teratogenecity / abnormal fetous development

teratogenecity

1. TERATOGENICITY STUDIES Subject incharge : Dr. Babitha S M Pharm Ph D Associate professor Presentation by: Shailesh C M 2 nd Sem M Pharm Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

2. Definition Teratogenicity or reproductive toxicity broadly refers to the occurrence of biologically adverse effects on the reproductive system. Results from chemical exposure to several environmental agents (The capability of producing fetal malformation ) Characterised by: Alterations to the female or male reproductive organs. E ndocrine system abnormalities. P regnancy outcomes like Irregular Body structures and Abnormal out growth of tissues and body organs. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

3. Teratogen: A teratogen is an agent that can produce a permanent alteration of structure or function in an organism exposed during embryonic or fetal life. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

4. Principles of teratogenicity Teratogenic susceptibility is determined by the genotype of the conceptus. Susceptibility to teratogenic agents depends on the development stage of the embryo or fetus at the time of exposure. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

5. These agents work by specific mechanisms on developing cells and tissues to initiate pathogenesis. Perturbations of developmental processes can result in death, malformations, growth retardation. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

6. Teratogenic   drugs : A teratogen is an agent that can disturb the development of the embryo or fetus. Teratogens halt the pregnancy or produce a congenital malformation (a birth defect). Classes of teratogens include radiation, maternal infections, chemicals, and drugs. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

7. Historical teratogens: Thalidomide Accutane Diethyl stilbestrol (DES) Alcohol Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

8. Basic Characteristics of Teratogen: Teratology: Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human “ birth defects ”, but it is much broader than that, taking other non-birth developmental stages, including “ puberty ” and other non-human life forms, including plants . A given teratogen may be organ specific. It may be species specific. It can be dose specific. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

9. Critical periods : Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

10. Drugs can affect the foetus at 3 stages : • Fertilization & implantation - conception to 17 days • Organogenesis -18 to 55 days of gestation • Growth & development - 56 days onwards Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

11. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

12. Risk Category of Drugs during Pregnancy : • Category A- Adequate studies in pregnant women have failed to demonstrate a risk to the foetus. • Category B- Adequate human studies are lacking, but animal studies demonstrate a risk to foetus. • Category C- No adequate studies in pregnant women & animal studies are lacking or have shown an adverse effect on foetus, but potential benefit may require use in pregnant women. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

13. • Category D- There is evidence of human foetal risk, but the potential benefits from use of the drug may be acceptable despite the potential risk. • Category X- Studies in animals or humans have demonstrated foetal abnormalities, and potential risk clearly outweighs possible benefits . Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

14. TERATOGENIC MECHANISMS: • Folate antagonism • Neural crest cell disruption • Endocrine disruption • Oxidative stress • Vascular disruption and specific receptor • Enzyme-mediated teratogenesis Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

15. Testing Protocols : Under the guidelines of FDA Under the guidelines of ICH Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

16. Tests under FDA: Multigenerational studies Single generational studies a) Segment I : Evaluation of Fertility and Reproductive Performance b) Segment II : Assessment of Developmental Toxicity c) Segment III : Postnatal Evaluation Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

17. Tests under ICH: Fertility Assessment Postnatal Evaluation and Pregnancy State Susceptibility Assessment of Developmental Toxicity Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

18. Multigenerational Study: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

19. Evaluation of Fertility and Reproductive Performance: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY Male rodents are treated for 70 days and non-pregnant females for 14 days. Treatment is continued in the females during Mating Pregnancy Lactation 50% of the females are killed and the fetuses are examined for the presence of malformations . The other 50% are allowed to give birth. After weaning, these offspring are killed and necropsied.

20. Postnatal Evaluation: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY Pregnant animals are treated from the last trimester of pregnancy until weaning. Evaluation: Parturition process Late fetal development Neonatal survival Growth Presence of any malformations

21. Fertility Assessment: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

22. Postnatal Evaluation and Pregnancy State Susceptibility: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY Comparing the degree of toxicity of the non-pregnant female to that of the pregnant female Evaluation : Maternal toxicity Growth Functional development (off springs)

23. Assessment of Developmental Toxicity: Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY Pregnant animals are exposed from implantation to organogenesis The study is conducted using atleast two species, one rodent and one non rodent. One day prior to birth, the animals are killed and fetuses are examined. Evaluation: Viability Body weight Presence of malformations

24. Alternative Test Methods: Micro mass test (cells from the limb buds & brains of rat embryos) Whole embryo culture test (whole embryos of rats) Embryonic stem cell test Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

25. Conclusion: Understanding the mechanisms of the induction of birth defects is key to determine how to prevent these effects. Further increasing the accuracy of experimental animal extrapolation will aid in the interpretation of experimental data in order to more accurately determine the risk of a given compound to elicit birth defects in humans. Department of Pharmacology SREE SIDDAGANGA COLLEGE OF PHARMACY

26. THANK YOU!