Method for long-term cerebrospinal fluid collection in the conscious dog.

In medical research there is often a need for cerebrospinal fluid (CSF) collection from conscious animals. A number of models have been published, but long-term use is often limited by factors such as damage to implant or loss of patency. When part of an implant is exteriorized, group housing is often not possible; even when singly housed, the instrumented animals might have to be fitted with protective devices such as collars, vests, or helmets. Over the last 10 years we have, through the use of this technique, managed to perform repeated CSF collections in 12 beagles. Time of implant duration has ranged from 2.3 to 6.8 years. The method uses two permanent stainless steel guide cannulas screwed into the parietal bone, positioned above but not penetrating the lateral ventricles of the brain. At the time of collection, one of the subcutaneous stainless steel cannulas is used to serve as a guide for a 20-gauge collection needle. The collection is performed under local analgesia and with minimal discomfort to the dog. With its long-term use, we feel that this model is very useful and of high ethical and welfare standards due to the virtual lack of postoperative complications, maintenance requirements, and housing restrictions.

A scoring system for gastric ulcers in the horse.

Five investigators familiar with gastric ulcer disease in horses met to establish a scoring system that could be utilised in future studies. Slides of gastric lesions were viewed and discussed and a scoring system established that required the nonglandular and glandular portions of the stomach to be graded separately. Each portion of the stomach (glandular and nonglandular) received a score for number of ulcers present and a score for severity of ulcers which resulted in each stomach receiving 4 separate scores. After the grading system was developed, each investigator independently graded 16 horses with gastric ulcer disease that had been previously recorded on video tape. The results of each investigator's scores were then compared. There was a variability between observers in the scores for severity of both nonglandular and glandular lesions but the variability was not significant. The variability between observers for the number of glandular lesions was also not significant. This implied that there was consistency between the 5 observers in the way severity of lesions was scored and the number of glandular lesions. However, there was a significant variability between observers for the number of nonglandular lesions which implied agreement on this observation was more variable.

Central nervous system kinetics of atenolol and metoprolol in the dog during long term treatment.

Beagle dogs with catheters chronically implanted into the lateral cerebral ventricle were used to study the distribution of atenolol and metoprolol between the cerebrospinal fluid (CSF) and blood plasma over a 24-hr period during long term treatment. The concentration of atenolol declined more slowly in CSF than in blood plasma and the CSF/plasma ratio of atenolol (after iv administration for 7 days) increased from 0.08 +/- 0.02 (2 hr after dose) to 0.83 +/- 0.14 (24 hr after dose) (mean +/- SD). Furthermore, the CSF concentration of atenolol, relative to the plasma concentration, increased during repeated drug administration. The CSF/plasma ratio 24 hr after an iv dose was 0.48 +/- 0.12 on day 1 and 0.83 +/- 0.14 on day 7. The CSF concentration of the more lipophilic beta 1-adrenoceptor antagonist metoprolol was almost the same as the concentration of the drug in blood plasma. After 7 days of oral treatment, the CSF/plasma ratio of metoprolol 24 hr after dosing was 0.81 +/- 0.10. The regional CSF concentration of atenolol along the neuraxis was determined in anaesthetized dogs after acute iv administration of the drug. The atenolol concentration in CSF from the lateral cerebral ventricle was similar to that in the cisterna magna but lower than the concentration in CSF sampled from the lumbar region. It is concluded that the CSF concentration of the moderately lipophilic beta 1-adrenoceptor antagonist metoprolol equilibrates with the plasma concentration of the drug more rapidly compared with the hydrophilic drug atenolol.

Evaluation of the oesophago-irritant potential of terodiline hydrochloride tablets in three animal models.

The oesophago-irritant potential of terodiline hydrochloride 25 mg tablets was evaluated by use of one acute and two recovery animals models, each documented to be sensitive for predicting local irritant and/or ulcerogenic effects of drugs on the human oesophageal mucosa. Both uncoated and coated terodiline hydrochloride tablets produced slight to moderate oesophageal lesions in cats sacrificed after 4 to 8 hours of tablet exposure, whereas emepronium bromide, a drug associated with oesophageal injury in man, showed moderate to severe oesophago-irritant properties when tested in the same model. No significant oesophageal changes were, however, observed with coated terodiline hydrochloride tablets in cats or pigs subjected to five days of recovery after an initial tablet exposure period of eight and five hours, respectively. The results indicate that the oesophago-irritant effect of terodiline hydrochloride 25 mg tablets is very mild and also transient. Thus no or only a minimal risk of oesophageal irritation after accidental lodging of the tablet in the oesophagus is to be anticipated in patients.

Diet and breeding performance in cats.

A conventional cat breeding colony with 70 queens (female cats) was studied during a 4 year period 1979-1982. During that time the fat content in the diet was increased from 15% to 27% of dry matter. An increase in the number of kittens per litter (from 4.5 to 5.5) and in the annual number of litters per queen (from 1.4 to 2.3) was found. In addition, the mortality decreased from over 20% to 9%. Bodyweight gain under the new diet was such that the males reached 2500 g in 4 months while the females showed this same weight at 5 months of age. Litter size and sex distribution as a function of queen age, litter interval and time of year are presented. It is concluded that husbandry and diet are factors which are of great importance in a cat breeding unit. It is shown that under our conditions it is possible to breed conventional cats with good results.

Comparative metabolic disposition of oral doses of omeprazole in the dog, rat, and mouse.

The metabolic disposition of [14C]omeprazole was studied in dogs, rats, and mice after the administration of pharmacologically active, single oral doses of drug in buffer solutions (pH 9). Averages of 38% (dogs), 43% (rats), and 55% (mice) of the radiolabeled doses were excreted in the urine in 72 hr. Most of the remaining dose was recovered in the feces. Omeprazole was extensively metabolized in all species studied and the metabolites were eliminated rapidly. No unchanged drug could be detected in the urine samples (less than 0.1% of dose). In each species at least 10 metabolites were detected in urine (pH 9) by gradient elution reverse phase HPLC. Based on liquid chromatographic retention data, the metabolic patterns were very complex and exhibited some quantitative differences between species. Bile was collected from rats and from chronic bile-fistulated dogs. Biliary excretion was a major route of elimination of omeprazole metabolites, and four polar metabolites were detected in the rat bile. The stability of omeprazole metabolites at varying pH values is discussed with reference to reductive metabolism of the parent compound.

Oesophageal ulcerations and plasma levels of different alprenolol salts: potential implications for the clinic.

The ulcerogenic effect of five different salts of alprenolol were tested against placebo in a porcine oesophageal test model. The salts with high water solubility, such as the hydrochloride and the fumarate, gave rise to the highest plasma concentrations of alprenolol and evoked serious oesophageal lesions, while the salts with low solubility-the benzoate, maleate and sebacate-had no irritative effect on the oesophagus. The plasma levels of alprenolol were much higher following administration of alprenolol hydrochloride in the oesophagus than after an identical intraduodenal dose of the same salt possibly because of the avoidance of the first-pass degradation during oesophageal absorption.

The ulcerogenic effect on the oesophagus of three beta-adrenoceptor antagonists, investigated in a new porcine oesophagus test model.

Drug-induced oesophageal lesions have attracted increasing attention during the past few years. A test model is presented for assessing irritative or ulcerogenic effects of potential drugs on the oesophagus. In this model the pig oesophagus is used, as it is more similar to the human oesophagus than models used in other techniques that have been suggested. The beta-blockers, alprenolol and propranolol, displayed the same ulcerogenic properties with this test model as reported with other test models in the literature. The beta 1-selective blocker metoprolol, did not have such ulcerogenic effects. The pig model is suggested as the method of choice in evaluating the potential irritative or ulcerogenic effects of pharmaceutical formulations intended for human use.