Progress and challenges in the discovery of macrofilaricidal drugs

Geary, Timothy G.; Mackenzie, Charles D.

doi:10.1586/eri.11.76

Cited by 50 publications

(39 citation statements)

References 98 publications

(101 reference statements)

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“…Some avermectins and moxidectin have unique characteristics that allow for greater flexibility in use. The longer half-life and safety profile of moxidectin allows it to be used in long-acting formulations (Prichard et al 2012), and interest has shifted on moxidectin as a filaricide (Geary and Mackenzie 2011 …”

Section: Discussionmentioning

confidence: 99%

Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage® Multi, Advocate®) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs

et al. 2015

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This study examined the efficacy of 10 % imidacloprid + 2.5 % moxidectin topical solution (Advantage ® Multi, Advocate ® , Bayer) for the treatment of circulating microfilariae from dogs naturally infected with Dirofilaria immitis. The study included two groups of 11 dogs each that consisted of two replicates. Replicate 1 contained 12 dogs (6 treated and 6 controls) and replicate 2 contained 10 dogs (5 treated and 5 controls). Six of the 10 dogs in replicate 2 were the controls from replicate 1. All dogs entering the study completed a physical examination including chest radiographs, blood collections for examination of Dirofilaria immitis circulating microfilariae, serum chemistry, complete blood counts and urinalysis. To qualify for the study each dog was required to have a geometric mean ≥ 300 microfilariae per ml of blood from 3 consecutive samples collected during the 8 day acclimation period and a heartworm disease classification of 1 or 2. Dogs were treated on study days 0 and 28. Post-treatment microfilarial counts were performed on study days 1, 2, 3, 7, 14, 21, 28, 29, 35, and 42. Percent microfilarial reduction was determined by comparing the geometric mean number of circulating microfilaria remaining in treated dogs with those remaining in the control dogs post-treatment. Seven days after the first treatment, the geometric mean microfilarial counts in treated dogs were reduced by > 99 % compared to the control dogs. Reduction remained at > 99 % through the end of the study at 42 days after the first treatment (14 days after the second treatment). The results of this study demonstrated that Advantage ® Multi for dogs is effcacious for treatment of circulating D. immitis microfilariae in naturally infected heartworm-positive dogs with no treatment-related adverse events observed. S166EndoparasitEs

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Section: Discussionmentioning

confidence: 99%

Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage® Multi, Advocate®) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs

et al. 2015

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“…These include a microfilaricidal effect combined with an embryostatic effect after a single dose and/or an adult worm (macrofilariae) sterilizing effect and/or a macrofilaricidal effect upon repeated exposure. Furthermore, repeated exposure to moxidectin might reduce the life time of the macrofilariae as discussed by Geary and Mackenzie [20] for the effect of long term treatment with ivermectin. Given a half life of 20–40 days in healthy volunteers [21]–[25] (around 20 days in the participants in this study, unpublished data, manuscript in preparation), a potential effect of moxidectin on the viability or development of transmitted L3 larvae could also be considered.…”

Section: Introductionmentioning

confidence: 99%

A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

Awadzi¹,

Opoku²,

Attah

et al. 2014

PLoS Negl Trop Dis

129

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BackgroundControl of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed.Methodology/Principal FindingsMen and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).Conclusions/SignificanceThe 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.Trial RegistrationClinicalTrails.gov NCT00300768

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“…Whilst it is inconclusive whether inflammatory reactions in patients post-treatment with anti-filarial drugs (e.g. "Mazzoti reactions") are a necessary component in the death of filariae or merely a response to dead and damaged worms [16] and the concomitant liberation of somatic antigens and Wolbachia endobacteria [32,33], the former has been proposed due to a general lack of efficacy of SAFD at physiological levels in vitro against filariae [34,35]. Further, various 'immuno-pharmacological' modes of action have been proposed for SAFD, including the prevention of immuno-modulatory secretions from mf by IVM [36] and the induction of host inducible nitric oxide and cyclooxygenase pathways by DEC [24].…”

Section: Discussionmentioning

confidence: 99%

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

Halliday

Guimarães

Tyrer

et al. 2014

Parasites & Vectors

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Background: New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model. Methods: The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7-15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca. Results: WT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.

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Progress and challenges in the discovery of macrofilaricidal drugs

Cited by 50 publications

References 98 publications

Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage® Multi, Advocate®) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs

Laboratory Evaluation of the Efficacy of 10 % Imidacloprid + 2.5 % Moxidectin Topical Solution (Advantage® Multi, Advocate®) for the Treatment of Dirofilaria immitis Circulating Microfilariae in Dogs

A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

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