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Sildenafil citrate, marketed as Viagra s , for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively. Plasma analyses were conducted to determine the exposure to sildenafil. We found species-specific effects in dogs (Beagle pain syndrome), mice (marked intestinal dilatation) and rats (adaptive reversible hepatocellular hypertrophy associated with secondary thyroid hypertrophy). All these effects in rodents and dogs have no relevance to humans. Morphometric thickness measurements of the retinal layers carried out in response to clinical observations of visual disturbances in humans indicated no difference between treated and control rats and dogs after up to 24 months of treatment. There was no evidence of histopathologic damage to any structures of the visual pathway. Sildenafil had no effects on fertility, no teratogenic potential, was not genotoxic and has no carcinogenic potential. In rats and dogs, safety ratios were 40:1 and 28:1, respectively, in terms of exposure over 24 h (AUC 24 h ) and 19:1 and 8:1, respectively, in terms of peak plasma concentration (C max ). These safety ratios illustrate the separation between exposure to sildenafil of animals at large nontoxic doses and the much smaller human therapeutic exposure. This profile highlights the very low risk of human toxicity for sildenafil. The favourable results of the nonclinical safety evaluation of sildenafil in established animal models have been confirmed by many years of clinical experience during the development and marketing of sildenafil.

Administration of fenoldopam mesylate (FM), a dopaminergic agonist, or of cyclic cAMP phosphodiesterase inhibitors (PDE III), for example theophylline and caffeine, induces arteritis in the rat. In this study we characterized the arteritis induced by UK-61,260, an investigational inotropic agent with vasodilatory properties which displays an inhibitory action on cyclic AMP phosphodiesterase, in comparison with lesions induced by FM. The compounds were administered to Sprague-Dawley rats by intravenous infusion over 24 h (FM and UK-61,260), orally or subcutaneously (UK-61,260); the rats were killed and necropsied for pathological examination at various times between 0 h and 28 days post-infusion. Infusion of UK-61,260 at doses of 100, 300 or 400 mg/kg produced arteritis mainly in the mesenteric arteries and occasionally in the renal, pancreatic, gastric and coronary arteries. There were no arterial lesions after infusion of 30 mg/kg, or after administration of 30, 100 or 200 mg/kg per day subcutaneously for 7 days, or after acute administration of 100, 300, 400 or 600 mg/kg orally. Infusion of rats with 72 or 144 mg/kg FM produced arteritis over a wider range of tissues than did UK-61,260. However, the arterial lesions produced by infusion of either drug have the same initial aspect and a similar evolution with time. Immediately after the end of the infusion, minimal necrosis and haemorrhage occurred in the media only, without involvement of the endothelium or the perivascular space. This indicates that the media of the artery is the primary site of injury. The lesions seen 1 and 3 days post-infusion were characterized by severe medial necrosis and haemorrhage with perivascular acute inflammation and appeared macroscopically as haemorrhagic spots on the vessels. On days 7, 14 and 28 post-infusion, no medial necrosis or haemorrhage were present, while perivascular chronic inflammation and moderate smooth muscle hyperplasia were seen. It appeared, therefore, that the lesions underwent repair in 28 days, but footprints of the damage were still present 28 days post-infusion. The similarity between arteritis induced in rats by fenoldopam or by UK-61,260, at doses inducing PDE III inhibition, is consistent with the view that they have a similar pathogenesis. In our view it is probable that these pharmacologically and chemically distinct drugs trigger an increase in intracellular levels of cAMP which in turn triggers vascular damage. The arterial changes observed in the current study after acute administration may explain the increased incidence of polyarteritis nodosa occurring in long term toxicity studies with FM or PDE III inhibitors.

ABSTRAC~The use of the argyrophilic (Ag) staining technique for nucleolar organizer regions (NORs) revealed nuclear changes in myocytes of the left atrium of 10 rats treated twice a week for 6 weeks with doxorubicin (1 mg/ kg body weight) iv and sacrificed after 6 weeks without treatment. The changes were easily detected qualitatively and further assessed by quantification. Cardiac myocytes of doxorubicin-treated rats had larger nuclei and/or a larger quantity of AgNORs that were either dispersed in a number of small dots or clustered in rounded, rod-shaped, or tortuous large structures. AgNOR alterations may reflect a defect of nucleolar association leading to an impairment ofprotein synthesis that could be involved in doxorubicin cardiotoxicity.