Off-label postoperative pharmacotherapy in a newborn with truncus arteriosus and challenges to pharmaceutical care: a case report

Off-label postoperative pharmacotherapy in a newborn with truncus arteriosus and challenges to pharmaceutical care: a case report Nikolay Nachev1, Yoana Nikolaeva2, Rumen Marinov3, Kostadin Angelov4, Emil Hristov1, Valentina Petkova5, Irfan Irfan6, Iva Parvova7 1 Laboratory of Social Pharmacy, Faculty of Chemistry and Pharmacy, Sofia University “Saint Kliment Ohridski”, 1 James Bourchier blvd., Sofia 1164, Bulgaria 2 National Council on Prices and Reimbursement of Medicinal Products, 15 Akademic Ivan Evstatiev Geshov blvd., Sofia 1431, Bulgaria 3 Clinic of Pediatric Cardiology, National Cardiology Hospital, 65 Konyovitsa str., Sofia 1309, Bulgaria 4 Department of Surgery, Medical University of Sofia, Alexandrovska University Hospital, 1, St. G. Sofiyski str., Sofia 1431, Bulgaria 5 Department of Organization and Economics of Pharmacy, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., Sofia 1000, Bulgaria 6 Clinic of Cardiology, University Hospital „Aleksandrovska“, 1 George Sofiiski blvd., Sofia 1431, Bulgaria 7 Department of Rheumatology, Medical University of Sofia, 1 Dimitar Mollov str., Sofia 1704, Bulgaria Corresponding author: Valentina Petkova ([email protected]) Received 19 September 2025♦ Accepted 1 October 2025♦ Published 30 October 2025 Citation: Nachev N, Nikolaeva Y, Marinov R, Angelov K, Hristov E, Petkova V, Irfan I, Parvova I (2025) Off-label postoperative pharmacotherapy in a newborn with truncus arteriosus and challenges to pharmaceutical care: a case report. Pharmacia 72: 1–7. https://doi.org/10.3897/pharmacia.72.e172589 Abstract Common arterial trunk (truncus arteriosus) is a critical congenital cardiac defect characterized by incomplete division of the common vascular trunk and the presence of a single vessel “riding” an interventricular defect, from which the systemic, pulmonary, and coronary circulations originate. This results in mixed blood entering the common circulation. Severe heart failure occurs from the day of birth. Treatment is definitively surgical, followed by pharmacological management, with patients undergoing periodic follow-ups for the rest of their lives. The main challenge is therapy for heart failure with ACE inhibitors, diuretics, anti-aggregants, anticoagulants, prophylaxis of infections caused by respiratory syncytial virus, and others. Optimizing pharmacotherapy is a considerable challenge because almost all medicinal products used have not been tested in a pediatric population, especially in the neonatal period. We present a clinical case of a patient born with truncus arteriosus type I after surgical treatment, addressing the challenges of off-label prescribing and dispensing of medicinal products, as well as the provision of pharmaceutical services and care. Keywords case report, congenital cardiac defect, heart failure, medicinal products, off-label treatment, pharmaceutical care, pharmaceutical services, truncus arteriosus Copyright Nachev N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pharmacia 72: 1–7 DOI 10.3897/pharmacia.72.e172589 Research Article Nachev N et al.: Off-label treatment of truncus arteriosis for pediatric pateints2 Introduction Truncus arteriosus (TA) is a critical congenital heart defect (CCHD) in which the two main blood vessels exiting the heart—the aorta and the pulmonary artery— are not separated during fetal development. There is only one large vessel, the arterial trunk (also known as the common trunk), which exits the heart through a ventricular septal defect and gives rise to the systemic, pulmonary, and coronary circulations (Fig. 1) (Cleveland Clinic 2025). The presence of a common trunk may be associated with several cardiac, aortic, and pulmonary anomalies (Park 2021). These anomalies include right-sided, interrupted, or hypoplastic aortic arches, abnormal coronary artery origins, pulmonary artery stenosis, and a common arterial trunk. As a result, blood flow is mixed. Since the pulmonary arteries originate directly from the trunk, pulmonary vascular resistance (PVR) determines pulmonary blood flow, which is usually increased. This leads to severe heart failure (HF) immediately after birth (Stoller et al. 2012). Without surgical intervention, death in childhood is the norm. Treatment is definitively surgical, followed by pharmacological therapy. Patients must undergo regular medical examinations for the rest of their lives. Rapid and accurate diagnosis immediately after birth is vital in order to restore hemodynamics, prevent multiple organ damage, and increase the likelihood of a favorable outcome (Merck Manual 2020). Epidemiological data indicate that TA is a very rare disease. TA accounts for approximately 4% of all CCHD and < 1% of all congenital heart defects (CHD). There are very few patients with the disease, as many do not survive to adulthood due to delayed diagnosis and poor disease control. Epidemiological data for Bulgaria are uncertain. The incidence of TA in European Union member states is approximately 75 cases per 1 million live births. The etiology of TA can vary: family history of CHD, chromosomal abnormalities, DiGeorge syndrome, use of various medications during pregnancy (lithium salts, phenytoin, warfarin), prenatal viral infections (e.g., rubella), poorly controlled gestational diabetes, obesity, alcohol consumption, and smoking during pregnancy. However, most often no clear cause can be identified. Congenital heart malformations account for 15–25% of all heart malformations, with a frequency of 1/1000 newborns (Garcia et al. 2017). They are divided into three groups: CHD with an arterial duct dependent on systemic blood flow, CHD with a pulmonary duct dependent on systemic blood flow, and CHD without an arterial duct dependent on systemic blood flow. The classification of TA (Table 1) includes four main pathomorphological types depending on the way pulmonary blood flow is routed, i.e., the location of the pulmonary arteries. In TA type I, pulmonary circulation is the most preserved of the four, while in TA type IV, pulmonary circulation is the least preserved. Life expectancy is highest in type I compared to the other three types of TA. Nowadays, all CHDs can and should be treated surgically, and it is recommended that surgery be performed as soon as possible after birth to prevent organ damage and optimize hemodynamics (Heymann and Rudolph 1975). Therefore, early diagnosis is crucial for the best outcome. According to pediatric, pediatric cardiology, and pharmacotherapy guidelines (Kraukauer et al. 2025; NCPR 2020), the diagnosis of TA goes through several stages: 1. determining the presence of a heart murmur; 2. echocardiography and Doppler, which visualize a single blood vessel and mixed blood flow; 3. pulse oximetry screening, which measures oxygen saturation. If oxygen saturation is 95% or higher, the test is considered negative. Screening should be performed between 24 and 48 hours after birth. A positive test result is considered an indication for echocardiography; 4. hyperoxic test, which measures Figure 1. Truncus arteriosus (Cleveland Clinic 2025). Pharmacia 72: 1–7 3 the partial pressure of oxygen (pO₂) and presents results that may indicate one of two possibilities: if pO₂ is greater than 100 mmHg, pulmonary pathology is likely, and if pO₂ is less than 70 mmHg, congenital heart malformation should be considered; 5. electrocardiography (ECG); and 6. chest X-ray. The clinical picture is dominated by symptoms of heart failure. There is marked cyanosis and severe dyspnea. Other symptoms such as fatigue, slow heart rate, dysrhythmia, possible development of pulmonary hypertension, and feeding difficulties leading to slow weight gain and delayed physical development may be present but are not mandatory or specific (Zaidi et al. 2020). We present a clinical case of a young child, currently aged 4 years, with type I TA, born with a weight of 3380 g and a height of 50 cm. The pregnancy proceeded normally. There is no family history of genetic or hereditary diseases. The birth was performed by surgical intervention (cesarean section). The mother was diagnosed with a urinary tract infection with Candida albicans in the first trimester and with an Escherichia coli infection in the second trimester. A complete gynecological examination was performed every month during the pregnancy. No fetal CCHD was detected during the morphological examination of the fetus. Immediately after birth, the newborn presented with good cardiopulmonary adaptation until the 12th hour, when tachydyspnea was established, with a drop in oxygen saturation to 88%. The newborn was transferred to the intensive neonatal unit, consulted by a pediatric cardiologist, underwent a series of instrumental examinations, including echocardiography, and was diagnosed with heart failure due to CHD—common arterial trunk type I, right aortic arch, systemic pulmonary hypertension, dilatation and hypertrophy of the right ventricle, with preserved systolic function of the left ventricle. The patient was transferred to a cardiology clinic. At 8 days of age, the diagnosis was fully confirmed, drug treatment for heart failure was started, and a decision was made to perform surgical reconstruction of the CHD at 1 month of age in order to optimally increase the newborn’s body weight. Intensive treatment of heart failure was started with diuretics, ACE inhibitors, parenteral nutrition, and infusion therapy with electrolyte solutions (Krastev 2010, 2022). At 28 days of age, under conditions of extracorporeal circulation and general anesthesia, reconstructive surgery was performed. The aim of the operation was to enable the common vascular trunk to function as an aorta and to sever the pulmonary artery and connect it to the right ventricle via a conduit. The trunk of the pulmonary artery was severed from the common trunk, and the ventricular defect was closed with horse pericardium. The conduit was reshaped and adapted to the patient’s age and size, forming two anastomoses—a distal anastomosis of the conduit adjacent to the tube valve and a proximal anastomosis above the ventriculotomy. The postoperative period was smooth, and the patient was in satisfactory postoperative condition, with minor stenosis along the axis of the right pulmonary artery and mild manifestations of heart failure, which remain to be monitored. The treatment prescribed before and after the surgical intervention is described in Table 2. In addition to the prescribed therapy, prophylaxis with palivizumab against human respiratory syncytial virus is administered. Prophylaxis against infectious endocarditis is also administered in cases of risk of bacteremia. Planned immunizations are temporarily postponed. Table 1. Classification of truncus arteriosus. Type I The aorta and the pulmonary artery, which is short and divided into left and right branches, exit the common arterial trunk. The presence of type I is around 60% of all patients with TA. Type II The two branches of the pulmonary artery exit from the posterior wall of the common trunk. Type III One of the branches of the pulmonary artery exits from the left side of the common trunk, whereas the other branch is from the right side. Type IV The pulmonary arteries are missing or are located and exit from the aorta descendens, and the pulmonary bloodstream is carried out predominantly from the bronchial arteries. Table 2. Pharmacological treatment before and after the surgical intervention. Pharmacological treatment before the surgical intervention Medicinal product Dose On-label/Off-label Posology according to SPC* Furosemide (BDA 2025b) 3 × 2 mg i.v On-label Heart failure Captopril (BDA 2025a) 3 × 1 mg p.o** Off-label (Efficacy and safety in the pediatric population have not been fully established.) Heart failure Solutio Kalii Cloridi 5% 3 × 2 ml p.o On-label Hypokalemia Pharmacological treatment after the surgical intervention Furosemide 3 × 2 mg i.v On-label Heart failure Captopril 3 × 1 mg p.o Off-label (Efficacy and safety in the pediatric population have not been fully established.) Heart failure Solutio Kalii Cloridi 5% 3 × 2 ml p.o.On-label Hypokalemia Spironolactone (BDA 2025d) 3 × 6.25 mg p.o. +/- (There is a lack of relevant information from clinical trials in children.) Heart failure Acetylsalicylic Acid (BDA 2025c) 1 × 15 mg p.o. Off-label (Not applicable to children under 16 years of age) Thrombosis prophylaxis *SPC—short product characteristics according to the marketing authorization. **Usually, the dose for children is determined in mg/kg of body weight. In this case, we indicate the total dose per intake according to the history of illness (medical dossier). Nachev N et al.: Off-label treatment of truncus arteriosis for pediatric pateints4 Two months after radical repair, bifurcation stenosis was found in the distal anastomosis of the conduit, underdevelopment of the right pulmonary artery with significant proximal stenosis, high-grade valve insufficiency of the conduit, right ventricular dilatation, postoperative heart failure, hepatomegaly, and poor weight gain. For diagnostic clarification, contrast aorto-arteriography was performed. Stenting of the right pulmonary artery was chosen as the method of correction, despite the particular remodeling during the operation of the distal anastomoses. After the procedure, the patient’s hemodynamics were stable. Anticoagulant therapy was started in the clinic: heparin, acetylsalicylic acid, and clopidogrel (EMA 2025a, 2025b). A significant reduction in the manifestations of heart failure was observed. Stenosis in the right pulmonary artery was overcome, and a significant reduction in dilatation and hypertrophy of the right ventricle was achieved. The treatment is described in Table 3. After the operation, the patient gained weight and height in a normal manner, corresponding to his calendar age. Body proportions also developed within the physiological norm, and there were no signs of deviations in his physical development. At 6 months of age, the patient’s planned immunizations were restored. Diuretics were discontinued 10 months after completion of the first prescription. Once the patient reached a weight of 10 kg, the dose of clopidogrel was increased to 2 mg daily. The dose of acetylsalicylic acid was calculated as 5 mg per 1 kg of body weight. Right heart catheterization and balloon catheter stent dilation were performed at 1 year and 5 months of age under ventilated conditions. There was mild stenosis in the left branch of the pulmonary artery, for which intervention was planned in the future. Treatment with clopidogrel, acetylsalicylic acid, and captopril off-label continued. Discussion As can be seen from the detailed description of the patient’s medical history, the patient was prescribed medicinal products outside their therapeutic indications. According to their marketing authorizations, the prescription falls within the definition of “off-label,” and the efficacy and safety of these medicinal products in the pediatric population is not fully established, or there is a lack of data from pre-registration clinical trials in the pediatric population. Off-label use refers to any intentional use of an authorized product not covered by the terms of its marketing authorization and therefore not in accordance with the SmPC. This may include the use for a different indication, use of a different dosage, dosing frequency or duration of use, use of a different method of administration, or use by a different patient group (e.g., children instead of adults). There are serious challenges from scientific, regulatory, ethical, and legal perspectives. Bulgarian health and pharmaceutical legislation does not provide a clear definition of “off-label” treatment. According to Article 7(1) of the Law on Medicinal Products in Human Medicine (LMPHU 2007): “Treatment, prophylaxis, and diagnosis are permitted only with medicinal products that have been authorized in accordance with the law or Regulation (EC) No. 726/2004 of the European Parliament and of the Council,” i.e., treatment with medicinal products without marketing authorization is not permitted, and by implication, treatment outside the scope of the marketing authorization is also not permitted (LMPHU 2007). Special cases are also specified in the LMPHU. Treatment of a specific patient with a medicinal product without marketing authorization, according to the law, is permitted upon special request by a hospital under conditions and procedures specified by an ordinance of the Minister of Health, with the head of the hospital being responsible for the administration of the treatment. Treatment with a medicinal product for compassionate use was approved in accordance with Article 83 of Regulation (EC) No. 726/2004 (EC 2004). Our patient does not fall under these hypotheses because he was treated with medicinal products that had valid marketing authorizations but were approved for a different age group. In 2020, at the height of the COVID epidemic, a change was made to Bulgarian legislation allowing, as an exception, in the absence of an alternative treatment for a specific patient and solely in the interest of their health, a medicinal product authorized for use in the country to be used outside the terms of its marketing authorization, provided that there was scientific evidence of the safety and efficacy of that product. A specific procedure was introduced whereby the medicinal product had to be prescribed by a committee of three doctors from a hospital with recognized expertise in the field of the disease, who justified the prescription for each individual patient, with treatment being carried out only in a hospital after obtaining the patient’s written informed consent (LMPHU 2007). This hypothesis does not fully cover our patient either, as in our case treatment began in the hospital but continued for a long period of time on an outpatient basis without daily medical supervision. Table 3. Pharmacological therapy after established stenosis. Medicinal product Dose On-label/Off-label Posology according to the SPC Furosemide 2 × 2 mg p.o. On-label Heart failure Clopidogrel 1 × 1 mg p.o.Off-label Thrombosis prophylaxis Spironolactone 1 × 6.25 mg p.o. On-label Heart failure Acetylsalicylic Acid 1 × 15 mg p.o.* Off-label Thrombosis prophylaxis *Usually, the dose for children is determined in mg/kg of body weight. In this case, we indicate the total dose per intake according to the history of illness (medical dossier). Pharmacia 72: 1–7 5 The LMPHU stipulates that the National Council of Pricing and Reimbursement (NCPR) accepts, revokes, or amends pharmacotherapeutic guidelines that include criteria for evaluating the results of the applied therapy and algorithms for treatment with medicinal products, in accordance with the Health Act, after receiving an opinion from the relevant expert council in the relevant medical specialty. Pharmacotherapeutic guidelines are adopted by regulations and published in the State Gazette (NCPR 2020). The Executive Agency for Medical Supervision monitors compliance with the approved pharmacotherapeutic guidelines and assesses the effectiveness of therapy, and anyone who works in violation of the approved pharmacotherapeutic guidelines or assesses the results of therapy in deviation from the established standards shall be punished with a fine, unless their actions constitute a criminal offense. The review of the Bulgarian pharmacotherapeutic guidelines for pediatrics—pediatric cardiology established that the Expert Council accepted that acetylsalicylic acid and clopidogrel can be used as antiplatelet agents in children with venous thromboembolism (NCPR 2020). It is explicitly stated that the indications for their use are relatively limited, the main indication being the prevention of thromboembolism in implanted biological prostheses, anastomoses, and stents in pediatric cardiology, with acetylsalicylic acid administered at a dose of 1–5 mg/kg once daily, and clopidogrel at 0.2 mg/ kg once daily in infants and 0.5–1 mg once daily in older children. Nowhere is it stated that this treatment is off-label. The extent to which pharmacotherapeutic guidelines can allow treatment outside the scope of the marketing authorization and circumventing the LMPHU is again a debatable issue that needs interpretation. At the EU level, following concerns arising from Member States and stakeholders and the adoption of a European Parliament Resolution calling for specific action regarding the off-label use of medicines, the EC decided in 2014 to commission a study to understand the ramifications of the issue of off-label use of medicinal products (EC 2017). The purpose of the study was to obtain a clear description of existing and foreseen practices of off-label use across Member States (drivers, prevalence, national frameworks) and a factual analysis of all parties’ positions toward the existing measures and possible tools on the off-label use of medicines. The study report, prepared by the Safe and Timely Access to Medicines for Patients (STAMP) EC Expert Group, was made publicly available on 28 February 2017 (EC 2017). The specific objectives of the study were to provide information on the prevalence and incidence of off-label use and on its drivers and to provide information on the national frameworks, regulatory and other, governing the off-label use of medicinal products in various EU Member States. This included describing how authorities addressed the issue and the different ways patients, healthcare professionals (HCP), and industry reacted to this and providing a factual analysis taking into account the EU legal framework for off-label use and practices in the EU Member States. EU legislation does not regulate the way medicinal products are ultimately used in medical practice. The prescribing of a medicinal product, on-label or off-label, is a decision taken within the relationship between a patient and his or her treating healthcare professional. The way Member States organize their healthcare systems and the way HCPs conduct their practice are not topics that fall within the remit of the EU. The EU has limited competence in the field of public health; the ultimate responsibility for the definition of health policy and the delivery of health services and medical care lies with the Member States (Article 168(7) TFEU). The European Court of Justice confirmed that “off-label prescribing is not prohibited, or even regulated, by EU law” and that “There is no provision which prevents doctors from prescribing a medicinal product for therapeutic indications other than those for which a marketing authorization has been granted” (T-452/14 Laboratoires CTRS v Commission, paragraph 79). Off-label use is, however, recognized as a concept by EU pharmaceutical law (recital 2 of the Paediatric Regulation and pharmacovigilance provisions in Directive 2010/84/EU) (Petkova et al. 2023). Although extremely thorough and detailed, the opinion of STAMP provides only a factual analysis and does not give recommendations. An important court case is EC v Republic of Poland, where the court clarified the meaning of Article 5(1) of Directive 2001/83 and emphasized that the exemption to the marketing authorization requirement cannot be applied for only financial considerations (EC 2001). National court cases about off-label use largely relate to reimbursement. These cases indicate that additional requirements may apply, including limitation to life-threatening or severe conditions and the absence of alternative treatment options. Other national court cases concern the professional liability of prescribing or dispensing medicinal products off-label. In addition to the legislative aspects, our clinical case raises a number of practical questions concerning direct pharmaceutical services, as well as the quality, safety, and efficacy of off-label use of medicinal products in accordance with good manufacturing practice (GMP), good pharmacy practice, good prescribing practice, good pharmacovigilance practice, and others. As already mentioned, prescribing on-label or off-label is a decision taken within the relationship between a patient (in our case, the parents) and his or her treating HCP. Once agreement has been reached, the HCP proceeds to prescribe the medicinal product in accordance with internal hospital rules and/or issue a prescription for outpatient treatment. In hospital settings, the dispensing of the medicinal product must be in accordance with hospital standards and protocols, and the involvement of the hospital pharmacist in the treatment decision is essential. Without his or her consent to dispense an off-label medicinal product, treatment cannot begin. It is not possible to administer the product—the smallest permitted dosage form of clopidogrel is 75 mg film-coated tablets at a prescribed dose of 1 × 1 mg p.o. daily. There are two possible courses of action: Nachev N et al.: Off-label treatment of truncus arteriosis for pediatric pateints6 (1) crushing a 75 mg tablet and fractionating it into 1 mg doses, or (2) preparing an extemporaneous form according to a pharmacopoeial recipe directly from the active substance clopidogrel. In hospital settings, this should not be a problem, but questions arise regarding product quality, uniformity of mass, secondary packaging, shelf life, oral administration in dissolved form (patient age 0–30 days), absorption, etc. Obviously, treatment monitoring must be based entirely on internal rules in the absence of generally accepted ones and with blurred competence and responsibility among the parties involved. The situation is completely different when treatment must be continued on an outpatient basis. The only realistic hypothesis is the dispensing of extemporaneous medicinal products, again under off-label prescription conditions. The extent to which it is permissible to use ready-made medicinal products, packaged primarily and secondarily, as raw materials for the ex tempore manufacture of medicinal forms for pediatric or other use in outpatient settings is a matter of fundamental importance for pharmaceutical services. There is no clear regulation at either the national or European level. Quite the contrary, Delegated Regulation (EU) 2016/161 of 2 October 2015 supplements the Falsified Medicines Directive (2011/62/EU) and Directive 2001/83/ EC of the European Parliament and of the Council, laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use, which prevent the integrity of the primary and secondary packaging of medicinal products from being compromised (EC 2011, 2016; Nedelkov et al. 2019). These features include a unique identifier (a 2D barcode with product code, serial number, batch number, and expiry date) and an anti-tamper device. These components enable authentication and verification of medicines at various points in the supply chain, allowing pharmacists to scan and “decommission” unique identifiers before dispensing, thereby ensuring patient safety. The regulation allows for the removal of safety indicators only under the conditions set out in Article 47a of Directive 2001/83/EC: i.e., the safety features shall not be removed or covered, either fully or partially, unless the following conditions are fulfilled: activities may only be carried out by a manufacturing authorization holder (MAH); the MAH verifies, prior to partly or fully removing or covering those safety features, that the medicinal product concerned is authentic and has not been tampered with; the MAH replaces those safety features with equivalent features regarding verification, identification, and evidence of tampering of the medicinal product. Such replacement shall be conducted without opening the immediate packaging; the replacement of the safety features is conducted in accordance with applicable GMP; and the replacement of the safety features is subject to supervision by the competent authority. Apparently, the use of finished medicinal products packaged in primary and secondary packaging as raw materials for the manufacture of pediatric forms in pharmacies is in violation of this regulation. The clinical case presented poses a serious pharmacotherapeutic challenge for treating physicians, as prescribers of treatment; for pharmacists, who dispense the prescribed therapy; and for the parents and/or guardians of pediatric patients, because they must give informed consent for their treatment. From the point of view of the four core bioethical principles, it is obvious that autonomy becomes more complex in the neonatal intensive care unit. Beneficence obligates clinicians to promote infant well-being, but defining “benefit” for extremely preterm neonates involves balancing immediate survival with potential long-term morbidity. The principle of non-maleficence presents particular challenges in physician decisions, as significant harm can result. Justice extends beyond individual cases to address general benefit (Mangarov et al. 2025). We prepared this case report in accordance with the CARE guidance (Riley et al. 2017), and we have attempted to lift the veil on a rarely discussed issue concerning the practical provision of medicines for newborns with serious congenital diseases. We do not claim to have covered the topic in its entirety, but we believe that science, regulation, and practice are not yet ready with answers to the problems of these patients. The responsibility for providing medicines still weighs heavily on the conscience and professional ethics of doctors and pharmacists, and the patient’s choice is Hamlet-esque: to be or not to be! Additional information Conflict of interest The authors have declared that no competing interests exist. Ethical statements The authors declare that no clinical trials were used in the present study. The authors declare that no experiments on humans or human tissues were performed for the present study. The authors declare that no informed consent was obtained from donors or donors’ representatives participating in the study. The authors declare that informed consent was obtained from the parents of a newborn. The authors declare that no experiments on animals were performed for the present study. The authors declare that no commercially available immortalized human or animal cell lines were used in the present study. Use of AI No use of AI was reported. Funding The authors acknowledge financial support from the European Union–NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project BG-RRP2.004-0004-C01. Author contributions All authors have contributed equally. Pharmacia 72: 1–7 7 Author ORCIDs Nikolay Nachev https://orcid.org/0009-0000-2764-2976 Yoana Nikolaeva https://orcid.org/0009-0008-1118-9087 Kostadin Angelov https://orcid.org/0000-0002-4802-8024 Emil Hristov https://orcid.org/0000-0002-4339-8202 Valentina Petkova https://orcid.org/0000-0002-6938-1054 Irfan Irfan https://orcid.org/0009-0004-1758-9314 Iva Parvova https://orcid.org/0000-0003-2775-5326 Data availability All of the data that support the findings of this study are available in the main text. 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