teratogenic drugs and teratogenicity tests
TRANSCRIPT
Teratogenicity of Drugs &
Teratogenicity Tests
Teratogenicity of
Drugs
• Any substance that can induce or increase the incidence of a congenital malformation
• Recognition of human teratogens offers the opportunity to prevent exposure
• 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
• 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
• 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.”
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
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.
• 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.
TERATOGENIC MECHANISMS:
• Folate antagonism
•Neural crest cell disruption
• Endocrine disruption
•Oxidative stress
• Vascular disruption and specific receptor
• Enzyme-mediated teratogenesis
Proven Human Teratogens:Drug AbnormalityThalidomide 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
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
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
• 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
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.
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.
Anticonvulsants:
• Use of anticonvulsants leads to double the risk
for malformations
• Malformations like cleft lip, cleft palate,
congenital heart disease, neural tube defects,
microcephaly
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
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.
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
Streptomycin and Kanamycin:
• Associated with congenital deafness
• Ototoxicity was reported with doses as low 1 g streptomycin
• Critical period of exposure- 1st trimester
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
ACE Inhibitor:
• It can cause- fetal hypotensionrenal failureoligohydromniosdeath
• Critical Period of exposure 2nd – 3rd trimester
Lithium:
• Malformations caused are–Hypotonia–Cyanosis– Lethargy
• Critical period of exposure 1st Trimester
Nicotine:
• Constrict blood vessels• This decreases oxygen delivery to the fetus
Alcohol:
• Malformation caused are– Low IQ–Growth Retardation– Foetal alcohol syndrome
Teratogenicity Test:
• 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
Testing Protocols:
• Under the guidelines of FDA • Under the guidelines of ICH
(International Conference on Harmonisation)
Test under FDA:
• Multigenerational studies
• Single generational studiesa) Segment I:Evaluation of Fertility and
Reproductive Performanceb) Segment II: Assessment of Developmental
Toxicityc) Segment III: Postnatal Evaluation
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
Evaluation of Fertility and Reproductive Performance:
Male rodents are treated for 70 days and nonpregnantfemales 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% areallowed to give birth. After weaning, these offspring are sacrificed and examined
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
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
Test under ICH:
• Fertility Assessment
• Postnatal Evaluation and Pregnancy State Susceptibility
• Assessment of Developmental Toxicity
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
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)
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
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
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
Thank you