ABSTRACT
The toxicological profile of bicalutamide in animals following acute and chronic dosing is closely associated with the drug's non-steroidal anti-androgenic pharmacological activity. Bicalutamide produces typical effects of an anti-androgen, including atrophy of the prostate, testis and seminal vesicles and Leydig cell hyperplasia resulting from inhibition of pituitary feedback by testosterone. Subsequent benign Leydig cell tumors were seen in rats, but Leydig cell hyperplasia has not been observed in patients. Bicalutamide causes liver enlargement and is a mixed function oxidase inducer in rodents and dogs, but not man. These effects lead to thyroid hypertrophy and adenoma in the rat and hepatocellular carcinoma in the male mouse. In vitro and in vivo genotoxicity studies have all given negative results. Bicalutamide also caused a reversible shortening of the electrocardiographic P-R interval in the dog without any associated pathology. This change was not detected in ECG monitoring during clinical trials. In conclusion, bicalutamide produced a range of pharmacological effects, as well as liver enlargement with enzyme induction and dog ECG changes in preclinical toxicity studies in rodents and dogs. Only the pharmacological changes were found to be relevant to human usage.
Subject(s)
Androgen Antagonists/toxicity , Anilides/toxicity , Receptors, Androgen/metabolism , Animals , Body Weight/drug effects , Dogs , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Female , Humans , Liver/drug effects , Liver/enzymology , Male , Mice , Mutagenicity Tests , Nitriles , Ovary/drug effects , Ovary/metabolism , Prostate/drug effects , Prostate/metabolism , Rats , Reproduction/drug effects , Seminal Vesicles/drug effects , Seminal Vesicles/metabolism , Testis/drug effects , Testis/metabolism , Testosterone/metabolism , Tosyl Compounds , Uterus/drug effects , Uterus/metabolismABSTRACT
The inotropic vasodilator, ICI 153,110, a phosphodiesterase inhibitor intended for the treatment of congestive heart failure, was administered to Alderley Park Wistar-derived rats for periods of up to 182 days. Treatment produced hypertrophy of salivary glands, hyperplasia of intestinal mucosa, and dacryoadenitis of the harderian gland. As the functions of these glandular tissues can be modified by factors which alter cyclic nucleotide metabolism, it is postulated that the glandular alterations produced by ICI 153,110 occurred as a result of phosphodiesterase inhibition.
Subject(s)
Dihydropyridines/adverse effects , Harderian Gland/drug effects , Intestinal Mucosa/drug effects , Phosphodiesterase Inhibitors/adverse effects , Pyridazines/adverse effects , Salivary Glands/drug effects , Vasodilator Agents/adverse effects , Animals , Digestive System/drug effects , Digestive System Physiological Phenomena , Dose-Response Relationship, Drug , Female , Harderian Gland/pathology , Hyperplasia , Hypertrophy , Intestinal Mucosa/pathology , Male , Myocardial Contraction/drug effects , Rats , Rats, Inbred Strains , Salivary Glands/pathology , Time FactorsABSTRACT
ICI 153,110 is an inotropic vasodilator compound intended for the treatment of congestive heart failure. It was administered to rats at dose levels of 5, 10, and 250 mg/kg/day for up to 6 months as part of its preclinical development program. Detailed clinical investigations were conducted during the course of the study and histopathological examination took place after 28 days and 182 days of treatment as well as 42 days following cessation of dosing. Changes were identified in blood vessels in the greater proportion of animals from the high dose group, although some of the changes were also observed at lower dose levels. Vascular tissues from a variety of sites were affected, particularly those of the mesentery, splanchnum, heart, testis, and the pampiniform plexus. Early changes characteristic of acute injury such as arterial medial necrosis and inflammation occurred, which were distinguishable from those following chronic administration of the compound where there was a pronounced arterial and venous wall thickening and accompanying plexiform vasculopathy. The essential components contributing to the thickening were a smooth muscle hypertrophy and hyperplasia of the media. At the end of the period following withdrawal of dosing, vascular thickening was still present and arteritis showed an increased incidence relative to that seen at termination of the main test. Systemic hypertension was not detected during these studies. Vasodilation occurring at or near normal blood pressure, resulting in breakdown of vascular autoregulation and excessive critical wall tension, may have been the cause of the pathological changes. Our findings indicate that medial necrosis is an early component in a sequence of adaptive, destructive, and reparative changes not only following a chemically induced perturbation of the hemodynamic status in arteries and veins but also following a shift back to the "normal state" on withdrawal of compound.
