Following infection with Ostertagia circumcincta there was considerable variation in worm burdens, worm size and number of inhibited larvae even among sheep matched for age, sex, breed, farm of origin and history of parasite exposure. There was also substantial variation among sheep in the concentration of mast cells, globule leucocytes, eosinophils, IgA-positive plasma cells and parasite-specific IgA in the abomasal mucosa. With the exception of faecal egg counts over time, the parasitological and immunological traits were all continually distributed among animals and sheep did not fall into discrete high and low-responder categories. The responses were correlated. Sheep with more mast cells also had more globule leucocytes, more eosinophils, more IgA plasma cells and greater amounts of parasite-specific IgA in the abomasal mucosa. Female worm length was strongly and positively correlated with the number of eggs in utero. Faecal egg counts were associated with variation in worm number and with variation in the number of eggs in utero. The worm burden was negatively correlated with the number of globule leucocytes in the abomasal mucosa, suggesting that worm numbers are regulated by immediate hypersensitivity reactions. Decreased female worm length was associated with an increased local IgA response to fourth stage larvae. The number of inhibited larvae was positively associated with the size of the local IgA response and positively associated with the size of the worm burden. The results suggest that variation among mature sheep in faecal egg counts is due, at least in part, to variation in local IgA responses which regulate worm fecundity and to variation in local immediate hypersensitivity reactions which regulate worm burdens.

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.

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Faecal egg counts and live weights were measured on approximately 200 predominantly twin-born Scottish Blackface lambs each year for 3 years, from 1 to 6 1'lonths of age. Measurements lvere made at 4-ti'eek mt/:'ltlals following anthelmintic treatment. Heritability estimates (with s.e.s) of log transformed faecal egg count at each age were 0.01,0.00,0.12 (0.10), 0.14 (0.12), 0.15 (0.07) ard 0.22 (0.13), for ages 1 to 6 months respectively. Therefore, genetic variation exists for acquired but apparentl~ not for innate resistance to infection. Maternal common environmental effects (with s.e.s) were 0.36 (0.11), 0.2b (0.05), 0.27 (0.09),0.06 (0.08), 0.15 (0.09) and 0.16 (0.08), for ages 1 to 6 months respectively. Genetic correlatiqns between faecal egg counts in Iambs older than 3 mpnths u'ere not significantly less than 1.0, indicating that faecal egg counts at different ages are expressions of the same trait. Phenotypic correlations between faecal egg colfnts were generally positive but small. Measurement ,error contributed one-third of the observed variation for indrvidual egg counts. The heritability of mean faecal egg count from.3 to 6 months was 0:33 (s.e. 0.15), .indicatin~ ~hat selection decisions can be ma~e mo~e accurately using multIple egg counts per anImal. PhenotypIc correlatIons between faecal egg counts and live weIght were generally negative but close to zero. However, genetic correlati~ns between faecal egg counts and live weight in lambs older than 3 months were close to -1.0, indicating that r~sistance to gastrointestinal parasites may be an important genetic determinant of growth rate in this environment.

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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.

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains a single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the racemate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+)(S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (Cmax 18 micrograms/ml, AUC0-24 118 micrograms h/ml) than the (+)(S) (Cmax 14 micrograms/ml, AUC0-24 67 micrograms h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but Cmax and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by Cmax and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B2 (T x B2) generation by platelets in clotting blood (serum T x B2), or prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis in inflammatory exudate.(ABSTRACT TRUNCATED AT 250 WORDS)