Preclinical safety profile of sildenafil.

Sildenafil citrate, marketed as Viagra, 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.

A phase I/IIA clinical study with a chimeric mouse-human monoclonal antibody to the V3 loop of human immunodeficiency virus type 1 gp120.

A phase I/IIA clinical trial with the chimeric mouse-human monoclonal antibody CGP 47,439 to the principal neutralization determinant in the V3 region of human immunodeficiency virus type 1 (HIV-1) strain IIIB envelope protein gp120 is reported. The trial was an uncontrolled single-center, open-label, multidose tolerability, immunogenicity, and pharmacokinetic study in homosexual men with advanced HIV disease. Patient groups were formed on the basis of the reactivity of the antibody with the gp120 of their HIV-1 isolates.

Reproduction toxicity studies with pamidronate.

Peroral Segment I, II and III reproduction toxicity studies in rats and peroral Segment II studies in rabbits were conducted with pamidronate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate, CGP 23339 A, CAS 57248-88-1). In addition, intravenous Segment II studies were carried out in rats and rabbits. Only about 2% of a peroral dose of pamidronate is absorbed from the gastro-intestinal tract.

CFC replacements: safety testing, approval for use in metered dose inhalers.

HFA-134a and HFA-227 (chlorine free hydrofluoro-alkanes) are at present in extensive nonclinical safety testing sponsored by two joint research consortia (IPACT-I, IPACT-II) of companies interested in metered dose inhalers (MDI). The rationale for toxicity testing of these CFC replacements is to predict safety of their use as drug propellants in MDI. Frequency of use, intervals and systemic exposure levels are key parameters.

Identification of immunotoxic effects of chemicals and assessment of their relevance to man.

Immunotoxicity is defined as the adverse effects of foreign substances (xenobiotics) on the immune system. Two types of effects are possible: immunosuppression (which may result in an increased susceptibility to infection or to the development of tumours) and immunopotentiation (which may manifest as an allergy or as autoimmunity). There is, as yet, little evidence that well controlled occupational exposure to industrial chemicals has led to clinically significant immunosuppression.

Early effects of high-dosed absorbable amoscanate on rat brain.

An oily suspension of the absorbable form of amoscanate was administered to young adult albino rats in single or repeated oral doses of 25, 125 and 500 mg/kg. At least 3 consecutive doses of 125 or 500 mg/kg were needed to induce a brain lesion. The early change consisted of necrosis of the ependyma of the lateral ventricles, indicating that intoxication may have occurred via the cerebrospinal fluid.

Humoral antibodies against spermatopoietic cells associated with mediastinal germinoma.

A case of mediastinal germinoma in a 21-yr-old male is reported. The neoplasm exhibited a morphology similar to that of a testicular seminoma and was heavily infiltrated by lymphocytes and plasma cells. Germinal centres were also present in lymph follicles.