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Biomedical subjects

J W McCall

Publications and source records attributed to J W McCall.

At least 19 recordsLinked to original sources

Evaluation of the efficacy of emodepside plus praziquantel topical solution against ascarid infections (Toxocara cati or Toxascaris leonina) in cats.

Eleven controlled studies were conducted in the United States and Europe to evaluate the efficacy of a topical solution of emodepside (3 mg/kg)+praziquantel (12 mg/kg) (Profender, Bayer AG, Leverkusen, Germany) against infection with various stages of the ascarid nematodes Toxocara cati and Toxascaris leonina. Infections were induced by administration of larvated ascarid eggs, and stage-specific efficacy was evaluated by treating cats at scheduled intervals post-inoculation. All studies featured random allocation to treatment groups, placebo-treated control animals and assessment of outcome measures by masked personnel. The product (emodepside+praziquantel topical solution) was 100% effective against mature adults and immature adult T. cati. In addition, it was 96.8% effective against third stage larvae and at least 99.4% effective against fourth stage larvae of T. cati, respectively. Efficacy against mature, immature adult and L4 stages of T. leonina exceeded 93.4%, but regulatory "adequacy of infection" criteria were not met in some studies. No adverse reactions to treatment were noted in cats treated with the emodepside+praziquantel topical solution.

Administration, Topical↗

Efficacy of long-term monthly administration of ivermectin on the progress of naturally acquired heartworm infections in dogs.

This study was designed to evaluate the efficacy of prolonged monthly ivermectin treatment against Dirofilaria immitis in client-owned dogs with naturally acquired infections and to clinically monitor the animal's response to the slow killing of heartworms, with death of the worms distributed over a period of up to 2 years. A total of 17 male and female dogs of different breeds and ages were used. Prior to treatment, all of the dogs tested positive for heartworm antigen (Ag) and all but two had microfilariae (mf). The dogs were randomly allocated to one group of seven dogs which received a commercial formulation of ivermectin (minimum, 6 mcg IVM/kg) plus pyrantel (minimum, 5 mg PP/kg) (Heartgard Plus Chewables, Merial, Ltd.), another group of seven dogs which received a commercial formulation of IVM (min, 6 mcg/kg) (Heartgard Chewables, Merial Ltd.), and a group of three dogs which served as an untreated controls. All dogs were evaluated prior to initiation of treatment and thereafter at 3- to 5-month-intervals for mf, Ag, and radiographic and echocardiographic findings. All of the 17 dogs, with the exception of two dogs in the IVM group, had circulating mf of D. immitis prior to the 1st monthly dose, and a few also had mf of Dirofilaria repens. After 4 monthly doses, only one dog in the IVM/PP group and two dogs in the IVM group had a patent heartworm infection, and no heartworm mf were seen in the 14 treated dogs thereafter. After 10 monthly doses, the number of Ag-positive dogs in both of the treated groups decreased gradually. Efficacy, based on the reduction in number of Ag-positive dogs, was similar for the IVM/PP and IVM groups, with overall efficacy scores for the 14 dogs of 21, 21, 43, and 71% after 10, 14, 19, and 24 monthly doses, respectively. Two of the seven dogs treated with IVM/PP, one of the seven treated with IVM, and two of the three untreated controls showed echocardiographic evidence of a parasitic burden prior to treatment, and all of these scores had decreased by the end of the study. Only one dog (IVM/PP group) had a cardiovascular pattern of heartworm disease by echocardiography prior to treatment, but this dog's score increased to two and the scores of two additional dogs increased from zero to two (IVM group) or three (IVM/PP group) by the end of the study. Only 1 (IVM/PP group) of the 17 dogs showed a pulmonary pattern of heartworm disease by radiography prior to treatment, but this dog's score increased to three by the end of the study. The radiographic scores of two additional dogs in the treated groups increased from zero to three (IVM/PP) or two (IVM) by the end of the study. Thus, monthly administration of IVM to dogs with clinical, radiographic or echocardiographic evidence of heartworm disease is ill-advised and such treatment of even the asymptomatic dog should be done only with much caution and frequent monitoring by the veterinarian.

Animals↗

Kidney ultrastructural lesions in dogs experimentally infected with Dirofilaria immitis (Leidy, 1856).

Kidneys of 16 beagles with experimentally induced heartworm (Dirofilaria immitis) infections and 4 heartworm-nai;ve dogs were studied by light and electron microscopy. The infections were induced either by subcutaneous injection of infective larvae or by the transplantation of adult parasites, and infection periods varied from 111 to 818 days and 365 to 923 days, respectively. One control group of heartworm-naïve dogs and four groups of heartworm-infected dogs, which were divided according to the type and the length of infection, were used. In the infected dogs, thickening of the glomerular basement membrane (GBM), the presence of dense deposits in the GBM, and foot process effacement were the most frequent lesions observed. In some dogs, electron dense deposits were seen in the GBM and the mesangium and/or enlargement of the mesangial matrix could be characterized. The longer the infection period, the thicker the GBM and the more common the occurrence of foot process effacement. In general, these alterations were more evident in animals that had been infected for more than 1 year, had high microfilaremia, and had 14 or more parasites in the main pulmonary artery and its branches. The presence of dense deposits suggests that the pathogenesis of kidney disease in dirofilariasis is associated with deposits of immune complexes in the membrane. The finding of ultrastructural changes in dogs with early prepatent infections suggests that immature heartworms, as well as microfilariae and possibly adult worms, contribute to the glomerulonephropathy.

Animals↗

Tetracycline treatment and sex-ratio distortion: a role for Wolbachia in the moulting of filarial nematodes?

Filarial nematodes harbour intracellular bacteria of the genus Wolbachia. These bacteria are thought to be beneficial to the host nematode. Indeed, tetracycline treatments reduce the population of Wolbachia in filarial worms and have detrimental effects on the nematode. Even though various antibiotic-curing experiments have been performed on filariae, the actual role of Wolbachia in the biology of these nematodes is not yet clear. To address this issue, we designed a first experiment on a model filaria (Brugia pahangi), maintained in the gerbil (Meriones unguiculatus). In this experiment, timing of tetracycline treatment was set on the basis of the larval stage of the nematode. This first experiment showed that 2 weeks of treatment started after the L(4)-L(5) moult of males, but before the moult of females, led to significant sex-ratio distortion of the nematodes. We thus hypothesised that tetracycline interferes with the moult in B. pahangi. To test this hypothesis, we designed a second experiment in which antibiotic treatments were started (1). before the moult of both sexes, (2). after the moult of males but before the moult of females, or (3). after the moult of both sexes. Treatment 1 determined a reduction of worm recovery with no sex bias. Treatment 2 led to a male-biased sex-ratio. Treatment 3 had no effect on either worm recovery or sex-ratio. These results thus support the hypothesis that tetracycline treatment interferes with the L(4)-L(5) moult of B. pahangi. The nematodes recovered from the treated and control animals were examined for the presence of Wolbachia using both immunohistochemistry and real-time PCR. In general, nematodes from treated animals showed a dramatic reduction in Wolbachia content. In one group, Wolbachia depletion, as observed at the end of the treatment, was followed by a rebound to 'normal' values 160 days later. Prospects for antifilarial therapy using Wolbachia-targeted tetracycline treatments should thus take into account the possibility of Wolbachia rebound.

Animals↗

Antigenic role of the endosymbionts of filarial nematodes: IgG response against the Wolbachia surface protein in cats infected with Dirofilaria immitis.

Filarial nematodes harbour intracellular endosymbiotic bacteria, which have been assigned to the genus Wolbachia. These bacteria appear to play an important role in the pathogenesis of filarial diseases through their lipopolysaccharides. In view of the presence of Wolbachia endosymbionts in the body of filarial nematodes, one might also expect that proteins from these bacteria play an antigenic role in humans and animals affected by filariases. To test this hypothesis, we produced in recombinant form the surface protein WSP and a portion of the cell-cycle protein FTSZ from the Wolbachia of Dirofilaria immitis. Western immunoblot assays were then performed using cat sera to test the immunogenicity of these proteins. Sera were collected from owners' cats, which were either sero-negative or sero-positive for D. immitis and from cats before and after experimental infection with D. immitis. FTSZ was recognized in Western blots by sera from both positive and negative cats and from both uninfected and experimentally infected cats. WSP was recognized only by sera from positive cats and from cats experimentally infected with D. immitis; this protein was not recognized by sera from negative cats and from cats before experimental infection with D. immitis. The results of Western blot assays on WSP thus support the hypothesis that infection with filarial nematodes induces the production of antibodies against Wolbachia proteins.

Amino Acid Sequence↗

Physicochemical studies of lidocaine-menthol binary systems for enhanced membrane transport.

The melting properties of lidocaine and l-menthol binary systems were studied using differential scanning calorimetry (DSC). A eutectic mixture was obtained for the lidocaine:menthol ratio of 30:70 (w:w) with a eutectic point of 26 degrees C. The binary melt systems formed within a range of 30:70-50:50 (w:w) remained as homogeneous oils at ambient temperature. The solubilities of pure lidocaine and lidocaine from the binary melt systems were determined with and without propylene glycol in pH 8.0 phosphate buffer. Lidocaine from the melt systems was less soluble in the buffers due to the partition of lidocaine between the oil and aqueous phases. The addition of propylene glycol to the buffer significantly increased both the solubility and heat of solubilization of lidocaine. The permeation rates of lidocaine from the binary melt systems across shed snake-skin were concentration dependent and significantly higher than those from the reference solutions.

Anesthetics, Local↗

Prevention of experimentally induced heartworm (Dirofilaria immitis) infections in dogs and cats with a single topical application of selamectin.

In a series of six controlled studies (four in dogs, two in cats), heartworm-free dogs and cats were inoculated with Dirofilaria immitis larvae (L(3)) prior to topical treatment with the novel avermectin selamectin or a negative control containing inert formulation ingredients (vehicle). Selamectin and negative-control treatments were administered topically to the skin at the base of the neck in front of the scapulae. In dogs, selamectin was applied topically at dosages of 3 or 6mgkg(-1) at 30 days post-inoculation (PI), or of 3 or 6mgkg(-1) at 45 days PI, or of 6mgkg(-1) at 60 days PI. Cats were treated topically with unit doses providing a minimum dosage of 6mgkg(-1) selamectin at 30 days PI. Of the animals that were treated 30 days PI, some dogs were bathed with water or shampoo between 2 and 96h after treatment, and some cats were bathed with shampoo at 24h after treatment. Between 140 and 199 days PI, the animals were euthanized and examined for adult D. immitis. Adult heartworms developed in all control dogs (geometric mean count, 18.7 worms) and in 88% of control cats (geometric mean count, 2.1 worms). Selamectin was 100% effective in preventing heartworm development in dogs when administered as a single topical dose of 3 or 6mgkg(-1) at 30 days after infection, 3 or 6mgkg(-1) at 45 days after infection, or 6mgkg(-1) at 60 days after infection. Selamectin was 100% effective against heartworm infections in cats when administered as a single topical unit dose of 6mgkg(-1). Bathing with water or shampoo between 2 and 96h after treatment did not reduce the efficacy of selamectin as a heartworm prophylactic in dogs. Likewise, bathing with shampoo at 24h after treatment did not reduce the efficacy of selamectin in cats. These studies demonstrated that, at the recommended dosage and treatment interval, a single topical administration of selamectin was 100% effective in preventing the development of D. immitis in dogs and cats.

Administration, Topical↗

Efficacy of selamectin against experimentally induced and naturally acquired infections of Toxocara cati and Ancylostoma tubaeforme in cats.

The efficacy of selamectin against experimentally induced and naturally acquired infections of adult ascarids (Toxocara cati) and adult hookworms (Ancylostoma tubaeforme) was evaluated in five controlled studies in cats. Two studies evaluated the efficacy of selamectin against both ascarid (natural or induced) and hookworm (induced) infections; two studies evaluated the efficacy of selamectin against single natural infections of T. cati or A. tubaeforme; and the fifth study evaluated the efficacy of selamectin against induced infections of A. tubaeforme. Cats received selamectin topically in unit doses designed to deliver a minimum of 6mgkg(-1). Treatments were applied to the skin on each animal's back at the base of the neck in front of the scapulae. For experimentally induced infections, cats were inoculated orally with approximately 500 embryonated eggs of T. cati 56 days prior to treatment and/or approximately 150-250 larvae (L(3)) of A. tubaeforme 30 or 42 days prior to treatment. For both induced and naturally acquired infections, cats were allocated randomly to treatments (6-12 cats per treatment) on the basis of fecal egg counts to receive either selamectin or a vehicle containing the inert formulation ingredients. In all studies, adult worm counts were performed at necropsy 14 days after the last treatment administration. Against T. cati, a single application of selamectin provided a 100% reduction in the geometric mean number of adult worms for both experimentally induced and naturally acquired infections. Against A. tubaeforme, a single administration of selamectin provided a 99.4% reduction in the geometric mean number of adult worms in cats with natural infections, and an 84.7-99.7% reduction in adult worms in cats with induced infections. Two doses of selamectin administered at monthly intervals provided a 91.9% reduction in the geometric mean number of adult A. tubaeforme worms in cats with experimentally induced infections. The geometric mean numbers of adult worms (T. cati and A. tubaeforme) from selamectin-treated cats were significantly (P< or =0.0018) lower than for vehicle-treated cats in all studies. Thus, a single topical unit dosage providing a minimum dosage of 6mgkg(-1) selamectin was highly effective in the treatment of naturally acquired and experimentally induced infections of T. cati and A. tubaeforme in cats.

Administration, Topical↗

Safety of selamectin in dogs.

Selamectin is a broad-spectrum avermectin endectocide for treatment and control of canine parasites. The objective of these studies was to evaluate the clinical safety of selamectin for topical use in dogs 6 weeks of age and older, including breeding animals, avermectin-sensitive Collies, and heartworm-positive animals. The margin of safety was evaluated in Beagles, which were 6 weeks old at study initiation. Reproductive, heartworm-positive, and oral safety studies were conducted in mature Beagles. Safety in Collies was evaluated in avermectin-sensitive, adult rough-coated Collies. Studies were designed to measure the safety of selamectin at the recommended dosage range of 6-12mgkg(-1) of body weight. Endpoints included clinical examinations, clinical pathology, gross and microscopic pathology, and reproductive indices. Selected variables in the margin of safety and reproductive safety studies were subjected to statistical analyses. Pups received large doses of selamectin at the beginning of the margin of safety study when they were 6 weeks of age and at their lowest body weight, yet displayed no clinical or pathologic evidence of toxicosis. Similarly, selamectin had no adverse effects on reproduction in adult male and female dogs. There were no adverse effects in avermectin-sensitive Collies or in heartworm-positive dogs. Oral administration of the topical formulation caused no adverse effects. Selamectin is safe for topical use on dogs at the recommended minimum dosage of 6mgkg(-1) (6-12mgkg(-1)) monthly starting at 6 weeks of age, and including dogs of reproducing age, avermectin-sensitive Collies, and heartworm-positive dogs.

Administration, Oral↗

Safety of selamectin in cats.

The safety of the avermectin, selamectin, was evaluated for topical use on the skin of cats of age six weeks and above, including reproducing cats and cats infected with adult heartworms. All studies used healthy cats. Acute safety was evaluated in domestic cross-bred cats. Margin of safety was evaluated in domestic-shorthaired cats, starting at six weeks of age. Reproductive, heartworm-infected, and oral safety studies were conducted in adult, domestic-shorthaired cats. Studies were designed to measure the safety of selamectin at the recommended dosage range of 6-12mgkg(-1) of body weight. Assessments included clinical, biochemical, pathologic, and reproductive indices. Selected variables in the margin of safety study and the reproductive studies were subjected to statistical analyses by using a mixed linear model. Cats received large doses of selamectin at the beginning of the margin of safety study when they were six weeks of age and at their lowest body weight, yet displayed no clinical or pathologic evidence of toxicosis. Similarly, selamectin had no adverse effect on reproduction in adult male and female cats. There were no adverse effects in heartworm-infected cats. Oral administration of the topical formulation, which might occur accidentally, caused mild, intermittent, self-limiting salivation and vomiting. Selamectin is a broad-spectrum avermectin endectocide that is safe for use in cats starting at six weeks of age, including heartworm-infected cats and cats of reproducing age, when administered topically to the skin monthly at the recommended dosage to deliver at least 6mgkg(-1).

Administration, Oral↗

Anticancer agents suppressive for adult parasites of filariasis in Mongolian jirds.

Eight chemical structures not previously reported to possess antifilarial activity have been identified. A total of 79 compounds with anticancer properties were evaluated for possible macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones unguiculatus). All eight active compounds were suppressive for the onchocerciasis type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the lymphatic form (Brugia pahangi). These new structures may represent a nucleus around which effective drugs can be synthesized.

Animals↗

Pharmacokinetics of UMF-078, a candidate antifilarial drug, in infected dogs.

The pharmacokinetics of the filaricidal benzimidazole compounds UMF-078 and UMF-289 were evaluated in beagle dogs experimentally infected with Brugia pahangi. Twenty-four infected microfilaremic beagles were selected and randomly allocated into 4 treatment groups of 6 dogs each: oral (PO) UMF-078, PO UMF-289 (the HCl salt form of UMF-078), intramuscular (IM) UMF-078, and untreated controls. Equivalent doses of 50 mg/kg of the free base were given twice a day for 3 days to the 3 groups of treated dogs. Oral absorption is rapid compared with IM dosing; the absorption half-life (K01-HL) for the IM treatment is approximately 14 hr compared with 1 and 2 hr for the PO regimen of salt and free base forms, respectively. The elimination half-lives (K10-HL) for the PO regimens are 13 and 15 hr for the salt and free base forms, respectively. Because of sustained absorption following IM dosing, the K10-HL is prolonged. In contrast to oral administration, IM dosing of UMF-078 provides sustained, relatively low plasma drug levels, with good tolerance and efficacy.

Administration, Oral↗

Spatial and temporal variation in the seroprevalence of canine heartworm antigen in the island fox.

Island foxes (Urocyon littoralis) are endemic to six of the eight California Channel Islands (USA). The island fox is classified as a threatened species by the State of California, and recently three of the six subspecies have experienced abrupt population declines. As part of a continuing effort to determine the cause of the declines, we tested island fox serum samples collected in 1988 (n = 176) and 1997-98 (n = 156) over the entire geographic range of the species for seroprevalence of canine heartworm (Dirofilaria immitis) antigen. Using a commercially available enzyme-linked immunosorbent assay (PetChek, Idexx Laboratories, Westbrook, Maine, USA) we detected heartworm antigen in four of the six populations of island foxes. On San Miguel and Santa Rosa Islands, seroprevalence in adult foxes was >85% (n = 62) in 1988 and increased to 100% (n = 24) in 1997-98. On Santa Cruz Island, seroprevalence in adult foxes decreased from 83% (n = 30) to 58% (n = 26), whereas on San Nicolas Island, seroprevalence increased from 25% (n = 32) to 77% (n = 30) during the same period. All of the pups assayed (n = 33) were seronegative. The seroprevalences of heartworm reported herein for the four populations of island foxes are the highest yet reported for a fox species. However, additional demographic data reported elsewhere suggests that heartworm has not been a major factor in the recent declines of island fox populations.

Animals↗

Utility of adult antigens of Dirofilaria immitis for the early detection of dirofilariosis and for the evaluation of chemoprophylactic treatment in experimentally infected cats.

Early detection of feline dirofilariosis was achieved by ELISA testing using adult somatic (SA) and excretory/secretory (E/S) antigens. Sera from experimentally infected cats showed significantly higher IgG levels at 2 months post-infection (p.i.) when compared to sera obtained prior to infection. This difference was apparent at all serum dilutions (1:100 to 1:800) in ELISA(SA) and at all dilutions except 1:800 when tested with ELISA(E/S). Changes in specific anti-SA and anti-E/S IgG levels were found in infected cats treated with the macrolid parasiticide. ELISA(E/S) was able to detect a significant decrease in IgG levels in ivermectin treated cats at 3 months post-treatment (p.t.), compared to infected, untreated controls. However, testing with ELISA(SA) showed a significant decrease in antibody levels in treated cats only at 4 months after treatment. Sera from untreated cats recognized previously identified specific markers for feline dirofilariosis on SA (22, 26, 30 and 40 kDa) and on E/S (22 and 25 kDa) in Western blot analysis. Sera from treated cats, on the other hand, gave only weak bands or none at all, indicating a decrease in antibody concentration. These results suggest that serologic testing with ELISA is useful in the early detection of Dirofilaria immitis infection and, together with Western blot analysis, can assist in the evaluation of response to chemoprophylactic treatment of feline dirofilariosis, two aspects of prime importance in the prevention of this disease in cats.

Animals↗

Effects of tetracycline on the filarial worms Brugia pahangi and Dirofilaria immitis and their bacterial endosymbionts Wolbachia.

Wolbachia endosymbiotic bacteria have been shown to be widespread among filarial worms and could thus play some role in the biology of these nematodes. Indeed, tetracycline has been shown to inhibit both the development of adult worms from third-stage larvae and the development of the microfilaraemia in jirds infected with Brugia pahangi. The possibility that these effects are related to the bacteriostatic activity of tetracycline on Wolbachia symbionts should be considered. Here we show that tetracycline treatment is very effective in blocking embryo development in two filarial nematodes, B. pahangi and Dirofilaria immitis. Embryo degeneration was documented by TEM, while the inhibition of the transovarial transmission of Wolbachia was documented by PCR. Phylogenetic analysis on the ssrDNA sequence of the Wolbachia of B. pahangi confirms that the phylogeny of the bacterial endosymbionts is consistent with that of the host worms. The possibility that tetracycline inhibition of embryo development in B. pahangi and D. immitis is determined by cytoplasmic incompatibility is discussed.

Animals↗

HPLC assay of Lidocaine in plasma with solid phase extraction and UV detection.

A sensitive and reliable method based on solid-phase extraction and reversed-phase liquid chromatography was developed and validated for the quantitation of Lidocaine (Lid) in dog plasma. Phenacemide was used as an internal standard (IS) in the extraction which employed C18 solid-phase extraction cartridges. The washing and eluting solutions were 2 ml acetonitrile-pH 9.0 phosphate buffer (10:90 v/v) and 0.5 ml acetonitrile-pH 4.0 phosphate buffer (40:60 v/v). respectively. The eluent obtained from the cartridge was directly analyzed on a reversed-phase ODS column with UV detection at 210 nm. A clean chromatogram and high sensitivity were achieved at this wavelength. The mobile phase was acetonitrile and pH 5.9 phosphate buffer (20:80 v/v). The retention times were 6.4 and 7.2 min for Lid and IS, respectively, at a flow rate of 1.0 ml min(-1). The mean absolute recovery was 96.6% (n = 9) with a CV of 3.8% for Lid and 81.7% with CV of 2.5% (n = 3) for IS. The limit of quantitation was 20 ng ml(-1), with the intra- and inter-day precisions (n = 5) of 4.4 and 3.4%, respectively, and the intra- and inter-day accuracies (n = 5) of -4.3 and -5.0%, respectively. For the analyses of Lid in spiked plasma samples at 20, 100 and 200 ng ml(-1), the overall mean intra- and inter-day precisions (n = 15) were 3.9 and 4.9%, respectively, and the overall mean intra- and inter-day accuracies (n = 15) were -3.7 and -4.6%, respectively. The correlation coefficients for calibration plots in the range 20-1000 ng ml(-1) in plasma were typically higher than 0.998. The suitability of the method was demonstrated by the study in a beagle dog receiving a low intravenous dose of Lid.

Acetonitriles↗

Polyamines: agents with macrofilaricidal activity.

There is a need for effective macrofilaricidal drugs. The polyamine metabolism of filarial worms has been recognized as a possible target for effective drug action. In an attempt to identify agents that might provide leads in developing an effective macrofilaricide, 78 polyamine compounds were selected from among > 250,000 structures that have been amassed by the Walter Reed Army Institute of Research, in the U.S.A. These thousands of agents have been chosen principally for drug-development programmes for other parasitic diseases. The 78 prospective drugs selected were evaluated for their macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae, in male Mongolian jirds (Meriones unguiculatus). The animal models using these two parasites were designed to mimic, in so far as possible, human lymphatic filariasis and onchocerciasis, respectively. Thirteen of the compounds were found to be active although none of these has been previously reported to be macrofilaricidal. Two were suppressive for B. pahangi and 11 for A. viteae. These active agents may represent a nucleus around which highly effective drugs can be synthesised.

Animals↗