Farmakoepidemiološka studija spontano prijavljenih hepatotoksičnih reakcija na lekove i biljne dijetetske suplemente

Abstract

Usled mogućih veoma ozbiljnih kliničkih posledica i velikih poteškoća pri otkrivanju i dijagnostikovanju, hepatotoksičnost lekova ili lekovima izazvano oštećenje jetre (Drug Induced Liver Injury – DILI) predstavlja veoma značajan rizik za bezbednost pacijenata i uvek aktuelan farmakoterapijski izazov za zdravstvene radnike, regulatorne agencije i farmaceutsku industriju. Iako se biljni lekovi i dijetetski suplementi (BLiDS) generalno smatraju bezbednim i imaju široku upotrebu, objavljeni pojedinačni slučajevi pojave toksičnog oštećenja jetre pri njihovoj primeni ukazuju na značaj ispitivanja hepatotoksičnog potencijala ovih proizvoda. Hepatotoksične reakcije (HR) uglavnom ostaju neidentifikovane tokom pretkliničkih i kliničkih ispitivanja i otkrivaju se tokom postmarketinškog praćenja leka (faza IV). U okviru ove disertacije istraživani su postmarketinški podaci o bezbednosti lekova i BLiDS evidentirani sistemom spontanog prijavljivanja. Primenom jasno definisnih kriterijuma izvršeno je pretraživanje dve baze bezbednosnih izveštaja o pojedinačnim slučajevima (Individual Case Safety Report – ICSR), i to: baze Svetske zdravstvene organizacije (SZO) (VigiBaseTM) i nacionalne baze Republike Srbije (baza Nacionalnog centra za farmakovigilancu - NCF). U identifikovanim slučajevima hepatotoksičnosti analizirane su dostupne informacije o prijavljenom suspektnom leku i/ili biljnoj vrsti, vrsti hepatotoksične reakcije, polu, uzrastu, upotrebi alkohola, osnovnim bolestima, istovremeno primenjivanim lekovima i/ili BLiDS, i zemlji porekla. Dobijeni su sledeći rezultati: 1) Istraživanje slučajeva lekovima izazvane hepatičke insuficijencije evidentiranih u VigiBaseTM tokom desetogodišnjeg perioda od 01.01.2000. do 31.12.2009. godine U navedenom periodu identifikovano je 6.370 slučajeva lekovima izazvane hepatičke insuficijencije (Drug Induced Hepatic Failure – DIHF) prijavljenih VigiBaseTM iz 38 zemalja. SAD su prijavile najveći broj ICSR (4.659; 73,1%). Od evropskih zemalja, najveći broj prijava DIHF dostavile su Nemačka (423; 6,6%) i Velika Britanija (316; 5,0%). Broj slučajeva u kojima su pacijenti bili ženskog pola (Ž) je bio statistički značajno veći i iznosio je 3.237 (50,82%) slučajeva, dok je 2.754 (43,23%) slučajeva bilo muškog pola (M) (p<0,001)...

Due to potential for very serious clinical consequences and difficulties in detection and diagnosis, drug-induced liver injury (DILI) is a highly significant safety risk for patients and ongoing pharmacotherapeutic challenge for health professionals, regulatory agencies and pharmaceutical industry. Although herbal medicines and dietary supplements are widely used and generally considered safe, individual case reports on toxic liver injury associated with their administration indicate significance of investigation on hepatotoxic potential of herbal products. Hepatotoxic reactions (HRs) are usually not identified in preclinical and clinical studies, and get detected during post-marketing surveillance (phase IV). This thesis involves research of post-marketing safety data on medicines and herbal products originating from the spontaneous reporting system. Clearly defined search criteria were applied for the investigation of two databases of individual case safety reports (ICSRs): the World Health Organization (WHO) database (VigiBaseTM) and the Serbian national database (the National Pharmacovigilance Centre - NPC database). In the identified cases of hepatotoxicity available data were analyzed with regards to suspected drug and/or herbal species, type of hepatotoxic reaction, gender, age, use of alcohol, underlying diseases, concomitant medications and/or HMDS, and reporting country. Following results were obtained: 1) Investigation of drug induced hepatic failure recorded in the VigiBaseTM during the 10-year period, from January 01, 2000 to December 31, 2009 There were 6,370 cases of drug induced hepatic failure (DIHF) reported from 38 countries to the VigiBaseTM in the analyzed period. The US reported the majority of ICSRs (4,659; 73.1%). Among the European countries, the highest number of DIHF reports was submitted by Germany (423; 6.6%) and the United Kingdom (316; 5.0%). Female gender (F) was reported in 3,237 (50.82%) cases of DIHF, whereas male gender (M) was found in 2,754 (43.23%) reports (p<0.001). The majority of ICSRs referred to age group 50-59 (875; 13.74%), followed by groups aged 60-69 (837; 13.13%) and 40- 49 years (831; 13.05%). After exclusion of reports of unknown gender or age, females accounted for 54.03%, and age under 55 years represented 56.48% DIHF cases (p<0.001)...