Discovery and Development of Veterinary Antiparasitic Drugs: Past, Present and Future

Woods, Debra J.; Vaillancourt, Valerie; Wendt, John A.; Meeus, Patrick

doi:10.4155/fmc.11.39

Cited by 26 publications

(16 citation statements)

References 37 publications

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“…For CPIs, it remains to be determined whether a spectrum of activity exists, nevertheless, the discovery of this new class of hookworm anthelmintic with a distinct mechanism of action from ABZ is potentially useful given the concerns regarding the future of benzimidazoles as effective drugs. In addition, as is now common in the animal health industry [16], [75] and in the treatment of many infectious diseases of humans [76], [77], [78], drug combinations must be considered if the efficacy of the few anthelmintic drugs available is to be protected. Thus, treatment of hookworm disease and other STHs might also benefit from drug combinations in which the contribution of CPIs could be substantial by improving either anthelmintic efficacy and/or spectrum of activity.…”

Section: Discussionmentioning

confidence: 99%

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

2012

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BackgroundHookworm disease is a major global health problem and principal among a number of soil-transmitted helminthiases (STHs) for the chronic disability inflicted that impacts both personal and societal productivity. Mass drug administration most often employs single-dose therapy with just two drugs of the same chemical class to which resistance is a growing concern. New chemical entities with the appropriate single-dose efficacy are needed.Methods and FindingsUsing various life-cycle stages of the hookworm Ancylostoma ceylanicum in vitro and a hamster model of infection, we report the potent, dose-dependent cidal activities of the peptidyl cysteine protease inhibitors (CPIs) K11002 (4-mopholino-carbonyl-phenylalanyl-homophenylalanyl- vinyl sulfone phenyl) and K11777 (N-methylpiperazine-phenylalanyl-homophenylalanyl-vinylsulfone phenyl). The latter is in late pre-clinical testing for submission as an Investigational New Drug (IND) with the US Federal Drug Administration as an anti-chagasic. In vitro, K11002 killed hookworm eggs but was without activity against first-stage larvae. The reverse was true for K11777 with a larvicidal potency equal to that of the current anti-hookworm drug, albendazole (ABZ). Both CPIs produced morbidity in ex vivo adult hookworms with the activity of K11777 again being at least the equivalent of ABZ. Combinations of either CPI with ABZ enhanced morbidity compared to single compounds. Strikingly, oral treatment of infected hamsters with 100 mg/kg K11777 b.i.d. (i.e., a total daily dose of 200 mg/kg) for one day cured infection: a single 100 mg/kg treatment removed >90% of worms. Treatment also reversed the otherwise fatal decrease in blood hemoglobin levels and body weights of hosts. Consistent with its mechanism of action, K11777 decreased by >95% the resident CP activity in parasites harvested from hamsters 8 h post-treatment with a single 100 mg/kg oral dose.ConclusionA new, oral single-dose anthelmintic that is active in an animal model of hookworm infection and that possesses a distinct mechanism of action from current anthelmintics is discovered. The data highlight both the possibility of repurposing the anti-chagasic K11777 as a treatment for hookworm infection and the opportunity to further develop CPIs as a novel anthelmintic class to target hookworms and, possibly, other helminths.

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Section: Discussionmentioning

confidence: 99%

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

2012

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“…Afoxolaner is a highly effective ectoparasiticide used against flea and tick infestations in dogs (Dumont et al ., ,b; Hunter et al ., ; Kondo et al ., ; Kunkle et al ., ,b; Mitchell et al ., ,b). The high potency against fleas and ticks is a hallmark of isoxazoline parasiticides (Ozoe et al ., ; Woods et al ., ). Afoxolaner has high specificity for a unique binding site in insect and acarid GABA‐gated chloride channels with no known relevant binding to the mammalian GABA receptor (Ozoe et al ., ; Shoop et al ., ).…”

Section: Introductionmentioning

confidence: 97%

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

Letendre¹,

Harriman²,

Drag³

et al. 2016

Vet Pharm & Therapeutics

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The pharmacokinetics of afoxolaner and milbemycin oxime (A3 and A4 forms) in dogs were evaluated following the oral administration of NexGard Spectra (Merial), a fixed combination chewable formulation of these two active pharmaceutical ingredients. Absorption of actives was rapid at levels that provide the minimum effective doses of 2.5 mg/kg and 0.5 mg/kg of afoxolaner and milbemycin oxime, respectively. The time to maximum afoxolaner plasma concentrations (t ) was 2-4 h. The milbemycin t was 1-2 h. The terminal plasma half-life (t ) and the oral bioavailability were 14 ± 3 days and 88.3% for afoxolaner, 1.6 ± 0.4 days and 80.5% for milbemycin oxime A3 and 3.3 ± 1.4 days and 65.1% for milbemycin oxime A4. The volume of distribution (V ) and systemic clearance (Cls) were determined following an IV dose of afoxolaner or milbemycin oxime. The V was 2.6 ± 0.6, 2.7 ± 0.4 and 2.6 ± 0.6 L/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The Cls was 5.0 ± 1.2, 75 ± 22 and 41 ± 12 mL/h/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The pharmacokinetic profile for the combination of afoxolaner and milbemycin oxime supports the rapid onset and a sustained efficacy for afoxolaner against ectoparasites and the known endoparasitic activity of milbemycin oxime.

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“…Current programs of anthelmintic drug discovery, especially those that operate in industrial settings, focus primarily on the discovery of new drugs for veterinary indications: mainly gastrointestinal nematodes of livestock and companion animals, and canine heartworm (Woods et al., 2007, Woods et al., 2011, Woods and Knauer, 2010, Geary et al., 2015). Furthermore, it is worthy of note that many of the anthelmintics used in human medicine were originally developed for the veterinary sector (Geary et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in ion channel genes of Dirofilaria immitis : Relevant knowledge for future anthelmintic drug design

Mani

Bourguinat

Keller

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite. Any new drug that targets these ion channels is likely to have a motility phenotype and should act to clear the worms from the host. Many of the successful anthelmintics in the past have targeted these ion channels and receptors. Knowledge about genetic variability of the ion channel and receptor genes should be useful information for drug design as receptor polymorphism may affect responses to a drug. Such information may also be useful for anticipation of possible resistance development. A total of 224 ion channel genes/subunits have been identified in the genome of D. immitis. Whole genome sequencing data of parasites from eight different geographical locations, four from ML-susceptible populations and the other four from ML-loss of efficacy (LOE) populations, were used for polymorphism analysis. We identified 1762 single nucleotide polymorphic (SNP) sites (1508 intronic and 126 exonic) in these 224 ion channel genes/subunits with an overall polymorphic rate of 0.18%. Of the SNPs found in the exon regions, 129 of them caused a non-synonymous type of polymorphism. Fourteen of the exonic SNPs caused a change in predicted secondary structure. A few of the SNPs identified may have an effect on gene expression, function of the protein and resistance selection processes.

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Discovery and Development of Veterinary Antiparasitic Drugs: Past, Present and Future

Cited by 26 publications

References 37 publications

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

Polymorphism in ion channel genes of Dirofilaria immitis : Relevant knowledge for future anthelmintic drug design

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