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Studies on Efficacy and Toxicity of Ionophores in Rabbits Infected with Intestinal Coccidiosis
依毒性試驗結果顯示，施用salinomycin劑量20及40mg/kg bw/day連續給藥36天，導致飼料效率分別減少33.1及41.9％，並引起肝細胞空泡化、心肌病變、腿肌細胞及腎小管玻璃樣變性等病變。施用maduraimicin劑量0.375、0.5及0.625mg/kg bw/day連續給藥30天，可導致飼料效率分別減少36.4、63.6及68.2％，亦引起肝細胞呈現脂肪變性及肌細胞玻璃樣變性之變化。上述兩藥之處理亦可造成血清中，血清楚腰酸草酸醋酸轉氨酵素、乳酸去氫酵素、肌酵素、五十尿素氮及肌酸酉干等數值之上升。至於死亡率方面，salinomycin 20mg/kg bw/day為17％(1/6)，maduramnicinb 0.375、0.5及0.625mg/kg bw/day時，則分別為20、20及60％(3/5)。本研究結果所得最大安全劑量salmnomycin為5mg/kg bw/day（連續給藥36天），maduramicin則為0.25mg/kg bw/day（連續給藥30天）。
在藥效試驗中，於接種前3天開始給藥，全程共給藥17天，接種7x105個芽抱化卵囊/隻，接種之兔腸型球蟲包括：Eimeria perforans、E. media、E. intestinalis及E. magna，評估salinomycin劑量為3、4.5及6mg/kg bw/day，maduramicin劑量為0.125、0.25及0.375mg/kg bw/day。在salinomycin藥效試驗結果中，與未給藥未接種組比較，未給藥接種組，飼料效率減少224％，在接種後最高卵囊排出量約為(1.0±0.2)106個/每克糞材卵糞(Oocyst per gram feces; O.P.G.)，腸病變指數（依據：水腫、出血程度、白色斑狀病灶及死亡率評分）為15.3，死亡率為80％（4/5，接種後7天）；給藥salinomyein 4.5mg/kg bw/day接種組，增重增加3％，飼料消耗及飼料效率與未給藥未接種組相近，在接種後最高卵囊排出量小於(5±0.8)103個/O.P.G.，顯示4.5 mg/kg bw/day為salinomycin預防兔腸型球蟲症的適當使用劑量。salinomycin停藥1週時，可測得飼料消耗、增量及飼料效率增加。在maduramicin藥效試驗結果中，與未給藥未接種組比較，未給藥接種組，增重減少111％，在接種後最高卵囊排出量約為(1.2±0.1)106個/O.P.G.，腸病變指數為14.6，死亡率為40％（2/5，接種後7天）；給藥0.25mg/kg bw/day maduramicin接種組中的飼料消耗、增重及飼料效率等各項並無顯著的差異，在接種後最高卵囊排出量小於(8.2±0.1)103個/O.P.G.，顯示此劑量maduramicin可有效預防兔腸型球蟲症。當salinomycin 4.5mg/kg bw/day合併使用tiamulin 6.25或12.5 mg/kg bw/day，雖部份血液生化值有輕微上升，但皆未達顯著的差異，顯示此兩種藥物於上述劑量之合併使用對兔隻未造成明顯毒性作用。比較salinomycin及maduramicin對於兔腸型球蟲症之控制，顯示前者須較高的劑量但其安全使用範圍大，而後者所須的劑量較少但安全使用範圍卻狹隘，此可提供政府訂定規範，推薦現場使用。
Anticoccidial activity and toxicity of ionophorous antibiotics including salinomycin and maduramicin and the influence of tiamulin when co-administered with salinomycin were evaluated in New Zealand white rabbit (Orycotolagus camellias).
In a toxicity trial, rabbits fed with salinomycin at 20 and 40 mg/kg bw/day for 36 days were found to have reduced feed conversion ratio by 33.1%, and 41.9%, respectively. Histological observations of the treated rabbits included vesicular degeneration of hepatocytes, myopathies, and hyaline degeneration of leg muscle fibers and renal tubules. Treatment with maduramicin at 0.375, 0.5, and 0.65 mg/kg bw/day for 30 days reduced feed conversion ratio by 36.4%, 63.6%, and 68.2%, respectively. Histological lesion observed included fatty steatosis in liver and hyaline degeneration of muscle fibers. Both drug treatments as mentioned above also resulted in elevations in biochemical blood parameters, such as the values of AST, LDH, CK, BUN, and creatinine. The mortality caused by salinomycin at 20 mg/kg bw/day was 17% (1/6), while that of mauduramicin at 0.375, 0.5, and 0.625 mg/kg bw/day were 20%, 20%, and 60% (3/5), respectively. However, no apparent side effect was observed when the rabbits were given salmomycin at the dose of 5 mg/kg bw/day or maduramicin at 0.25 mg/kg bw/day.
Efficacy trials were performed by first giving each rabbit the drug for 3 days followed by challenging orally with 7x105 sporulated oocysts of rabbit intestinal coccidia (Eimeria perforans, E. media, E. intestinalis, and E. magna) and then treating with the same drug for 14 days. The following doses of ionophores (salinomycin: 3, 4.5, 6 mg/kg bw/day; maduramicin: 0.125, 0.25, 0.375 mg/kg bw/day) were treated. In the salmomycin efficacy trials, the feed conversion ratio in non-treated but infected group of rabbits was found to be 224% lower than that of the non-treated uninfected animals (control group). In addition to a lesion score (as determined by edema, hemorrhage, white plaque-like lesions and death) of 15.3 and 80% (4/5) mortality at day 7 postinfection (PI). In infected but treated with salinomycm at 4.5 mg/kg bw/day group of animals a weight gain of 3% coupled with no differences in feed consumption and feed conversion was observed as compared with the non-treated, uninfected control group. The average of peak oocyst output of the treated group was (5 0.8) 103 /Oocyst per gram feces (O.P.G.), while in the untreated infected group it was (1.0 0.2) 106 /O.P.G. Thus, salinomycm at 4.5 mg/kg bw/day was found to be effective against the intestinal coccidiosis in rabbits. The feed consumption, weight gain and feed conversion were increased during the 1-week withdrawal period of salinomycin.
In the maduramicin trial, the weight gain in non-treated infected group was observed to be 111% lower than that of the non-treated uninfected control group. Besides, the average of peak O.P.G. in the untreated group was (1.20.1) 106/O.P.G., a lesion score was 14.6 and the mortality was 40% (2/5) at day 7 PI. No differences in weight gain, feed consumption and feed conversion ratio were observed in infected animals treated with maduramicin at 0.25 mg/kg bw/day as compared with the control group. The average of peak O.P.G. in the treated group was (8.20.1) 103 /O.P.G. Thus maduramicin at 0.25 mg/kg bw/day was found to be effective against the intestinal coccidiosis in rabbits. No toxic effect was observed when tiamulin at 6.25 or 12.5 mg/kg bw/day was administered together with salinomycin at 4.5 mg/kg bw/day in rabbits. Nevertheless, the safety margin of salinomycin was found to be wider than that of maduramicin.
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