Ac ion o asco bic acid on clinical cou se o in ec ion ela ed b onchial as hma and on
eac i e oxygen me aboli es by BAL cells [in Ge man]
Sche ling M, Winsel K, Mülle S, Henning R, Meiske W, Slapke J
Z. Klin. Med. 45(1990), 1770–1774
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Z. Klin. Med. 45 (1990), Issue 20 Page 1
F om he Be lin-Buch Resea ch Ins i u e o Pulmona y Diseases and Tube culosis
(O icial Di ec o : D . P. Lu he )
Ac ion o asco bic acid on clinical cou se o in ec ion ela ed b onchial as hma and on
eac i e oxygen me aboli es by BAL cells
By MARGIT SCHERTLING, KLAUS WINSEL, STEFAN MÜLLER, RUDOLF HENNING, WOLFGANG
MEISKE and JÜRGEN SLAPKE
Z. Klin. Med. 45(1990), 1770–1774 Manusc ip ecei ed: 10 Ap il 1989
Manusc ip accep ed: 25 Ap il 1989
Key wo ds
In ec ion- ela ed b onchial as hma, asco bic acid, an ioxidan , peak low, b onchial hype eac i i y, b oncho-
al eola la age, al eola di e en ial cell coun , chemiluminescence, eac i e oxygen me aboli es
Au ho ’s add ess: D . M. Sche ling, Resea ch Ins i u e o Pulmona y Diseases and Tube culosis,
Ka owe S asse 11, Be lin, DDR-1115
Lis o abb e ia ions
AM Al eola mac ophages
BAL B onchoal eola la age
BHR B onchial hype eac i i y
CL Chemiluminescence
DCC Di e en ial cell coun
ROM Reac i e oxygen me aboli es
RAW Ai way esis ance (measu ed by occlusi e p essu e echniques)
Z. Klin. Med. 45 (1990), Issue 20 Page 2
Summa y (Au ho s‘ summa y in english)
Possible an i-as hma ic e ec i eness o asco bic acid was checked, in a double blind s udy, on pa ien s
wi h in ec ion- ela ed b onchial as hma. Basic medica ion o 29 ou -pa ien s was accompanied by
h ee o al doses o 5 g/day o asco bic acid, as compa ed o placebo, h ough 35 days. Tes ing pe iods
we e andomised by c oss-o e design wi h se en-day washou pe iods. The ollowing pa ame e s
we e in es iga ed and we e e alua ed:
- Daily as hma symp om sco e;
- Fou measu emen s pe day o expi a o y peak low, h oughou he en i e s udy;
- Th ee checks h oughou s udy o b onchial hype eac i i y, using his amine p o oca ion;
- B oncho-al eola la age a he end o es ing pe iods, wi h de e mina ion o al eola di e en ial
cell coun and measu emen o me abolic ac i i y o b oncho-al eola cells, using
chemiluminescence;
- Global assessmen o e ec i eness and ole ance by doc o and pa ien .
Asco bic acid exhibi ed me ely poo b oncholy ic ac ion. Symp om sco es we e sligh ly imp o ed in
he cou se o ea men , and peak low alues we e sligh ly inc eased, as well. Hence, clinically
ele an an i-as hma ic and, mo e speci ically, b oncholy ic e ec s we e no obse ed. Howe e ,
b onchial hype eac i i y was educed by up ake o asco bic acid in 52 pe cen o all as hma pa ien s
in ol ed. Al eola di e en ial cell coun in pa ien s wi h in ec ion- ela ed b onchial as hma was
cha ac e ised by al eola lymphocy osis. Chemiluminescence measu emen s we e applied o al eola
mac ophages and e ealed educed chemiluminescence esponse unde he impac o asco bic acid.
These indings a e likely o suppo he assump ion ha asco bic acid, an an i-oxidan , educed he
buildup o eac i e oxygen me aboli es in pa ien s wi h in ec ion- ela ed as hma and hus coun e ac ed
he in lamma o y pa hogene ic mechanism and, consequen ly, migh be conduci e o mode a e
lowe ing o b onchial hype eac i i y. The use o asco bic acid o p ophylac ic medica ion on pa ien s
wi h b onchial hype eac i i y o mild o ms o as hma appea s o be a possible op ion, as a esul o
his s udy. Due conside a ion should be gi en o con aindica ions o adminis a ion o an i-oxidan s,
such as pu ulen in ec ions.
Summa y (T ansla ion om Ge man; English ansla ion by o iginal au ho s abo e)
The po en ial an i-as hma ic e ec i eness o asco bic acid was s udied in pa ien s wi h
in ec ion- ela ed b onchial as hma. In addi ion o he basic medica ion, 29 ou pa ien s we e
addi ionally ea ed o a pe iod o 35 days wi h 5 g/day o asco bic acid in compa ison o o al placebo
in 3 daily doses. The alloca ion o he es ing pe iods was andomized by c oss-o e design wi h 7-day
washou pe iods. The ollowing pa ame e s we e in es iga ed and e alua ed: daily as hma symp om
sco e, measu emen o he expi a o y peak low 4 imes pe day du ing he en i e cou se o he s udy,
es ing o b onchial eac i i y using his amine p o oca ion a 3 ime poin s du ing he cou se o he
s udy, b oncho-al eola la age a he end o he s udy pe iods wi h de e mina ion o he al eola
di e en ial cell coun and measu emen o me abolic ac i i y o he b onchoal eola cells using
chemiluminescence, and global assessmen o he e icacy and ole abili y by doc o and pa ien .
Asco bic acid exhibi ed a weak b oncholy ic e ec . Du ing ea men , symp om sco es we e
sligh ly imp o ed and he e was also a sligh inc ease in peak low alues. Hence, a clinically ele an
an i-as hma ic and in pa icula , b oncholy ic e ec was no obse ed. Howe e , b onchial
hype eac i i y was educed by aking asco bic acid in 52 pe cen o he as hma pa ien s. The al eola
di e en ial cell coun was cha ac e ized by al eola lymphocy osis in pa ien s wi h in ec ion- ela ed
b onchial as hma. Chemiluminescence measu emen s o al eola mac ophages e ealed a educed
chemiluminescence esponse unde he impac o asco bic acid. These indings sugges ha asco bic
acid, as an an ioxidan , educes he o ma ion o eac i e oxygen me aboli es in pa ien s wi h
in ec ion- ela ed as hma and hus coun e ac s he in lamma o y pa homechanism and consequen ly
migh be able o b ing abou mode a e lowe ing o b onchial hype eac i i y. The use o asco bic acid
as p ophylac ic medica ion o pa ien s wi h b onchial hype eac i i y o mild o ms o as hma appea s
o be a possibili y as a esul o his s udy. Due conside a ion should be gi en o possible
con aindica ions o adminis a ion o an ioxidan s, e.g., he p esence o pu ulen in ec ions.
Z. Klin. Med. 45 (1990), Issue 20 Page 3
In oduc ion
In he pas 40 yea s, a numbe o wo ks ha e been published ha deal wi h he e ec o
asco bic acid (4, 29) on he clinical cou se o b onchial as hma o on he his amine, an igen o
me acholine induced b onchospasm, al hough some o he esul s ha we e achie ed we e
con adic o y. While in some s udies, a p o ec i e e ec (1, 12, 15, 19, 28, 35) o asco bic
acid on he pha macodynamic o alle gen induced b onchospasm o clinical cou se o
b onchial as hma was es ablished, in o he cases, no e ec o asco bic acid (16, 17) could be
ound. The possible posi i e e ec o asco bic acid on b onchial as hma could be due o i s
an ioxida i e p ope ies (2, 3, 5, 9). Lipid pe oxide and eac i e oxygen me aboli es (ROM)
(O2–, H2O2, OCl–, OH–) which can be o med in excess in he lungs unde pa hological
condi ions s imula e, e.g., a achidonic acid me abolism and lead o he o ma ion o cyclo-
oxygenase and lipoxygenase p oduc s which ha e a b onchocons ic i e e ec , such as
p os aglandins and leuko ienes (8, 12).
In gene al, in i o, a ious an ioxidan s (including asco bic acid) and an ioxidan
enzymes, so-called adical sca enge s p o ec he lungs om damage due o eac i e oxygen
me aboli es and lipid pe oxide (10). In he p esence o inc eased ac i i y o he pulmona y
in lamma o y cells (e.g., al eola mac ophages, g anulocy es) wi h b onchial as hma, he
equilib ium be ween oxida i e and an ioxida i e capaci y in he lungs may be displaced in
a o o he oxida i e p ocess, such ha addi ional adminis a ion o asco bic acid a a high
dose (5 g/day) and o e a longe pe iod o ime may be expec ed o p o ide a he apeu ic
e ec . In he p esen wo k, he hypo hesis o an an i-as hma ic e ec o asco bic acid is o be
es ed (6, 7).
Z. Klin. Med. 45 (1990), Issue 20 Page 4
Ma e ials and me hods
A o al o 29 pa ien s wi h in ec ion- ela ed b onchial as hma (18 men and 11 women om 18 o 60
yea s o age) we e ec ui ed o he double blind c osso e s udy unde ambula o y condi ions.
Inhaled and sys emic co icos e oids, enal disease and acu e and se ious pu ulen in ec ions we e
conside ed o be exclusion c i e ia. The s udy was conduc ed o e a pe iod o 35 days. I was
di ided in o a 2-week placebo pe iod, 1-week wash-ou es and 2-week asco bic acid pe iod. The
sequence o he es pe iods was chosen a andom (Fig. 1).
Fo he p esen s udy, in addi ion o he basic medica ion, a daily dose o 5 g asco bic acid
(Asco i con aining 500 mg) was de ined in compa ison o o al placebo in 3 indi idual doses.
Coa ed able s om VEB Jenapha m, Clinical Resea ch Di ision, lo numbe s 150485 and 050886
we e used. The pa ien s ecei ed packages u nished wi h lo numbe s ha we e coded acco ding o
he double blind s udy condi ions. The code was no b oken du ing he s udy.
Du ing a p e-pe iod o 2 weeks, he s a ing alues o pulmona y unc ion pa ame e s we e
o be de e mined unde he an i-as hma ic ea men up o ha ime. A he same ime du ing his
pe iod, he pa ien s we e o lea n how o comple e he dia y and de e mine he maximum expi a o y
peak low wi h he peak low me e .
Du ing he 35-day double blind ea men pe iod, he pa ien s we e seen 4 imes: on he 8 h,
14 h, 29 h and 35 h day a e he s a o ea men . In he middle o he e um [HH: e um = ac i e
in e en ion] and placebo pe iods, measu emen s o b onchial hype eac i i y we e pe o med again
and a he end o he es pe iod, a b oncho-al eola la age wi h cy ological examina ion and
chemiluminescence measu emen we e pe o med.
In p inciple, he e icacy o an an i-as hma ic agen canno be de e mined by a single a ge
pa ame e . E en as hma symp oms a e exp essed in dis inc ly di e en ways. To eco d he
symp oms, he complain s we e lis ed sepa a ely in a dia y (Table 1).
Each pa ien was gi en a peak low moni o (Vi alog aph) a he s a o he s udy o
measu e he maximum expi a o y eloci y du ing he cou se o he s udy. The measu emen was
pe o med 4 imes a day (6 a.m., 9 a.m., 12 noon, and 6 p.m.) by he pa ien s while si ing. The
highes alue (l/min) ou o each o h ee measu emen s was no ed in he dia y.
The measu emen o nonspeci ic BHR was pe o med on he B onchosc een Measu ing
S a ion (Jaege , Wue zbu g/Wes Ge many) unde he use o his amine dihyd ochlo ide a a
concen a ion o 1 mg/ml as he pha macodynamic p o oca ion subs ance [20]. The ad an age o
his me hod is ha in con as o con en ional measu ing p ocedu es, be e quan i ica ion o he
b onchial eac ion can be achie ed wi h a dis inc educ ion in ime needed o he examina ion. The
his amine ae osol adminis a ion was pe o med b ea h o b ea h du ing he inspi a o y phase
du ing spon aneous espi a ion (nebulize ou pu pe b ea h: 5 µmol). The b onchial eac ion was
simul aneously de e mined on he same ins umen wi h he ai way esis ance me hod (RAW). As
a ge c i e ia o he BHR, a 50% inc ease in espi a o y ac esis ance (RAW) in compa ison o he
s a ing alue wi h simul aneous exceedance o he RAW alue o 0.3 kPa/(l ∙ s) pos p o oca ion was
de ined. The ollowing pulmona y unc ion pa ame e s p io o inhala i e p o oca ion we e alid as
exclusion c i e ion o he examina ion: RAW > 0.5 kPa/(l ∙ s) o FEV1 < 80 % o he a ge alue.
Th ough p e- es ing, BHR o a cumula i e his amine dose o ≤8 µmol was demons a ed o all 29
pa ien s. To enable a semiquan i a i e e alua ion in he hype eac i i y zone, du ing he es pe iods,
he h eshold dose o he BHR o 1 µmol his amine was de e mined ha co esponds o 40
espi a ions. The BHR (PD50RAW) was de ined as posi i e a a cumula i e p o oca ion dose o ≤1
µmol his amine, and nega i e a >1 µmol his amine.
Z. Klin. Med. 45 (1990), Issue 20 Page 5
B oncho-al eola la age (BAL): The al eola mac ophages (AM) we e ob ained unde
ou pa ien condi ions by b oncho-al eola la age. The BAL was pe o med in he medial lobe wi h
a ibe op ic b onchoscope unde local anes hesia wi h s e ile physiological NaCl solu ion in
indi idual po ions (20 ml 57 imes) (18, 20, 21, 31). The inse luid was pooled in a siliconized
E lenmeye lask cooled in ice wa e , hen il e ed h ough a wi e sie e (250 µm) and cen i uged a
4°C (500 g, 10 min). The cell sedimen was ea ed o 10 min. a 4°C wi h 10 ml s e ile e y h ocy e
lysis bu e (pH = 7.4) and hen washed wice wi h phospha e bu e ed physiologic saline solu ion
(PBS) and se o a cell densi y o 106 AM/ml PBS.
Cy ologic in es iga ions: The o al cell coun and he p opo ion o AM in he cell
suspension we e de e mined in he cell chambe acco ding o Neubaue using mo phological c i e ia
and by an es e ase es wi h α-naph hyl ace a e. The cell di e en ia ion was pe o med a e s aining
he cell suspension wi h a mix u e o equal pa s o 1 % aqueous Nile blue chlo ide and hionine
a a ic acid solu ion acco ding o Fey e (1 g hionine + 0.5 g a a ic acid/100 ml dis illed H2O) a
a 1:1 a io.
Chemiluminescence (CL) measu emen
Measu ing echnique: The measu emen was pe o med wi h he liquid scin illa ion coun e
Isocap300 (Sea le Nuclea Chicago Di ision, Holland) in ou -o -coincidence mode and ecycling
ope a ing mode. The measu ing ime pe sample was 0.2 min a an in e al o app oxima ely 6 min.
Polyp opylene es ubes (so-called mini ials) we e used (measu emen empe a u e 24°C). The
wo k oom was comple ely da kened and equipped wi h da k oom illumina ion (33).
Reagen s: As a medium o he CL measu emen was e onal bu e ed physiological NaCl
solu ion wi h an adju an o albumin, glucose, Ca2+ and Mg2+ acco ding o in o ma ion p o ided by
Wul e al. (34). The yeas cell walls o he s imula ion o he AM we e isola ed om bake ’s yeas
(23). The opsoniza ion o he yeas cell walls was pe o med wi h human se um (concen a ion o
he yeas cell wall dispe sion 5 mg/1 ml PBS). Luminol (CL in ensi ie ) was b ough in o solu ion a
a concen a ion o 6 mg/3 ml PBS wi h he addi ion o 24 µl die hylamine by ul asound ea men .
Lucigenin (Cl in ensi ie ) was dissol ed in PBS (10.2 mg/2 ml).
Measu ing echnique: 2 ml e onal bu e , 20 µl Luminal o Lucigenin solu ion and 100 µl
o AM suspension (1 ∙ 105 AM) we e mixed in a measu ing ube and p e-incuba ed o
app oxima ely 15 minu es wi h liquid scin illa ion coun e . A e wa ds, he yeas cell wall
suspension (500 µg) was added and he CL measu emen pe o med.
The Luminol and Lucigenin in ensi ied CL was measu ed in pa allel o his1). Fo
quan i a i e analysis o he measu emen esul s, he peak heigh s (IPM) and a eas unde he CL
cu es (IP) we e de e mined wi hin 200 min a e s imula ion wi h he yeas cell wall suspension.
Fo cha ac e iza ion o he pha macokine ics o asco bic acid o he he apy egimen used,
he daily p o ile o he se um le el o asco bic acid was de e mined enzyma ically wi h he L-
asco bic acid colo es (Boeh inge , Mannheim, Wes Ge many). Global e alua ion o e icacy and
ole abili y we e eco ded by pa ien and physician.
The a i hme ic mean (x) and he s anda d de ia ion (s) we e de e mined o he s a is ical
analysis o he measu ed a iables.
The s a is ical compa ison o he g oups was pe o med wi h he pai ed - es and he
Wilcoxon es .
1) The Lucigenin in ensi ied chemiluminescence shows he o ma ion o supe oxide anion (O2–),
while he Luminol dependen chemiluminescence is speci ic o hypohalogeni e.
Z. Klin. Med. 45 (1990), Issue 20 Page 6
Fig. 1: Schedule o he con olled double blind ial wi h asco bic acid/placebo in pa ien s wi h
in ec ion- ela ed b onchial as hma. BHR – b onchial hype eac i i y, BAL – b oncho-al eola
la age
Tes pe iods
P e-
pe iod
Placebo-Ve um Washou
pe iod
Ve um-Placebo
Days 8 14 21 29 35
Peak low dia y 4 imes a day [o e all s udy]
Physician consul a ion * * * * *
BHR * * *
BAL * *
Asco bic acid se um
le el measu emen
* * * *
No e [HH]:
Ve um: ac i e ea men , he e i amin C
Table 1: Symp om sco es
Analysis o as hma ic symp oms:
0 = no symp oms
1 = mild o b ie symp oms ha do no equi e addi ional use o medica ion
2 = mo e se e e symp oms ha a e elie ed wi hin 15 minu es by addi ional medica ion
3 = mo e se e e symp oms ha do no espond adequa ely o o in a delayed manne o addi ional
medica ion o equi e epea ed use
Symp oms can include: in e mi en dyspnea, wheezing, sensa ion o igh ness in he mo ning o d y
i i a ing cough
Z. Klin. Med. 45 (1990), Issue 20 Page 7
Resul s
The o e all mean peak low alue o all as hma ics was 410 l/min in he placebo
phase and 419 l/min in he e um phase. This sligh inc ease o an a e age o 9 l/min in
he asco bic acid g oup was s a is ically no signi ican and may also no be clinically
ele an . A simila imp ession esul ed om he analysis o he symp om sco es. The mean
in he placebo phase was 0.72 poin s and unde asco bic acid i was 0.65 poin s.
Consequen ly, a sligh dec ease in symp oms could be obse ed in he ea men pe iod
wi h asco bic acid.
The in es iga ions on b onchial hype eac i i y we e pe o med a each o
3 ime poin s, in he p e-pe iod, a e 8 days and on he 29 h day. The cou se o b onchial
hype eac i i y in 23 subjec s du ing he in es iga ion pe iod is p esen ed in Table 2.
In 11 as hma ics, no change occu ed du ing bo h pe iods. In 12 subjec s, b onchial
hype eac i i y was de ec able du ing he placebo phase, while in he asco bic acid phase,
a nega i e eac ion was obse ed. The opposi e case did no occu . This asymme y is
signi ican (p ≤ 0.0003; es on he basis o he binomial dis ibu ion). As a esul o his,
in 52% o pa ien s wi h b onchial as hma, b onchial hype eac i i y could be e ec i ely
lowe ed.
The analysis o he b onchial la age showed ha 8 ou o 24 pa ien s exhibi ed
an al eola di e en ial cell coun ha was commensu a e wi h s anda ds du ing bo h es
pe iods. In 5 pa ien s, no maliza ion o he al eola cell coun esul ed unde asco bic acid
ea men , and in 6 o he pa ien s, he al eola lymphocy es p ima ily p esen subsided.
In 3 cases, al eola eosinophilia pe sis ed. O no e, he e was conside able lymphocy osis
(>28%) in 3 pa ien s du ing bo h pe iods (Table 3).
The esul s o he CL measu emen s on AM om he BAL luid show ha unde
asco bic acid, a educ ion in he chemiluminescence esponse esul s wi h he Lucigenin
as well as he Luminol in ensi ica ion (Table 4).
The di e ence be ween he wo g oups (placebo pe iod, asco bic acid pe iod)
is s a is ically signi ican o he peak heigh s (p ~ 0.03).
The changes in he al eola mac ophage ac i i y measu ed on he basis o
he o ma ion o ROM do no co ela e o only weakly co ela e wi h he changes
in peak low alues and symp om sco es ( | | < 0.04 in all cases).
In he analysis o he esul s, mo e p ecise cha ac e iza ion o hose pa ien s
o whom de ini e he apeu ic o hype eac i i y lowe ing e ec s could be p o en was
a emp ed (Fig. 2). Howe e , he sea ch o esponde - ypical commonali ies was
unsuccess ul.
The se um le el on he 8 h day was 13.8–26.8 mg and 10.1–28.4 mg asco bic
acid/l on he 14 h day, co esponding o he adminis a ion hy hm. As was expec ed,
hey we e conside ably abo e he no mal ange o men (Fig. 3).
The e alua ion o he ole abili y o he es p epa a ion by he physician and
he pa ien did no e eal any ele an di e ences be ween he es pe iods.
Only 1 pa ien complained o nausea du ing he asco bic acid pe iod; ano he
indica ed inc eased sensa ion o hi s o e he en i e es pe iod. 3 pa ien s no ed
empe a u e inc eases up o 38.2°C once in he e ening on he day o he b oncho-al eola
la age.
Z. Klin. Med. 45 (1990), Issue 20 Page 8
Table 2: Cou se o b onchial hype eac i i y (BHR) wi h o al asco bic acid (5 g/day o 35 days) in
compa ison o placebo (n = 23)
Posi i e c i e ia: PD50RAW ≤ 1 µmol his amine
BHP in he i amin C pe iod
Posi i e Nega i e To als
BHR in he
placebo pe iod
Posi i e 9 12 21
Nega i e 0 2 2
To als 9 14 23
Table 3: Cell dis ibu ion in he b oncho-al eola luid in pa ien s wi h in ec ion- ela ed b onchial as hma:
0 = con o ms o s anda ds, ↑ = ele a ed, ↑↑ = s ongly ele a ed
(es ima ion o esul s based on no mal alues acco ding o Hunninghake and C ys al [31])
Placebo pe iod Asco bic acid pe iod
n Lymphocy es Eosinophils Lymphocy es Eosinophils
8 0 0 0 0
2 0 (5%) ↑ 0 0
3 (15%) ↑ 0 0 0
3 (15%) ↑ (5%) ↑ 0 (5%) ↑
3 (34%) ↑ (3%) ↑ (53%) ↑↑ 0
1 (16%) ↑ (8%) ↑ (14%) ↑ (25%) ↑
1 0 (8%) ↑ (18%) ↑ 0
1 (17%) ↑ 0 0 (5%) ↑
1 0 0 (53%) ↑↑ 0
1 (16%) ↑ 0 (26%) ↑ (8%) ↑
24 (To al)
Table 4: Compa ison o he pa ame e o he chemiluminescence (CL) cu es o he al eola mac ophages o
pa ien s wi h in ec ion- ela ed b onchial as hma (n = 24)
A ea unde he CL cu e Peak heigh
IP 10-8 * IPM 10-6 **
x ± s x ± s
Placebo pe iod
Lucigenin 1.78 ± 1.51 2.11 ± 1.93
Luminol 2.17 ± 2.94 2.23 ± 2.77
Asco bic acid pe iod
Lucigenin 1.29 ± 0.74 1.41 ± 0.87
Luminol 1.81 ± 1.72 1.91 ± 2.07
S a is ics a:c p ~ 0.08 a:c p ~ 0.03
Wilcoxon es b:d p ~ 0.09 b:d p ~ 0.03
* IP = impulses
** IPM = impulses pe minu e
Z. Klin. Med. 45 (1990), Issue 20 Page 9
