ABSTRACT
Vertical transmission of larvae is a major pathway in the life cycle of several species of Strongyloides, but evidence for it occurring in humans or dogs with Strongyloides stercoralis is absent. In an effort to determine if vertical transmission could occur with S. stercoralis, each of 3 female dogs was infected with filariform larvae at a different stage of the reproductive cycle, i.e., preconception, gestation, or postpartum. Results showed that none of 6 pups born to a female infected before conception or any of 6 pups born to another female infected during gestation harbored any stage of S. stercoralis when necropsied at parturition. Conversely, all 5 pups that nursed from the female infected immediately postpartum became infected with adult S. stercoralis in their small intestines (range, 56-129 adult worms). Significantly, live filariform larvae of S. stercoralis were observed on 2 different occasions from milk samples taken from the lactating female. Because arrested development of larvae is not known in S. stercoralis, there is no reservoir of larvae in the parenteral tissues of females to queue for passage to the pups and, thus, it is not surprising that only timely infections, perhaps very late in gestation and during lactation, can be successful. These data support previous work in dogs with S. stercoralis, which concluded that vertical transmission through prenatal pathways does not occur, but they are the first from the dog to indicate that vertical transmission of this parasite through transmammary routes is possible. Whether transmammary transmission of S. stercoralis occurs in humans remains unknown but given its immense pathological potential, it should not be overlooked.
Subject(s)
Dog Diseases/parasitology , Infectious Disease Transmission, Vertical/veterinary , Milk/parasitology , Strongyloides/growth & development , Strongyloidiasis/veterinary , Animals , Dog Diseases/transmission , Dogs , Feces/parasitology , Female , Intestine, Small/parasitology , Lactation , Pregnancy , Strongyloidiasis/parasitology , Strongyloidiasis/transmissionABSTRACT
Nodulisporic acid A (NSA) is a novel natural product from a new structural class that was shown previously to have insecticidal activity against blowfly larvae. To determine if there was useful systemic efficacy against fleas (Ctenocephalides felis). NSA was evaluated in an artificial membrane flea feeding device and in dogs. In the artificial membrane flea feeding device, adult C. felis were allowed to feed on bovine blood containing various concentrations of NSA through a Parafilm membrane. NSA killed the fleas with a 50% lethal concentration of 0.68 microg/ml and was approximately 10-fold more potent than the systemic insecticide ivermectin. In the initial probe dog test, a single beagle was challenged with 100 C. felis before oral dosing with 15 mg/kg of NSA. Flea counts conducted at 72 hr postdosing showed an 88% reduction relative to control. Re-challenge of the same dog at 5 days postdosing showed 50% reduction of fleas at day 7, demonstrating some residual flea activity. In a confirmatory study, 8 dogs were challenged with 100 fleas just before oral dosing with 15 mg/kg of NSA (4 dogs) or vehicle (4 dogs). There was 99% reduction of fleas at 48 hr postdosing in the NSA-treated dogs relative to control. Additional challenges with 100 fleas were performed on these 8 dogs at 48-hr intervals to determine the duration of efficacy, and there was 97, 51, and 0% reduction of fleas relative to control on days 4, 6, and 8, respectively. No adverse effects were observed in the dogs in these studies. These data show that NSA has potent oral activity in the dog for the control of fleas, while lacking overt mammalian toxicity.
Subject(s)
Ancylostomiasis/veterinary , Dog Diseases/drug therapy , Ectoparasitic Infestations/veterinary , Indoles/therapeutic use , Insecticides/therapeutic use , Siphonaptera , Administration, Oral , Ancylostoma , Ancylostomiasis/drug therapy , Animals , Dogs , Ectoparasitic Infestations/drug therapy , Female , Indoles/administration & dosage , Indoles/blood , Injections, Intravenous/veterinary , Insecticides/administration & dosage , Membranes, Artificial , Parasite Egg Count/veterinary , Random Allocation , Specific Pathogen-Free OrganismsABSTRACT
Eprinomectin (MK-397 or 4"-epi-acetylamino-4"-deoxy-avermectin B1) is a novel avermectin selected for development as a topical endectocide for all cattle, including lactating dairy cows. Herein, we show its anthelmintic, insecticidal and miticidal activity. To determine its anthelmintic capabilities, eprinomectin was tested topically on Jersey calves at 0.08, 0.2, or 0.5 mg kg-1 in a probe formulation against experimental infections of adult Haemonchus placei, ostertagia ostertagi, Trichostrongylus axei, T. colubriformis, Cooperia oncophora, C. punctata, Nematodirus helvetianus, Oesophagostomum radiatum and Dictyocaulus viviparus. Eprinomectin removed > or = 99% and > or = 98% of the adult stage of every species at the 0.5 and 0.2 mg kg-1 dosage levels, respectively. The lowest dosage (0.08 mg kg-1) produced maximal or near maximal efficacy against most of the adult endoparasites with the exception of T. colubriformis (87%) and C. oncophora (88%). In a separate test, eprinomectin was evaluated topically against the immature stages of species at the same dosages. Results showed > or = 99% and > or = 98% removal of the immature stages of each species at the 0.5 and 0.2 mg kg-1 dosage levels, respectively. The 0.08 mg kg-1 dosage maintained > or = 97% efficacy against 6 species with reduced activity against H. placei (42%) and N. helvetianus (66%). For ectoparasites, eprinomectin was tested topically at 0.16, 0.24, 0.32 or 0.5 mg kg-1 on mixed breed cattle naturally infested with the sucking louse, Linognathus vituli. Complete elimination of lice at all dosages was observed by day 14. Topical delivery of eprinomectin at 0.16, 0.24, 0.32 or 0.5 mg kg-1 to Holstein calves experimentally challenged with horn fly, Haematobia irritans, produced 100% efficacy to challenge by week 2 post-treatment in all dosages groups and 94% and 99% efficacy to challenge at the 0.32 and 0.5 mg kg-1 dosage groups, respectively, at week 4. Topical delivery of eprinomectin at 0.16, 0.24 or 0.5 mg kg-1 to Deutsches Fleckvieh cattle infested with mange mites, Chorioptes bovis, produced > or = 95% control at all dosages levels by day 14 post-treatment and was maintained at or near this efficacious level for the 6-week duration of the trial. No adverse reaction was observed in any animal in any of these tests. In summary, these experimental data indicate that eprinomectin is an excellent broad-spectrum endectocide for cattle and is suitable for topical delivery.
Subject(s)
Anthelmintics/therapeutic use , Cattle Diseases , Helminths/drug effects , Ivermectin/analogs & derivatives , Mite Infestations/veterinary , Nematode Infections/veterinary , Sheep Diseases , Administration, Topical , Animals , Anthelmintics/administration & dosage , Anthelmintics/toxicity , Cattle , Diptera , Drug Design , Female , Ivermectin/administration & dosage , Ivermectin/therapeutic use , Ivermectin/toxicity , Lactation , Mite Infestations/drug therapy , Mites , Nematode Infections/drug therapy , Sheep , Structure-Activity RelationshipABSTRACT
Few studies have examined activity against trematodes for the avermectin/milbemycin class of anthelmintics. To gain insight into this, 12 different members of the avermectin/milbemycin mode of action class were tested against juvenile Fasciola hepatica in a mouse model. The compounds chosen were Avermectin A1, Avermectin A2, Avermectin B1, Avermectin B2, Ivermectin, Ivermectin monosaccharide, Ivermectin aglycone, 13-deoxy ivermectin aglycone, Moxidectin, 13-O-methoxyethoxymethyl ivermectin aglycone, 4"-deoxy-4"-epi-methylamino avermectin B1, and 4"-deoxy-4"-epi-acetylamino avermectin B1 5-oxime. Each of these compounds was administered orally to 4 mice at 2.0 mg kg-1. These mice had been administered 3 metacercariae of F. hepatica 14 days prior to treatment and all mice were necropsied 4 days after treatment. At necropsy, none of the individual avermectin or milbemycin-treated groups showed any significant activity (P > 0.05) against juvenile F. hepatica relative to a vehicle-treated control. In a receptor binding study, adult F. hepatica that had been obtained from sheep were homogenized, their membranes incubated in the presence of 3H-ivermectin, and then measured for high affinity binding sites. The same was done with the free-living nematode, Caenorhabditis elegans. While the C. elegans membranes displayed high affinity 3H-ivermectin binding sites over the range of ivermectin concentrations tested (5-100 nM), no significant 3H-ivermectin binding sites were detected in the F. hepatica membranes. Based on these data, it seems unlikely that any avermectin or milbemycin will show activity against F. hepatica, and certainly makes one pessimistic about possible activity of this mode of action class against trematodes in general.
Subject(s)
Antiplatyhelmintic Agents/metabolism , Antiplatyhelmintic Agents/therapeutic use , Fasciola hepatica , Fascioliasis/drug therapy , Ivermectin/metabolism , Ivermectin/therapeutic use , Animals , Anti-Bacterial Agents , Binding Sites , Caenorhabditis elegans/metabolism , Cell Membrane/metabolism , Fasciola hepatica/isolation & purification , Fasciola hepatica/physiology , Ivermectin/analogs & derivatives , Liver/parasitology , Macrolides/metabolism , Macrolides/therapeutic use , Mice , Structure-Activity RelationshipABSTRACT
To determine whether there is mutual resistance to avermectin and milbemycin anthelmintics, ivermectin and moxidectin sheep drenches were tested against ivermectin-resistant and susceptible isolates of Ostertagia circumcincta and Trichostrongylus colubriformis in sheep. None of the isolates had been exposed to moxidectin previously. The dosage of ivermectin required to remove 95 per cent of the ivermectin-resistant O circumcincta and T colubriformis were 23 times and six times larger, respectively, than the dosages required to remove the same percentage of susceptible isolates. The dosages of moxidectin required to remove 95 per cent of the ivermectin-resistant O circumcincta and T colubriformis were 31 times and nine times larger, respectively, than the dosages required to remove the same percentage of susceptible isolates. It is concluded that the worms resistant to ivermectin were also resistant to moxidectin.
Subject(s)
Anthelmintics/therapeutic use , Ostertagiasis/veterinary , Sheep Diseases/drug therapy , Trichostrongylosis/veterinary , Administration, Oral , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Drug Resistance , Female , Ivermectin/administration & dosage , Ivermectin/therapeutic use , Macrolides , Male , Ostertagia/drug effects , Ostertagia/isolation & purification , Ostertagiasis/drug therapy , Ostertagiasis/parasitology , Random Allocation , Sheep , Sheep Diseases/parasitology , Trichostrongylosis/drug therapy , Trichostrongylosis/parasitology , Trichostrongylus/drug effects , Trichostrongylus/isolation & purificationSubject(s)
Anthelmintics/administration & dosage , Anti-Bacterial Agents/administration & dosage , Dog Diseases/prevention & control , Hookworm Infections/veterinary , Macrolides , Administration, Oral , Ancylostomatoidea/isolation & purification , Animals , Dog Diseases/parasitology , Dogs , Female , Hookworm Infections/prevention & control , Intestines/parasitology , Male , Random AllocationABSTRACT
Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei and P charlesii, is a new anthelmintic with potential broad-spectrum use. In initial trials, it had an excellent safety profile in cattle and sheep at doses efficacious against a dozen or more helminths, but recently it produced unexpected and severe toxicosis in dogs at doses far below those that were safe in the ruminants. To provide data on which to build rational safety tests in the future, we tested the acute toxicity of paraherquamide administered PO to male CD-1 mice and compared its profile with the most potent anthelmintic known, ivermectin. The estimated doses lethal to 50% of a group of mice were 14.9 and 29.5 mg/kg of body weight for paraherquamide and ivermectin, respectively. The no-effect doses were 5.6 and 18.0 mg/kg for paraherquamide and ivermectin, respectively. Signs of intoxication in paraherquamide-treated mice, if they developed, emanated within 30 minutes of administration, irrespective of dose, and consisted of either mild depression with complete recovery or a 5- to 10-minute period of breathing difficulty followed by respiratory failure and death by 1 hour after treatment. Gross necropsy findings in paraherquamide-treated mice that died in the high-dose group were normal. Ivermectin-related toxicity was slower and more predictable, taking place over a 3-day period, with dose-dependent signs of intoxication consisting of tremors, ataxia, recumbency, coma, and death. Necropsy of ivermectin-treated mice that died in the high-dose group revealed dehydration, a condition most likely resulting from the coma-induced state.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Anthelmintics/toxicity , Indolizines/toxicity , Spiro Compounds/toxicity , Animals , Ivermectin/toxicity , Male , MiceABSTRACT
Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei and Penicillium charlesii, was tested against the adult stages of nine common gastrointestinal and lung nematodes of calves at single, oral dosages of 0.5, 1.0, 2.0 or 4.0 mg kg-1. At dosages 1.0-4.0 mg kg-1 there was 95% or more removal of Haemonchus placei, Ostertagia ostertagi, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia oncophora, Nematodirus helvetianus, Oesophagostomum radiatum, and Dictyocaulus viviparus. Cooperia punctata, the dosage-limiting species, was virtually unaffected by any dosage except the highest, which produced an efficacy of 89%. The 0.5 mg kg-1 dosage was 95% or more efficacious against H. placei, O. ostertagi, C. oncophora, and D. viviparus, but weaknesses were evident against the other five species. No adverse reaction was observe in any calf.
Subject(s)
Anthelmintics/therapeutic use , Cattle Diseases/drug therapy , Indolizines/therapeutic use , Nematode Infections/veterinary , Spiro Compounds/therapeutic use , Animals , Cattle , Intestinal Diseases, Parasitic/drug therapy , Intestinal Diseases, Parasitic/veterinary , Lung Diseases, Parasitic/drug therapy , Lung Diseases, Parasitic/veterinary , Male , Nematode Infections/drug therapyABSTRACT
Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei and Penicillium charlesii, was tested against the common gastrointestinal nematodes of dogs at a single oral dosage of 0.5, 1.0, or 2.0 mg kg-1. Efficacy was poor (less than 85%) against Ancylostoma caninum, Uncinaria stenocephala, Toxascaris leonina, Trichuris vulpis, and Strongyloides stercoralis at the low- and mid-dosage levels. At the high dosage level, good efficacy (91%) was observed only against S. stercoralis. Adverse reactions were observed in all dogs at every dosage level and included depression, ataxia, and protrusion of the nictitating membrane.
Subject(s)
Anthelmintics/therapeutic use , Dog Diseases/drug therapy , Indolizines/therapeutic use , Nematode Infections/veterinary , Spiro Compounds/therapeutic use , Animals , Dog Diseases/parasitology , Dogs , Nematode Infections/drug therapy , Nematode Infections/parasitologyABSTRACT
Specific binding sites for ivermectin (IVM; 22,23-dihydroavermectin-B1) were identified and characterized in a crude membrane fraction prepared from the nematode, Caenorhabditis elegans (C. elegans). Specific [3H]IVM binding was saturable with an apparent dissociation constant, Kd, of 0.26 nM and a receptor concentration of 3.53 pmol/mg protein. [3H]IVM binding in C. elegans was linear with tissue protein concentration, and optimal binding occurred within a pH range of 7.3 to 7.6. Kinetic analysis of the binding showed that the reaction proceeded by a two-step mechanism. Initially, a rapidly reversible complex was formed and, after additional incubation, this complex was transformed to a much more slowly reversible complex. Stereospecificity of [3H]IVM binding to C. elegans membranes was demonstrated by competition with a series of avermectin derivatives. The in vivo effects of IVM and its derivatives on C. elegans motility were concentration dependent and correlated well with their relative binding affinities. Several putative neurotransmitters including gamma-aminobutyric acid (GABA), carbamyl choline, taurine, glutamate and dopamine were tested and found to have no effect on IVM binding. Specific IVM binding sites were also identified in rat brain; however, the affinity was approximately 100-fold lower than that observed in C. elegans and stereospecificity studies demonstrated structural differences in the two binding sites. These results are the first direct demonstration of a specific IVM binding site in nematodes and thus are important in furthering our understanding of its mode of action.