Conversion of spironolactone to an active metabolite in target tissues: formation of 7α-thiospironolactone by microsomal preparations from guinea pig liver,adrenals, kidneys,and testes

Previous studies had established that much of the biological activity of the mineralocorticoid antagonist, spironolactone, depended upon its metabolism, but little was known about the nature of spironolactone metabolites in tissues. A method employing high pressure liquid chromatography has been developed for the separation and mfeasurement of several potential metabolites of spironolactone. Incubation of spironolactone with guinea pig hepatic, adrenal, renal, or testicular microsomal preparations resulted in the production of 7α-thiospironolactone (SC-24813), a compound which is a potent mineralocorticoid antagonist and which promotes the destruction of adrenal and testicular cytochromes P-450. Identification of 7α-thiospironolactone as the tissue metabolite was confirmed by mass spectrometry. The relative rates of production of 7α-thiospironolactone by the microsomal preparations were liver > kidney > adrenal > testis. Spectral data suggest that the effects of spironolactone on adrenal cytochromes P-450 may depend, at least in part, upon its conversion to 7α-thiospironolactone. The results establish that 7α-thiospironolactone is a tissue metabolite of spironolactone and may contribute to the therapeutic actions as well as some of the side effects of the parent drug.     

Primary pneumonic plague in the African Green monkey as a model for treatment efficacy evaluation

Background Primary pneumonic plague is rare among humans, but treatment efficacy may be tested in appropriate animal models under the FDA ‘Animal Rule’. Methods Ten African Green monkeys (AGMs) inhaled 44–255 LD₅₀ doses of aerosolized Yersinia pestis strain CO92. Continuous telemetry, arterial blood gases, chest radiography, blood culture, and clinical pathology monitored disease progression. Results Onset of fever, >39°C detected by continuous telemetry, 52–80 hours post‐exposure was the first sign of systemic disease and provides a distinct signal for treatment initiation. Secondary endpoints of disease severity include tachypnea measured by telemetry, bacteremia, extent of pneumonia imaged by chest x‐ray, and serum lactate dehydrogenase enzyme levels. Conclusions Inhaled Y. pestis in the AGM results in a rapidly progressive and uniformly fatal disease with fever and multifocal pneumonia, serving as a rigorous test model for antibiotic efficacy studies.     

Growth responses of Sphagnum hollows to a growing season lengthening manipulation in Alaskan Arctic tundra

The global increase in surface air temperature has produced an overall lengthening of the growing season by 3–5 days/decade in the Northern Hemisphere during the last 30 years. The direct impact of a longer growing season has not been well documented for Sphagnum moss communities in the Arctic. We hypothesized that an increase in the growing season length may be detrimental to Sphagnum growth as a result of photoinhibition caused by the plants emerging from snow near the seasonal peak of solar irradiance. We conducted an experiment from 1999 to 2002, lengthening the growing season in arctic Alaska, to determine the effects that this simulation of climate change had on the growth of hollows dominated by Sphagnum angustifolium. The lengthened growing season was associated with a decrease in annual moss height increment of 78 and 69 % for 1999 and 2000, respectively. These growth reductions may be related to freeze/thaw episodes and prolonged periods of cold in those years. The growth of individuals exposed to snow removal was also reduced by high global radiation. Overall, snow removal did not significantly affect the seasonal dynamics of growth, but seasonal patterns of growth strongly differed among years. These differences in seasonal dynamics suggest that Sphagnum growth is driven by opportunistic responses to favorable conditions rather than ontogenetic drivers. In addition, we compared environmental variation and growth between control and snow removal plots. Growth of Sphagnum in both treatments was stimulated by warmer soil temperatures and drier conditions. With earlier snowmelt as a result of warmer temperatures, it is likely that S. angustifolium will be subjected to higher levels of radiation and possibly greater photoinhibition which may lead to lower growth rates and significant implications for moss production in tussock tundra.