avermectin-b(1)a and Trichostrongylosis

Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.

Topics: Administration, Oral; Animals; Anthelmintics; Cattle; Cattle Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation; Female; Injections, Subcutaneous; Insecticides; Intestinal Diseases, Parasitic; Ivermectin; Male; Micelles; Mite Infestations; Mites; Nematode Infections; Rabbits; Random Allocation; Rats; Rats, Wistar; Trichostrongylosis

In a critical study, 40 female mixed-breed lambs with experimental infections of Cooperia spp, Trichostrongylus colubriformis, Ostertagia circumcincta, T axei, and Haemonchus contortus were allocated to 8 groups in 1977. Groups 1 and 5 served as controls. Groups 2 to 4 were treated orally with avermectin B1a at dosage levels of 25, 50, and 100 micrograms/kg of body weight, respectively. Groups 6 to 8 were given oral dihydroavermectin B1a at dosage levels of 50, 100, and 200 micrograms/kg, respectively. The lambs were euthanatized and necropsied 6 days after treatment. The compounds were greater than 99% effective at all dosage levels.

Topics: Animals; Anthelmintics; Drug Evaluation; Female; Gastrointestinal Diseases; Haemonchiasis; Intestinal Diseases, Parasitic; Ivermectin; Lactones; Ostertagiasis; Sheep; Sheep Diseases; Trichostrongyloidiasis; Trichostrongylosis

Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation conditions generated from both 1 and 3 the identical aromatic diacetate 11. Good anthelmintic activities in gerbils and sheep for 4"-acetylated derivatives 4 and especially 7 prompted the preparation of additional 4"-acylated derivatives of 2 with pivaloyl, n-octanoyl, succinoyl, carbamoyl, dimethylcarbamoyl and N-acetylglycyl substituents, prepared from the 5-O-tert-butyldimethylsilyl-protected intermediate 12. Other key intermediates were the trichloroethyoxysuccinoyl derivative 18 and 4-nitrophenyl carbonate 21. Anthelmintic activities against Trichostrongylus colubriformis in gerbils comparable in potency to the natural product 2 are shown by the more polar substituted derivatives 20, 23, and 27. Substitution of the 5-hydroxy group or its loss due to aromatization results in drastically reduced anthelmintic potency.

Topics: Animals; Anthelmintics; Chemical Phenomena; Chemistry; Gerbillinae; Haemonchiasis; Ivermectin; Lactones; Ostertagiasis; Sheep; Trichostrongylosis

Two formulations of avermectin B1a, C-076 and MK-933, were examined for anthelmintic activity in two trials, each using 20 calves with experimentally produced nematode infections. In one trial, C-076 was given orally, and in the other trial, MK-933 was given by injection at dosages of 50, 100, and 200 micrograms/kg of body weight. Treated calves were held for 7 to 8 days and then, together with nontreated controls, were euthanatized and were examined for nematodes in their gastrointestinal tracts and lungs. Efficacy of C-076 approached 100% for Dictyocaulus viviparus, Ostertagia ostertagi, Trichostrongylus axei, T colubriformis, and Oesophagostomum radiatum at 50 micrograms/kg. A dosage level of 100 micrograms/kg was required to achieve 97% efficacy against Cooperia punctata. Efficacy of MK-933 at 50 micrograms/kg was variable, but at 100 micrograms/kg, it approached 100% for D viviparus, O ostertagi, Haemonchus placei, T axei, and T longispicularis. Activity against C oncophora was less, reaching 80% efficacy at 200 micrograms/kg.

Topics: Animals; Anthelmintics; Cattle; Cattle Diseases; Dictyocaulus Infections; Ivermectin; Lactones; Nematode Infections; Oesophagostomiasis; Trichostrongylosis