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Biomedical subjects

R S Hirth

Publications and source records attributed to R S Hirth.

At least 19 recordsLinked to original sources
PubMed1989

Cardiac, renal, and pulmonary toxicity of several mitomycin derivatives in rats.

The potential cardiotoxicity, nephrotoxicity, and pulmonary toxicity of several mitomycin (MMC) derivatives, BMY-25067 (N-7-[2-(4-nitrophenyldithio)ethyl]MMC), BMY-26107 (N-7-[2-(4-aminophenyldithio)ethyl]MMC), BMY-26605 (N-7 acetyl-MMC), BMY-25690 (7-N-(dimethylaminomethylene)-10-[1-morpholinomethyleneamino)carbo nyl- oxy]MMC), BMY-26646 (N-7-[2-(4-fluorophenyldithio)ethyl]MCC), and BMY-25551 (7-(2-hydroxyethyl)mitosane), were evaluated in rats. Groups of 10 male Sprague-Dawley rats were given single intravenous doses of the test compounds and were then observed for 10 weeks. Doses represented 67 and 33% of the respective mouse LD10 (corrected for body size on a mg/m2 basis) of each test compound. BMY-25282 (7-N-(dimethylaminomethylene)MMC), a mitomycin derivative that produces cardiac, renal, and arterial lesions, was used as a reference drug. Hematologic and blood chemical parameters were monitored at 3 days and at 3, 6, and 10 weeks after drug administration. Heart, kidney, and lung were examined histopathologically. Drug-related cardiac changes with late onset were seen histopathologically in rats treated with BMY-26605, BMY-25282, BMY-25551, and BMY-25690 (in order of decreasing severity). Drug-related renal changes, consisting of tubular degeneration and glomerulopathy, were seen in rats treated with BMY-25690, BMY-26107, BMY-25282, BMY-25551, BMY-26605, and BMY-25067 (in order of decreasing severity). Pulmonary arterial lesions were noted inconsistently in rats treated with BMY-26605, BMY-25282, and BMY-25551. Neither cardiac, renal, nor pulmonary changes were seen in rats administered BMY-26646, and only minor drug-related renal changes were seen in rats treated with BMY-25067.

Animals↗
PubMed1988

Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341.

Oral administration of BL-6341 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day 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 cell hyperplasia 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-6341, while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 mg/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-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis.

Animals↗
PubMed1987

Single-dose and multiple-dose intravenous toxicity studies of BMY-25282 in rats.

Single-dose and multiple-dose (daily X 5 and weekly X 5) intravenous toxicity studies in rats were conducted to determine the possible acute and delayed toxicity of BMY-25282 (7-N-(dimethylaminomethylene) mitomycin C), a potential anticancer drug. Rats in the single-dose study received either 0.05, 0.25, or 0.50 mg/kg (0.3, 1.5, or 3.0 mg/m2) of BMY-25282; rats in the daily X 5 multiple-dose study received doses of 0.005, 0.025, or 0.050 mg/kg (0.03, 0.15, and 0.3 mg/m2) of BMY-25282 once each day for 5 days; and rats in the weekly X 5 multiple-dose study received 0.05 mg/kg of BMY-25282. All doses were in 0.1% Pluronic F-68 diluent. Acute toxicities included gastrointestinal epithelial necrosis, myelosuppression, and splenic lymphoid depletion in the high and intermediate dose groups in the single-dose study and myelosuppression in the high dose group of the daily X 5 multiple-dose study. One death in a high dose male of the single-dose study was attributed to acute gastrointestinal and lymphoid toxicity. Between the interim necropsy on Day 5 or 9 and termination of the 9-week dose-free observation period, 9/20 rats of the high and intermediate dose groups of the single-dose study and 4/10 high dose rats in the daily X 5 multiple-dose study died, primarily due to hydrothorax and congestive heart failure caused by delayed, drug-related myocardial degeneration. The most prominent drug-related histopathologic changes observed in rats of both the single-dose study and the daily X 5 studies were myocardial degeneration (cardiomyopathy), glomerulopathy with tubular degeneration, and necrotizing arteritis. These three changes, observed at 0.5 and 0.25 mg/kg in the single-dose study and at 0.05 mg/kg/day in the multiple-dose (daily X 5) study, were delayed in onset and irreversible. Drug-related tubular degeneration and slight glomerulopathy were observed in male BMY-25282-treated rats in the weekly X 5 study, but cardiotoxicity, pulmonary arteritis, hydrothorax, and lethality were not observed. The diluent, Pluronic F-68, was not associated with any morphologic or clinico-pathologic changes. A single-dose of 0.05 mg/kg or 5 daily doses of 0.025 and 0.005 mg/kg of BMY-25282 were considered nontoxic doses in rats. A cumulative dose of 0.25 mg/kg, which caused cardiotoxicity in the daily X 5 study, was not cardiotoxic in the weekly X 5 study. These results indicate that the delayed cardiotoxicity of BMY-25282 is schedule dependent.

Animals↗
PubMed1987

Cutaneous neoplasms in dogs associated with canine oral papillomavirus vaccine.

A spectrum of proliferative cutaneous lesions occurred in 12 dogs at the injection site of live canine oral papillomavirus (COP) vaccine, suggesting a viral etiology for the masses. Lesions included epidermal hyperplasia, epidermal cysts, squamous papilloma, basal cell epithelioma, and squamous cell carcinoma. Peroxidase-antiperoxidase staining of tumor sections revealed nuclei which stained for group-specific papillomavirus antigen in five of 12 masses. Electron microscopic examination of tumor sections did not reveal virions. In transmission studies, macerated tumor tissue did not produce oral papillomas on the scarified mucosa of puppies; this procedure did protect the puppies from development of lesions when challenged with infectious papilloma material. These findings are evidence that COP can induce hyperplastic and neoplastic lesions in sites other than oral, pharyngeal, and ocular mucosa.

Animals↗
PubMed1984

Tallysomycin S10b: experimental antitumor activity and toxicity.

Tallysomycin S10b (TLM S10b), a structural analog of bleomycin (BLM), was evaluated and compared with BLM for antitumor activity in several murine tumor systems and for toxic effects in mice and rats. Neither TLM S10b nor BLM was effective against IP P388 and L1210 leukemias, whereas both drugs were active against IP P388/J leukemia (a BLM-sensitive subline). TLM S10b and BLM were both active against murine solid tumors, including SC B16 melanoma, IV Lewis lung carcinoma, SC Madison 109 lung carcinoma, SC CD8F1 mammary carcinoma and SC Colon 38 carcinoma. In human tumor xenograft models, TLM S10b was active against a colon tumor and had slight activity against breast and lung tumors. Compared with TLM S10b, BLM had less activity against the colon tumor, comparable activity against the breast tumor, and no effect against the lung tumor. A consensus of the antitumor data indicated that compared with BLM, TLM S10b had comparable or greater activity and was about twice as potent. TLM S10b and BLM had approximately equivalent LD50 values in mice. TLM S10b had minimal effects on WBC counts, blood urea nitrogen levels, and serum glutamic pyruvic transaminase levels in mice during the time periods monitored. These effects were comparable to or less pronounced than those of BLM. Both drugs caused dose-related increases in the whole-lung hydroxyproline content in mice, but the dose-response curves were not parallel. TLM S10b caused a larger increase than BLM at the lower doses and a smaller increase than BLM at the highest doses. In rats, TLM S10b and BLM caused comparable, significant decreases in lung mechanics; however, histopathological examination of the lungs indicated that TLM S10b caused less evidence of pulmonary toxicity than did BLM at comparable dose levels. TLM S10b was, therefore, generally comparable to BLM in causing pulmonary toxicity in mice and showed possibly less pulmonary toxicity in rats, while demonstrating approximately equivalent to four-fold greater potency, depending on the test system. It also appeared that TLM S10b caused less pulmonary toxicity than BLM in both mice and rats at doses approaching maximally tolerated levels. TLM S10b is currently undergoing phase I clinical evaluation.

Animals↗
PubMed1984

The toxicological evaluation of tallysomycin s10b--biosynthetic tallysomycin derivative.

Tallysomycin S10b, a biosynthetic derivative of tallysomycin B, was subjected to intravenous toxicologic studies in mice and dogs. LD50 and LD10 values from lethality studies in mice were utilized to establish dose levels for single and five daily dose toxicity studies in mice and dogs. Nephrotoxicity was the most consistent and prominent drug-related alteration in single and multiple dose studies in both species and was considered the dose limiting toxicity. Other toxicities included pulmonary toxicity, lymphopenia and necrosis of extremities in mice and dogs and testicular degeneration and focal vacuolation of adrenal cortical cells in the dog. Bleomycin was administered to dogs as a reference control agent at a single dose of 270 mg/m2 which was approximately equivalent to the highest tallysomycin S10b dose of 240 mg/m2. Tallysomycin S10b showed a greater nephrotoxic potential than bleomycin at earlier time periods. However, at termination there was no meaningful difference in the degree of chronic nephrotoxicity. The pulmonary toxicity of both drugs was comparable.

Animals↗
PubMed1983

The toxicologic evaluation of marcellomycin--an antineoplastic anthracycline antibiotic.

Dose-related toxicologic effects of marcellomycin, an antineoplastic anthracycline antibiotic, were observed in single-dose studies in mice iv (43.05-67.65 mg/m2) and dogs iv (41.0-90.2 mg/m2), and in multiple-dose studies in dogs iv (9.8-29.6 mg/m2 2X/week for 6 weeks) and rats sc (9 weekly doses at 26.2-72.2 mg/m2). Toxicity was primarily manifested by suppression of myeloid tissue, especially the erythrocytic and thrombocytic series, and lymphoid tissues. Initially a neutrophilic leukocytosis was observed in dogs and rats, which was considered possibly to be due to mobilization of the marginal and bone marrow neutrophil pools. In dogs, this was followed by a marked, dose-related neutropenia; and, in rats that died, there was marked depletion of bone marrow cells. Other toxicities observed included enteropathy, severe subcutaneous serofibrinous inflammatory edema and necrosis at injection sites, prostate and seminal vesicle atrophy, uterine hypoplasia, testicular and pancreatic degeneration, thyroid follicular proliferation and hemorrhage in various organs. In general, these toxicities were reversible in surviving animals during recovery periods. Significant cardiotoxicity was not demonstrated.

Animals↗
PubMed1980

A murine model for listerial meningitis and meningoencephalomyelitis: therapeutic evaluation of drugs in mice.

Meningitis and meningoencephalomyelitis caused by Listeria monocytogenes were experimentally established in mice. The pathological changes in brain and spinal cord resulting from the infection resemble those observed in man and domestic animals. The efficacy of 24 antibiotics in treating this experimental infection was determined. Minocycline and chlortetracycline were the most efficacious antiotics followed by amoxicillin, which was 2- to 4-fold less active than the former. However, the acute toxicity of amoxicillin to the murine central nervous system was at least 10-fold lower than that of the tetracyclines. Since parenteral amoxicillin may be of value in the management of listerial meningitis and meningoencephalomyelitis in man and domestic animals, clinical trials seem warranted.

Animals↗
PubMed1976

Preliminary investigation of the life history of Filaroides hirthi Georgi and Anderson, 1975.

Filaroides hirthi lungworm infection increased as a function of age among 47, 9 to 32 week old Beagle pups at a commercial breeding establishment. Probit analysis of these data yielded an estimate of 50% infection was by age 17.4 +/- 3.7 weeks. This parasite and/or its associated lesions remained in at least 40% of infected Beagles at least 10 months after exposure to infection had ceased. Reinfection rendered improbable by the nature of the new environment, a laboratory animal colony. Repeated efforts have failed to demonstrate by the Baermann technique eggs or larvae of this parasite in the feces, bronchial mucus, or intact lung tissue of infected Beagles. All efforts to identify an intermediate or alternate definitive hosts have likewise proved unavailing. Piperazines, dichlorvos, thiabendazole, dithiazanine iodide, and levamisole appear to be without effect on the proportion of Beagles infected. The diet, which contained uncooked meat, was fed in a controlled experiment to 10 Beagles from an uninfected source without producing a single case of F. hirthi infection. Life cycles of other members of the superfamily Metastrongyloidea and possible explanations for the non-patency of F. hirthi infection are discussed.

Age Factors↗
PubMed1975

Pneumococcal meningitis-therapeutic studies in mice.

A technique for inducing pneumococcal meningitis in mice and a description of the histopathologic changes that accompany this experimentally produced disease are provided in the present report. This infection of mice was investigated to determine whether it could serve as a suitable model for detecting agents that have potential therapeutic utility in bacterial meningitis in man. 21 antibiotics, belonging to six major classes were evaluated for efficacy in the experimental infection. The three most active agents proved to be amoxicillin, cephaloridine, and chlortetracycline. Up to this time, amoxicillin has not been commercially available as an injectable dosage form. However, in view of the compound's outstanding efficacy in the present experiments, it would be desirable to investigate its effectiveness in the naturally occurring disease in man.

Animals↗