A global pharmaceutical company initiative: an evidence-based approach to define the upper limit of body weight loss in short term toxicity studies.

Short term toxicity studies are conducted in animals to provide information on major adverse effects typically at the maximum tolerated dose (MTD). Such studies are important from a scientific and ethical perspective as they are used to make decisions on progression of potential candidate drugs, and to set dose levels for subsequent regulatory studies. The MTD is usually determined by parameters such as clinical signs, reductions in body weight and food consumption.

Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas.

Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis.

A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development.

Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose.

Mesenteritis precedes vasculitis in the rat mesentery after subacute administration of a phosphodiesterase type 4 inhibitor.

Inhibitors of phosphodiesterase type 4 (PDE4) are currently exploited as potent drugs for pulmonary diseases. Some PDE4 inhibitors induce necrotizing panarteritis in the mesentery of rats, comparable to spontaneous polyarteritis nodosa in rats and vascular alterations that are induced by various vasoactive compounds, such as fenoldopam and inhibitors of PDE3. The mechanism of toxicity is unknown.