Search PubMed⌕ Search

Biomedical subjects

Q A McKellar

Publications and source records attributed to Q A McKellar.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacological approaches towards rationalizing the use of endoparasitic drugs in small animals.

Parasitic diseases are an important health concern to small animal veterinarians worldwide, and their zoonotic potential is also of relevance to human medicine. The treatment and control of such conditions relies heavily on pharmaceutical intervention using a range of antiparasitic drugs and/or their biologically active metabolites. Broad spectrum agents have been produced, although narrow and even monospecific drugs are used in some situations. Their efficacy may depend on dosage, the target pathogen(s), the host species and/or the site of infection. Optimal use of antiparasitics requires a detailed consideration of the pharmacokinetic and pharmacodynamic properties of the drugs in specific clinical contexts. This review summarizes the present status of knowledge on the metabolism, and physicochemical and pharmacological properties of the major antiparasitic drugs currently used in small animal veterinary practice. In addition, data relevant to therapeutic dosage, efficacy and clinical indication/contraindication, particularly in relation to combination drug therapy, are included.

Animals↗
PubMed2005

Effects of formulation concentration on intravenous pharmacokinetics, chirality and in vitro solubility of oxfendazole and its metabolites in sheep.

This study compared pharmacokinetic (PK) profiles in sheep dosed intravenously with three different concentrations of oxfendazole (OFZ). An in vitro plasma OFZ solubility study provided additional information on plasma saturation. For the PK study, 18 adult, parasite-free, female Suffolk cross sheep, allocated into three groups (n = 6), were treated intravenously, at a dose rate of 5 mg/kg bodyweight, with aqueous formulations containing at 4, 8 or 16% OFZ. Plasma drug concentrations were measured, for up to 72 h post-treatment, by a validated high performance liquid chromatography method with UV detection. OFZ and fenbendazole sulphone (FBZSO2) were the main metabolites detected in all three experimental groups. In animals given the 4% formulation, OFZ depleted according to a biexponential concentration vs. time curve. In contrast, those given 8 or 16% preparations produced atypical curves fitted by monoexponential equations. No statistically significant differences in area under concentration-time curves (AUC) were observed, but concentration-dependent differences in distribution and mean residence time (MRT) were evident. Compared with 4% OFZ, animals treated with 8 and 16% formulations had slower half-lives of metabolite formation, and lower AUC's, suggesting that OFZ sulphonation may have been modified. In vitro there was evidence of plasma saturation associated with 8 and 16% OFZ preparations. It is concluded that differences in PK profiles were related to OFZ solubility and/or tissue drug precipitation.

Animals↗
PubMed2005

Changes to oxfendazole chiral kinetics and anthelmintic efficacy induced by piperonyl butoxide in horses.

REASONS FOR PERFORMING THE STUDY: The study of novel pharmacological strategies to control parasitism in horses is required since many parasite species have developed resistance to anthelmintic drugs. OBJECTIVES: To evaluate the effects of piperonyl butoxide (PB) (a metabolic inhibitor) on the plasma availability and enantiomeric behaviour of oxfendazole (OFZ) given orally to horses, and to compare the clinical efficacy of OFZ given either alone or co-administered with PB in naturally parasitised horses. METHODS: Fifteen naturally parasitised crossbred male ponies were allocated into 3 groups (n = 5) and treated orally as follows: Group I (control) received distilled water as placebo; Group II was dosed with OFZ (10 mg/kg bwt); and Group III was treated with OFZ (10 mg/kg bwt) co-administered with PB (63 mg/kg bwt). Jugular blood samples were obtained over 120 h post treatment. Three weeks after treatments, all experimental horses were subjected to euthanasia. RESULTS: The observed maximum plasma concentration (Cmax) and area under the concentration vs. time curve (AUC) values for OFZ increased 3- and 5-fold, respectively, in the presence of PB. The plasma concentration profiles of fenbendazole (FBZ), a metabolite generated from OFZ, were significantly lower after the treatment with OFZ alone (AUC = 0.8 microg x h/ml) compared to those obtained after the OFZ + PB treatment (AUC = 2.7 microg x h/ml). The enhanced pharmacokinetic profiles correlated with increased anthelmintic efficacy. The combination OFZ + PB showed 100% efficacy against mature nematode parasites. The efficacy against cyathostome L3 larvae increased from 94% (Group II) to 98.7% (Group III). Consistently, the number of L4 larvae recovered from OFZ + PB treated horses (Group III) (n = 146) was significantly lower (P<0.05) than that recovered from Group II (n = 1397). CONCLUSIONS: The use of PB as a metabolic inhibitor may be useful to enhance OFZ activity against mature and migrating larvae of different parasite species in horses. POTENTIAL RELEVANCE: Metabolic inhibitors may be used to enhance the activity of benzimidazole anthelmintics and extend the effective lifespan of benzimidazole drugs in the face of increasing resistance.

Administration, Oral↗
PubMed2004

Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine.

The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC(0-24)) and minimum inhibitory concentration (MIC), maximum plasma concentration (C(max)) and MIC and time during which plasma concentrations exceed the MIC have been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding the MIC for a prolonged percentage of the inter-dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is 'bug and drug' specific, although ratios of 125 for AUC(0-24):MIC and 10 for C(max):MIC have been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceeding MIC by 1-5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration-dependent antimicrobials by achieving an AUC(0-24):MIC ratio of greater than 100 or a C(max):MIC ratio of greater than 8. The relationships between time greater than MIC and resistance selection for time-dependent antimicrobials have not been well characterized.

Animals↗
PubMed2003

Dexamethasone decreases plasma levels of the prochiral fenbendazole and its chiral and achiral metabolites in sheep.

1. The effect of co-administration of either short- or long-acting formulations of DXM on hepatic function and the plasma pharmacokinetic behaviour of prochiral fenbendazole (FBZ) and its metabolites was evaluated in sheep. 2. Neither DXM treatment markedly affected any of the biochemical markers of hepatic function tested. In contrast, both formulations significantly modified the plasma pharmacokinetic behaviour of FBZ and its metabolites. 3. Plasma FBZ concentrations and the associated area under the time-concentration curves were significantly lower, although the plasma detection period was longer (72 versus 48 h) in the DXM pretreated animals compared with those given FBZ alone. 4. DXM also appeared to alter the pattern of FBZ absorption, possibly through effects on abomasal pH. The shape of the plasma concentration-time curves for oxfendazole (OFZ) and fenbendazole sulphone (FBZSO(2)) were similar to FBZ, raising the possibility that DXM treatment may have altered the liver biotransformation of the parent drug. 5. The concentrations of the (+) chiral metabolite of OFZ were significantly lower in DXM pretreated animals compared with those given FBZ alone. The trend was similar for the (-) antipode, although the differences between DXM pretreated and non-pretreated animals were not statistically significant.

Administration, Oral↗
PubMed2002

The genetic control of IgA activity against Teladorsagia circumcincta and its association with parasite resistance in naturally infected sheep.

Previous studies in deliberately infected sheep have shown an association between IgA activity against 4th-stage larvae of Teladorsagia circumcincta and parasite growth, development and fecundity. The purpose of this research was to determine if these results could be confirmed in naturally infected sheep and to explore the hypothesis that plasma IgA activity could help to identify resistant lambs with shorter adult nematodes. Plasma IgA activity was skewed with most animals having relatively low levels of IgA activity. Plasma IgA activity was repeatable and highly heritable. Animals with increased IgA activity had lower egg counts and shorter adult female T. circumcincta. Therefore, under conditions of natural parasite challenge, plasma IgA activity may help to identify lambs resistant to T. circumcincta.

Animals↗
PubMed2002

Eosinophilia as a marker of resistance to Teladorsagia circumcincta in Scottish Blackface lambs.

Faecal egg counts and peripheral blood eosinophil counts were taken from Scottish Blackface lambs following natural, predominantly Teladorsagia circumcincta infection. Peripheral eosinophil concentrations were higher in animals with lower egg counts but only in lambs that were at least 3 months of age. The reduced egg counts were due to reduced fecundity of T. circumcincta; there was no association with the number of adult T. circumcincta. Associations with the number of parasites from other species of gastrointestinal nematodes appeared to be neutral or favourable. Estimated heritabilities for eosinophil concentrations in 4- and 5-month-old lambs were 0.48 +/- 0.16 and 0.43 +/- 0.17, respectively. Therefore, under defined circumstances, eosinophil concentrations may be a useful indicator of resistance to predominantly T. circumcincta infection.

Animals↗
PubMed2002

Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheep.

Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6-8-month-old, parasite-free, female Dorset sheep (30-40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO(2)) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration--time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO(2) following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed T(max) and a significantly delayed (> 45%) elimination (t(1/2)(el)). Although AUC values for FBZSO(2) were not significantly different between groups, this metabolite was depleted more slowly from plasma (t(1/2)(el) > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of anti-parasite therapy against BZD-resistant parasite strains.

Administration, Oral↗
PubMed2002

Plasma disposition, faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses.

Oxibendazole (OBZ) was administered to eight horses at an oral dose of 10 mg kg(-1) bodyweight each. Parent OBZ could only be detected in plasma at the 0.5 and 1.0 hours post administration sampling times and the mean maximum plasma concentration was 0.008 microg ml(-1). Parent OBZ was detected in faeces between 12 and 72 hours after administration and the highest dry faecal concentration was detected at 24 hours. An unidentified metabolite was detected in plasma between 0.5 and 72 hours. The unidentified metabolite in the plasma of treated horses corresponded to the second eluted metabolite in the in vitro study. Metabolism of OBZ to its metabolite in vitro was significantly inhibited by co-incubation with the cytochrome P450 inhibitor piperonyl butoxide. These results indicated that first-pass metabolism decreases OBZ bioavailability in horses. The in vitro metabolism of OBZ was significantly inhibited by piperonyl butoxide and this could be utilised to extend the exposure of nematodes to the parent molecule.

Administration, Oral↗
PubMed2002

Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.

The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P < 0.001) following FBZSO than FBZ. In feces the administered parent molecule predominated. The combined AUC for active benzimidazole moieties following oral administration of FBZ (10 mg/kg) in horses was almost 4 times as high in unfed horses (2.19 microg x h/ml) than in fed horses (0.59 microg x h/ml), and coadministration of piperonyl-butoxide significantly increased the AUC and C(max) of active moieties following intravenous administration of FBZSO and oral administration of FBZ. When FBZSO was administered i.v. as a racemate, the first enantiomer of oxfendazole (FBZSO-1) predominated in plasma, however, following coadministration with piperonyl-butoxide, the second enantiomer of oxfendazole (FBZSO-2) predominated for 10 h. Piperonyl-butoxide significantly reduced the oxidative metabolism of FBZSO and FBZ in equine liver microsomes and altered the ratio of enantiomers FBZSO-1/FBZSO-2 from >4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide.

Administration, Oral↗
PubMed2001

Fructosamine concentration and resistance to natural, predominantly Teladorsagia circumcincta infection.

Fructosamine concentrations reflect protein status and because infection with Teladorsagia circumcincta can induce a relative protein deficiency, we examined the usefulness of fructosamine concentrations as markers of the intensity of infection in naturally infected lambs. Fructosamine concentration was a heritable trait and variation in fructosamine concerntrations was associated with differences in body weight, and a variety of parasitological variables; animals with increased fructosamine concentrations grew more quickly, had increased faecal egg counts in one of the three study years, had decreased pepsinogen concentrations and decreased IgA activity against 4th-stage larvae of T. circumcincta. Fructosamine concentrations were also associated with variation in the subsequent acquisition of nematodes and in the length of adult female T. circumcincta; lambs with increased fructosamine concentrations had fewer nematodes but the mean length of adult female T. circumcincta was longer. Therefore fructosamine concentrations are potentially useful indicators of the severity of nematode infection and may predict magnitude of subsequent infection.

Abomasum↗
PubMed2001

Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses.

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.

Administration, Oral↗
PubMed2000

The influence of relative resistance and urea-supplementation on deliberate infection with Teladorsagia circumcincta during winter.

The consequences for lambs of infection over the winter with Teladorsagia circumcincta were quantified by deliberate, trickle infection of selected animals at 7 months of age. Infected and control uninfected animals were each allocated into four groups, relatively resistant animals on a normal diet, relatively resistant animals on an isocaloric diet supplemented with urea, and relatively susceptible animals on the same two diets. Resistance and susceptibility was assessed by faecal egg counts following natural infection during the summer preceding the deliberate infection. During the deliberate infection egg counts remained low and most parasites recovered at necropsy were inhibited larvae. Nonetheless, infection reduced weight gain, decreased albumin and fructosamine concentrations and provoked a noticeable pepsinogen and eosinophil response. As most larvae were inhibited these responses may have been largely a consequence of immuno-inflammatory responses in the host rather than the direct action of parasites themselves. Relatively resistant animals on the supplemented diet allowed fewer larvae to establish and had higher fructosamine concentrations, higher albumin concentrations and decreased pepsinogen responses. Therefore, a combination of relatively resistant sheep and nutritional supplementation appears most efficient at controlling infection.

3-Hydroxybutyric Acid↗
PubMed2000

The influence of age on the variation among sheep in susceptibility to natural nematode infection.

A longitudinal study of faecal nematode egg counts was made in naturally infected Scottish Blackface sheep over two grazing seasons to 75 weeks of age. Although egg counts were lower in the second grazing season the variation among animals was greater. Egg counts were repeatable from 3 months of age. The repeatability of faecal egg counts within and between grazing seasons was about 0.3. Animals with lower than average egg counts in the first grazing season tended to have lower than average egg counts in the second grazing season. Therefore lambs with relatively low faecal egg counts after 3 months of age are likely to retain their advantage in the following year.

Aging↗
PubMed1999

The distribution of pepsinogen within the abomasa of cattle and sheep infected with Ostertagia spp. and sheep infected with Haemonchus contortus.

The effect of nematode infections on the production of pepsinogen by ruminants was investigated immunohistochemically and biochemically. Abomasal tissues were collected from parasite-naive cattle and sheep, from sheep infected with predominantly Ostertagia circumcincta, sheep infected experimentally with Haemonchus contortus and cattle infected with Ostertagia ostertagi. Pepsinogen was also assayed biochemically in homogenates of fundic mucosae from sheep infected with predominantly O. circumcincta. Infection with Ostertagia spp. parasites was associated mainly with nodular hyperplasia, resulting in increased numbers of cells that produce both pepsinogen and mucus. Measured biochemically, nodules contained more pepsinogen than adjacent more normal mucosa (p < 0.05), and this effect was largely attributable to the greater mass of nodules. Infection of sheep with H. contortus was associated with generalised hyperplasia, characterised by increased numbers of mucopeptic cells and in at least one animal with reductions in parietal cell numbers. At the same time, the zymogen granule content of chief cells was reduced. Similar changes were occasionally seen in sheep infected predominantly with O. circumcincta. Generalised hyperplasia is likely to be indicative of the presence of ambulatory parasitic stages as opposed to those confined to nodules. The potential for the enhanced production of pepsinogen by increased numbers of cells with a joint mucous cell and zymogenic cell phenotype may offset decreases in the numbers of chief cells or reductions in chief cell activity.

Abomasum↗
PubMed1998

Pharmaceutical quality of anthelmintics sold in Kenya.

Nine anthelmintic products in pharmacies and from agricultural merchants in Kenya were tested for pharmaceutical quality. The concentration of active drug was compared with the claim on the label, and the variability of several products was tested between batches and between bottles within the same batch. All the products purchased claimed to contain levamisole but its mean (sd) concentration varied from 0 to 118.0 (13.3) per cent of the claimed. The concentration of levamisole in different batches of the same product ranged from 0 to 85.4 per cent of that claimed. One product consisting in part of mebendazole was found to contain 73.2 (9.4) per cent of the claimed concentration of this active component and two products consisting in part of oxyclozanide were found to contain 106.0 (14.4) and 120.6 (6.1) per cent of the expected concentration of oxyclozanide.

Animals↗