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The effect of indenopyridine hydrochloride on spermatogenesis in male rats and dogs
Fu, Lin Yung
|摘要:||Indenopyridine衍生物是一種有效之抑制造精作用的藥物。本論文實驗乃藉由觀察大鼠及犬的睪丸病變病程、分析公犬精液性狀變化及檢測血中睪固酮濃度來了解同屬indenopyridine衍生物的Indenopyridine Hydrochloride (IH)對造精作用抑制的情形。公犬及公大鼠口服30 mg IH /kg BW單一劑量之後，發現睪丸生精上皮細胞發生變性及脫落病變，同時在穿透式電子顯微鏡觀察下，大鼠的生殖細胞在IH投藥後第1天便開始顯現細胞凋亡(apoptosis)傾向。公大鼠連續兩次隔週投藥30 mg IH/kg BW抑制造精作用的病程與單一劑量並無明顯差異。公犬口服60 mg IH/kg BW單一劑量後二至八週會有寡精及甚至無精的現象，在投藥後三個月，其每次射精的精子總數又恢復至投藥前的正常數量，；而服用IH後的兩個月內其精漿鹼性磷酸酶(Alkaline Phosphatase)活性顯著上升(p<0.05)，表示睪丸的造精作用已有受到破壞。內泌素分析方面，發現公犬的血漿中睪固酮濃度並不受影響，此外公犬在服藥後依然具有正常的交配能力。另在毒物學試驗方面IH除抑制造精作用外，並無肝腎毒性，對腸道及骨髓等增殖分裂快速的細胞亦無毒性，且經Salmonella/microsome 檢側確定無致變性。IH會造成可逆的造精作用抑制，控制公犬授精能力達三個月之久，經毒物學測試無一般毒性，經進一步的試驗，可開發成理想之雄性避孕藥劑。|
Indenopyridine derivatives are known to be effective antispermatogenic agents. An indenopyridine derivatives, indenopyridine hydrochloride (IH), was examined in this study to understand its extent of antispermatogenic effect. Examinations including testicular histopathology, semen characteristics, and sera testosterone profiles, were conducted. Either male dogs and rats treated with single oral dosage of 30 mg IH/kg BW, resulted in germ cells degeneration, that sloughed into the lumen of the seminiferous tubule. When rats were administrated by 30 mg IH/kg BW for 24 hours, the germ cells showed heterochromatin margination, a character of cell apoptosis observed under the transmissible electron microscopy. From two weeks onwards to eight weeks after IH administration, the dogs exhibited oligospermia or azoospermia. Three months later, the sperm counts per ejaculate recovered. Alkaline phosphatase in seminal plasma elevated significantly (p<0.05) during experimental periods. This suggests that process of spermatogenesis was interrupted. When rats were administrated with double dosage of 30 mg IH/kg in one week apart, the antispermatogenic effect was not different from those treat with single dose. Testosterone profiles were normal in all dog cases examined. Sexual behaviors including, libido, erection capability, and ejaculation were not impaired by IH. IH treatment showed no toxicity to hepatic- renal- functions. Similarly, this compound didn't affect bone marrow and intestinal epithelium, nor mutagenic potential. Conclusively, IH exclusively inhibits spermatogenesis in a reversible manner. This might result in an episode of male infertility. IH possesses the clinical potential in development of male chemical castration medicine.
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