Teratogenic Drugs and Teratogenicity Tests


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Teratogenicity of Drugs and Teratogenicity Tests.

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Teratogenic Drugs and Teratogenicity Tests

  1. 1. Teratogenicity of Drugs & Teratogenicity Tests
  2. 2. Teratogenicity of Drugs
  3. 3. • Any substance that can induce or increase the incidence of a congenital malformation • Recognition of human teratogens offers the opportunity to prevent exposure
  4. 4. • Frequency of congenital malformations in women exposed is greater • This data is sometimes not available for humans & is not unbiased • There are clearly species differences between teratogenic effects
  5. 5. • Drugs are classified as to their teratogenic potential, based on anecdotal information or animal studies • Less than 2% of congenital malformations are caused by drugs or chemicals • Teratogenic drugs should be avoided either during or prior to conception
  6. 6. • Women to avoid all medications in the first 8 weeks after conception • Effects of teratogens, during the developmental period, results in an “all or none effect.”
  7. 7. 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
  8. 8. Risk Category of Drugs during Pregnancy: • Cat A- Adequate studies in pregnant women have failed to demonstrate a risk to the foetus • Cat B- Adequate human studies are lacking, but animal studies demonstrate a risk to foetus • Cat 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.
  9. 9. • Cat D- There is evidence of human foetal risk, but the potential benefits from use of the drug may be acceptable despite the potential risk. • Cat X- Studies in animals or humans have demonstrated foetal abnormalities, and potential risk clearly outweighs possible benefits.
  10. 10. TERATOGENIC MECHANISMS: • Folate antagonism • Neural crest cell disruption • Endocrine disruption • Oxidative stress • Vascular disruption and specific receptor • Enzyme-mediated teratogenesis
  11. 11. Proven Human Teratogens: Drug Abnormality Thalidomide Phocomelia, multiple defects Anti-neoplastic drugs Multiple defects, foetal death Androgens Virilization, esophageal, cardiac defects Progestins Virilization of female foetus Stilboestrol Vaginal carcinoma Tetracyclines Discoloured teeth, bone defects Warfarin Nose, Eye, Hand defects, Growth retardation Phenytoin Cleft lip/palate, microcephaly, hypoplastic phalanges
  12. 12. Alcohol Low IQ, Growth Retardation, Foetal alcohol syndrome ACE inhibitors Hypoplasia of organs, growth retardation, foetal loss Lithium Foetal goiter, Cardiac abnormality Antithyroid Drugs Foetal goiter, hypothyroidism Indomethacin Premature closure of ductus arterious Isotretinoin Craniofacial, Heart & CNS defects
  13. 13. Thalidomide: (Thalidomide disaster 1958-61) • Hypnotic agent widely used in Europe in 1959 • An estimated 7000 infants born with thalidomide syndrome or focomelia • Characteristic features include limb abnormalities
  14. 14. • Other malformations - Absence of the internal and external ears, hemangiomas, congenital heart disease & urinary tract malformations • Critical period of exposure  24 to 36 days after fertilization
  15. 15. Retinoic acid or Vitamin A derivatives: • Even at very low doses isotretinoin is potent teratogen • Malformations include  Craniofacial dysmorphisms,  Cleft palate,  Thymic aplasia  Neural tube defects • Critical period of exposure 2nd to 5th week of gestation.
  16. 16. Anti-neoplastic/chemotherapeutic agents: • Highly teratogenic  inhibit rapidly dividing cells • Malformations include cranial defects, leukopenia and malformed extremities • Occasionally used in the 3rd trimester when they are urgently needed to treat the mother.
  17. 17. Anticonvulsants: • Use of anticonvulsants leads to double the risk for malformations • Malformations like cleft lip, cleft palate, congenital heart disease, neural tube defects, microcephaly
  18. 18. Anticoagulants : • Warfarin (Coumarin) has been associated with Chondrodysplasia punctata • Other malformations like nasal hypoplasia, bone stippling seen on radiologic examination, bilateral optic atrophy and mental retardation
  19. 19. Thyroid and Antithyroid Drugs • Propylthiouracil (PTU) and methimazole both cross the placenta and may cause some degree of fetal goiter • Goal of such therapy during pregnancy is to keep the mother slightly hyperthyroid to minimize fetal drug exposure.
  20. 20. Tetracycline: • Protein synthesis inhibitor • Readily cross the placenta. • Brown discoloration of the deciduous teeth, hypoplasia of the enamel, and inhibition of bone growth • Critical period of exposure- 2nd & 3rd trimester
  21. 21. Streptomycin and Kanamycin: • Associated with congenital deafness • Ototoxicity was reported with doses as low 1 g streptomycin • Critical period of exposure- 1st trimester
  22. 22. Androgenic Steroids: • Androgens may masculinize a developing female fetus • Danazol to produce mild clitoral enlargement and labial fusion • Critical period of exposure 10 to 12 weeks after conception
  23. 23. ACE Inhibitor: • It can cause- fetal hypotension renal failure oligohydromnios death • Critical Period of exposure 2nd – 3rd trimester
  24. 24. Lithium: • Malformations caused are –Hypotonia –Cyanosis –Lethargy • Critical period of exposure 1st Trimester
  25. 25. Nicotine: • Constrict blood vessels • This decreases oxygen delivery to the fetus
  26. 26. Alcohol: • Malformation caused are –Low IQ –Growth Retardation –Foetal alcohol syndrome
  27. 27. Teratogenicity Test:
  28. 28. • Only Mammalian Species are to be used • Studies are carried in two animal species (rats & rabbits) • Drug is given after mating, during the period of organogenesis • Foetus is then examined for visceral or skeletal abnormalities
  29. 29. Testing Protocols: • Under the guidelines of FDA • Under the guidelines of ICH (International Conference on Harmonisation)
  30. 30. Test 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
  31. 31. Multigenerational Study: The animals are mated. Continuous exposure of a rodent species (usually mice) F1 Exposed shortly after weaning (30–40 days of age) The effects of the test is monitored through each generation. The measured parameters : Fertility Litter size Neonatal viability F2F3
  32. 32. Evaluation of Fertility and Reproductive Performance: Male rodents are treated for 70 days and nonpregnant females for 14 days . Treatment is continued in the females during Mating Pregnancy Lactation 50% of the females are sacrificed and the foetus are examined for presence of malformations. The other 50% are allowed to give birth. After weaning, these offspring are sacrificed and examined
  33. 33. Assessment of Developmental Toxicity: Treatment of pregnant females only during implantation through organogenesis One day prior to birth, the animals are sacrificed Fetuses examined for 1. Viability 2. Bodyweight 3. Presence of malformation
  34. 34. Postnatal Evaluation: 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
  35. 35. Test under ICH: • Fertility Assessment • Postnatal Evaluation and Pregnancy State Susceptibility • Assessment of Developmental Toxicity
  36. 36. Fertility Assessment: • 1. • 3. Males Females Exposed for four weeks before mating Two weeks before mating Evaluation Evaluation Reproductive organs weight Fertility Histological analysis Litter size Sperm count & mobility Viability of conceptus
  37. 37. Postnatal Evaluation and Pregnancy State Susceptibility: Comparing the degree of toxicity of the non pregnant female to that of the pregnant female Evaluation : Maternal toxicity Growth Functional development(off springs)
  38. 38. Assessment of Developmental Toxicity: Pregnant animals are exposed from implantation through organogenesis The study is conducted using atleast two species, one rodent and one non rodent. One day prior to birth , the animals are killed & foetus are examined. Evaluation : Viability Body weight Presence of malformation
  39. 39. Alternative Test Methods: • Micro mass test ( cells from the limb buds & brains of rat embroys) • Whole embryo culture test(whole embryos of rats) • Embryonic stem cell test
  40. 40. Conclusions:  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
  41. 41. Thank you