Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves.

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 µg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.

The effects of different ages and dosages on the plasma disposition and hair concentration profile of ivermectin following pour-on administration in goats.

The effects of different ages and dosages on the plasma disposition and hair concentration profile of ivermectin following pour-on administration in goats. J. vet. Pharmacol. Therap.34, 70-75. The effects of different ages and dosages on the plasma disposition and hair degradation of ivermectin (IVM) were investigated following pour-on administration in goats. Twenty-eight female Saanen goats allocated into two groups of 14 animals according to their ages as young (5-6 months old) and old (12-24 months old) groups. Each age group was divided into two further of seven goats and administered pour-on formulation of IVM topically at the in recommended dosage rate of 0.5 mg/kg bodyweight The recommended cattle dosages rate of 0.5 mg/kg or at the higher dosage of 1.0 mg/kg. Blood samples were collected at various times between 1 h and 40 days. In addition, hair samples (>0.01 g) were collected using tweezers from the application sites and far from application sites of the all animals throughout the blood sampling period. The plasma and hair samples were analyzed by high performance liquid chromatography (HPLC) using fluorescence detection following solid and liquid phase extractions, respectively. Dose- and age-dependent plasma disposition of IVM were observed in goats after pour-on administration. In addition, relatively high concentration and slow degradation of IVM in hair samples collected from the application site and far from the application site were observed in the present study. The differences between young and old goats are probably related to differences in body condition and/or lengths of haircoat. The systemic availability of IVM following pour-on administration is relatively much lower than after oral and subcutaneous administrations but the plasma persistence was prolonged. Although, the longer persistence of IVM on hairs on the application site may prolong of efficacy against ectoparasites, the poor plasma availability could result in subtherapeutic plasma concentrations, which may confer the risk of resistance development in for internal parasites after pour-on administration in goats.

Pharmacological assessment of netobimin as a potential anthelmintic for use in horses: plasma disposition, faecal excretion and efficacy.

This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster's technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO(2)) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53+/-0.14microg/ml) and ABZSO(2) (0.36+/-0.09microg/ml) were observed at (t(max)) 10.50 and 19.50h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration (C(max)) of (-)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.

The effect of sesame and sunflower oils on the plasma disposition of ivermectin in goats.

The effect of sesame oil (SSO) and sunflower oil (SFO) (the excipients) on the plasma disposition of ivermectin (IVM) following intravenous (i.v.) and subcutaneous (s.c.) administration at a dosage of 200 microg/kg was investigated in goats. Ten clinically healthy crossbred goats were used in the study. The animals were allocated by weight and sex into two groups of five animals each. Group 1 (n = 5) received the drug and excipient by the i.v. route only and group 2 received drug and excipient by the s.c. route only. The study was designed according to a two-phase crossover design protocol. In the first phase three animals in group 1 were i.v. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. In group 2 during the first phase, three animals were s.c. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals were received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. A 4-week washout period was allowed between the two phases. In group 2 significantly increased dermal thickness was observed at the s.c. injection site of the all animals which received IVM during phase I regardless of the excipient. There was almost no change observed at the injection site of any animal during the second phase of the study following s.c. administration. In group 2 the plasma concentrations of IVM in the second phase for both excipient combinations were much higher than the plasma concentrations following first administration and appeared to be related with the dermal changes. The mean plasma disposition of IVM in combination with SSO or SFO was similar following i.v. administration. Longer terminal elimination half-lives and resultant longer mean resident time were observed after s.c. administration of the both combinations compared with i.v. administration.

Comparative plasma disposition of fenbendazole, oxfendazole and albendazole in dogs.

The plasma disposition of fenbendazole (FBZ), oxfendazole (OFZ) and albendazole (ABZ); and the enantiospecific disposition of OFZ, and ABZSO produced were investigated following an oral administration (50 mg/kg) in dogs. Blood samples were collected from 1 to 120 h post-administration. The plasma samples were analysed by high performance liquid chromatography (HPLC). The plasma concentration of FBZ, OFZ, ABZ and their metabolites were significantly different from each other and depended on the drug administered. The sulphone metabolite (FBZSO2) of FBZ was not detected in any plasma samples and the parent molecule ABZ did not reach quantifiable concentrations following FBZ and ABZ administration, respectively. OFZ and its sulphone metabolite attained a significantly higher plasma concentration and remained much longer in plasma compared with FBZ and ABZ and their respective metabolites. The maximum plasma concentrations (Cmax), area under the concentration time curve (AUC) and mean residence time (MRT) of parent OFZ were more than 30, 68 and 2 times those of FBZ, respectively. The same parameters for ABZSO were also significantly greater than those of FBZSO. The ratio for total AUCs of both the parent drug and the metabolites were 1:42:7 for following FBZ, OFZ and ABZ administration, respectively. The enantiomers were never in racemic proportions and (+) enantiomers of both OFZ and ABZSO were predominant in plasma. The AUC of (+) enantiomers of OFZ and ABZSO was, respectively more than three and seven times larger than that of (-) enantiomers of both molecules. It is concluded that the plasma concentration of OFZ was substantially greater compared with FBZ and ABZ. The data on the pharmacokinetic profile of OFZ presented here may contribute to evaluate its potential as an anthelmintic drug for parasite control in dogs.

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.

Interactions of Ostertagia species with their bovine and ovine hosts.

Ostertagia spp. affect their hosts in several complex interactions involving structural, biochemical, hormonal, nutritional and immunological mechanisms. Following infection with Ostertagia spp. the specialised secretory function and junctional integrity of gastric epithelial cells is lost. The pH of the abomasal contents is elevated and pepsinogen concentration in the plasma increases. There is a concurrent elevation in the concentration of blood gastrin. The effects may be a response to the physical interaction of parasite with epithelial cells, may be mediated through parasite excretory/secretory products, or by neural mechanisms. There may also be interactions between the responses since elevated abomasal pH stimulates secretion of gastrin. Hormonal changes may also have a role in the increased susceptibility of host to parasite during the periparturient period. Prolactin was considered the most likely hormone candidate although there is now a body of evidence to suggest that elevated prolactin concentrations are not solely responsible. Infection with Ostertagia spp. causes a marked inappetance, negative nitrogen balance and reduction in apparent gross energy digestion. The level of nutrition may also affect the response of the host to the parasites and establishment of O. circumcincta is lower in animals on a low plane of nutrition than those on a high plane. Immunity of Ostertagia spp. develops slowly and once established is manifest following challenge by an initial hypersensitivity response, followed by a cell mediated response and then an antibody response. Parasites may fail to establish or may be expelled from immune animals and if they do establish may be stunted with small vulval flaps and lower biotic potential and may become inhibited at the early fourth stage of development.

The effects of excretions/secretions of Ostertagia circumcincta on ovine abomasal tissues in vitro.

Products excreted/secreted by Ostertagia circumcincta stimulated the in vitro release of pepsinogen from intact abomasal mucosal sheets and caused the contraction of strips of abomasal smooth muscle, also in vitro. However, responses occurred only when tissues had been derived from animals that were assumed to have experienced prior exposure to the parasite. The overall median responses for pepsinogen secretion in response to ES, expressed as the ratio of stimulated secretion to basal secretion, were 1.8 for previously exposed animals and 0.9 for parasite-naive animals. For the smooth muscle from the previously exposed animals, the overall median response to ES, expressed as a percentage of the maximal response to carbachol in the same tissues, was 27.0. No responses were seen in muscle from any parasite-naive animal. These results suggest that the responses obtained were hypersensitivity reactions to antigens released by the worms during in vitro culture, and occurring in tissues from animals sensitised by exposure to O. circumcincta in the natural environment.

The pharmacokinetics of albendazole metabolites following administration of albendazole, albendazole sulfoxide and netobimin to one-month- and eight-month-old sheep.

The principal metabolites detected in plasma of sheep following oral administration of albendazole (ABZ), albendazole sulfoxide (ABSO) and netobimin (NTB) each at 5.0 mg kg-1 body weight were ABSO and albendazole sulfone (ABSO2). The areas under the plasma concentration-time curve (AUC) for ABSO and ABSO2 were significantly (P < 0.05) larger following administration for ABSO than NTB in 1-month- and 8-month-old sheep. The AUC for the ABSO and ABSO2 metabolites were larger following administration of ABZ than NTB in 1-month- but not 8-month-old sheep and the AUC of the ABSO and ABSO2 metabolites were greater following ABSO than ABZ as parent compound in 8-month-old sheep only. The larger AUC values for metabolites following administration of ABSO as the parent compound were generally coincident with significantly higher maximum (Cmax) concentrations and not with persistence in the body, since mean residence times (MRT) of the metabolites were not significantly different from those determined following ABZ and NTB as parent compounds. The lower metabolite concentration following administration of NTB may have been a feature of its requirement for metabolic conversion and its larger molecular weight. Correction of AUC values for molecular weight removed any significant differences between AUC values for either metabolite in 8-month-old lambs. The corrected metabolite AUCs following NTB were, however, significantly lower than those following ABSO administration in 1-month-old lambs, suggesting that immature metabolic processes in these animals contributed to the lower relative bioavailability of NTB in this age group. Age did not affect the disposition of metabolites following ABZ or ABSO but the AUC of the ABSO metabolite following NTB was significantly (P = 0.014) lower in 1-month- than in 8-month-old sheep.

The repeatability of faecal egg counts, peripheral eosinophil counts, and plasma pepsinogen concentrations during deliberate infections with Ostertagia circumcincta.

Faecal egg counts, peripheral blood eosinophil counts and plasma pepsinogen concentrations were monitored during 2 successive, deliberate infections in 24 Scottish Blackface sheep. For all 3 techniques, the repeatability of replicate counts or of measurements made at short intervals were high which suggests that all 3 assays were reliable. Within an infection the repeatability of different samples from the same animal decreased as the interval between samples increased. The repeatability between infections was only moderate for faecal egg counts but high for peripheral eosinophil counts and plasma pepsinogen concentrations. Of the 3 variables, faecal egg count was the most strongly associated with the worm burden. Together, the three variables accounted for, in a statistical sense, one half of the variation in worm burden. The three variables, if measured concurrently, should provide a more effective identification of resistant and susceptible lambs.

An ovine major histocompatibility complex DRB1 allele is associated with low faecal egg counts following natural, predominantly Ostertagia circumcincta infection.

Infection with Ostertagia circumcincta is a major constraint on sheep production in temperate areas of the world. A potential control strategy is the use of genetically resistant sheep. Therefore we examined the association between MHC-DRB1 alleles and faecal egg counts following natural, predominately O. circumcincta infection in a flock of Scottish Blackface sheep. Nineteen DRB1 alleles were identified by a combination of variation in the length of simple repetitive sequences within the intron between exons 2 and 3 and hybridisation of selected oligonucleotides to polymorphisms within exon 2. Faecal samples were taken from 200 lambs from one to six months of age at intervals of 4 weeks. Genetic effects were strongest at 6 months of age. Least-squares analysis indicated that substitution of the most common allele (I) by allele G2 would result in a 58-fold reduction in faecal egg counts in 6-month-old lambs and a 22-fold reduction in 5-month-old lambs. These results suggest that the major histocompatibility complex plays an important role in the development of resistance to O. circumcincta.

An ovine lymphocyte antigen is associated with reduced faecal egg counts in four-month-old lambs following natural, predominantly Ostertagia circumcincta infection.

Ovine lymphocyte antigen is associated with reduced faecal egg counts in 4-month-old lambs following natural, predominantly Ostertagia circumcincta infection. International Journal for Parasitology 26: 423-428. Ten lymphocyte antigens were defined in a flock of Scottish Blackface sheep known to be naturally exposed to infection with Ostertagia circumcincta. Population and family studies suggested that the 10 antigens were products of class I loci. Antigen G13br was in linkage disequilibrium with allele g2 at the DRB1 locus. The g2 allele has previously been associated with reduced faecal egg counts in a different crop of lambs from the same farm. In this study antigen G13br was also associated with a reduction in faecal egg counts. The results provide partial confirmation of the role of the major histocompatibility complex in resistance to natural, predominantly O. circumcincta infection.

Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships.

Tolfenamic acid was administered to beagle dogs at 2, 4 and 8 mg/kg bodyweight i.m. and the concentration of drug in plasma and in inflamed (administered carrageenan) and non-inflamed subcutaneous tissue cage fluid was measured. The concentration of thromboxane B2 in serum from blood allowed to clot under standardized conditions was determined and the concentrations of prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and leucocyte numbers were measured in fluid from the carrageenan administered tissue cages. Skin temperature was also measured over each tissue cage following administration of drug. Tolfenamic acid displayed linear pharmacokinetics since the area under the plasma concentration time curve (AUC) values were 13.74 +/- 1.88, 29.82 +/- 6.53 and 50.52 +/- 5.73 micrograms/ml.h following administration of 2, 4 and 8 mg/kg, respectively. Tolfenamic acid proved to be a potent inhibitor of ex vivo thromboxane B2 generation in clotting blood. Maximal inhibition was greater than 80% at all dose rates and 97% at the 8 mg/kg dose rate 1 h after drug administration. It also proved to be a potent inhibitor of prostaglandin E2 production in inflammatory exudate, and significantly (P < 0.05) decreased prostaglandin E2 production at all dose levels. Tolfenamic acid did not significantly alter 12-HETE generation or white blood cell accumulation in inflammatory exudate. Tolfenamic acid significantly reduced the elevated skin temperature over carrageenan administered cages at all dose levels.

Measurement of cyclooxygenase inhibition in vivo: a study of two non-steroidal anti-inflammatory drugs in sheep.

The anti-inflammatory effects of the non-steroidal anti-inflammatory drugs phenylbutazone (PBZ) and flunixin meglumine (FM) and the relationship between the effects and drug concentration in vivo were studied using a subcutaneous tissue-cage model in sheep. Intracaveal injection of carrageenan induced prostaglandin (PG) E2 production in tissue-cage exudate (maximal concentration, 101 nM) with significant increases in white blood cell (WBC) numbers, skin temperature over the inflamed cage and exudate leukotriene B4 (LTB4) concentration (P < 0.05). Intravenous PBZ, 4.4 mg kg-1 produced mild inhibition of exudate PGE2 generation (10%), but greater inhibition of serum TXB2 (75.3%). The IC50 for TXB2 was 36.0 microM. Phenylbutazone did not alter effects on skin temperature, WBC numbers or exudate LTB4 concentrations. Intravenous FM, 1.1 mg kg-1, significantly inhibited carrageenan-induced exudate PGE2 formation (Emax, 100%, IC50, < 0.4 nM) and serum TXB2 generation (Emax, 100%, IC50, 17 nM) for up to 32 h. Flunixin meglumine significantly inhibited the rise in skin temperature but had a limited effect on exudate WBC. Phenylbutazone and FM have distinct effects on carrageenan-induced cyclooxygenase (COX-2) and platelet COX (COX-1). Flunixin meglumine was a more potent COX inhibitor than PBZ and was more selective for the inducible form of COX in vivo.

Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications.

The effect of the cytochrome P450 inhibitor, piperonyl butoxide on the pharmacokinetics and anthelmintic efficacy of the benzimidazole compound fenbendazole was studied in sheep and goats. Pretreatment of goats with the inhibitor caused a greater than three-fold increase in the relative bioavailability of fenbendazole and fenbendazole sulphoxide. A pharmacokinetic dose titration study was carried out in sheep with fenbendazole (5 mg kg-1) and piperonyl butoxide administered orally at 0, 15, 31, 63, 125 and 250 mg kg-1. The AUC of fenbendazole and the sulphoxide were significantly increased when fenbendazole was co-administered with piperonyl butoxide at dose rates equal to or higher than 31 mg kg-1. Peak plasma concentrations (Cmax) and mean residence time (MRT) were also significantly increased. The efficacy of the combination was assessed in sheep against two species of benzimidazole-resistant abomasal nematodes; Ostertagia circumcincta and Haemonchus contortus. The percentage reduction in the total number of O. circumcincta worms was 7.9% (fenbendazole) and 97.8% (fenbendazole-piperonyl butoxide). For H. contortus, the percentage reduction was 84.8% (fenbendazole) and 99.0% (fenbendazole-piperonyl butoxide). The in-vitro S-oxidation of fenbendazole and fenbendazole sulphoxide was studied using microsomal preparations from rat liver. Piperonyl butoxide inhibited significantly the sulphoxidation and sulphonation of fenbendazole. It was concluded that piperonyl butoxide inhibited the oxidative conversion of fenbendazole into inactive metabolites and this resulted in a potentiated anthelmintic action.

Ecotoxicology and residues of anthelmintic compounds.

Anthelmintics and endectocides used for the treatment and prophylaxis of Ostertagia sp. in ruminants include benzimidazoles, levamisole, morantel and the avermectins and milbemycins. Most of these agents are excreted to some extent in the faeces of treated animals and it has been demonstrated that members of the avermectin/milbemycin group may have deleterious effects on non-target organisms utilising the faeces. The environmental impact of antiparasitic chemotherapy depends on the deleterious effect which the agent or its metabolites have on organisms in the locus of the excreta, the amount of active agent excreted, the temporal nature of the excretion and the stability of the ecotoxic residues. These have to be considered in the context of the overall proportion of excreted faeces from a herd which is contaminated and thus the availability of non-contaminated faeces which may act as refugia for dung utilising organisms. The contribution which weathering, faunal inhabitants, trampling by cattle and disturbance by birds have on the rate of dung degradation must also be considered. The greatest ecotoxicological risk is associated with sustained release delivery devices, delivering endectocides with potent activity against dipteran flies and coleopteran beetles. The relatively large proportion of most cattle herds excreting faeces with no endectocidal contamination is likely to reduce the impact that such treatment or prophylactic strategies have on non-target organisms.

Chemotherapy and delivery systems--helminths.

The milbemycins are the only novel broad spectrum anthelmintic chemicals to reach the market place in the last 10 years. Many new systems for delivery and strategies for rational use have, however, been introduced. Boluses which are retained by virtue of specific gravity and by variable geometry are now available. They contain benzimidazoles, morantel, ivermectin and levamisole. Their release mechanisms involve preferential corrosion of a retaining metal core, constant diffusion from a laminated ethylene acetate sandwich, and a hydrostatic pump driven by osmotic pressure. Some are biodegradable. Experimental delivery systems have been developed incorporating ear implants and liposomes. The anthelmintic efficacy of some drugs has been potentiated by the synergistic action of metabolic inhibitors and these combinations hold promise for the future. Much new information is now available on those factors which affect anthelmintic efficacy such as concurrent administration with food and the presence of the target parasites themselves. This knowledge provides a sound basis for the rational use of anthelmintic drugs.

Effect of parasitism with Nematodirus battus on the pharmacokinetics of levamisole, ivermectin and netobimin.

The pharmacokinetics of levamisole, ivermectin and netobimin administered orally and by subcutaneous injection were compared in lambs exposed to a moderate challenge with Nematodirus battus and in parasite naive lambs. There were no significant differences (P greater than 0.05) in the bioavailability of any of the anthelmintics tested between parasitized and non-parasitized animals. Levamisole reduced nematode faecal egg output by more than 99% when administered by either route. Ivermectin was also highly effective (greater than 99%). Orally administered netobimin reduced egg output by more than 98% seven days after administration. However egg output was only reduced by 89% 21 days after administration, suggesting poor activity against the early parasitic stages of N. battus. Netobimin was not effective against N. battus when administered by the subcutaneous route and this was probably because very low plasma concentrations of its active albendazole metabolites were achieved.

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.

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.