Uji Teratogenik

1. UjiTeratogenik • Untukmemprediksiapakahsuatusenyawamenimbulkancacatbawaanpadamanusia

2. Trageditalidomid 1961 • Senyawakimiadapatmenimbulkanefekteratogenikpadahewancoba • Seb. 1961 senyawakimiabarutdksecararutindilakukanpemeriksaanteratogenik (bagiandarievaluasikeamanan)

3. Hewancobaygdigunakan : Dianjurkanpada minimal 2 spesiesbintang. Kebanyakantikusataumencit, dankelinci • Pilihan strain , sedapatnya strain bebasdrmalformasispontan • Usia, BB hewankuranglebihsama • Ditempatkan pd kondisilingkunganygbaik, Panas, cahaya, kegaduhanseminimummgk • Waktu, carapemberian , lama paparanobatpentingdlmmenentukanefekteratogenik pd hewancoba

4. Makananygsama. • Biasanyadigunakantiga level dosis • Dosistinggi : toksik, tetapitdkmematikan pd induk • Dosisrendahmemberikanefekklinik • Dosis intermediate diataraduadosislainnya • Cara pemberianobatpadahewancobasamasptpenggunaannyadiklinik • Bila oral melaluisondelambung.

5. Senyawadiberikanpadaharike 6 -15 kehamilanpadatikusdanmencit,padakelinciharike 6-18 • Jumlahhewancoba: pada rodent sekurangnya 20 ekorbetinahamil, pada non-rodent 8-10 betinahamil per kelompok • Hewancobadikandangkanmasing Hewancobabetinadanjantandikandangkanbersamahanyautkwaktusingkat (1 hari) pd saattikus/mencitmasaproestrus/estrus

6. waktu mating perluditentukanuntukmenentukanpermulaankehamilan • Kopulasidiketahui dg adanya vaginal plug danspermapada vaginal smear

7. Hewancobadieperiksatiaphari, BB ditimbangsecararutin, tiaphariselamakehamilan • Careful handling • Perdarahan per vagina mungkinberhubungan dg resorpsi, aborsi

8. KehamilanharusdiakhiritdklebihdarisatuharisebelumperkiraanmelahirkanKehamilanharusdiakhiritdklebihdarisatuharisebelumperkiraanmelahirkan • Dilakukansectiocaesaria: pd mencitharike 19, tikusharike 21, kelinciharike 29 • Indukdimatikan dg eter, fraktur cervical, atausuntikan iv magnesium sulfatjenuh

9. Dihitungdandicatatjumlah corpus luteumjumlah fetus hidup, danresorpsi • Masing2 fetus ditimbang • Semua fetus diperiksautkmalformasi external • Fetus ditempatkanpadaalkohol 70 % utkpemeriksaantulang, danpadacairanBouin’sutkpemeriksaan visceral (selang-seling) • Tiapbotoldiberinomer

10. Pemeriksaan visceral • Tikusbiasanyadibiarkanselama 2 minggu pd cairanBouin’ssebelumdiperiksa • Setelah fetus diperiksakembaliutkmalformasieksternaldilakukan potongan2 (Freehand,razor-blade sections) dilakukanmenggunakantehnik Wilson (1965). • Potongankmddperiksadibawahmikroskoputkmelihatmalformasi. • Bilaperludilakukanpemeriksaanhistologis

11. Pemeriksaantulang Tikus • Setelah 2 haripadaalkohol 70 % dilakukanincisikecilpadadinding abdomen laludimasukkankembalike alkohol70 % selama 3 hari. Selanjutnya visceral fetus dikeluarkandiperiksaabnormalitas visceral . Fetus dimasukkankembalikealkoholsampaikeesokanharinyadansemalamdalamaceton

12. Selanjutnyaditempatkanpada potassium hydroxide/alizarin solution selama 2 hari, laludicuci dg air dandibersihkan dg campuran ethanol, glycerol dan benzyl alcohol selama 2 hari • Laludipindahkan pd alkohol 70 % utkpemeriksaan • Pd beberapa lab utkpemeriksaantulangrutindgn X ray, alizarin hanyadigunakanbilahasilmeragukan

13. FDA menganjurkan: 1/3 utkpemeriksaan visceral, 2/3 utkpemeriksaantulang recommended by the U.S.A. Food & Drug • Utkkelinci : semua fetus diperiksa external, visceral, dantulang

14. Categorization of drug risks to the fetus (FDA) Category A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. • Category B Either animal studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

15. Category C Either studies in animals have revealed adverseeffectson the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. • Category D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

16. Category X Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

17. Thank You