Pregled v nosečnosti kontraindiciranih zdravilnih učinkovin ter alternativnih metod za vrednotenja njihove reproduktivne toksičnosti

Malek, Tina (author), Peterlin Mašič, Lucija (mentor)

Na svetovnem trgu je veliko zdravil, ki so kontraindicirana v nosečnosti, saj lahko povzročajo razvojne nepravilnosti na plodu. V predkliničnih in kliničnih fazah vrednotenja novih zdravil se izvajajo testi reproduktivne in razvojne toksičnosti, s katerimi se ugotavljajo vplivi zdravil na zarodek oz. plod. Ker so ti testi v večini primerov izvedeni na živalskih modelih, znanstveniki v zadnjih desetletjih razvijajo alternativne metode testiranja, ki bi zmanjšale uporabo živali. Namen magistrske naloge je narediti pregled smernic o testiranju novih zdravil na reproduktivno in razvojno toksičnost, pregledati alternativne in vitro metode, ki se uporabljajo za testiranje, ter preučiti izbor v nosečnosti kontraindiciranih zdravilnih učinkovin in njihove mehanizme toksičnega delovanja na plod. Priporočila za testiranje zdravil na reproduktivno in razvojno toksičnost so zapisana v smernici ICH S5 (R3). Za pregled alternativnih metod testiranja smo uporabili znanstvene članke iz baze PubMed, z iskalnim profilom »(reproductive OR developmental) AND toxicity AND testing AND alternative methods« ter omejitvami: raziskave v angleščini, pregledni članki in sistematični članki v obdobju 2017–2022. V nosečnosti kontraindicirane zdravilne učinkovine smo pregledali v bazah eMedExpert in MPR, mehanizme pa preučili v bazi Google Učenjak, z iskalnim profilom »izbrana ZU v angleščini« ter »teratogenic mechanism«, »teratogenicity« in »mechanism of reproductive toxicity«. Smernice za testiranja vključujejo informacije o strategijah testiranja, testnih vrstah, časovnih okvirjih in ciljih testiranj. Ker se večina eksperimentalnih živali na svetu uporabi v študijah toksičnosti za razvoj, so vedno bolj v veljavi in vitro metode, najbolj znane so test kulture celotnih zarodkov glodalcev, test kulture mišjih embrionalnih matičnih celic in test kulture ribe navadne cebrice. Med številnimi zdravilnimi učinkovinami, ki so kontraindicirane v nosečnosti, smo jih izbrali 14, ki so na voljo na slovenskem trgu. Mehanizmi njihovega teratogenega delovanja so antagonizem folatov, motnje v celicah nevralnega grebena, endokrine motnje, oksidativni stres, motnje v ožilju ter teratogeneza, posredovana s posebnimi receptorji ali encimi npr. HMG-CoA reduktazo. Alternativne metode testiranja se v zadnjih letih veliko uporabljajo, ampak še dolgo ne bodo mogle nadomestiti klasičnih testiranj na živalih, podrobnejši mehanizmi teratogenosti pa so zaradi svoje kompleksnosti še vedno velika neznanka.

• Language: Slovenian
• Keywords: reproduktivna in razvojna toksičnost, smernice testiranja, in vitro alternativne metode, kontraindicirane zdravilne učinkovine
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-143482
• Publication date in RUL: 22.12.2022

Secondary language

• Language: English
• Title: Overview of medicines contraindicated in pregnancy and of alternative methods for corresponding reproductive toxicity testing

Abstract

There are many drugs on the world market that are contraindicated during pregnancy, as they can cause developmental abnormalities in the fetus. In preclinical and clinical phases of evaluating new drugs, tests of reproductive and developmental toxicity are carried out, which determine the effects of the drugs on the embryo or fetus. Since these tests are in most cases carried out on animal models, scientists have been developing alternative testing methods in recent decades that would reduce the use of animals. The purpose of this thesis is to review the guidelines on new drug testing for reproductive and developmental toxicity, to review alternative in vitro methods used for testing and examine the selection of medicines contraindicated in pregnancy and their mechanisms of toxic action on the fetus. Recommendations for drug testing for reproductive and developmental toxicity are set out in ICH S5 (R3) guideline. To review alternative testing methods, we used scientific articles from the PubMed database, using search profile "(reproductive OR developmental) AND toxicity AND testing AND alternative methods" and restrictions: research in English, review articles and systematic articles from 2017–2022. Medicines contraindicated in pregnancy were examined in the eMedExpert and MPR databases, and the mechanisms in the Google Scholar database, with the search profile " active substance in English" and "teratogenic mechanism", "teratogenicity" and "mechanism of reproductive toxicity". Testing guidelines include information on testing strategies, test types, timeframes, and testing goals. Since most of the world's experimental animals are used in developmental toxicity studies, in vitro methods are used, the most famous being rodent whole embryo culture test, mouse embryonic stem cells test and zebrafish. Among many medicinal substances that are contraindicated in pregnancy, we have selected 14 available on the Slovenian market. The mechanisms of their teratogenic action are folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and teratogenesis mediated by specific receptors or enzymes e. g. HMG-CoA reductase. Alternative testing methods have been widely used in recent years, but they will not be able to replace classic animal testing for a long time, and the more detailed mechanisms of teratogenicity are still a big unknown due to their complexity.

• Keywords: reproductive and developmental toxicity, testing guidelines, in vitro alternative methods, contraindicated medicines