BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.

Three analogs of thymidine, D4T [2',3'-didehydro-2',3'-dideoxythymidine; 1-(2,3-dideoxy-P-D-glyceropent-2-enofuranosyl)thymine], , and AZT (3'-azido-3'-deoxythymidine), were compared in biological tests designed to assess their potential utility as anti-human immunodeficiency virus (HIV) agents. The in vitro potencies of these compounds against HIV infection in CEM cells were measured, with FddT and AZT being more potent than D4T. The cytotoxicities of D4T, FddT, and AZT for CEM cells were comparable. The triphosphates of these three derivatives inhibited purified HIV reverse transcriptase, and their affinities for this polymerase were found to be 1 or 2 orders of magnitude greater than that for the normal substrate, dTTP. D4T was less toxic than FddT or AZT for cultured human and mouse bone marrow cells (granulocyte-macrophage CFU). The three compounds had similar toxicities for human progenitor erythrocyte burst-forming units. In a 30-day mouse toxicity study, AZT and FddT produced a similar spectrum of hematopoietic toxicities. These toxic effects occurred at much lower doses of FddT than of AZT. At the higher doses of FddT, a significant incidence of lethality occurred. By contrast, D4T was considerably less toxic than both AZT and FddT in this study. The dose-limiting toxicity of D4T in mice was hepatotoxicity. The very different phosphorylation patterns of D4T, its lower toxicity, and its comparable potency relative to FddT and AZT suggest that the potential of D4T as an anti-HIV agent should be further explored. Acquired immunodeficiency syndrome (AIDS) arises from infection by human immunodeficiency virus (HIV) (5, 24).HIV infection results in immunosuppression, rendering the patient susceptible to opportunistic infections. These opportunistic infections lead to a high incidence of morbidity and mortality. Research on potential anti-HIV agents has focused to a large extent on analogs of deoxyribonucleosides. 3'-Azido-3'-deoxythymidine (AZT; Fig. 1), an analog of thymidine (Fig. 1), has shown good activity against HIV in infected cells in vitro (22). AZT has also exhibited beneficial results in clinical trials (9) and is currently the only drug approved for the treatment of AIDS.The mechanism of action of nucleoside analogs requires that host kinases phosphorylate the nucleoside substrate to the corresponding nucleoside mono-, di-, and triphosphates. It is the triphosphate which is responsible for the antiviral effect, either as an inhibitor of virus-specified reverse transcriptase (RT) or as a terminator of the growing viral DNA chain (29). However, the same triphosphate can also serve as a substrate for host DNA polymerases and thereby be incorporated into host DNA. The incorporation of the drug into host DNA is a potential source of toxicity. For good selectivity, the nucleoside triphosphate should be a good substrate or inhibitor of virus-specified RT but a poor substrate or inhibitor of host DNA polymerases.While AZT is an efficacious drug, toxicity problems are associated with AZT therapy. The most ...

Oral administration of BL-634 1 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 rng/kdday resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromaffin-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse hyperplasia, focal adenomatous hyperplasia, and carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL celI hyperpIasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound, cimetidine (950 mg/ kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of BL-6341. Dose-related elevations of serum gastrin were observed with BL-634 1 , while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-634 1. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 rng/kg dose of BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell carcinoid neoplasia. All genetic toxicology tests performed with BL-634 1 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis. INTRODU~IONThe toxicologic testing of new, potent, long-acting histamine H,-receptor antagonists and H+, K+-ATPase inhibitors has resulted in several types of proliferative gastric changes in chronic rat studies. The most noteworthy of these is the occurrence of gastric carcinoid tumors in the oxyntic mucosa (2, 18, 34). These proliferative endocrine changes are distinct from those produced by the gastric carcinogen, N-methyl-N-nitro-N-nitrosoguanidine (MNNG), that produces adenocarcinomas primarily in the pylonc region of the stomach (28). The histamine H,-blocker, tiotidine, has produced a dysplasiakarcinoma syndrome in rats that resembles the lesions associated with MNNG (38).This report describes the occurrence of proliferative, gastric, endocrine cell changes in the fundic stomach of rats administered the long-acting H,-antagonist, BL-6341 hydrochloride. It discusses the significance of these lesions, proposes a mechanism of tumorigenesis, and compares these observations with similar findings associated with other anti-secretagogues and those reported in man. METHODS Two-Year RatStudy. The carcinogenicity study was composed of 60 male and 60 female Charles R.iver, Sprague-pawley CD rats per dose group, and 110 male and 110 female negative controls. Rats were 8 weeks of age when the study was initiated.. They were administered ei...

The effects of high toxic doses of the anticancer drugs, etoposide and its phosphate derivative, BMY- Ultrastructurally, ganglion cell bodies had focally extensive dilation of the rough endoplasmic reticulum, mitochondrial swelling, increased numbers of phagolysosomes and prominent aggregations of microfilaments (globular filamentous bodies). Ultrastructural axonal changes occurred primarily in large, myelinated fibers and consisted of axonal swelling or loss, thinning of myelin sheaths, and a decrease in the number of organelles. This is the first report of etoposide-related sensory neuropathy in laboratory animals, a model that may be useful for the study of etoposide-related peripheral neuropathy in humans.

The evaluation and development of didanosine as a therapy for HIV-infection has demonstrated thatresults of cell-culture studies are only approximate predictors of clinical effects. Whereas the antiviral activity of didanosine is achieved in cell culture at concentrations much higher than those of zidovudine, ,---the two drugs appear to achieve similar effects on markers of HIV-infection at similar clinical doses. The effect of the differing intracellular-half-life of the respective nucleoside triphosphates on the clinical effects is unknown. Similarly, preclinical toxicology studies, while suggesting a low potential for didanosine-induced haematological toxicities, did not predict the findings of peripheral neuropathy and pancreatitis in clinical studies. Thus, the results of controlled clinical studies are required in order to more fully define the therapeutic and safety profile of didanosine.