Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

Abstract

The availability of a safe macrofilaricidal drug would help to accelerate onchocerciasis elimination. A trial was conducted in Cameroon to evaluate the effects of a subcutaneous injectable long-acting formulation of ivermectin (LAFI) on the microfilariae (mf) and adult stages of Onchocerca ochengi. Ten zebu cattle naturally infected with the parasite were injected subcutaneously with either 500 mg (group A, N = 4), or 1000 mg long-acting ivermectin (group B, N = 4) or the vehicle (group C, N = 2). Skin samples were collected from each animal before, and 6, 12, and 24 months after treatment to measure microfilarial densities (MFDs). Nodules excised before, and 6 and 12 months after treatment were examined histologically to assess the adult worms’ viability and reproductive status. Blood samples were collected at pre-determined time-points to obtain pharmacokinetic data. Before treatment, the average O. ochengi MFDs were similar in the three groups. Six months after treatment, all animals in groups A and B were free of skin mf, whereas those in group C still showed high MFDs (mean = 324.5 mf/g). Only one ivermectin-treated animal (belonging to group A) had skin mf 12 months after treatment (0.9 mf/g). At 24 months, another animal in group A showed skin mf (10.0 mf/g). The histologic examination of nodules at 6 and 12 months showed that LAFI was not macrofilaricidal but had a strong effect on embryogenesis. The new LAFI regimen might be an additional tool to accelerate the elimination of human onchocerciasis in specific settings.

Proof-of-concept study for a long-acting formulation of ivermectin injected in cattle as a complementary malaria vector control tool

“…For the two tested formulations, intra- and inter-animal variability in the pharmacokinetic profiles were observed. Fluctuation in ivermectin concentration has also been observed in other studies [ 38 ]. In addition, physiological factors, such as body mass index, unique to each individual animal, may carry some degree of variability.…”

“…The alternative injectable long-acting formulations of ivermectin were designed using the BEPO ® technology [ 37 ] and prepared as described in [ 38 ]. Briefly, a triblock copolymer, PLA 97 –PEG 45 –PLA 97 , and two diblock copolymers, mPEG 45 –PLA 130 and mPEG 7 –PLA 41 , were synthesized by ring-opening polymerization in bulk condition as already described (patent US 9023897 B2).…”

“…Next, 1.5 ml of the supernatant (i.e., the blood plasma) was transferred in plastic tubes and stored at −20 °C until further processing. Samples were analyzed for their ivermectin content as described by Boussinesq et al [ 38 ].…”

“…The depot progressively bioresorbs while delivering the active pharmaceutical ingredient with the desired pharmacokinetics. This technology was previously used to develop an ivermectin formulation which was tested for its microfilaricidal effect against Onchocerca ochengi [ 38 ].…”

Development of a recombinant vaccine against human onchocerciasis

“…ochengi natural transmission model is therefore a valuable tool for human onchocerciasis research allowing the evaluation and quantification of key aspects of infection and the lifecycle, including disease kinetics, adult worm and microfilarial burdens, female worm fecundity and viability. It has been also used extensively to aid investigations into basic parasite biology, including host-parasite interactions, vector biology and epidemiology as well as more applied clinical studies focused on testing vaccine candidates and efficacy trials of micro-and macrofilaricidal drugs [85][86][87][88][89][90][91][92][93][94][95] (Figure 2).…”