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Biomedical subjects

B F Michael

Publications and source records attributed to B F Michael.

At least 19 recordsLinked to original sources
PubMed2005

Anthrax lethal factor inhibition.

The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) approximately 50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.

Animals↗
PubMed2002

Transmammary transmission of Strongyloides stercoralis in dogs.

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.

Animals↗
PubMed2001

Systemic efficacy of nodulisporic acid against fleas on dogs.

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.

Administration, Oral↗
PubMed2001

Systemic efficacy of nodulisporamides against fleas on dogs.

Nodulisporic acid A (NSA) has been shown previously to be safe in dogs and to deliver >90% flea control for 4 days following a single oral administration. Three newly prepared nodulisporamide derivatives were subsequently identified from an artificial membrane flea feeding system as exhibiting potency substantially greater than NSA. To determine if they have superior in vivo activity, these 3 nodulisporamides, as well as NSA, were evaluated in dogs at 15 mg/kg/os. Parasite challenges were made by placing 100 live Ctenocephalides felis fleas onto the dorsum of dogs every 48 hr and examining efficacy at each of those intervals over a 22-day period. Results showed that NSA produced >90% efficacy at day 2 and 81% efficacy at day 4, and its residual flea killing fell to approximately 50% by day 6 posttreatment. All dogs treated with the 3 new experimental nodulisporamides were 100% protected from flea challenges to day 8 posttreatment, and 2 of the compounds continued to produce >90% residual activity to 2 wk posttreatment. Pharmacokinetic analysis showed that plasma profiles and half-lives of NSA and these 3 new compounds correlated closely with flea efficacy. These results demonstrate that specific substitutions to the pharmacophore of NSA can substantially increase the duration of activity against fleas.

Administration, Oral↗
PubMed1998

Synthesis of gem-difluoro-avermectin derivatives: potent anthelmintic and anticonvulsant agents.

A series of gem-difluoro-avermectin derivatives was synthesized from the corresponding ketones at positions 4", 4', 13, and 23 using diethylaminosulfur trifluoride (DAST). These fluorinated avermectins exhibit potent antiparasitic activity in a new Haemonchus contortus larval assay and are equipotent to ivermectin. In addition, 23-gem-difluoro-ivermectin displays useful anticonvulsant activity in mouse models.

Animals↗
PubMed1996

Eprinomectin: a novel avermectin for use as a topical endectocide for cattle.

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.

Administration, Topical↗
PubMed1996

Efficacy of an ivermectin and pyrantel pamoate combination against adult hookworm, Ancylostoma braziliense, in dogs.

A chewable tablet incorporating ivermectin and pyrantel was tested in 12 Beagle dogs for efficacy against the adult hookworm, Ancylostoma braziliense. The dogs were administered infective larvae of A braziliense orally. Twenty-one days after infection the dogs were weighed and allocated randomly to receive either an oral treatment with ivermectin and pyrantel in a beef-based chewable tablet or no treatment. The chewable tablet was a commercially available product, which was made to deliver ivermectin at 6 micrograms/kg and pyrantel at 5.0 mg/kg to each dog. Seven days after treatment the dogs were euthanased, necropsied, and examined for adult hookworms. At necropsy, no adult A braziliense was observed in any of the 6 treated dogs and all 6 dogs that had been left untreated were infected with adult A braziliense (range, 48 to 161). It was concluded that this combination product is 100% efficacious against adult A braziliense.

Administration, Oral↗
PubMed1995

Avermectins and milbemycins against Fasciola hepatica: in vivo drug efficacy and in vitro receptor binding.

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.

Animals↗
PubMed1994

Comparison of thumb-counting and comb-counting methods to determine Ctenocephalides felis infestation levels on dogs.

Comb-counting and thumb-counting were compared in a cross-over study to determine which was more accurate for quantifying flea infestation levels on dogs. Twenty beagle dogs were used in the study and infested with either 50 or 100 adult fleas (Ctenocephalides felis). Two groups of five dogs each were infested with either 50 or 100 fleas per dog, and then comb-counted with a fine-toothed flea comb for 8 min periods. An additional two groups of five dogs each were also given 50 or 100 fleas, and then thumb-counted. The counting time for this technique is both lower and more variable because the fleas are only observed and not captured; thus, the speed at which the dog is covered must be increased in order to prevent counting the same fleas more than once. The mean time of thumb-counting per dog was 3.2 min. Fleas removed during comb-counting were placed back on the dog they were taken from after the count was concluded. At the cross-over point, the ten dogs that had been comb-counted were then thumb-counted and the ten dogs that had been thumb-counted were comb-counted. The results showed that comb-counting recovered significantly (P < or = 0.05) more fleas than did thumb-counting. On dogs given 50 and 100 fleas, comb-counting gave mean percentage recoveries of 67.6% and 75.4%, respectively, whereas thumb-counting found means of 8.8% and 7.7%, respectively. The order in which the counting methods were employed produced no significant effect (P > 0.05) on the number of fleas counted.

Animals↗
PubMed1993

Mutual resistance to avermectins and milbemycins: oral activity of ivermectin and moxidectin against ivermectin-resistant and susceptible nematodes.

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.

Administration, Oral↗
PubMed1992

Anthelmintic activity of paraherquamide in calves.

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.

Animals↗
PubMed1992

Acute toxicity of paraherquamide and its potential as an anthelmintic.

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)

Animals↗
PubMed1991

Anthelmintic activity of paraherquamide in dogs.

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.

Animals↗
PubMed1986

Critical test and safety evaluations of an oral paste preparation of mebendazole and trichlorfon in horses.

Critical tests were done on 24 naturally parasitized horses to compare the antiparasitic activity of an oral paste preparation of mebendazole and trichlorfon with that of the marketed powder formulation. Each formulation was administered at the recommended dosages of 8.8 mg of mebendazole and 40 mg of trichlorfon/kg of body weight. Efficacy of the paste formulation ranged from 97.7% to 100% against 2nd- and 3rd-stage Gasterophilus spp, adult Strongylus vulgaris, S edentatus, Parascaris equorum, small strongyles; and larval and adult forms of Oxyuris equi. Adverse effects were generally limited to slight softening of the feces. Mild and transient restlessness or sweating were also observed in 2 of 12 horses treated with the paste formulation. The toxic effects of the paste, administered at 2.2 times the therapeutic dose, were examined in 6 horses and compared with the effects of a nonmedicated paste, administered in similar volumes to 6 other horses. Drug-related changes were not detected in clinical chemical analyses, hematologic values, or liver function tests. Transient clinical signs of organophosphate toxicosis (primarily the passage of loose feces) and prolonged inhibition of erythrocyte cholinesterase activity were evident within 1 hour after drug treatment. These effects were similar to those reported for the 2.2 X dose of marketed powder formulation.

Animals↗
PubMed1985

Activity of closantel in the prevention of Gasterophilus and Strongylus vulgaris larval infections in equine foals and yearlings.

Two controlled tests were conducted in equine foals and yearlings to determine the optimal oral dosage and the duration of activity of closantel for the prevention of Gasterophilus spp larval infections. Additional data were collected on the activity of closantel against Strongylus vulgaris larval infections. In experiment 1, 12 foals and 12 yearlings were equally allocated to 4 experimental groups, and were given oral treatments with closantel at dosages of 0 (nontreated controls), 2, 5, or 8 mg/kg of body weight every 2 months during bot season. The foals and yearlings were allowed to graze on open pasture throughout the experiment to provide a natural source for bot and helminth infections. All animals were euthanatized and necropsied 6 weeks after the final treatment. Closantel was highly effective (98.6% to 100%) at all doses in preventing Gasterophilus spp larval infections in the foals, but only the 8 mg/kg dose had significant (P less than 0.05) activity (99.7%) in the yearlings. This dose also significantly reduced the numbers of 4th-stage and immature adult S vulgaris (86.0%) in the mesenteric arteries as compared with nontreated controls. In experiment 2, 9 foals and 9 yearlings received a single oral treatment of 8 mg of closantel/kg of body weight; 3 foals and 3 yearlings were kept as nontreated controls. Groups of 6 treated (3 foals, 3 yearlings) and 2 control (1 foal, 1 yearling) animals were euthanatized and necropsied 1, 2, and 3 months after treatment. Closantel remained effective for 2 months in preventing infections of G intestinalis larvae in these foals and yearlings. Clinical signs of toxicosis were not observed in the treated animals of either study.

Animals↗
PubMed1984

Controlled and clinical evaluations of the anthelmintic activity of a levamisole pour-on formulation against gastrointestinal nematodes in cattle.

Beef-type calves (n = 107) with naturally occurring helminth infections were used in a series of 3 controlled experiments to study the anthelmintic activity of a new pour-on formulation of levamisole. In the 1st experiment, the efficacy of a single treatment of levamisole pour-on at a rate of 10 mg/kg of body weight was determined, using a placebo pour-on in a similar volume as a control. In the 2nd experiment, calves were treated with levamisole pour-on at doses 0 (nontreated control), 7.5, 10, or 12.5 mg/kg of body weight. In the 3rd experiment, the anthelmintic efficacy of the optimal dose of levamisole pour-on (10 mg/kg of body weight) was compared with that of injectable levamisole at the recommended rate (6 mg/kg of body weight). In all 3 studies, levamisole pour-on, at a dosage of 10 mg/kg of body weight, was efficacious (90% to 100%) against the adult forms of Trichostrongylus axei, Haemonchus placei, Ostertagia ostertagi, Cooperia spp, Oesophagostomum radiatum, Nematodirus spp, and Bunostomum phlebotomum. Efficacy was moderate to good against Capillaria bovis, and poor or inconsistent against Strongyloides papillosus and Trichuris ovis. Clinical tests of anthelmintic efficacy and local tolerance of levamisole pour-on were conducted in 371 beef and dairy cattle in Mexico. Fecal egg counts were consistently reduced 2 weeks after a single application of levamisole pour-on at a dosage of 10 mg/kg of body weight. Local reactions were limited to various degrees of dry hair coat for up to 2 weeks at the application site. Hair loss or skin abnormalities were not observed in any of the treated cattle.

Animals↗
PubMed1983

The activity of closantel as an equine antiparasitic agent.

Eighteen pony foals were experimentally infected with 500 third stage larvae of Strongylus vulgaris at 2 weeks, and at 2, 4, 6 and 8 months after birth. For the duration of the study, all foals were kept in the same pasture with their mothers to allow natural infection with other parasites by exposure to a contaminated environment. Twelve of the foals were utilized in groups of 3 and treated orally five times at two month intervals starting at one month of age with closantel at doses of 5, 10, 20 or 40 mg kg-1. Ten months after birth the foals were necropsied to determine the parasitic burdens in the gastrointestinal tracts and the cranial mesenteric arteries. The results indicate a high antiparasitic activity of closantel against larval stages of Gasterophilus intestinalis and S. vulgaris, as well as against adult S. vulgaris, S. edentatus, Anoplocephala perfoliata and Triodontophorus spp., when used at doses of 20 or 40 mg kg-1.

Animals↗