ion o pa en ed, p ope ly manu ac u ed, ad anced design zinc ace a e lozenges as ea men o common colds can begin.
The NDA is no he end o he s o y ei he -- bu he beginning o he end o long pe iods o illness om common colds.
E en i a high- ech compe ing p oduc such as Gwal ney's pa en ed "in e e on cock ail" (a mix u e o in e e on o s op i al eplica ion, and wo an i-in lamma o y agen s,
ip a opium and nap oxen)(12) a i es on he scene, he likelihood o i being as sa e, as e ec i e, and as inexpensi e as ZIA 100 o 185 zinc ace a e lozenges is
ex emely emo e, and is p obably impossible.
Consequen ly, a pha maceu ical company wishing o ha e a monopoly on a me hod o sho en he du a ion o colds, o cu e common colds, needs o e-examine zinc
lozenges, and pa icula ly ad anced design zinc ace a e lozenges.
The second edi ion o his handbook will include he esul s o comp ehensi e la o -masking and placebo selec ion s udies, new clinical e idence o e icacy, he esul s
o a New D ug Applica ion, and o he ea u es and indings o he ongoing esea ch.
Chap e 9 Re e ences
1. B iggs J, Finch P, Ma ulewicz MC, Weigel H, 1981, Complexes o coppe (II), calcium, and o he me al ions wi h ca bohyd a es: Thin-laye ligand-exchange
ch oma og aphy and de e mina ion o ela i e s abili ies o complexes. Ca bohyd a e Resea ch. 97:181-188.
2. Ka lowski TR, Chalme s TC, F enkel LD, e al. 1975. Asco bic acid o he common cold: A p ophylac ic and he apeu ic ial. Jou nal o he Ame ican Medical
Associa ion. 231:1038-1042.
3. Pauling L. Vi amin C and he Common Cold. Jou nal o he Ame ican Medical Associa ion. 971;216:332.
4. Shul PA, Dick EC, Olande D, e al. 1990. Diminished hino i us (RV) illness se e i y co ela es wi h inc eased leukocy e asco bic acid (AA) Le els. Thi ie h
In e science Con e ence on An imic obial Agen s and Chemo he apy, A lan a, GA, Abs ac 1285.
5. Fa BM, Gwal ney JM. Zinc glucona e o he common cold: An e alua ion o placebo ma ching. Jou nal o Ch onic Diseases. 1987;40:875-879.
6. Eby GA, Da is DR, Halcomb WW. Reduc ion in du a ion o common cold symp oms by zinc glucona e lozenges in a double blind s udy. An imic obial Agen s and
Chemo he apy. 1984; 25:20-24.
7. Al-Nakib W, Higgins PG, Ba ow I. e al. P ophylaxis and ea men o hino i us colds wi h zinc glucona e lozenges. Jou nal o An imic obial Chemo he apy. 1987;20:
893-901.
8. Osol A. As ingen s and an ipe spi an s. In: Osol A. ed. Reming on's Pha maceu ical Sciences, 16 h Edi ion. Eas on:Mack Publishing Co. 1980;720-722.
9. Ma kowi z ME, Rosen JF, Miz uchi M. Ci cadian a ia ions in se um zinc (Zn) concen a ions: co ela ion wi h blood ionized calcium, se um o al calcium and phospha e
in humans. Ame ican Jou nal o Clinical Nu i ion. 1985;41:689-696.
10. Molokhia M, S u niolo G, Shields R, e al. A simple me hod o measu ing zinc abso p ion in man using a sho -li ed iso ope (69mZn). The Ame ican Jou nal o Clinical
Nu i ion. 1980;33:881-886.
11. Pas e nak CA. A no el o m o hos de ense: memb ane p o ec ion by calcium and zinc ions. Bioscience Repo s. 1987;7:81-91.
12. Rade sky P. Cold F on - Wha 's new and wha wo ks. Ame ican Heal h. 1993;12(8):56-62.
Appendix: P inciple A icles
P ophylaxis and ea men o hino i us colds wi h zinc glucona e lozenges (G ea B i ain Medical Resea ch Cen e Common cold Uni - 1987)
Reduc ion in Du a ion o Common colds by Zinc Glucona e Lozenges in a double-Blind S udy (Eby e al. 1984)
How Handbook o Cu ing he Common Cold was Concei ed
Handbook o Cu ing he Common Cold is inally compe e. How was he handbook concei ed? F om whe e did he insigh come? The answe s a e so s ange mos
eade s will only shake hei head in amazemen , and disbelie . Howe e , he pu e u h, no ma e how s ange, is impo an and should be eco ded. Below is he
au ho 's s ange bu ue s o y o disco e y, and i s pain ul o igin.
The au ho , M . Geo ge A. Eby, o Aus in, Texas, was o ced in o biomedical esea ch on Valen ine's day in 1979 when his 3-yea old daugh e , Ka en, was diagnosed wi h
acu e T-cell lymphocy ic leukemia. On Ma ch 5, 1979, she had a bone ma ow leukemic blas coun o ze o. One mon h a e diagnosis, a massi e p oli e a ion o heal hy
e iculocy es (young ed blood cells) added mo e e idence ha he eco e y was occu ing a an as onishingly apid a e. He oncologis , Paul Zel ze , M.D., o he
Uni e si y o Texas Heal h Science Cen e a San An onio, ema ked, "M . Eby, he blood pic u e has se a new s anda d in imp o emen . I wonde why. Pe haps one o
hose eno mous i amin and mine al supplemen s you ha e been gi ing he bene icially in e ac ed wi h ou chemo he apy. You migh look in o ha idea, because i you
s op he ope a i e supplemen , she migh ge wo se. Who knows, and I am only guessing, bu i would keep you busy."
A i s Eby el comple ely unable o cope wi h he awesome ask ahead as he was no educa ed as a physician o scien is . Ra he , Eby had a B.S. in ma hema ics om
he Uni e si y o Texas a Pan Ame ican. A e a s in on he Apollo P ojec a Hous on's NASA, he changed ca ee ields, and g adua ed om Texas A&M Uni e si y in
1970 wi h a mas e s deg ee in ci y planning. He p ac iced ci y planning in se e al Texas ci ies un il 1979. Wi hou any doub , his academic and p o essional backg ound
was comple ely inadequa e o he ask a hand.
Using his modes ma hema ical and planning abili y, he accep ed he challenge o iden i ying he mys e y nu ien . Eby de eloped a plan o so h ough he many possible
in e ac ions. He used a ma ix wi h i amins and mine als on he Y-axis, and each o Ka en's condi ions on he X-axis. On he X-axis we e equen colds, p ima y immune
ane gy, absence o weigh gain, ex emely oul body odo , le ha gy, ano exia, anemia, adia ion he apy, leukemia, emissions, d ug in e ac ions and o he signs and
symp oms o leukemia.
A e se e al mon hs o lib a y esea ch, he ma ix illed in spa sely and andomly excep o he nea ly ull zinc line. Eby consequen ly ocused his a en ion squa ely on
zinc as he nu ien mos likely o ha e had he adju an ac ion on Ka en's chemo he aphy. Child en on immunosupp essi e chemo he apy o en ha e se e e common
colds, so igh ing colds became ano he p io i y. Taking zinc supplemen s seemed no mo e ha m ul, and no less easonable han aking Vi amin C because hese
nu ien s, as well as o he s, a e needed by he p ima y T-cell immune sys em o igh cance , leukemia, and i al in ec ions. Un o una ely, gi ing die a y supplemen s o
i amin C, zinc and o he nu ien s did no seem use ul in igh ing Ka en's colds.
Abou ou mon hs a e Ka en's diagnosis o leukemia, she de eloped a pa icula ly se e e cold. He h oa was swollen and oo pain ul o he o swallow a zinc
glucona e (50 mg zinc) able . Eby asked Ka en o chew he able ins ead. Ka en was oo exhaus ed o chew o long, and she soon wen o sleep wi h mos o he
c ushed able emaining in he mou h. Se e al hou s la e , Ka en came in o he li ing oom playing wi h he oys, saying, "I'm all well, Mom!" Ka en, s ill
immunosupp essed om chemo he apy, was comple ely o e he cold. He cold did no e u n, e en hough no subsequen ea men was gi en. The e ec s o zinc
glucona e lozenges on Ka en's colds we e impossible o Eby o igno e.
Eby's ascina ion wi h zinc and zinc glucona e lozenges inc eased. La e , clinical ials e i ied ha zinc glucona e lozenges sho ened common colds. Howe e , hey
lacked comme cial u ili y because hei as e was insu icien ly pleasan . Fi een yea s a e Ka en's diagnosis o leukemia, Handbook o Cu ing he Common Cold