Ivermectin B1b

The importance of the blood brain barrier (BBB) and the contribution to its function by the efflux transporter P-glycoprotein (P-gp) in teleosts were examined using the P-gp substrates and central nervous system neurotoxins ivermectin (22,23-dihydroavermectin B1a+22,23-dihydroavermectin B1b) [IVM]) and emamectin benzoate (4″-deoxy-49″epimethylaminoavermectin B1 benzoate [EB]). Trout were injected intraperitoneally with 0.01-1.0 and 1-50mg/kg of IVM or EB, respectively either alone or in combination with cyclosporin A (CsA: a P-gp substrate) at 1mg/kg. IVM affected the swimming performance (critical swimming speed, burst swimming distance, and schooling) at significantly lower concentrations than EB. When fish were exposed to IVM or EB in the presence of CsA, alterations to swimming were increased, suggesting that competition for P-gp in the BBB by CsA increased IVM and EB penetration into the CNS and decreased swimming capabilities. The effect of co-administration of CsA on swimming-related toxicity was different between IVM and EB-treated fish; EB toxicity was increased to a greater extent than IVM toxicity.

Anthelmintic activities of 22,23-dihydroavermectin B1 (comprised to greater than or equal to 95% 22,23-dihydroavermectin B1a and less than or equal to 5% 22,23-dihydroavermectin B1b) against gastrointestinal nematodes in calves were evaluated in 2 controlled experiments. Infective larvae of Haemonchus contortus, Ostertagia ostertagi, Trichostrongylus axei, T colubriformis, Cooperia oncophora, and C punctate were given to 11-week-old calves and Oesophagostomum radiatum had been given 21 days earlier to allow all larvae to attain adulthood at the same time. Each experiment had 4 groups of 5 calves each. Treatment was given to the calves at 14 weeks of age, and 7 to 8 days after treatment, the calves were necropsied. In experiment 1, group 1 control calves had a geometric mean of 11,054 nematodes; groups 2, 3, and 4 calves (at 14 weeks of age) given 22,23-dihydroavermectin B1 orally at doses of 50, 100, or 200 microgram/kg had reductions of 73.

Anthelmintic efficacy of ivermectin (greater than or equal to 80% 22,23-dihydroavermectin B1a and less than or equal to 20% 22,23-dihydroavermectin B1b) was evaluated in a controlled experiment against immature nematodes. Twenty calves raised to about 8 weeks of age under nematode-free conditions were allocated into 4 groups. Infective larvae of Haemonchus contortus, Ostertagia ostertagi, Trichostrongylus axei, T colubriformis, Cooperia oncophora, C punctata, Oesophagostomum radiatum, and Dictyocaulus viviparus were given orally to each calf on a staggered schedule 6 to 14 days before treatments. The drug was given subcutaneously when the nematodes were in the early 4th stage of development, and the calves were killed 23 or 24 days later. Group 1 nonmedicated control calves had a geometric mean of 25,102 nematodes; groups 2, 3, and 4 calves given ivermectin at dose rates of 50, 100, or 200 micrograms/kg had reductions of 88.2%, 98.0%, and 99.

Ivermectin, 22, 23-dihydroavermectin B1, is commercially important in human, veterinary medicine, and pesticides. It is currently synthesized by chemical reduction of the double bond between C22 and C23 of avermectins B1, which are a mixture of B1a (>80%) and B1b (<20%) produced by fermentation of Streptomyces avermitilis. The cost of ivermectin is much higher than that of avermectins B1 owing to the necessity of region-specific hydrogenation at C22-C23 of avermectins B1 with rhodium chloride as the catalyst for producing ivermectin. Here we report that ivermectin can be produced directly by fermentation of recombinant strains constructed through targeted genetic engineering of the avermectin polyketide synthase (PKS) in S. avermitilis Olm73-12, which produces only avermectins B and not avermectins A and oligomycin. The DNA region encoding the dehydratase (DH) and ketoreductase (KR) domains of module 2 from the avermectin PKS in S.