Testicular distribution and toxicity of a novel LTA4H inhibitor in rats.

JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the Tmax of M1 was 48h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed.

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation.

INTRODUCTION: Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the monkey telemetry model as a preclinical predictor of QT interval prolongation in humans. METHODS: Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with Moxifloxacin (MOX), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). RESULTS: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 (Cmax=5.5+/-0.6 microM), 100 (Cmax=16.5+/-1.6 microM), and 175 (Cmax=17.3+/-0.7 microM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively (p

Sudden productivity collapse associated with the Triassic-Jurassic boundary mass extinction.

The end-Triassic mass extinction is one of the five most catastrophic in Phanerozoic Earth history. Here we report carbon isotope evidence of a pronounced productivity collapse at the boundary, coincident with a sudden extinction among marine plankton, from stratigraphic sections on the Queen Charlotte Islands, British Columbia, Canada. This signal is similar to (though smaller than) the carbon isotope excursions associated with the Permian-Triassic and Cretaceous-Tertiary events.

Oxygen free radical activity during live E. coli septic shock in the dog.

Free radicals generated during purine catabolism or by activated granulocytes cause tissue injury by peroxidation of lipid membranes. In a canine model of sepsis initiated by intravenous live Escherichia coli, fluorescent products of lipid peroxidation (FP) were measured in serum. Four groups of five dogs infused with 10(9)E. coli/kg were analyzed--I: no further treatment; II: prior depletion of granulocytes with a cytotoxic antibody; III: pre-treatment with superoxide dismutase and catalase; and IV: resuscitation after bacterial infusion to maintain cardiac output greater than 80% of pre-bacteremic levels. In Groups I, II, and III, cardiac output fell to less than 50% of baseline within 1 hr and remained there throughout the study. FP in Groups I and II rose to greater than 200% of baseline (P less than .02 and less than .03). In Groups III and IV, FP did not rise significantly from baseline. The rise in serum FP and the prevention of this rise by-treatment with antioxidants indicate generation of oxygen radicals. Their presence had no effect on hemodynamic parameters. Granulocyte depletion did not alter appearance of FP; however, prevention of low cardiac output blocked FP formation. These data suggest that oxygen free radicals were generated by tissue ischemia, rather than by granulocytes, in this model of septic shock.

Vaccination of fish: a practical view.

Commercial vaccines giving protection against three important bacterial fish diseases (enteric redmouth, furunculosis and vibriosis) became available in the United Kingdom in 1983. The degree of protection obtained and the cost effectiveness vary according to the method of presentation (injection, dipping or spraying and oral dosing). These methods and the optimum time for vaccination are described.

Prolonged heparin therapy in pregnancy causes bone demineralization.

The relation of heparin therapy to osteoporosis was assessed in a retrospective analysis of 20 women treated during and after pregnancy with subcutaneous heparin for thromboembolism prophylaxis. The phalangeal cortical area ratio was significantly less after long term therapy (greater than 25 weeks) compared with that after short term therapy (less than 7 weeks). The same trend was found in the metacarpal area ratio, although this did not reach statistical significance. The changes were most marked in a woman who had received heparin also in a previous pregnancy. No correlations were found between duration of therapy and back pain, conventional radiology of lumbar spine or the Singh index of femoral trabecular pattern which were within the normal range in all patients. The findings indicate a dose-related demineralization process associated with prophylactic heparin therapy in pregnancy. The correct methods of and criteria for thromboembolism prophylaxis in pregnancy need critical re-examination.

Identification of staphylococcal Panton-Valentine leukocidin as a potent dermonecrotic toxin.

The Panton-Valentine leukocidin of Staphylococcus aureus was shown to exhibit a potent dermonecrotic effect when injected intradermally into rabbits. This effect could be abrogated by immunizing animals with the F component or both components, but immunization with the S component appeared to exacerbate certain of the intradermal responses.

Effect immunization with highly purified alpha- and beta-toxins on staphylococcal mastitis in rabbits.

Experiments were carried out to determine whether immunization of female rabbits with highly purified staphylococcal alpha- or beta-toxins would protect them against intramammary challenge with staphylococci. High circulating anti-alpha-toxin titers reduced the lethal hemorrhagic edematous form of the disease ("blue-breast") produced by strains BB and Compton 201 to a localized chronic abscess form. No such protection was afforded by high anti-beta-toxin titers. Immunization with alpha- or beta-toxins produced no change in the clinical picture of the disease produced by CN.6708, a strain of Staphylococcus responsible for a natural outbreak of abscess-type rabbit mastitis. From these experiments it would appear that alpha-toxin is a key antigen in the blue-breast form of rabbit mastitis. Since the abscess form of the disease was not prevented by immunization with either alpha- or beta-toxin, other virulence factors must be acting to produce this more localized disease.