Doramectin concentration profiles in the gastrointestinal tract of topically-treated calves: Influence of animal licking restriction

Endectocide compounds are extensively used for broad-spectrum parasite control and their topical administration to cattle is widespread in clinical practice. Pour-on formulations of moxidectin, ivermectin, eprinomectin and doramectin (DRM) are marketed internationally for use in cattle. However, variability in antiparasitic efficacy and pharmacokinetic profiles has been observed. Although the tissue distribution pattern for different endectocide molecules given subcutaneously to cattle has been described, only limited information on drug concentration profiles in tissues of parasite location after topical treatment is available. Understanding the plasma and target tissue kinetics for topically-administered endectocide compounds is relevant to optimise their therapeutic potential. The current work was designed to measure the plasma and gastrointestinal (GI) concentration profiles of DRM following its pour-on administration to calves. The influence of natural licking behaviour of cattle on DRM concentration in mucosal tissue and luminal content of different GI sections was evaluated. The trial was conducted in two experimental phases. In Phase I, the DRM plasma kinetics was comparatively characterised in free-licking and in 2-day licking-restricted (non-licking) calves. The pattern of distribution of topical DRM to mucosal and luminal contents from abomasum, duodenum, ileum, caecum and spiral colon was assessed in free-licking and non-licking calves restricted over 10 days post-administration (Phase II). The prevention of licking caused marked changes on the plasma and GI kinetics of DRM administered pour-on. In 2-day licking restricted calves, DRM systemic availability was significantly lower (29%) than in free licking animals during the first 9 days post-treatment. Following a 10-day long licking restriction period, DRM concentrations profiles in both mucosal tissue and luminal contents of the GI tract were markedly higher in animals allowed to lick freely. This enhancement in drug concentrations in free-licking compared to non-licking calves, was particularly pronounced in the abomasal (38-fold higher) and duodenal (six-fold higher) luminal content. As shown earlier for ivermectin, licking behaviour may facilitate the oral ingestion of topically-administered DRM in cattle. This would be consistent with the marked lower drug concentration profiles measured in the bloodstream and GI tract of the animals prevented from licking. The work reported here provides relevant information on the pattern of DRM distribution to the GI tract after pour-on treatment, and contributes to understand the variability observed in the antiparasitic persistence of topically-administered endectocides in cattle. The implications of natural licking in topical treatments are required to be seriously assessed to achieve optimal parasite control and to design parasitological and pharmacological studies within the drug approval process.     

Biochemical analysis of the articular cartilage and subchondral and trabecular bone of the metacarpophalangeal joint of horses with early osteoarthritis

OBJECTIVE: To assess whether site-related changes in biochemical composition are present in the cartilage and subchondral and trabecular bone of the metacarpophalangeal joint of horses with early osteoarthritis. SAMPLE POPULATION: Right metacarpophalangeal joints from 59 mature warmblood horses. PROCEDURE: Biochemical data (cross-link, amino acid, DNA, and ash contents; denatured collagen and glycosaminoglycan [GAG] concentrations; bone mineral density; and mineral composition) were obtained from 2 differently loaded sites of phalanx I cartilage and subchondral and trabecular bone samples; data were compared with previously published values from nonosteoarthritic equine joints. RESULTS: Compared with findings in nonosteoarthritic joints, GAG concentration was lower in cartilage from osteoarthritic joints and there was a loss of site differences in cellularity and lysylpyridinoline (LP) cross-link content. In subchondral bone, LP cross-link content was decreased overall and there was a loss of site differences in osteoarthritic joints; ash content was higher in the osteoarthritic joints. Hydroxyproline content in trabecular bone from osteoarthritic joints was greater than that in nonosteoarthritic trabecular bone. In all 3 layers and at both sites, the linear increase of the pentosidine cross-link content with age had diminished or was not apparent in the horses with osteoarthritic joints. CONCLUSIONS AND CLINICAL RELEVANCE: In equine metacarpophalangeal joints with early osteoarthritis, distinct biochemical changes were detected in the cartilage and subchondral and trabecular bone. The dissimilarity in response of the different tissues and differences between the sites that are affected may be related to differences in biomechanical loading and transmission and dissipation of force.     

Activin A: from sometime reproductive factor to genuine cytokine

The growth factor, activin A, was initially characterized as a putative reproductive hormone but is now known to have many other divergent roles. One of these is during inflammation. Following intravenous injection of bacterial lipopolysaccharide (LPS) into sheep, activin A is released extremely rapidly into the circulation. The release of activin A appears to be independent of fever, prostaglandins or other key proinflammatory cytokines such as TNF-alpha or IL-1beta. While the precise roles and function of this factor in inflammation are yet to be elucidated, the activin response occurs in other mammalian species besides the sheep and elevated activin has been documented for a number of clinical inflammatory conditions. Activin A therefore seems to be part of the regulatory component of the innate immune response.     

Estimation of linkage disequilibrium in a sample of the United Kingdom dairy cattle population using unphased genotypes

The association between genetic marker alleles was estimated for two regions of the bovine genome from a random sample of 50 young dairy bulls born in the United Kingdom between 1988 and 1995. Microsatellite marker genotypes were obtained for six markers on chromosome 2 and seven markers on chromosome 6, spanning 38 and 20 cM, respectively. Two different methods, which do not require family information, were used to estimate population haplotype frequencies. Haplotype frequencies were estimated for pairs of loci using the expectation-maximization algorithm and for all linked loci using a Bayesian approach via a Markov chain-Monte Carlo algorithm. Significant (P = 0.0007) linkage disequilibrium was detected between pairs of loci in syntenic groups (that is, loci in the same linkage group), extending to about 10 cM. No significant linkage disequilibrium was detected between markers in nonsyntenic regions. Given the observed level of linkage disequilibrium, mapping methods based on population-wide association might provide a better resolution than traditional quantitative trait loci mapping methods in the U.K. dairy cattle population and may reduce the required sample sizes of the experiments.     

Field trials of an immunization procedure against hemorrhagic enteritis of turkeys

The efficacy of oral vaccination for hemorrhagic enteritis of turkeys was assessed by comparing flocks raised on the same premises, under the same management, with and without vaccination. The immunizing virus, a strain of marble spleen disease virus of pheasants, was administered via the drinking water. Vaccinated and unvaccinated turkeys differed significantly in feed conversion rates and spleen weights after challenge.     

Adrenocortical suppression in the dog given a single intramuscular dose of prednisone or triamcinolone acetonide

Adrenocortical function was assessed in dogs given a single intramuscular dose of either prednisone or triamcinolone acetonide (TCA; or saline solution to controls) to determine the duration of adrenocortical suppression caused by 2 commonly used glucocorticoids. The glucocorticoids were administered at recommended therapeutic doses; therefore, dogs given prednisone received a greater amount of glucocorticoid activity than did in dogs given TCA. Basal and ACTH-stimulated plasma cortisol concentrations, as determined by radioimmunoassay, were obtained once a week. Total intravascular eosinophil concentration and skin responses to intradermally injected histamine phosphate were quantitated. Dogs given TCA showed suppressed basal and ACTH-stimulated plasma cortisol concentrations 1 week after injection; the latter change persisted 2 weeks after injection. Adrenocortical function in 1 of 4 dogs given TCA remained suppressed for 4 weeks. In contrast, prednisone did not significantly alter adrenocortical function. Although intravascular eosinophil concentrations did not vary among groups, skin responses to intradermally injected histamine phosphate were reduced 6 days after prednisone and TCA were given.     

Canine cyclic hematopoiesis: blood gas and 2,3-diphosphoglyceric acid studies

Cyclic hematopoiesis in gray Collies was first described in 1967. These dogs are anemic in comparison with the healthy littermates, and their erythropoiesis is abnormal. Although the basic disorder appears to be an as yet unidentified abnormality of hematopoietic progenitor cells, an inherent difference in responses to blood gas control mechanisms remains as a possible cause. In a study of these mechanisms in dogs with cyclic hematopoiesis, the P50 and 2,3-diphosphoglyceric acid concentrations were increased. Differences in pH, PCO2, PO2, and oxygen saturation were not observed.     

The pharmacokinetics and tissue levels of polymyxin B, colistin and gentamicin in calves

Following a single intravenous injection of polymyxin B, colistin (5 mg/kg, each) and gentamicin (3 mg/kg) to calves, the decline in serum antibiotic concentration generally suggested a three-compartment (open system) pharmacokinetic model. Tissue binding is a dominant factor in the distribution and elimination kinetics of the drugs. Less than 65% of the dose of polymyxin B and colistin was recovered in the urine during 48 h after treatment. Concentrations of nonbound polymyxin B and colistin in the kidney, liver, lung, heart, and skeletal muscles were similar to total (free and bound) serum drug levels, but considerably higher concentrations were found, in bound form, in chloroform-ethanol extracts of these organs.
At 24 h after treatment, more than 50% of the doses of polymyxin B and colistin were present bound to the tissues; the largest amount was in the skeletal muscles. Gentamicin was concentrated in the kidney, predominantly in the free form. At 48 h after treatment the amount of gentamicin in the kidney was 6.3% of the administered dose, being more than five times greater than the corresponding amounts of polymyxin B and colistin.
The extent of tissue uptake of polymyxin B and colistin limits the usefulness of kinetic values, which are derived from the analysis of serum drug levels, for the purpose of designing dosage schedules. The strong affinity of the polymyxins to the muscle tissue, and gentamicin to the kidney, can result in drug residues persisting in the body for several weeks.