Impact of gavage dosing procedure and gastric content on adverse respiratory effects and mortality in rat toxicity studies.

Unscheduled mortality preceded by adverse respiratory clinical signs in rats dosed by oral gavage may not only be caused by technical gavage error or systemic toxicity but may also be caused by gastro-esophageal reflux and subsequent aspiration of high concentrations of drug formulation. In a 3 week oral gavage rat toxicity study for an early drug development compound, preterminal deaths (approximately 20% of animals) at high doses (≥1000 mg kg(-1) ) and concentrations (≥60 mg ml(-1) ) were preceded by recurrent dyspnea, rales or excessive salivation, without evidence of accidental intrapulmonary gavage error. Histological evaluation revealed extensive necrosis and inflammatory changes in the upper respiratory tract, especially in the nasal turbinates and/or nasopharynx. The presence of food particles in inflammatory exudates suggested a retrograde aspiration of stomach content with test formulation via the nasopharyngeal duct into the posterior region of the nose. In contrast, no mortality or adverse respiratory effects were observed in rats following 2 week intravenous administration at comparable exposures or oral gavage administration at lower concentrations (≤20 mg ml(-1) ). In a pharmacology study, the compound caused a dose-dependent increase in gastric content (partly due to inhibition of gastric emptying), providing a pharmacological basis for the suspected gavage-mediated gastroesophageal reflux. Reducing the dose volume and dosing fasted animals substantially reduced or eliminated the respiratory effects and mortality at the high test article concentrations, demonstrating that the adverse effects are related to the gavage method.

[The effect of treatment with vitamin E or selenium on the course of salinomycin poisoning in swine]. / Einfluss einer Behandlung mit Vitamin E oder Selen auf den Verlauf einer Salinomycin-Intoxikation beim Schwein.

Experimentally induced salinomycin toxicosis in weanling pigs showed typical clinical signs of an intoxication with a polyether antibiotic. Severe ataxia and recumbency were the most prominent symptoms, which could be attributed to acute skeletal muscle necrosis by estimation of muscle enzyme activities (creatine kinase, aspartate aminotransferase) and histopathological examination. Intoxication had neither influence on concentrations of vitamin E and selenium-dependent glutathione peroxidase in plasma and different organs nor on contents of fatty acids in skeletal muscles. No signs of increased lipid peroxidation in muscle tissue could be found. Prophylactic application of vitamin E or selenium one day before administration of salinomycin as well as treatment on the following days produced no protective effects. The treated pigs showed equal clinical and pathomorphological alterations as the untreated animals, although applications caused a significant increase of alpha-tocopherol and glutathione peroxidase concentrations in blood and different organs.

[Scanning electron microscopic findings of the navicular bone and deep flexor tendon in podotrochlosis of horses]. / Rasterelektronenmikroskopische Befunde an Strahlbein und tiefer Beugesehne bei der Podotrochlose des Pferdes.

In 25 adult horses the podotrochlea of 49 forelimbs was examined by means of light and electron microscopy in order to correlate clinical and morphological findings. According to the clinical diagnosis the animals were divided into three groups: lameness due to syndrome of podotrochlosis (group 1) or due to tendopathy (group 2) and horses without lameness (group 3). The most striking pathological findings of the navicular bone and the opposite surface of the deep flexor tendon were found in horses with podotrochlosis, consisting of loss of cartilage and tendon matrix with denudation of collagen fibrils, superficial degeneration and necrosis, focal occurrence of fissures and far-reaching defects, sometimes accompanied by adhesions between tendon and navicular bone surface. In radiologically only slightly altered tendons and navicular bones light and scanning electron microscopy often revealed moderate to severe pathological changes, which sometimes could also be seen in clinically healthy horses. The distribution of the lesions indicate that in course of podotrochlosis the initial alterations caused by repeated microtraumata start at the surface of the deep flexor tendon and subsequently spread to the opposite facies flexoria of the navicular bone. An involvement of the cartilage and the synovial layer of the hoof joint in cases with podotrochlosis could only be rarely observed and is to regard as a secondary manifestation.

[Tibial aplasia and agenesis in a rabbit (case report)]. / Tibiale Aplasie und Agenesie bei einem Kaninchen (Fallbericht).

The occurrence of a tibial aplasia (left side) and agenesia (right side) in a rabbit (aged 4 weeks) is reported. Apart from extreme distorsions of the fibular bones, there were no other skeletal malformations.

Streptococcus canis arthritis in a cat breeding colony.

This is the first description of a pathologic condition--arthritis in cats affecting mainly one joint, i.e. monarthritis--caused by Streptococcus canis (S. canis), of the Lancefield serologic group G. Six cases were recorded in a closed cat breeding colony during a 6 month period in 1988, and one additional case in 1990. Therapy with penicillin and streptomycin led to full recovery in four of six cases. The bacterium had been detected from different purulent processes sporadically--including one case of purulent arthritis in 1982--as a nosocomial infection since 1980, the year the breeding colony was established. A possible genetic predisposition (high inbreeding) may have contributed to the accumulation of the six cases in 1988. Although S. canis was isolated in mouse, rat, rabbit and dog, cat and man seem to be more frequently affected. There are some similarities between S. canis-arthritis in cat and man.

Ultrastructural findings in horses with chronic obstructive pulmonary disease (COPD). II: Pathomorphological changes of the terminal airways and the alveolar region.

Extensive light and electron microscope studies (transmission and scanning electron microscopy) of the bronchioles and alveolar region, in 28 horses suffering chronic obstructive pulmonary disease (COPD) and eight control horses, revealed good correlation between clinical severity and morphological changes. In the bronchiolar epithelium the non-ciliated bronchiolar epithelial (Clara) cells, in particular, showed ultrastructural alterations and, even in the mild stages of disease, these presented degenerative changes and lack of differentiation. Together with loss of granulation in the Clara cells and metaplasia of the goblet cells, cells were seen with unusual intracytoplasmic lamellar inclusion, the number of which increased sharply with clinical severity. The focal changes in the alveolar region were necrosis of type I epithelial cells, alveolar fibrosis of varying degrees with type II epithelial transformation and emphysema or hyperinflation, with an increase in Kohn's pores. Some horse also showed morphological signs of interference with the surfactant system, in the form of marked cysts with lamellar structure. The alveolar changes were mostly in the peribronchiolar region and were, therefore, interpreted as reactive processes. No conclusions as to the aetiology of equine COPD can be derived from these morphological investigations.

Detection of canine distemper viral antigen in formalin-fixed and paraffin-embedded tissue of a fitch (Mustela putorius), using an immunoperoxidase technique.

The present study describes how a naturally infected fitch (Mustela putorius) caused an outbreak of canine distemper in a colony of insufficiently vaccinated dogs. The detection of canine distemper virus (CDV) on paraffin sections of different organs of the fitch and one of the dead dogs was achieved using a monoclonal antibody against the nucleocapsid protein (NP) of CDV and the avidin-biotin-peroxidase complex (ABC) technique.