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Complementary and alternative medicine refers to the use of products and practices that are not part of standard medical care. These therapies include a wide range of herbal and nutritional products, and studies show that up to 90% of cancer patients use them during at least part of their oncological treatment. However, only 25% of patients report this to their physician. Despite limited data on the safety and efficacy of herbal products, the use of herbal remedies and complementary medicine is increasing worldwide. This phenomenon is attributed to patients’ desire for holistic treatment, personal control over therapeutic choices, and, understandably, the hope of a cure. However, these products, like synthetic and natural medicines, can alter physiological processes and cause toxicity. They are insufficiently regulated by law, easily available (especially via the internet), and their active ingredient content and impurity levels may vary. One of the main under-researched risks is their concurrent use with oncology drugs and the potential for interactions. The most common mechanism of interactions is pharmacokinetic—inhibition or induction of metabolic enzymes or transport proteins—which leads to altered plasma concentrations of the drug. Interactions are particularly risky with drugs that have a narrow therapeutic window, such as chemotherapeutics used in oncology. One study found that 78% of patients receiving chemotherapy used herbal and complementary preparations, and 27% of patients were at risk of clinically significant interactions. Oncology drugs are associated with a range of acute and chronic toxicities, and the risk may increase with concurrent use of drugs that affect their metabolism. Therefore, it is important to know (and specifically ask) which medications and other preparations patients are taking. Potential for Interactions Most research has focused on laboratory studies, which do not necessarily reflect the clinical significance of interactions. However, for certain interactions between herbal preparations and chemotherapeutics, case reports and clinical studies exist that have confirmed the possibility of clinically observable interactions of many herbal products with oncology drugs. A study investigating reported cases of interactions between oncology drugs and 10 selected herbal products in the World Health Organization’s VigiBase database identified 1,057 individual adverse event reports  as possible consequences of such interactions. The most commonly reported were hepatotoxicity, hematological toxicity, and nausea. Some of the pharmacokinetic interactions between oncology drugs and herbal products documented in the literature are shown in Table 1 . Table 1 . PK interactions between oncology drugs and herbal products. Herbal product   (Latin name) Oncology drug Study type Result Echinacea (Echinacea purpurea) Etoposide Case report Significant reduction in platelet count Echinacea (Echinacea purpurea) Docetaxel Prospective study in 10 patients No significant effect on docetaxel PK Garlic (Allium sativum) Docetaxel Prospective, controlled study Decreased clearance of docetaxel Ginseng (Panax ginseng) Imatinib Case report Hepatotoxicity; recovery after discontinuation of ginseng Grapefruit (Citrus paradisi) Docetaxel Case report Increased concentration and prolonged t½ of docetaxel Grapefruit (Citrus paradisi) Nilotinib Open-label, randomized study Increased concentration of nilotinib Milk thistle (Silybum marianum) Irinotecan PK study Decreased clearance of irinotecan (not statistically significant) Milk thistle (Silybum marianum) Gefitinib Multiple adverse event reports (VigiBase) PK:  ↑ toxicity (pruritus, dry mouth, somnolence, etc.) Milk thistle (Silybum marianum) Sorafenib Multiple adverse event reports (VigiBase) PK:  ↑ toxicity (alopecia, nail discoloration) Milk thistle (Silybum marianum) Imatinib Adverse event report (VigiBase) PK:  ↑ toxicity (anemia, pyrexia) Milk thistle (Silybum marianum) Capecitabine Multiple adverse event reports (VigiBase) PK:  ↑ toxicity (pruritus, nausea) Milk thistle (Silybum marianum) Doxorubicin Adverse event report (VigiBase) PK:  ↑ toxicity (arrhythmia) Ginger (Zingiber officinale) Imatinib Adverse event report (VigiBase) PK:  ↑ hepatotoxicity Ginger (Zingiber officinale) Dabrafenib/Trametinib Adverse event report (VigiBase) PK:  ↑ thrombocytopenia, rectal bleeding Ginger (Zingiber officinale) Crizotinib Adverse event report (VigiBase) PK:  ↑ hepatotoxicity Green tea (Camellia sinensis) Erlotinib Adverse event report (VigiBase) PK:  ↑ hemoptysis, rash Cannabis (Cannabis sativa) Everolimus Adverse event report (VigiBase) PK:  ↑ nausea Cannabis (Cannabis sativa) Nintedanib Adverse event report (VigiBase) PK:  ↑ elevated transaminases Cannabis (Cannabis sativa) Palbociclib Adverse event report (VigiBase) PK:  ↑ tumor markers, discomfort Turmeric (Curcuma longa) Everolimus + Palbociclib Adverse event report (VigiBase) PK:  ↑ triglycerides, dry skin Turmeric (Curcuma longa) Ibrutinib Multiple adverse event reports (VigiBase) PK:  ↑ toxicity (thrombocytopenia, bleeding, hypertension, etc.) Turmeric (Curcuma longa) Palbociclib Adverse event report (VigiBase) PK:  ↑ hematologic toxicity Turmeric (Curcuma longa) Bortezomib Multiple adverse event reports (VigiBase) PK:  ↑ toxicity (constipation, leukopenia, sweating) St. John’s wort (Hypericum perforatum) Docetaxel PK study Significant decrease in docetaxel concentration St. John’s wort (Hypericum perforatum) Imatinib Two open-label studies Decrease in imatinib concentration by 32% and 30% Most oncology drugs are substrates of CYP enzymes and transport proteins, and many herbal products act as their inducers or inhibitors. The most common clinically significant interactions involve the cytochrome P450 (CYP) enzyme CYP3A4, but CYP2D6, CYP1A2, CYP2C9, and CYP2C19 are also important. Pharmacokinetic interactions at the level of CYP enzymes occur through inhibition or induction of the enzyme, resulting in either an increase (with an inhibitor) or a decrease (with an inducer) of the concentration of the substrate drug. An increase in drug concentration above therapeutic levels raises the risk of toxicity, while a decrease reduces treatment efficacy. Table 2  presents selected CYP enzymes, their substrates, and herbal products that may induce or inhibit their metabolic activity. Metabolic enzyme CYP enzyme inducer CYP enzyme inhibitor Substrate(s) CYP1A1/1A2 Cannabis (THC – tetrahydrocannabinol) St. John’s wort (extract: biapigenin) axitinib, bendamustine, bortezomib, dacarbazine, etoposide, exemestane, flutamide, pazopanib, pomalidomide, tegafur CYP2A6 — — cyclophosphamide, ifosfamide, letrozole, tegafur CYP2B6 St. John’s wort — busulfan, cyclophosphamide, docetaxel, doxorubicin, ifosfamide, procarbazine, thiotepa CYP2C8 — — anastrozole, dabrafenib, cyclophosphamide, enzalutamide, ifosfamide, imatinib, lapatinib, nilotinib, paclitaxel, pazopanib, tegafur CYP2C9 — Milk thistle; St. John’s wort (extracts: biapigenin, hyperforin, hypericin) busulfan, ifosfamide, idarubicin, ruxolitinib, tamoxifen CYP2C19 St. John’s wort Ginkgo axitinib, bortezomib, cyclophosphamide, ifosfamide, lapatinib, pomalidomide, tamoxifen, thalidomide CYP2D6 — St. John’s wort (extracts: hyperforin, hypericin); Cannabis (cannabidiol) brentuximab, doxorubicin, gefitinib, idarubicin, pomalidomide, tamoxifen, vinblastine, vinorelbine CYP2E1 St. John’s wort — dacarbazine, etoposide, cisplatin, vinorelbine CYP3A4/3A5 Echinacea, kava-kava, St. John’s wort, garlic, ginseng Echinacea, ginkgo, grapefruit, milk thistle, St. John’s wort (extract: biapigenin, hypericin), turmeric, ginger anastrozole, axitinib, bortezomib, bosutinib  (orig. “bositinib”), brentuximab, cabazitaxel, cisplatin, crizotinib, cyclophosphamide, dabrafenib, dasatinib, docetaxel, doxorubicin, enzalutamide, etoposide, exemestane, gefitinib, imatinib, fulvestrant, ifosfamide, irinotecan, lapatinib, letrozole, mitoxantrone, nilotinib, olaparib, paclitaxel, pazopanib, pomalidomide, ponatinib, procarbazine, regorafenib, ruxolitinib, sorafenib, sunitinib, temsirolimus, teniposide, thiotepa, topotecan, trabectedin, vandetanib, vemurafenib, vinblastine, vincristine, vinorelbine P-glycoprotein (ABCB-1, MDR-1) Echinacea, St. John’s wort Green tea, cannabis, turmeric, ginger axitinib, bicalutamide, bosutinib, cytarabine, dactinomycin, dasatinib, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, gefitinib, idarubicin, imatinib, irinotecan, methotrexate, mitoxantrone, paclitaxel, sunitinib, vincristine The most frequently recorded interactions occur at the level of CYP3A4, since most oncology drugs, as well as drugs in general, are metabolized by this enzyme. Oncology drugs metabolized by CYP3A4 include tyrosine kinase inhibitors, MEK and BRAF inhibitors, CDK4/6 inhibitors, taxanes, cyclophosphamide, and many others. In addition to those listed, other herbal products also have the potential to interact with oncology drugs. For many herbal products, especially combined formulations, the risk cannot be assessed due to lack of data. Phytovigilance The importance of pharmacovigilance is well recognized for understanding the benefits and risks of various drugs in real-world conditions outside controlled clinical trials. In recent years, there has been increasing recognition of the need for phytovigilance , which refers to the systematic monitoring of adverse effects and interactions of herbal products. Phytovigilance is supported by the European Medicines Agency and the European Food Safety Authority, and it is particularly important for ensuring the safe use of oncology drugs. Conclusion Knowledge of the potential impact of herbal preparations on medications is important for both physicians and patients. Physicians should ask patients about their use of herbal products and discuss possible risks and benefits. Since patients often do not disclose their use of complementary and alternative products, it is important to approach them with understanding and without judgment. Studies show that patients are willing to discontinue herbal product use if they know these may negatively affect cancer treatment. This highlights the importance of open communication with patients and active listening. Such an approach helps build trust and encourages better patient adherence to treatment. References: 1. McCune JS, Hatfield AJ, Blackburn AA, i sur. Potential of chemotherapy-herb interactions in adult cancer patients. Support Care Cancer. 2004;12(6):454-62. doi: 10.1007/s00520-004-0598-1. 2. Fasinu PS, Rapp GK. Herbal Interaction With Chemotherapeutic Drugs-A Focus on Clinically Significant Findings. Front Oncol. 2019 3;9:1356. doi: 10.3389/fonc.2019.01356. 3. NaturalMedicines. https://naturalmedicines.therapeuticresearch.com/ 4. Pochet S, Lechon AS, Lescrainier C, i sur. Herb-anticancer drug interactions in real life based on VigiBase, the WHO global database. Sci Rep 2022;12,:14178. https://doi.org/10.1038/s41598-022-17704-z

Introduction Obesity is a chronic disease associated with an increased risk of more than 200 complications that impair health and shorten life expectancy, including many cardiovascular diseases and type 2 diabetes. With the alarming spread of the obesity epidemic, therapies based on incretin hormones have marked a major advance in treatment. These therapies harness the body’s natural hormonal response to food intake, focusing primarily on enhancing the effects of incretins—hormones that stimulate insulin secretion after meals. They positively affect appetite regulation and energy balance, which are key problems in obese individuals. Drugs such as GLP-1 (glucagon-like peptide-1) receptor agonists—including liraglutide, semaglutide, and the newer addition tirzepatide—have demonstrated significant efficacy in weight reduction and glucose control, representing an important breakthrough in therapy. For individuals with overweight or obesity requiring pharmacological treatment, the choice of drug depends on patient preference, comorbidities, and drug availability. Clinical guidelines recommend incretin-based therapy as first-line treatment, where available. A holistic approach, including pharmacotherapy, balanced diet, and physical activity, is strongly advised. The European Medicines Agency (EMA) approved tirzepatide under the brand name Mounjaro  in May 2022 for the treatment of type 2 diabetes and obesity, in combination with dietary changes and increased physical activity. The U.S. Food and Drug Administration (FDA) approved tirzepatide under the name Zepbound  in November 2023. In Croatia, the Health Insurance Fund (HZZO) currently reimburses GLP-1 agonists only for the treatment of type 2 diabetes. Tirzepatide is not included in the HZZO reimbursement list. How does tirzepatide work? Tirzepatide is a long-acting dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, which are present in pancreatic α and β cells, the heart, blood vessels, immune cells, intestines, kidneys, and in brain regions important for appetite regulation. It reduces food intake and enhances satiety. It is administered subcutaneously once weekly, starting with 2.5 mg for 4 weeks, followed by 5 mg weekly, and may be increased by 2.5 mg increments every 4 weeks up to a maximum of 15 mg weekly. Clinical trials: efficacy of tirzepatide Two randomized, double-blind, placebo-controlled trials in adults with obesity showed weight loss of 12% to 18% with 15 mg weekly (SURMOUNT-1 and SURMOUNT-2). More than 80% of participants lost at least 5% of body weight, compared to 35% in the placebo group. Side effects were mild and mostly gastrointestinal. The SURMOUNT-3 trial demonstrated an additional weight reduction of 18.4% with tirzepatide compared with a 2.5% weight gain with placebo, following intensive lifestyle interventions that had already achieved ≥5% weight loss before randomization. SURMOUNT-4, an open-label study, reported a 20.9% weight loss over 36 weeks with maximum tolerated doses of tirzepatide (10 mg or 15 mg sc weekly). After randomization, those continuing tirzepatide lost an additional 5.5% of body weight, while those switched to placebo regained 14%, reversing improvements in cardiovascular risk factors. A meta-analysis of 6 randomized controlled trials found tirzepatide 5 mg, 10 mg, and 15 mg to be more effective than placebo, with mean weight changes of –7.7 kg, –11.6 kg, and –11.8 kg, respectively (–8.1%, –11.9%, –12.4%). The SURPASS trial showed significantly greater weight reduction with tirzepatide compared to semaglutide after 40 weeks: –1.9 kg (5 mg), –3.6 kg (10 mg), and –5.5 kg (15 mg) versus semaglutide 1 mg sc. The primary endpoint was HbA1c reduction, in which tirzepatide was both non-inferior and superior to semaglutide. However, the semaglutide dose used was lower than the maximum approved dose (2.4 mg sc), which likely underestimates semaglutide’s potential efficacy. GLP-1 agonists have consistently shown reductions in atherosclerotic cardiovascular risk. However, cardiovascular benefit with tirzepatide has not yet been proven. The ongoing SURPASS-CVOT trial is comparing cardiovascular event rates between tirzepatide and dulaglutide in adults with type 2 diabetes and established cardiovascular disease, with results expected no earlier than October 2024. Safety of tirzepatide The adverse effect profile of tirzepatide is similar to that of GLP-1 agonists. The most commonly reported side effects were gastrointestinal and increased heart rate, usually mild to moderate and dose-dependent. Unlike selective GLP-1 agonists, tirzepatide has also been associated with elevated pancreatic enzymes and occasional increases in serum calcitonin. Current studies are too short to rule out potential risks of pancreatic or thyroid cancers. Tirzepatide is contraindicated in pregnancy and in individuals with a history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN2A or MEN2B). Routine calcitonin monitoring or thyroid ultrasound is not required. Patients should be monitored for depression and suicidal ideation. Long-term safety data remain insufficient, especially given the likelihood of lifelong use in obesity management. Economic challenges The high cost of tirzepatide and other GLP-1 agonists may limit widespread use, although pharmacoeconomic studies suggest they are cost-effective due to significant health benefits of weight reduction. According to the Croatian Agency for Medicinal Products and Medical Devices, the maximum approved price of Mounjaro (tirzepatide) is €360.96 per pack for 10 mg, 12.5 mg, and 15 mg, and €199.08 for 2.5 mg. Since tirzepatide is given as a weekly subcutaneous injection, the monthly cost of treatment is at least €1,443.84. Place of tirzepatide in obesity treatment Incretin-based obesity therapies such as tirzepatide are highly effective, but their long-term benefit depends on continuous treatment. This is not surprising, given that obesity is a chronic, relapsing disease requiring lifelong management. The efficacy of tirzepatide compared with GLP-1 agonists is likely similar. The only head-to-head trial used lower semaglutide doses (1 mg vs 2.4 mg sc), limiting firm conclusions. Evidence on long-term safety and cardiovascular protection remains lacking. At present, the role of tirzepatide—especially compared to GLP-1 agonists—cannot be definitively determined. References: 1. Jastreboff AM, Aronne LJ, Ahmad NN, i sur; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4. PMID: 35658024. 2. Garvey WT, Frias JP, Jastreboff AM, i sur; SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613-626. doi: 10.1016/S0140-6736(23)01200-X. 3.Frías JP, Davies MJ, Rosenstock J, i sur; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. doi: 10.1056/NEJMoa2107519. 4. de Mesquita YLL, Pera Calvi I, i sur. Efficacy and safety of the dual GIP and GLP-1 receptor agonist tirzepatide for weight loss: a meta-analysis of randomized controlled trials. Int J Obes (Lond). 2023;47(10):883-892. doi: 10.1038/s41366-023-01337-x. 5. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014;311(1):74-86. doi: 10.1001/jama.2013.281361. 6. Sažetak opisa svojstava lijeka, Mounjaro, Elly Lilly. https://www.ema.europa.eu/en/documents/product-information/mounjaro-epar-product-information_en.pdf Pristupljeno 25.3.2024. 7. Perreault L, Reid TJ. Obesity in Adults: Drug Therapy. UpToDate. 8. Aronne LJ, Sattar N, Horn DB, i sur.; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024 2;331(1):38-48. doi: 10.1001/jama.2023.24945. 9. HALMED. Popisi cijena lijekova. Dostupno na: https://www.halmed.hr/Promet-proizvodnja-i-inspekcija/Najvisa-dozvoljena-cijena-lijeka-na-veliko/Popis-lijekova-s-odredenom-najvisom-dozvoljenom-cijenom-na-veliko-i-iznimno-visom-od-najvise-dozvoljene-cijene-na-veliko/ Pristupljeno 25.3.2024. 10. Olivieri, AV., Muratov, S., Larsen, S. I sur. Cost-effectiveness of weight-management pharmacotherapies in Canada: a societal perspective. Int J Obes 2024. https://doi.org/10.1038/s41366-024-01467-w 11. IQVIG. Tirzepatid (Mounjaro). Dostupno na: https://www.akdae.de/fileadmin/user_upload/akdae/Arzneimitteltherapie/NA/Archiv/202402-Mounjaro.pdf Pristupljeno 11.4.2024. 12. Valentine WJ, Hoog M, Mody R, i sur. Long-term cost-effectiveness analysis of tirzepatide versus semaglutide 1.0 mg for the management of type 2 diabetes in the United States. Diabetes Obes Metab. 2023;25(5):1292-1300. 13. Nicholls SJ, Bhatt DL, Buse JB, i sur; SURPASS-CVOT investigators. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am Heart J. 2024;267:1-11. 14. Marx N, Husain M, Lehrke M, i sur. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. Circulation. 2022 Dec 13;146(24):1882-1894. doi: 10.1161/CIRCULATIONAHA.122.059595. Epub 2022 Dec 12. PMID: 36508493.

The use of X-rays, ultrasound waves, computed tomography (CT), nuclear medicine techniques, and magnetic resonance imaging (MRI) has become an indispensable part of modern medicine. Consequently, during pregnancy, many women will either incidentally or based on clear indications undergo some of these diagnostic techniques. Concerns about the safety of radiological examinations in pregnant or breastfeeding women, as well as the safety of the fetus, often lead to unnecessary avoidance of useful diagnostic procedures. During pregnancy, radiation exposure applies not only to the mother but also, potentially, to the fetus. It should be emphasized from the outset that in most situations where a pregnant woman may be exposed to radiation—such as diagnostic medical imaging or occupational exposure—the radiation doses fall within prescribed limits and are unlikely to cause adverse health effects in the fetus. The human embryo and fetus are sensitive to ionizing radiation at doses exceeding 0.1 Gy (100 mGy). Depending on the stage of fetal development, health consequences may occur at doses above 0.5 Gy (500 mGy), which can be severe. A fetal radiation dose below 50 mGy carries negligible risk for miscarriage or malformations compared to other pregnancy risks. A fetal dose below 100 mGy should not be considered a reason for medical termination of pregnancy. Table 1. Fetal Radiation Exposure in Common Radiological Procedures Very Low Dose Examinations (<0.1 mGy): Cervical spine X-ray (AP and lateral): <0.001 Head and neck CT: 0.001–0.01 Extremity X-ray: <0.001 Mammography: 0.001–0.01 Chest X-ray: 0.0005–0.01 Low to Moderate Dose Examinations (0.1–10 mGy): Abdominal X-ray: 0.1–3.0 Lumbar spine X-ray: 1.0–10 Intravenous pyelography: 5–10 Chest CT or pulmonary CT angiography: 0.01–0.66 Nuclear medicine low-dose perfusion scan: 0.1–0.5 Bone scintigraphy with technetium: 4–5 Pulmonary digital subtraction angiography: 0.5 High Dose Examinations (10–50 mGy): Abdominal CT: 1.3–35 Pelvic CT: 10–50 Whole-body PET-CT: 10–50 Radiation Exposure in Specific Imaging Procedures Ultrasound (US):  Uses sound waves and does not involve ionizing radiation. When performed correctly with properly calibrated equipment, it poses no risk to the fetus or pregnancy. Magnetic Resonance Imaging (MRI):  Uses magnetic fields rather than ionizing radiation. There are no pregnancy-specific contraindications. MRI Contrast Agents:  Gadolinium-based contrast agents should be used only when the diagnostic benefit clearly outweighs potential risks. X-rays:  Often indicated during pregnancy or performed inadvertently before pregnancy is detected. Examinations not directly involving the abdomen or fetus result in radiation doses far below the natural background radiation exposure during pregnancy. Dental, chest, and extremity X-rays are therefore considered safe. Even multiple diagnostic X-rays rarely expose the fetus to significant radiation. Computed Tomography (CT):  With or without contrast, CT may be performed during pregnancy if there is a clear clinical indication and the benefits outweigh the risks. Nuclear Medicine:  Pregnancy is not always a contraindication for nuclear medicine procedures, particularly those using radionuclides with short half-lives, provided there is a strong clinical indication and radiation-free alternatives are unsuitable. In life-threatening maternal conditions, radionuclides may be used, with prior evaluation of the absorbed fetal dose and risks. Professional Recommendations for Radiological Imaging in Pregnancy The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists (2019)  summarized the following guidance: Ultrasound and MRI  are not associated with radiation risks and are the first-line imaging choices during pregnancy. They should, however, be used judiciously, only when they are expected to answer relevant clinical questions or provide medical benefit. With few exceptions, radiation doses from conventional X-rays, CT, or nuclear medicine are well below thresholds associated with fetal harm. If clinically indicated, these examinations should not be withheld from pregnant women. Gadolinium-based contrast agents  in MRI should be restricted to cases where they significantly improve diagnostic accuracy or outcomes for mother or fetus. Conclusion Radiological imaging techniques are widely used in medicine and may also be indicated during pregnancy. Although some involve ionizing radiation, fetal exposure is typically below levels that could cause congenital malformations, miscarriage, or termination. For most pregnant women, ultrasound and MRI remain first-line diagnostic tools , but when clinically necessary, ionizing radiation-based procedures should not be denied. References: ACOG. Guidelines for Diagnostic Imaging During Pregnancy and Lactation. Dostupno na: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/10/guidelines-for-diagnostic-imaging-during-pregnancy-and-lactation Pristupljeno 25.4.2024. Lowe S. Diagnostic imaging in pregnancy: Making informed decisions. Obstet Med. 2019 Sep;12(3):116-122. doi: 10.1177/1753495X19838658. Epub 2019 Apr 11. PMID: 31523267; PMCID: PMC6734637. Kruskal JB. Diagnostic imaging in pregnant and lactating patients. UpToDate. Pristupljeno 29.4.2024.

INTRODUCTION With aging poplation, dementia is becoming an increasing global problem. Alzheimer's disease is the most common form of dementia in the elderly and accounts for 60-80% of cases (1). Therefore, a growing interest in research into the prevention and treatment of dementia is justified. In this context, the use of vitamin D has been investigated for a long time. Below is an overview of currently available evidence on the effectiveness of vitamin D in this indication. WHY IS VITAMIN D IMPORTANT? Vitamin D is a vitamin that is synthesized in the skin after exposure to sunlight. After binding to the receptor, dihydroxy-vitamin D further participates in the expression of a number of genes involved in bone development and other functions. It's in vitro effect has been studied in many diseases. In addition to its effect on bone, vitamin D is also linked to the functioning of the immune system, and has been studied in the prevention and treatment of cardiovascular diseases and malignancies. Vitamin D deficiency has been associated with risk of developing immune diseases, neurological diseases (multiple sclerosis) and infections (especially respiratory) including COVID-19. But the American Food and Nutrition Board (FNB) concludes that the evidence for any effect attributed to vitamin D, other than a positive effect on bone health, is insufficient or contradictory. Due to its positive effect on bones, it is recommended that all adults take sufficient daily doses of vitamin D, preferably with food. The Recommended Daily Intake (RDA) of vitamin D is 600 IU (International Units; 15 mcg) in adults up to the age of 70. For persons older than 70, the RDA is 800 IU (20 mcg), but may be even higher (2). For pregnant and lactating women, the RDA is 600 IU (15 mcg). The optimal serum concentration of vitamin D for maintaining bone health is controversial, but according to the literature it is between 50 and 100 nmol / L. Levels below 30-50 nmol / l are considered deficient and <30 insufficient. The optimal serum concentration for other indications is not known. SIDE EFFECTS OF HIGH DOSES OF VITAMIN D Daily vitamin D intake of more than 4,000 IU in healthy individuals is generally not recommended. In patients with malabsorption (eg, celiac disease, gastrectomy, inflammatory bowel disease), the recommended doses will depend on the patient's ability to absorb vitamin D; high doses ranging from 10,000 to 50,000 IU are usually given. However, possible signs of toxicity should be monitored in these patients. Symptoms of toxicity are usually described at doses greater than 60,000 IU and are attributed to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness (3). Chronic intoxication can cause nephrocalcinosis, bone demineralization, and pain. VITAMIN D AND PREVENTION OF DEMENTIA Vitamin D deficiency is being investigated as a possible risk factor for the development of dementia (4). The brain has the ability to synthesize the active form of vitamin D (1.25 hydroxyvitamin D) within many cell types and brain regions, predominantly in the hypothalamus and the large neurons within the substantia nigra. Many genes important in the production of responses to routine signals and stimuli are regulated by vitamin D. Functionally, vitamin D plays a role in neuroprotection by modulating the production of nerve growth factor, neurotrophin, glial cell neurotrophic factor, nitric oxide synthase, and actylcholine transferase. But knowing the importance of vitamin D for the normal functioning of the organism does not automatically mean that its application in deficient conditions would be clinically useful. Such conclusions can only be drawn on the basis of evidence from properly designed randomized controlled trials with sufficient subjects involved, if available. There is some evidence that vitamin D deficiency is associated with cognitive deficits in the elderly but the clinical significance of this is unknown. One meta-analysis and systematic review included 37 studies with a comparative group (5). The majority of the studies included were cross-sectional studies, followed by controlled case studies and cohort studies (two), and only 3 studies were randomized controlled studies (highest level of evidence), but with a relatively small number of patients involved. The number of subjects included ranged from 27 to 17,099, and most included subjects older than 65. Studies included patients with Alzheimer's and other dementias. All studies determined the level of vitamin D (1.25 hydroxyvitamin D). Most studies used MMSE (Mini-Mental State Examination) as a test of cognitive function. In most studies, the relationship between vitamin D and cognitive function was determined by comparing vitamin D concentrations between patients diagnosed with dementia and controls, or the result of cognitive function tests between groups with different vitamin D concentrations. The main objections to the quality of the studies included in this meta-analysis were the process of blinding participants, selection of subjects, lack of adjustment for age and gender in results analysis, lack of knowledge on the methodology used in determining vitamin D levels, lack of knowledge on methods used for handling missing data. One of the main objections was the lack of data on the knowledge of the patient's cognitive status assessor about his vitamin D status. Thus, the included studies differed in the number of subjects, design, cognition tests used, methodology for determining vitamin D levels and patient grouping. It is therefore not surprising that a statistically significant heterogeneity was found between the included studies (cross-sectional studies and case studies with controls were included in the meta-analysis) regarding the evaluation of differences in vitamin D levels [mean difference was −15.0 nmol / L 25 (OH) D [−26.2, −3.9)] as well as in the evaluation of differences in MMSE results [mean difference in MMSE results was 1.2 (0.5, 1.9)] between the compared groups. For those less familiar with the meta-analysis methodology, statistically significant heterogeneity points to significant differences between the included studies that do not allow valid conclusions to be drawn from the obtained meta-analysis results (6). Although the heterogeneity of the included studies was significant in this meta-analysis, its results suggested a possible association between vitamin D levels and cognitive impairment, but this effect appears to be modest, if any, and of unknown clinical significance. As previously mentioned, three randomized controlled clinical trials were included in the systematic review. The intervention in 2 of the 3 randomized controlled clinical trials was the administration of a multivitamin preparation that also contained vitamin D, and in only one placebo-controlled study the intervention was the administration of 9,000 IU of vitamin D2 over 8-40 weeks; no significant differences in cognitive outcomes were observed in this study. However, it should be noted that the number of included patients was small (n = 82). Most of these studies did not take into account the variability in vitamin D status. In addition, people with cognitive impairment have a higher risk of malnutrition and spend less time outdoors. Due to these objections, it is impossible to exclude reverse causality as an alternative explanation of the study results (dementia as a cause of vitamin D deficiency, and not vice versa). Two previously published meta-analyzes found no significant association between 1.25 hydroxyvitamin D levels and dementia (7.8). Whether vitamin D supplementation in healthy individuals or those with vitamin D deficiency reduces the risk of cognitive decline or dementia is unclear, but limited evidence does not support this. For valid conclusions, we need the results of controlled randomized intervention studies with a sufficient number of patients included. Meanwhile, due to the lack of evidence of its usefulness, prescribing vitamin D to prevent dementia is not recommended. OTHER INTERVENTIONS IN PREVENTION OF DEMENTIA In general, physical activity, social interaction, and cognitive activities are recommended for all patients, especially those at risk for developing dementia. Timely and good treatment of hypertension is especially important because of the proven association with an increased risk for vascular dementia and Alzheimer’s disease (9). Although a healthy diet is associated with positive health outcomes, including cognitive health, the evidence is insufficient to conclude that specific dietary regimens or dietary supplements are useful in reducing the risk of developing dementia. This applies to the use of omega-3 fatty acids, the Mediterranean diet and small amounts of alcohol. Prospective and randomized controlled clinical trials have not shown the benefit of the use of vitamins, statins, cholinesterase inhibitors, estrogen substitution, or the use of nonsteroidal antirheumatic drugs in the prevention of dementia. OTHER VITAMINS Multivitamin preparations have not shown efficacy in preventing dementia or slowing cognitive decline in dementia (10,11). Despite some evidence that elevated serum homocysteine ​​levels and / or decreased folate, vitamin B6, and vitamin B12 levels may be associated with cognition impairment and dementia risk, there is no convincing evidence from clinical trials of the benefit of vitamin use in dementia prevention (12,13). Although vitamin E has not been shown to be useful in preventing dementia, it may have limited benefit in slowing the progression of mild to moderate Alzheimer's disease (14,15). However, data from randomized studies are ambiguous (16). As high doses of vitamin E have been consistently associated in clinical trials with increased mortality and heart failure in patients with cardiac disease, the use of vitamin E in the prevention of dementia and for other forms (except mild to moderate Alzheimer's disease) of dementia is not recommended. CONCLUSION The only proven beneficial effect of vitamin D is its effect on bone health. In other indications in which the effect of vitamin D supplementation has been investigated, clinical trials do not provide solid evidence to justify recommendations for its use. These include the prevention and treatment of dementia, cardiovascular disease, multiple sclerosis, malignancies and infections including COVID-19. Evidence for the effect of vitamin D on the prevention of dementia is qualitatively modest, but does not provide justification for routine prescribing of vitamin D in this indication. The only evidence-based indication for prescribing vitamin D is deficiency / insufficiency and the use of recommended doses in the prevention of osteoporosis. REFERENCES: 1. Livingston G, i sur. Lancet. 2017 Dec 16;390(10113):2673-2734. 2. Dietary Reference Intakes for Calcium and Vitamin D. https://www.nap.edu/resource/13050/Vitamin-D-and-Calcium-2010-Report-Brief.pdf Pistup 11.06.2021. 3. Barger-Lux MJ, i sur. J Clin Endocrinol Metab. 2002 Nov;87(11):4952-6. 4. Buell JS, i sur. Mol Aspects Med. 2008 Dec;29(6):415-22. 5. Balion C, i sur. Neurology. 2012 Sep 25;79(13):1397-405. 6. Higgins JPT, i sur. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook. 7. Annweiler C, i sur. Neuropsychobiology. 2010 Aug;62(3):139-50. 8. Barnard K, i sur. Am J Geriatr Pharmacother. 2010 Feb;8(1):4-33. 9. Barnes DE, Yaffe K. Lancet Neurol. 2011 Sep;10(9):819-28. 10. Grima NA, i sur. J Alzheimers Dis. 2012;29(3):561-9. 10. Grima NA, i sur. J Alzheimers Dis. 2012;29(3):561-9. 11. Grodstein F, i sur. Ann Intern Med. 2013 Dec 17;159(12):806-14. 12. Livingston G, i sur. Lancet. 2017 Dec 16;390(10113):2673-2734. 13. Aisen PS, i sur. JAMA. 2008 Oct 15;300(15):1774-83. 14. Dysken MW, i sur. JAMA. 2014 Jan 1;311(1):33-44. 15. Sano M, i sur. N Engl J Med. 1997 Apr 24;336(17):1216-22. 16. Galasko DR, i sur. Arch Neurol. 2012 Jul;69(7):836-41.

In the editorial of the March issue of the New England Journal of Medicine (NEJM), it is clearly stated that compelling results from the randomized, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic Acid and ACL-Inhibiting Regimen) Outcomes study could and should increase the use of bempedoic acid in patients with established atherosclerosis who have a high cardiovascular (CV) risk and cannot or do not want to take statins due to side effects. This clinical trial included a composite primary endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization) in patients on bempedoic acid 180 mg (n=6992) reduced by 13% compared to patients on placebo (n=6978). The primary outcome occurred in 11.7% of patients on bempedoic acid compared to 13.3% on placebo; the absolute risk reduction was 1.6% (risk ratio 0.87; 95% confidence interval, 0.79 to 0.96; P=0.004). The participants were followed for 6 months. Bempedoic acid did not have a significant effect on CV death or all-cause mortality. The editor emphasizes that bempedoic acid cannot be considered an alternative to statins. High-quality evidence exists for the benefits of statins, and clinicians should continue to prescribe them at the maximum tolerable doses for appropriate patients. Although bempedoic acid also lowers LDL cholesterol levels in patients taking statins, the clinical benefit of simultaneous use is not known/confirmed. The editor also highlights that two observations from the CLEAR Outcomes study should be further investigated - the suggestion that bempedoic acid has a greater effect in primary prevention and the finding that there was no effect of the drug on mortality. Is this due to effective concomitant therapy, a short follow-up period, or an actual lack of the drug's effect on mortality? With this report, bempedoic acid is added to the list of alternatives to statins for primary and secondary prevention in patients with a high CV risk. The study has provided numerous data and clarified the effectiveness and safety of the drug. The drug is approved in the European Union under the name Nilemdo and is intended for standalone use as well as for use with statins and other lipid-lowering medications. It is not on the list of drugs covered by the Croatian Health Insurance Fund (HZZO). LiteraturE: 1. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019;322(18):1780–1788. doi:10.1001/jama.2019.16585 2. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. DOI: 10.1056/NEJMoa2215024

INTRODUCTION Fingolimod (Gilenya) is an oral immunosuppressant used as a disease-modifying drug in the treatment of relapsing-remitting multiple sclerosis. The guideline of the Croatian Health Insurance Institute for the use of fingolimod (N457) is: "As monotherapy in highly active relapsing-remitting multiple sclerosis with phases of relapse and remission with EDSS <= 6 and absence of pregnancy- I. in patients with active disease and who have not responded to a complete and appropriate treatment regimen with at least one course-modifying therapy (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate), or when the criteria for discontinuation of the therapy according to current guidelines in the drug list are met. The disease is considered active despite previous therapy when following criteria are met a) >= 4 new T2 hyperintensive lesions on MR, or b) >= 2 relapses. Treatment is approved by the Hospital Drug Committee for the next 6 months at the expense of the hospital budget, and afterwards at the expense of the Croatian Health Insurance- Fund for very expensive drugs. Treatment for patients with severe rapidly progressive relapsing-remitting multiple sclerosis is approved at the expense of the hospital budget. "(1). FINGOLIMOD AND LIVER DAMAGE One of the most common reasons for discontinuation of fingolimod therapy is an increase in transaminases, indicative of inflammation or damage to liver cells. During clinical trials with fingolimod, an increase in transaminase levels of at least 3-fold the upper limit of normal (ULN) was observed in 8% of adults and up to 5-fold the ULN in 1.8% of subjects. In addition, reintroduction of fingolimod into therapy was observed to result in liver damage in some patients, suggesting causality. In clinical trials, elevations in transaminases were recorded at different times during treatment, although most occurred during the first 12 months of treatment. Transaminase levels returned to normal within approximately 2 months after cessation of treatment (3). In late 2020, the European Medicines Agency (EMA) reported cases of liver failure in patients on fingolimod, including three cases requiring liver transplantation. Other drug agencies around the world have also issued warnings about the link between fingolimod and liver damage. The first signs of liver damage in these patients were elevated liver enzymes and bilirubin. The occurrence of these laboratory abnormalities was noted as early as 10 days after the first dose, but also after prolonged use of the drug (2). Due to the severity of this side effect, the Summary of Product Characteristics was amended; The EMA recommended monitoring of hepatic function, including bilirubin, before and during fingolimod treatment (at 1, 3, 6, 9, and 12 months during treatment) and 2 months after cessation of therapy due to the long half-life of fingolimod of 6 to 9 days ( 2). Pharmacokinetics of fingolimod Absorption of fingolimod is slow (12-16 hours) and extensive (bioavailability about 93%), and is not significantly affected by food. The pharmacologically active metabolite responsible for its efficacy is fingolimod phosphate. Fingolimod and fingolimod phosphate are highly bound to plasma proteins (> 99%) and are extensively distributed to tissues. Fingolimod is transformed in humans by reversible stereoselective phosphorylation into the already mentioned pharmacologically active (S) -enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation catalyzed mainly by CYP4F2 (or CYP3A4) and possibly other isoenzymes, followed by degradation similar to that of fatty acids to inactive metabolites. Following oral administration, approximately 81% of the dose is slowly excreted in the urine in the form of inactive metabolites. The elimination half-life (t1/2) of fingolimod is 6-9 days. CONCLUSION Since the introduction of fingolimod on the market, numerous side effects have been reported with its use. The post-marketing data confirm the possibility of serious side effects, especially cardiac and hepatic. Adverse cardiac side effects have already been reported during clinical trials, and in 2017, based on additional safety data collected, the use of fingolimod in patients with severe heart disease was contraindicated (2). What does this mean for the clinical practice? Based on a limited number of randomized controlled clinical trials, indirect comparisons of therapeutic lines, observational studies, and clinical experience, the clinical utility of fingolimod compared to other disease-modifying drugs (eg interferon beta-1a, the only drug fingolimod was compared to in a randomized placebo-controlled trial ) is relatively modest (4, 5). Due to potentially serious side effects, the benefit-risk balance should be carefully weighed when deciding to initiate fingolimod or change the treatment line to fingolimod. In persons on fingolimod who have elevated transaminases 3x the ULN, more frequent monitoring of transaminase levels is recommended. Fingolimod therapy should be discontinued in subjects with a transaminase level greater than 5 times the ULN or a transaminase level greater than 3 times the ULN, with a concomitant increase in bilirubin to a value greater than 2x the ULN. Furthermore, fingolimod should be discontinued in case of liver damage without a known cause. References: 1. HZZO. Tražilica za lijekove. Gilenya (fingolimod). https://hzzo.hr/trazilica-za-lijekove?query=gilenya Pristup 11.7.2021. 2. Sažetak opisa svojstava lijeka Gilenya (fingolimod), Novartis Europharm Limited, 16.11.2020. 3. Direct Healthcare Professional Communication Gilenya (fingolimod) – Updated recommendations to minimise the risk of drug-i nduced liver injury (DILI). https://www.ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communication-dhpc-gilenya-fingolimod-updated-recommendations_en.pdf Pristup 11.7.2021. 4. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. Comparative efficacy. UpToDate, 2021. 5. NICE. Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis. https://www.nice.org.uk/guidance/ta254 Pristup 7.11.2021.

INTRODUCTION The invention of COVID-19 vaccines represents probably the greatest success so far in the fight against the pandemic caused by the SARS-CoV2 virus. Despite numerous efforts and research, there is still no specific drug for the treatment of COVID-19. Therefore, it could be concluded that population vaccination and the acquisition of so-called "herd immunity" is currently the best way to combat this pandemic, or at least to slow it down. However, like any other intervention or drug used in medicine, vaccines carry a certain risk of mild or severe side effects and allergic reactions. This may cause fear of vaccination in general or fear of vaccination with a particular type of vaccine against COVID-19. Furthermore, an additional problem is the necessity to produce and distribute huge quantities of vaccines, where delays in the production of individual vaccines could lead to delays in vaccination with the second dose. The third problem is the fact that the virus itself is prone to mutations and result in the emergence of new variants, some of which in the future may be resistant to immunity acquired by some or all previously available vaccines (1, 2). Do we have a solution to some of the above problems? MIX AND MATCH One of the potential solutions is the application of a "mix and match" vaccination regime. The name "mix and match" represents a well-known approach where one vaccine is used in the first vaccination, and then another vaccine in the re-vaccination. Regarding the available COVID-19 vaccines, this would mean the following: if a person is vaccinated with the first dose of one of the available mRNA vaccines (Pfizer- BioNTech or Moderna), then a vector vaccine can be used for the second dose (eg, AstraZeneca or Johnson & Johnson ), and the reverse approach is applicable where a person primarily vaccinated with a vector vaccine could be vaccinated with an mRNA vaccine. The idea behind such a vaccine combination approach is that different vaccines stimulate the immune system in different ways (because vaccines differ) and thus could trigger a more comprehensive and stronger immune response (1, 3). However, the question arises whether we have enough data or clinical studies that confirm that this approach is really effective and safe? According to the guidelines of the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) - not yet. Namely, the current position and recommendation of the WHO is that there is not enough data based on studies conducted so far to recommend this approach, so the current recommendation is to use the same vaccine for both doses, and the same position is shared by the US CDC (4, 5). However, some countries, such as Germany, Canada and Italy, have already approved the mix and match approach based on the data available so far (6). WHAT DO THE DATA SAY? Unfortunately, there are still no published studies or peer-reviewed and publishe scientific articles in this regard. Nevertheless, unreviewed results and data from several studies conducted in Germany, Spain, and the United Kingdom are available online. A Spanish study was conducted on more than 600 subjects, and the data suggest that people vaccinated with Pfizer-BioNTech after receipt of the first dose of AstreZeneca have a significant increase in IgG antibody titers and the presence of neutralizing antibodies in 100% of subjects. Subjects developed common adverse reactions such as injection site pain, headache, and muscle aches, but no serious adverse reactions were reported. However, it should be noted that the study was conducted in people over 60 years of age and that there was no control group of persons vaccinated according to the currently approved protocol, ie with two doses of the same vaccine (eg AstraZeneca vaccine), which prevents comparisons of post-vaccination responses between the mix and match protocol and the standard vaccination protocol (7). Another study, conducted on a cohort of 340 health professionals in Germany, provides a partial answer to this question. In this study, subjects were vaccinated with two doses of Pfizer BioNTech vaccine or a combination of AstraZeneca (1st dose) / Pfizer-BioNTech (2nd dose). According to their preliminary analyzes, the combination of AstraZeneca / Pfizer-BioNTech vaccine is well tolerated (comparable number of systemic reactions to the vaccine with the group vaccinated with two doses of Pfizer-BioNTech vaccine), results in comparable immunogenicity with even slightly increased avidity (total binding strength) of IgG antibodies and a stronger T lymphocyte response in a mixed vaccination protocol (8). But the clinical significance of these findings is not yet clear. Similar results were obtained by other groups of researchers from Germany, with subjects receiving the AstraZeneca / Pfizer-BioNTech vaccine combination having a significantly higher number of specific CD4 and CD8 T lymphocytes with a high titer of neutralizing antibodies against several virus strains (B.1.1.7 , B.1.351 and P.1) (9, 10). Preliminary data from a multicenter randomized study conducted in the United Kingdom called Com-COV are also available (11). This study aims to examine several different mix and match vaccination protocols, including a group of subjects who will receive one of the available vector vaccines after an mRNA vaccine, which has not been studied so far. Preliminary data from this study show that the number of systemic adverse reactions in the mixed protocol after the second dose of vaccine is higher compared to standard protocols, which is inconsistent with data from other studies, but may be due to different age of included subjects or different time periods elapsed between two doses of COVID-19 vaccine (8). In addition to the studies mentioned here, it is necessary to highlight two other clinical studies that are currently ongoing. The first is a US study conducted by the National Institute of Health (NIH), which, among other things, aims to examine the safety and efficacy of vaccination with a third dose of COVID-19 vaccine in people who are fully vaccinated according to the standard protocol. Subjects will receive a different vaccine for the third vaccine dose (mRNA vs vector vaccine). The significance of this study is reflected in the fact that it is still unknown whether additional re-vaccination will be required for those who have been vaccinated. In this regard, the use of a different vaccine could be of particular importance. Namely, the problem of frequent use of vector vaccines could be the development of an immune response to the vector itself, for example the adenovirus, where the person's immune system could eliminate the adenovirus, and thus the message it carries before it reaches cells, which could lead to reduced vaccine efficacy. On the other hand, a problem with mRNA vaccines can be created by the increased frequency of side effects with revaccination (12, 13). Another study is a Canadian study called MOSAIC, which aims to examine the safety and efficacy of COVID-19 vaccines with respect to the different time intervals between two doses of the same or different vaccines, and the duration of the protective effect in such conditions (14). CONCLUSION The combination of different types of COVID-19 vaccines, if shown to be safe and effective, could be useful in several ways - it would enable vaccination of persons with history of severe immediate-type allergic reactions with a different type of vaccine as well as continuation of vaccination programs if problems in vaccine production or distribution arise. Preliminary data suggest that this regimen could lead to a stronger and more comprehensive immune response and thus provide greater protection against mutated strains of the virus as well. However, currently available data are too limited to recommend the "mix and match" vaccination regime, although it has been approved in a few countries. In addition, most studies addressing this question monitor the effects of vaccination when a vector vaccine (Vaxzevria) is used for the first dose and an mRNA vaccine for the 2nd dose. Data on the reverse order are extremely limited (Com-COV study). This is certainly an interesting approach for which there is a rational. We have to be patient and wait for the final results of ongoing clinical studies and evaluation of their results from the competent authorities. Until then, it should be pointed out once again that according to the current guidelines of all relevant health organizations, the benefits of vaccination with any available vaccine, if there are no contraindications, far outweigh the potential risks. Accordingly, we once again recommend vaccination as the best way to combat the COVID-19 pandemic. What are the current recommendations in Croatia? The website of the Croatian Institute of Public Health states the possibility of an exception to the rule that both doses of vaccine should be from the same manufacturer; this is a situation when a person develops a serious side effect following the first dose of the vaccine (only Vaxzevria vector vaccine from AstraZenec is listed as an example) such as a bleeding disorder or thromboembolism that cannot be explained by another reason, etc. The physician who treated the side effect should be involved in the decision to vaccinate the patient with the same or a different vaccine (10). References: 1. Covid-19 vaccine mixing: the good, the bad and the uncertain. https://www.clinicaltrialsarena.com/analysis/covid-19-vaccine-mixing-the-good-the-bad-and-the-uncertain/ . Access: 18.06.2021. 2. A mix-and-match approach to COVID-19 vaccines could provide logistical and immunological benefits. https://www.pbs.org/newshour/health/a-mix-and-match-approach-to-covid-19-vaccines-could-provide-logistical-and-immunological-benefits. Access: 21.06.2021. 3. COVID: Are mix-and-match vaccines the way forward? https://www.dw.com/en/mix-and-match-vaccines-biontech-astrazeneca-better-than-one-shot/a-57819127. Access: 21.06.2021. 4. Interim recommendations for use of the Pfizer–BioNTech COVID-19 vaccine, BNT162b2, under Emergency Use Listing. https://apps.who.int/iris/bitstream/handle/10665/341786/WHO-2019-nCoV-vaccines-SAGE-recommendation-BNT162b2-2021.2-eng.pdf?sequence=1&isAllowed=y. Access: 20.06.2021. 5. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid-19%2Finfo-by-product%2Fclinical-considerations.html#Interchangeability. Access: 20.06.2021. 6. Factbox: Countries weigh 'mix and match' COVID-19 vaccines. https://www.reuters.com/world/middle-east/countries-weigh-mix-match-covid-19-vaccines-2021-05-24/ Access: 20.06.2021. 7. Borobia AM, i sur. Reactogenicity and immunogenicity of BNT162b2 in subjects having received a first dose of ChAdOx1S: initial results of a randomised, adaptive, phase 2 trial (CombiVacS). Dostupno putem linka: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3854768. 8. Hillus D, i sur. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study. Available through: https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2. 9. Barros-Martins J, i sur. Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.01.21258172v1. 10. Schmidt T, i sur. Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1. 11. Shaw RH, i sur. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. Lancet. 2021;397(10289):2043-2046. doi: 10.1016/S0140-6736(21)01115-6. 12. NIH clinical trial evaluating mixed COVID-19 vaccine schedules begins. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-evaluating-mixed-covid-19-vaccine-schedules-begins. Access: 22.06.2021. "MIX AND MATCH"CHens when you mix doses of the Pfizer and AstraZeneca vaccines? A new study is starting to reveal the answer. https://fortune.com/2021/05/12/what-happens-when-you-mix-doses-of-the-pfizer-and-astrazeneca-vaccines-a-new-study-is-starting-to-reveal-the-answer/. Access: 22.06.2021. 14. MOSAIC: Mix and Match COVID-19 Vaccines. https://centerforvaccinology.ca/study/mosaic-mix-and-match-covid-19-vaccines/ Pristup: 22.06.2021. 10. HZJZ. Privremena dopuna preporukama o cijepljenju protiv bolesti COVID-19. https://www.hzjz.hr/sluzba-epidemiologija-zarazne-bolesti/privremena-dopuna-preporukama-o-cijepljenju-protiv-bolesti-covid-19/ Access 6.7.2021."

Metamizole (also known as dipyrone) is an analgesic, antipyretic, and spasmolytic that has been used in various countries since 1922.  It is well known for its effectiveness in treating moderate to severe pain, including postoperative pain, cancer-related pain, and migraines, and offers certain advantages compared with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Specifically, it is associated with lower gastrointestinal, cardiovascular, and renal toxicity. However, despite these benefits, metamizole has been linked to a rare but serious adverse reaction: agranulocytosis , a condition that can lead to life-threatening infections due to a sudden and significant reduction in granulocytes. Availability of Metamizole The availability and use of metamizole vary greatly worldwide. It is banned in several countries, including the United Kingdom, the United States, Canada, and parts of Scandinavia (Norway, Denmark, Sweden), primarily due to concerns about agranulocytosis. On the other hand, metamizole is widely available in many European and non-European countries, including Spain, Germany, Brazil, Russia, and Mexico. These differences largely reflect long-standing debates regarding the drug’s safety profile. In Croatia, metamizole is available by prescription. What is the risk of agranulocytosis with metamizole? Agranulocytosis is a rare but potentially fatal adverse reaction to metamizole, defined as a drop in neutrophil count (a type of white blood cell) below 500 cells per mm³ of blood. This condition severely compromises the immune system, making patients highly vulnerable to severe infections. Agranulocytosis may occur at any time during treatment or shortly after discontinuation, and it can develop rapidly, especially in patients with prior exposure to the drug. The risk increases with longer treatment duration, though it is not dose-dependent. Certain groups, including women and older adults, appear to be at greater risk. Reports on the incidence of metamizole-induced agranulocytosis vary significantly across studies and regions. The International Agranulocytosis and Aplastic Anemia Study (IAAAS) , conducted in the 1980s, was one of the first large-scale investigations. It reported an incidence of 1 case per 1.1 million user-weeks, or approximately 6.2 cases per million users per year, suggesting a very low risk. Subsequent European studies generally confirmed a low incidence, between 0.6 and 1.4 cases per million within 7–10 days of exposure. However, some studies reported higher rates: a widely cited Swedish study found 1 case per 1,431 prescriptions, while a German study estimated 1 case per 1,602 prescriptions. These discrepancies may reflect methodological differences or population-based genetic factors, making risk assessment challenging. EMA safety measures Due to these concerns, the European Medicines Agency (EMA)  has periodically reviewed metamizole’s safety. In September 2024 , the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)  recommended new measures to reduce the risk of serious consequences of metamizole-induced agranulocytosis. This review was triggered by Finland’s national medicines agency after continued reports of agranulocytosis despite earlier risk minimization measures. The review of available data, including post-marketing surveillance and spontaneous reports from healthcare professionals, confirmed that agranulocytosis remains a serious and unpredictable adverse event of metamizole. PRAC concluded that, although the benefits of metamizole in treating pain and fever outweigh the risks, stricter safety measures are necessary. These include: Updating product information:  EMA recommended updates for all metamizole-containing products in the EU to better inform healthcare professionals and patients about the risk of agranulocytosis and to facilitate early recognition and treatment. Patient warnings:  Healthcare providers are now required to advise patients to stop taking metamizole immediately and seek medical attention if they develop symptoms such as fever, sore throat, chills, or mucosal ulcerations. Since agranulocytosis can progress rapidly and cause severe infections, early recognition is critical. Restrictions for at-risk groups:  PRAC advised against prescribing metamizole in patients at increased risk, including those with a history of metamizole-induced agranulocytosis or reactions to similar pyrazolone derivatives, and patients with bone marrow disorders or coagulation abnormalities. ⚠️ Note: The pyrazolone derivative propyphenazone  is present in certain combination analgesics on the Croatian market (e.g., Caffetin, Saridon, Plivadon). Mechanism of agranulocytosis The exact mechanism by which metamizole causes agranulocytosis is not fully understood. Evidence suggests an immune-mediated mechanism , where metamizole or its metabolites may trigger an abnormal immune response leading to granulocyte destruction. Another theory proposes a direct toxic effect on bone marrow precursors. Genetic studies have not identified consistent risk markers, complicating definitive conclusions. Efficacy and safety compared with other analgesics In terms of analgesic efficacy, metamizole has shown pain relief comparable to paracetamol, NSAIDs, and opioids. One of its main advantages over NSAIDs is the lower risk of gastrointestinal, cardiovascular, and renal adverse effects, making it particularly useful for patients intolerant to these complications. However, the risk of agranulocytosis remains the key concern , requiring careful risk-benefit assessment, especially with longer treatment durations. Conclusion Metamizole remains available as an analgesic and antipyretic in many countries, including Croatia (by prescription), particularly for patients needing alternatives to NSAIDs or opioids. Its long history of use underscores its efficacy in treating pain and fever. However, although the incidence of metamizole-induced agranulocytosis is low, it is a serious and unpredictable adverse event that requires close monitoring and implementation of risk reduction measures. Therefore, metamizole should be considered a second-line option  for pain or fever management, reserved for patients where other therapies are unsuitable. References: Hearn L, Derry S, Moore RA. Single dose dipyrone (metamizole)for acute postoperative pain in adults. Cochrane Database Syst Rev.2016;4:CD011421. Kötter T, da Costa BR, Fässler M, et al. Metamizole‐associatedadverse events: a systematic review and meta‐analysis. PLoS ONE.2015;10:e0122918.5. Summary of product characteristic, Alkagin 500 mg, April 21, 2022. Available at: https://halmed.hr/upl/lijekovi/SPC/Analgin-SPC.pdf Risks of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. The International Agranulocytosis and Aplastic Anemia Study. JAMA. 1986 Oct 3;256(13):1749-57. van der Klauw MM, Goudsmit R, Halie MR, van't Veer MB, Herings RM, Wilson JH, Stricker BH. A population-based case-cohort study of drug-associated agranulocytosis. Arch Intern Med. 1999 Feb 22;159(4):369-74. doi: 10.1001/archinte.159.4.369. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol. 2002 Jul;58(4):265-74. doi: 10.1007/s00228-002-0465-2. Epub 2002 Jun 6. Klose S, Pflock R, König IR, Linder R, Schwaninger M. Metamizole and the risk of drug-induced agranulocytosis and neutropenia in statutory health insurance data. Naunyn Schmiedebergs Arch Pharmacol. 2020 Apr;393(4):681-690. doi: 10.1007/s00210-019-01774-4. Cascorbi I. The Uncertainties of Metamizole Use. Clin Pharmacol Ther. 2021 Jun;109(6):1373-1375. doi: 10.1002/cpt.2258.

Introduction Patients with atrial fibrillation (AF) and severe chronic kidney disease (CKD) face an increased risk of both bleeding and thromboembolism. Selecting an anticoagulant for patients with CKD is critical yet challenging due to limited data on the safety of these drugs in this population. Recently published observational studies suggest that among direct oral anticoagulants (DOACs), apixaban is a safer choice compared to alternatives such as rivaroxaban or warfarin, due to its lower risk of bleeding. Overview of Available Oral Anticoagulants Apixaban: The Preferred Choice Apixaban is often preferred for patients with AF and severe CKD, including those on dialysis. Compared to other DOACs, apixaban relies less on renal clearance, making it safer for patients with impaired kidney function. Observational studies suggest that apixaban is associated with a lower risk of major bleeding compared to warfarin and rivaroxaban, with similar efficacy in preventing stroke and systemic embolism. The standard dose is 5 mg twice daily, but in patients with two or more of the following criteria—age ≥80 years, body weight ≤60 kg, or serum creatinine ≥133 µmol/L—the dose is adjusted to 2.5 mg twice daily. However, data on safety in patients with creatinine clearance (CrCl) <15 mL/min and those on dialysis remain insufficient. Rivaroxaban Rivaroxaban is an alternative for patients with AF and CKD with a CrCl of 15–50 mL/min. The recommended dose for patients with CrCl >50 mL/min is 20 mg once daily with the largest meal of the day. For patients with CrCl 15–50 mL/min, the recommended dose is 15 mg once daily with the largest meal. However, in patients with CrCl <15 mL/min or on dialysis, rivaroxaban should generally be avoided due to the higher risk of bleeding. Dabigatran The use of dabigatran in CKD is limited due to its significant renal elimination (80–85%). It is recommended for patients with CrCl >30 mL/min at a dose of 150 mg twice daily. In those with CrCl between 15–30 mL/min, the dose is reduced to 75 mg twice daily, but its use is discouraged in this group due to insufficient safety data. Dabigatran is contraindicated in patients with CrCl <15 mL/min or on dialysis. Edoxaban Edoxaban can be used in patients with CKD and CrCl 15–50 mL/min, with dosing adjustments according to the degree of renal impairment. In patients with CrCl >95 mL/min, its efficacy is reduced due to high renal clearance. For patients with CrCl >50–95 mL/min, the recommended dose is 60 mg once daily. In patients with severe CKD (CrCl 15–30 mL/min), a reduced dose of 30 mg once daily is recommended. Data on use in patients with CrCl <15 mL/min are lacking, and it is not recommended. Warfarin as an Alternative in Advanced CKD In patients with severe CKD, especially those on dialysis, warfarin remains an alternative to DOACs. It allows therapeutic monitoring and dose adjustment, which is beneficial in cases of acute worsening of renal function. The target INR is 2.0–3.0, and maintaining >70% time in therapeutic range is considered optimal. However, variability in effect and numerous drug and food interactions remain major challenges with warfarin therapy. Why Is Apixaban the DOAC of Choice in CKD? Its lower dependence on renal clearance (approximately 25%) makes it less affected by impaired kidney function compared to other DOACs. Studies consistently show that apixaban carries a lower risk of major bleeding compared to warfarin and rivaroxaban in patients with severe CKD, with similar efficacy in stroke prevention. In patients with AF and severe CKD not requiring dialysis, apixaban has demonstrated a more favorable safety profile, supporting its role as the first-choice anticoagulant in this population. Evidence Supporting Apixaban in CKD Patients ARISTOTLE study:  A subgroup analysis of 269 patients with AF and CrCl 25–30 mL/min demonstrated a significantly lower risk of major bleeding with apixaban compared to warfarin (HR 0.34). Observational studies:  An observational study of 6,794 adults with severe CKD not on dialysis found that apixaban was associated with a lower risk of major bleeding compared to warfarin (1.5 vs. 2.9 per 100 person-years) and rivaroxaban, while rates of stroke/systemic embolism and mortality were similar. Rivaroxaban was associated with a higher risk of major bleeding (4.9 vs. 2.9 per 100 person-years) without differences in stroke/systemic embolism or death. Compared with rivaroxaban, apixaban was associated with a reduced risk of major bleeding (HR 0.53 [95% CI, 0.36–0.78]). DOACs and Renal Function Renal elimination rates for each DOAC are a key factor in determining suitability: Dabigatran: 80–85% Edoxaban: 35% Rivaroxaban: 35% Apixaban: 25% Because of their reliance on renal clearance, DOACs must be prescribed with caution in CKD patients. In severe CKD (CrCl <30 mL/min), warfarin or adjusted doses of low-molecular-weight heparin are often preferred over DOACs. However, new evidence supports the safe and effective use of apixaban even in patients with significant renal impairment. DOAC Selection by Kidney Function Mild to moderate CKD (CrCl 30–50 mL/min):  All DOACs are generally safe with appropriate dose adjustments. Severe CKD (CrCl <30 mL/min) or dialysis:  Apixaban is the preferred option based on observational data. Warfarin remains an alternative due to better monitoring options. Advanced CKD (CrCl <15 mL/min):  Data on DOACs are insufficient. Warfarin or adjusted low-molecular-weight heparin are recommended as first-line therapy. Conclusion Selecting an anticoagulant for patients with AF and severe CKD requires careful consideration of the balance between bleeding risk and thromboembolism prevention. Among available DOACs, apixaban stands out for its favorable safety profile and lower dependence on renal clearance. However, for patients with CrCl <15 mL/min or those on dialysis, warfarin remains the recommended alternative. Clinicians must consider patient-specific factors, including age, weight, bleeding risk, and renal function, when choosing an anticoagulant therapy. Note:  Clinicians must also remain mindful of significant pharmacokinetic interactions between DOACs and other drugs, as the risk of clinically important interactions is higher in CKD patients. For more on safe prescribing of DOACs, see our previous blog posts: Anticoagulant Therapy in Patients with Impaired Renal Function Anticoagulant Therapy in Elderly Patients with Atrial Fibrillation References: 1. Xu Y, Ballew SH, Chang AR, Inker LA, Grams ME, Shin JI. Risk of Major Bleeding, Stroke/Systemic Embolism, and Death Associated With Different Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease. J Am Heart Assoc. 2024 Aug 20;13(16):e034641. doi: 10.1161/JAHA.123.034641. 2. Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, Wojdyla DM, Garonzik S, Byon W, Hijazi Z, Lopes RD, Alexander JH, Wallentin L, Granger CB. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation. 2020 Apr 28;141(17):1384-1392. doi: 10.1161/CIRCULATIONAHA.119.044059. 3. Sažetci opisa svojstava lijeka za DOAK-e. Dostupno na: HALMED. Baza lijekova: https://www.halmed.hr/lijekovi/baza-lijekova/

Historical background Milk thistle ( Silybum marianum ) has been used for centuries, with its application dating back to classical Greece, where it was used to treat liver and gallbladder diseases and to protect the liver from toxins. More recently, it has been investigated as a potential cytoprotective agent, anticancer compound, and supportive therapy for liver damage caused by poisoning with Amanita phalloides . The main active substance in milk thistle is silymarin  (with silybin as the most important active component), which is found primarily in the seeds. Because silymarin undergoes enterohepatic recirculation, it reaches higher concentrations in liver cells than in serum. Availability of silymarin products in Croatia According to European Medicines Agency (EMA) regulatory requirements, herbal medicines can be categorized into three groups: New herbal medicine  – efficacy demonstrated by new clinical trials conducted according to current guidelines. Well-established use  – efficacy supported by scientific literature but without new clinical trials, with at least 10 years of use in the European Union. Traditional use  – no direct evidence of efficacy, but used traditionally for at least 30 years, including 15 years in the EU. Registration is allowed only for indications considered safe for use without medical supervision. In Croatia, products containing silymarin are registered as dietary supplements or as traditional herbal medicines, with dosages varying by manufacturer. According to the EMA Committee on Herbal Medicinal Products (HMPC), silymarin does not meet the criteria for registration as a “well-established use” herbal medicine due to insufficient scientific evidence of efficacy in investigated indications. Mechanism of action and results of non-clinical studies Laboratory studies show that silymarin stabilizes cell membranes and stimulates the synthesis and activity of detoxification enzymes, particularly glutathione S-transferase, influencing intracellular glutathione levels (a potent antioxidant). It can also neutralize a wide range of free radicals. In vitro  studies demonstrate that silymarin regulates key inflammatory mediators such as TNF-alpha, various interleukins, nitric oxide, and interferon-gamma. Additional mechanisms include stimulation of neuronal differentiation, inhibition of leukotriene synthesis in Kupffer cells, and reduction of lipid peroxidation. Animal studies have shown protective effects of milk thistle against drug-induced damage to the liver, pancreas, and kidneys (e.g., from paracetamol, cisplatin, and vincristine). Preclinical data also suggest anticancer potential. However, it is important to emphasize that positive preclinical results do not guarantee efficacy in clinical practice . Human pharmacokinetics, dosing, absorption, and interactions may differ significantly, highlighting the need for well-designed clinical trials before routine clinical use. Evidence for clinical use Liver disease Numerous clinical trials have investigated herbal preparations, including milk thistle, in chronic liver disease. However, most have the following limitations: Poor study design Unclear effective dosage Small sample sizes Randomized placebo-controlled trials of silymarin in steatohepatitis, hepatitis B and C, and alcoholic liver disease  generally did not show benefits compared with placebo. Two meta-analyses concluded that due to significant methodological flaws, there is insufficient evidence to confirm clinical efficacy of milk thistle. Key limitations include patient heterogeneity, lack of standardized dosing, insufficiently defined inclusion criteria, and confounding factors such as co-existing viral hepatitis or ongoing alcohol use. Anticancer effects Preclinical studies suggest possible benefits such as inhibition of tumor cell growth and enhanced chemotherapy effects. However, clinical studies in humans have not provided sufficient evidence  to recommend milk thistle for cancer treatment or prevention. Professional societies do not recommend its use outside well-designed clinical trials. Amanita phalloides  poisoning Milk thistle shows potential as adjunct therapy in acute poisoning with Amanita phalloides  (“death cap mushroom”). Silymarin inhibits toxin binding to hepatocytes and interrupts enterohepatic circulation. Case reports suggest possible benefits, but because milk thistle was always used as part of combination therapy, its independent effect cannot be determined. Clinical trials are still needed to confirm efficacy. Safety and side effects Milk thistle is generally well tolerated. Reported adverse effects are rare and usually mild, mainly gastrointestinal (laxative effect, occasional nausea, or dyspepsia). Allergic reactions are uncommon. Serious adverse events are rare, and significant drug interactions are unlikely, as silymarin inhibits CYP2D6 and CYP3A4 only at very high doses not typically reached with oral use. Theoretical concerns exist that concurrent use with chemotherapy could reduce efficacy, particularly for agents whose cytotoxicity relies on free radical generation. This warrants caution and further study. Conclusion Milk thistle is a relatively safe dietary supplement or traditional herbal medicine, typically associated with rare and mild side effects. However, clinical efficacy in both acute and chronic liver disease remains uncertain . Potential exists in acute amatoxin poisoning, but it should not be recommended for cancer prevention or treatment outside of clinical trials. Despite the lack of strong clinical evidence, its favorable safety profile means milk thistle will likely remain one of the most commonly used herbal supplements. Clinicians should educate patients on the limitations of current evidence , especially regarding viral hepatitis and alcoholic liver disease. In oncology, careful consideration of risks and benefits is warranted before recommending its use during chemotherapy. Key Points for Clinicians: Hepatoprotection : Evidence is insufficient for routine use in chronic liver disease; may be considered only as adjunctive therapy. Mushroom poisoning : Some evidence supports its role in Amanita phalloides  intoxication, though intravenous silibinin is not widely available. Cancer : Limited and conflicting evidence; not recommended outside clinical trials. Safety : Generally well tolerated, with mostly mild gastrointestinal side effects. Evidence limitations : Existing trials suffer from poor design, small sample sizes, and inconsistent dosing. Regulation : Available as a supplement or traditional herbal medicine, not subject to the same regulatory standards as approved drugs. References: Rainone F. Milk Thistle. Am Fam Physician. 2005;72(7):1285-92. EMA. Assessment report on Silybum marianum (L.) Gaertn., fructus, 5.6.2018. Dostupno na: https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-silybum-marianum-l-gaertn-fructus_en.pdf Pristupljeno 31.10.2023. EMA. Guideline on the assessment of clinical safety and efficacy in the preparation of EU herbal monographs for wellestablished and traditional herbal medicinal products. https://www.ema.europa.eu/en/assessment-clinical-safety-efficacy-preparation-eu-herbal-monographs-well-established-traditional-herbal-medicinal-products-scientific-guideline Pristupljeno 31.10.2024. National Cancer Institute. Milk Thistle- Health Professional Version. Dostupno na: https://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq Pristupljeno 23.10.2024. NHS. Achufusi TGO, Pellegrini MV, Patel RK. Milk Thistle. Dostupno na: https://www.ncbi.nlm.nih.gov/books/NBK541075/ Pristupljeno 23.10.2024. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003620. DOI: 10.1002/14651858.CD003620.pub3. Pristupljeno 23.10.2024. de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol. 2017 Jul 21;23(27):5004-5017. doi: 10.3748/wjg.v23.i27.5004. Mohtashaminia F, Amini MR, Sheikhhossein F, Djafarian K, Shab-Bidar S. Effects berberine-silymarin on liver enzymes: A systematic review and meta-analysis of randomized controlled trials. Clin Nutr ESPEN. 2022 Jun;49:181-186. doi: 10.1016/j.clnesp.2022.01.037. Fried MW, Navarro VJ, Afdhal N, et al. Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy: A Randomized Controlled Trial.JAMA. 2012;308(3):274–282. doi:10.1001/jama.2012.8265 Saper RB. Overview of herbal medicine and dietary supplements. In:UpToDate, Elmore JG, Seres D (ed), Wolters Kluwer. Pristupljeno 23.10.2024.

Paracetamol is an analgesic and antipyretic widely recommended and used for the management of pain and fever during pregnancy. The U.S. Food and Drug Administration (FDA)  and the European Medicines Agency (EMA)  consider paracetamol to carry minimal risk during pregnancy (1,2). However, in 2021, a group of 91 experts published a consensus statement recommending avoidance of paracetamol use in pregnancy due to the possibility of various adverse outcomes for the newborn (3). The consensus statement summarized research suggesting unfavorable neurological, urogenital, and reproductive outcomes associated with maternal and perinatal use of paracetamol, particularly disorders such as autism  and attention-deficit/hyperactivity disorder (ADHD) . Based on a review of experimental and epidemiological literature, the experts cautioned that pregnant women should refrain from paracetamol use unless it is medically indicated. At the same time, the statement acknowledged the clear limitations of the existing epidemiological literature, emphasized the need for rigorous meta-analyses, and noted that multiple biases could explain the observed associations between paracetamol use and neurodevelopmental anomalies/disorders. The results of a study published in April 2024 in the Journal of the American Medical Association (JAMA)  (4) are therefore significant. This was a national sibling-controlled cohort study  that included over 2.4 million children  born in Sweden between 1995 and 2019, with follow-up through December 31, 2021. Paracetamol use during pregnancy was determined from the national Medical Birth Register, and information on early exposure to the drug was prospectively collected throughout pregnancy. The primary outcomes were autism, ADHD, and diagnoses of intellectual disability, identified using International Classification of Diseases (ICD) codes. Although the study had several strengths (a large, nationally representative sample; an extensive control group with adjustment for numerous potential confounders; systematic, prospective recording of paracetamol use and clinical diagnoses of neurodevelopmental disorders), there were also limitations. First, in a small proportion of patients, diagnoses of autism and ADHD were not confirmed, and the mean age of diagnosis was higher than in other studies. In addition, information on paracetamol use was not entirely precise (dose, duration, or timing in relation to pregnancy), and prescription records may not fully reflect over-the-counter use. Therefore, more specific aspects of exposure could not be evaluated, and it cannot be definitively excluded that use of paracetamol above a certain dose at a critical time point might represent a potential risk. Nevertheless, the conclusion of the study is important: paracetamol use during pregnancy was not associated with an increased risk of autism, ADHD, or intellectual disability  in sibling-controlled analyses. References US Food and Drug Administration. FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy.  January 9, 2015. Accessed March 19, 2024. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-has-reviewed-possible-risks-pain-medicine-use-during-pregnancy Pharmacovigilance Risk Assessment Committee. PRAC recommendations on signals: adopted at the 12–15 March 2019 PRAC meeting.  European Medicines Agency. April 8, 2019. Accessed March 19, 2024. Available at: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-12-15-march-2019-prac-meeting_en.pdf Bauer AZ, Swan SH, Kriebel D, et al. Paracetamol use during pregnancy: a call for precautionary action.  Nat Rev Endocrinol. 2021;17(12):757-766. doi:10.1038/s41574-021-00553-7 Ahlqvist VH, Sjoqvist H, Dalman C, et al. Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability.  JAMA. 2024;331(14):1205-1214. doi:10.1001/jama.2024.3172

Despite widespread anti-smoking campaigns at the population level, 28% of adults (aged ≥15 years) in Europe still smoke.  The use of electronic cigarettes (e-cigarettes) has emerged and gained significant popularity in response to the well-known harmful effects of tobacco smoking, although their safety remains in question. The modern device innovation is attributed to Hon Lik, a Chinese pharmacist who in 2003 developed this method of inhaling aerosols (vaping) and patented the device in 2007. Advocates present these devices as a “less harmful” option or as an aid to smoking cessation. However, the reality is much more complex and requires thorough scientific and public health analysis. In many countries, e-cigarettes are not subject to the same strict regulations as conventional tobacco products. As a result, their promotion in media and online is often permitted, reaching not only adults but also young people. While the popularity of specific types of e-cigarettes varies across time and countries, it is universally recognized that an increasing number of children, adolescents, and adults are using them. E-cigarettes are often promoted as a safer alternative to smoking traditional cigarettes and as a way to reduce or quit smoking. However, evidence suggests they are not harmless. What Are E-Cigarettes and How Do They Work? E-cigarettes are devices that heat a liquid—so-called e-liquid —to produce an aerosol inhaled by the user. This liquid typically contains nicotine, propylene glycol or vegetable glycerin, and flavorings available in a wide variety (fruit, mint, chocolate, desserts, etc.). Although nicotine-free e-liquids exist, those containing nicotine are far more common. Two main types exist: Disposable and refillable devices resembling traditional cigarettes Tank systems and vaporizers Unlike conventional cigarettes, e-cigarettes involve no combustion, meaning users are less exposed to tar and carbon monoxide. Still, this does not mean they are risk-free. Prevalence of E-Cigarette Use Between 2015–2019, e-cigarette use varied widely across countries—from virtually nonexistent (Egypt, 0%) to very high (Lithuania, 56.6%). In Poland, 35% of young people reported using e-cigarettes in the previous 30 days. The sharpest increase has been among youth. Studies show an exponential rise in prevalence, from 5% to as high as 25% between 2013 and 2019.  E-cigarettes have become a social trend, seen as “cool” or even a “healthier option.” Youth and E-Cigarettes Young people are especially vulnerable to e-cigarettes. Flavors such as strawberry, candy, or menthol make them attractive, and social media marketing amplifies their reach. Research shows that youth who never smoked but use e-cigarettes are twice as likely to later begin smoking traditional cigarettes. In addition to fostering nicotine addiction, e-cigarettes may: Negatively affect cognitive development  in adolescents (attention, memory, emotional regulation) Contribute to respiratory conditions  such as asthma Harm pregnancy and fetal development, since nicotine interferes with placental circulation and blood vessel growth Cardiovascular Risks: Lower Than Cigarettes, but Still Present Although e-cigarettes are promoted as less harmful to the cardiovascular system because they lack combustion products, nicotine and other aerosol components can still have adverse effects. Research indicates: Increased blood pressure and heart rate after use Greater arterial stiffness (linked to higher heart attack risk) Impaired endothelial function Increased oxidative stress and autonomic nervous system changes Currently, there is no direct clinical trial evidence or long-term cohort data on cardiovascular outcomes of e-cigarettes, and the consequences of chronic use remain largely unknown. Epidemiological data from two large U.S. surveys (National Health Interview Survey, 2014 [N=36,697] and 2016 [N=33,028]) suggest an elevated risk of myocardial infarction among e-cigarette users (odds ratio 1.79; 95% CI 1.20–2.66), though lower than among cigarette smokers (2.72; 95% CI 2.29–3.24). Do E-Cigarettes Help with Smoking Cessation? The evidence is mixed. Some randomized clinical trials show e-cigarettes may aid cessation when combined with psychological support. However, real-world outcomes differ: Many users continue using both e-cigarettes and conventional cigarettes In practice, e-cigarettes are no more effective than nicotine patches or gums Long-term data on sustained abstinence are limited Overall, available evidence does not allow a definitive conclusion on whether e-cigarettes reliably help smokers quit. Limitations of current studies include inconsistent exposure measurement, inclusion of non-cessation users, confounding factors, and varied definitions of “quit success.” Some studies suggest e-cigarettes combined with behavioral therapy may improve abstinence rates, but they also emphasize the need for intensive, repeated counseling . Use outside professional supervision may undermine cessation attempts for many adult smokers. More high-quality research—particularly pragmatic randomized trials—is needed. For now, experts recommend that e-cigarettes should not be considered a first-line tool  for smoking cessation. Regulatory Challenges E-cigarette legislation is relatively new, and no global consensus exists on their regulation. While most nicotine-containing e-cigarettes can be included under tobacco laws, nicotine-free products present a regulatory gray area. As of now, 98 countries have some form of e-cigarette regulation, but with wide variation: Some countries (e.g., Brazil, Turkey) enforce a total ban In the EU, most countries regulate them as tobacco-related products, with limits on nicotine concentration, advertising, and packaging Many online sellers lack age verification Influencer-driven advertising often circumvents regulations The rapid evolution of the e-cigarette market continues to outpace legislation, enabling frequent loopholes and abuses. Recommendations from the European Association of Preventive Cardiology (EAPC) Healthcare professionals should remain cautious and avoid recommending e-cigarettes without a defined cessation strategy and support. E-cigarettes should be considered only as part of an official smoking cessation program. Regulations should be as strict as for conventional tobacco, especially regarding youth-targeted marketing. Flavors appealing to children (e.g., candy, fruit, dessert) should be banned. Strict age verification should be enforced for online and retail sales. Education campaigns in schools and on social media should highlight potential dangers. As with cigarettes, complete abstinence during pregnancy  should be advised. Conclusion Although e-cigarettes may expose users to fewer harmful substances than conventional cigarettes, their growing popularity—particularly among youth—cannot be viewed as harmless. Their long-term health effects, including on cardiovascular disease, brain development, and nicotine addiction, remain insufficiently studied. Continued research, stronger regulation, and above all, protection of vulnerable groups—especially children and adolescents—are essential to prevent addiction and counter misleading industry messages. Adapted from: Maryam Kavousi, et al. Electronic cigarettes and health with special focus on cardiovascular effects: position paper of the European Association of Preventive Cardiology (EAPC). Eur J Prev Cardiol. 2021;28(14):1552–1566. doi:10.1177/2047487320941993.