moxidectin and Filariasis

Onchocerca lupi and Cercopithifilaria spp. are vector-borne filarioids of dogs, which harbour skin microfilariae (mfs), the former being of zoonotic concern. Proper treatment studies using compounds with microfilaricidal activity have not been performed. Therefore, this study aimed to assess the efficacy of a commercially available spot-on formulation containing moxidectin 2.5%/imidacloprid 10% for the treatment of O. lupi or Cercopithifilaria spp. skin-dwelling mfs in naturally infected dogs.. Privately owned dogs (n = 393) from southern Portugal were sampled via skin biopsies to identify and count mfs in 20 µl of skin sediment. A total of 22 mfs-positive dogs were allocated to treatment group (n = 11; G1) or left untreated as a control (n = 11; G2). As a pilot investigation to test the treatment efficacy, five dogs assigned to G1 were treated four times at monthly intervals with moxidectin 2.5%/imidacloprid 10% spot-on formulation on SDs 0, 28 (± 2), 56 (± 2), and 84 (± 2). Based on the negative results for both O. lupi and/or Cercopithifilaria spp. mfs of dogs in the pilot study from SD28 onwards, the remaining six dogs in G1 were treated at SD0 and assessed only at SD28.. Of the 393 animals sampled, 78 (19.8%) scored positive for skin-dwelling mfs. At the pilot investigation, a mean number of 19.6 mfs for O. lupi was recorded among five infected dogs whereas no mfs were detected at SD28. At SD0, the mean number of Cercopithifilaria spp. larvae was 12.6 for G1 and 8.7 for G2. The mean number of mfs for G2 was 20.09.. Results herein obtained suggest that a single treatment with moxidectin 2.5%/imidacloprid 10% spot-on formulation is efficacious against skin-dwelling mfs in dogs. The microfilaricidal effect of moxidectin could also be useful in reducing the risk of O. lupi infection for humans.

Topics: Animals; Anthelmintics; Dog Diseases; Dogs; Drug Compounding; Female; Filariasis; Filarioidea; Macrolides; Male; Neonicotinoids; Nitro Compounds; Onchocerca; Onchocerciasis; Pilot Projects; Portugal; Treatment Outcome

Cercopithifilaria bainae is a tick-vectored filarioid nematode associated with erythematous dermatitis in dogs. It has not been reported previously in the United States.. To describe clinical, histological and parasitological diagnosis and treatment of C. bainae in a dog.. An 11-month-old golden retriever/standard poodle mixed breed dog from Florida (USA).. The dog had no travel history within or outside the United States, was presented with a one month history of annular erythematous plaques on the head and ulcers on the medial canthi. Lesions were unresponsive to antibiotic treatment.. Histopathological evaluation of skin biopsies revealed an eosinophilic to lymphohistiocytic perivascular dermatitis with multiple microgranulomas and rare 5-10 μm diameter microfilariae within microgranulomas. Microfilarial morphology was consistent with C. bainae. PCR and sequencing of 18S rRNA and mitochondrial cytochrome oxidase subunit I genes confirmed the nematodes as C. bainae. The dog was treated with a commercial spot-on containing imidacloprid and moxidectin, and clinical resolution occurred.. To the best of the authors' knowledge, this is the first report of C. bainae in a dog in the United States and the first description of dermatological lesions caused primarily by C. bainae.

Topics: Administration, Cutaneous; Animals; Antinematodal Agents; Disease Transmission, Infectious; Dog Diseases; Dogs; Drug Therapy, Combination; Ectoparasitic Infestations; Female; Filariasis; Filarioidea; Florida; Macrolides; Nematoda; Neonicotinoids; Nitro Compounds; Rhipicephalus sanguineus; Skin

Despite the widespread distribution of Cercopithifilaria bainae among canine and tick populations worldwide, this filarioid is currently considered of 'minor importance' in veterinary medicine, particularly when compared to related filarioids, such as Dirofilaria immitis and Dirofilaria repens. To date, only a single case of dermatological alterations possibly associated to infection by C. bainae had been reported in a dog. In the present study, we describe the first case of systemic alterations associated to C. bainae infection in a dog suffering from diffused chronic polyarthritis. The animal had a previous history of reluctance to move and stiff gait and displayed multiple joint pain during manipulation of limbs. No biochemical, haematological and X-ray alterations were detected; microfilariae were observed in the synovial fluids collected from the joints. In spite of the morphological and molecular identification of these microfilariae as C. bainae, the dog did not respond to multiple microfilaricidal treatments with milbemicyn oxyme. The potential role of C. bainae in the pathogenesis of this clinical condition is discussed. Given the potential pathogenicity of this parasite, improved knowledge of this little known tick-borne nematode is warranted in order to assist the development of novel and effective treatment strategies.

Topics: Animals; Anthelmintics; Arthritis; Chronic Disease; Dog Diseases; Dogs; Filariasis; Filarioidea; Italy; Macrolides; Microfilariae; Sequence Analysis, DNA; Synovial Fluid; Tick-Borne Diseases

Moxidectin is a macrocyclic lactone belonging to milbemycin family closely related to ivermectin and is currently progressing towards Phase III clinical trial against human infection with the filaria Onchocerca volvulus (Leuckart, 1894). There is a single report on the microfilaricidal and embryostatic activity of moxidectin in case of the human lymphatic filarial parasite Brugia malayi (Brug, 1927) in Mastomys coucha (Smith) but without any adulticidal action. In the present study, the in vitro and in vivo antifilarial efficacy of moxidectin was evaluated on, B. malayi. In vitro moxidectin showed 100% reduction in adult female worm motility at 0.6 μM concentration within 7 days with 68% inhibition in the reduction of MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye) (which is used to detect viability of worms). A 50% inhibitory concentration (IC50) of moxidectin for adult female parasite was 0.242 μM, for male worm 0.186 μM and for microfilaria IC50 was 0.813 μM. In adult B. malayi-transplanted primary screening model (Meriones unguiculatus Milne-Edwards), moxidectin at a single optimal dose of 20 mg/kg by oral and subcutaneous route was found effective on both adult parasites and microfilariae. In secondary screening (M coucha, subcutaneously inoculated with infective larvae), moxidectin at the same dose by subcutaneous route brought about death of 49% of adult worms besides causing sterilisation in 54% of the recovered live female worms. The treated animals exhibited a continuous and sustained reduction in peripheral blood microfilaraemia throughout the observation period of 90 days. The mechanism of action of moxidectin is suggested to be similar to avermectins. The in silico studies were also designed to explore the interaction of moxidectin with glutamate-gated chloride channels of B. malayi. The docking results revealed a close interaction of moxidectin with various GluCl ligand sites of B. malayi.

Topics: Animals; Brugia malayi; Catalytic Domain; Chloride Channels; Female; Filariasis; Filaricides; Gerbillinae; Helminth Proteins; Macrolides; Male; Murinae; Protein Binding; Protein Conformation

Information on the efficacy of pharmaceutical protocols for the prevention of the major canine filarioses (i.e., Dirofilaria immitis, Dirofilaria repens, and Acanthocheilonema reconditum) under natural conditions is scant. Chemoprophylaxis for canine filarioses under field conditions deserves to be studied more fully and information about vector biology, ecology, and seasonality has to be well appreciated to correctly set control protocols. It is advisable that researchers planning field trials to assess the efficacy of any product for the prevention of canine vector-borne diseases should consider different eco-epidemiological aspects of diseases, including their dynamics of transmission, which are driven by complex interactions between animals, pathogens, and vectors.

Topics: Acanthocheilonema; Administration, Topical; Animals; Antinematodal Agents; Biomedical Research; Chemoprevention; Dirofilaria immitis; Dirofilaria repens; Dog Diseases; Dogs; Filariasis; Imidazoles; Macrolides; Neonicotinoids; Nitro Compounds; Treatment Outcome

This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 microg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (C(max)) of 234.0 +/- 64.3 ng/ml (mean +/- SD) were obtained for moxidectin and 132.6 +/- 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 +/- 149.3 h) than for ivermectin treated group (80.3 +/- 29.8 h). A significantly (p< 0.01) larger V(ss)/F was obtained for moxidectin (19.21 +/- 3.61 l/kg) compared with ivermectin (5.35 +/- 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 +/- 0.00381 and 0.0498 +/- 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time.

Topics: Administration, Oral; Animals; Area Under Curve; Brugia pahangi; Chromatography, High Pressure Liquid; Data Interpretation, Statistical; Dogs; Female; Filariasis; Filaricides; Half-Life; Indicators and Reagents; Ivermectin; Macrolides; Male; Spectrometry, Fluorescence

To study the pharmacokinetics and dose proportionality of moxidectin in beagle dogs experimentally infected with the filarial parasite Brugia pahangi, and to evaluate and compare the results obtained from population pharmacokinetic analysis and individual compartmental analysis.. Thirty-six infected dogs were selected and randomly allocated into six treatment groups of six dogs each. Doses of 250 or 1000 microg/kg were given orally. The plasma drug concentration-time data were analyzed by population compartmental and individual compartmental methods.. The best pharmacokinetic model was a two-compartment model with first-order absorption. According to the results obtained from population compartmental analysis, moxidectin is a low clearance drug with a relatively high volume of distribution, resulting in a mean terminal half-life of 458 h. Absorption was rapid with a mean absorption half-life of 0.6 h and T(max) of 2.75 h. Significant weight effect was found on Vc. These results were compared with results obtained from individual compartmental approach. A statistically significant (p<0.01) gender difference in T1/2beta was observed with the 250 microg/kg dose, and a trend was observed with a greater T1/2beta in females at the 1000 microg/kg dose. No gender effect on other pharmacokinetic parameters was found.. A pronounced distribution phase was observed and there was a significant weight effect on Vc. Dose proportionality of moxidectin was assessed by comparing the AUC (0-last determination) values for 250 and 1000 microg/kg. The pharmacokinetics are independent of dose over this dose range.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Brugia pahangi; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Filariasis; Macrolides; Male; Models, Biological

Effects of ivermectin and moxidectin were compared on two filarial species: Monanema martini which presents dermal microfilariae and induces Onchocerca-like lesions in its natural murid host Lemniscomys striatus, and Litomosoides sigmodontis (= L. carinii). M. martini microfilariae showed an unusual resistance to ivermectin, in vitro and in vivo; moxidectin was no more efficient. However, the two drugs used at high concentrations deeply altered the uterine embryogenesis, but had no lethal effect on adult filariae. L. sigmodontis blood microfilariae showed a great susceptibility to moxidectin, similar to that previously described for ivermectin. The two drugs also induced a long term effect because they inhibited the insemination of the female filariae. This result reinforces the observations made by other authors on the human parasite, Onchocerca volvulus.

Topics: Animals; Anti-Bacterial Agents; Antinematodal Agents; Drug Resistance; Female; Filariasis; Filarioidea; Gerbillinae; Ivermectin; Macrolides; Male; Microfilariae; Muridae; Reproduction

The avermectins ivermectin and doramectin and the milbemycins milbemycin A4 oxime and moxidectin were tested for filaricidal activity in Mastomys coucha infected with Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi, and B. pahangi. Single subcutaneous doses of 0.005-5 mg/kg (L. carinii), 0.0005-0.5 mg/kg (A. viteae), 0.5 and 5 mg/kg (B. malayi), and 5 mg/kg (B. pahangi) were injected. Necropsies were performed 42 days after treatment. The avermectins caused a strong and rapid reduction of microfilaraemia in L. carinii and A. viteae infections within a few hours after treatment but showed only moderate efficacies on microfilariae of Brugia spp. The effects of the milbemycin derivatives on L. carinii and A. viteae microfilariae were generally weaker than those of the avermectins. However, moxidectin was comparatively active against microfilariae of Brugia spp. Subsequently the parasitaemia levels of L. carinii and A. viteae infected animals remained either almost completely depressed or tended to reincrease in a dose dependent manner whereas there was generally a continuous decrease of microfilaraemia levels in Brugia spp. infected animals. Adulticidal effects were limited to A. viteae although with neither dose of neither drug > 95% reductions of adult worm counts were reached. However, pathogenic influences of the drugs were observed on intrauterine embryonic stages of the parasites.

Topics: Animals; Anthelmintics; Anti-Bacterial Agents; Brugia; Dipetalonema; Dose-Response Relationship, Drug; Female; Filariasis; Filarioidea; Ivermectin; Macrolides; Male; Microfilariae; Muridae; Parasitemia; Recurrence

Topics: Animals; Anti-Bacterial Agents; Cricetinae; Dipetalonema; Dipetalonema Infections; Female; Filariasis; Lactones; Macrolides; Male; Mebendazole

The filaricidal effect of milbemycin D, a compound closely related to ivermectin, was studied in vivo and in vitro using Litomosoides carinii. Microfilaria (mf) densities in the peripheral blood of cotton rats, Sigmodon hispidus, were reduced to less than 3% of initial densities within 24 hours after treating either subcutaneously or orally at doses of 0.05 to 50 mg/kg body weight. In cotton rats treated with diethylcarbamazine at a single dose of 200 mg/kg, mf densities were reduced transiently but recovered to initial levels within 2 weeks, whereas they remained at less than 20% of the initial levels in rats treated with milbemycin D even with a single dose of 0.05 mg/kg. No microfilaricidal effect was observed in cotton rats treated with milbemycin D at a dose of 50 mg/kg for 5 consecutive days. The microfilaricidal effect of milbemycin D was also shown in vitro in RPMI 1640 medium. The minimal effective dose of this compound was estimated to be between 1 and 10 micrograms/ml of medium.

Topics: Animals; Anti-Bacterial Agents; Arvicolinae; Blood; Diethylcarbamazine; Filariasis; Kinetics; Lactones; Macrolides; Microfilariae