Farmakoepidemiološka studija spontano prijavljenih hepatotoksičnih reakcija na lekove i biljne dijetetske suplemente
Pharmacoepidemiological study of spontaneously reported hepatotoxic reactions of drugs and herbal dietary supplements
Докторанд
Petronijević, Marija M.Ментор
Ilić, KatarinaЧланови комисије
Le Louet, HerveUgrešić, Nenad
Dobrić, Silva
Erić, Slavica
Метаподаци
Приказ свих података о дисертацијиСажетак
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 j...e 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)...