Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Probenecid is a white crystalline solid commonly used as a uricosuric agent in the treatment of gout. Because of its inhibitory effects on renal tubule transport processes, probenecid is also used as a therapeutic adjunct to enhance blood levels of penicillin and its action. Toxicology and carcinogenicity studies were conducted by administering probenecid (>99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex once daily, 5 days per week in 14-day, 13-week, and 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Doses used in the 14-day studies for both rats and mice were 0, 200, 400, 800, 1,600, or 3,200 mg/kg. Of the animals receiving 3,200 mg/kg, all rats, all female mice, and two of five male mice died during the studies. No deaths occurred among the other dose groups. There was a significant reduction in body weight gain in male and female rats receiving 1,600 mg/kg and in female rats receiving 800 mg/kg. No gross lesions were attributed to probenecid administration in rats or mice of either sex. 13-Week Studies: Doses used in the 13-week studies were 0, 50, 100, 200, 400, or 800 mg/kg for rats and 0, 100, 200, 400, 800, or 1,600 mg/kg for mice. No rats died during the 13-week studies. In mice, 5 of 10 males and 3 of 10 females receiving 1,600 mg/kg and 1 of 10 males receiving 800 mg/kg died during the study. Significant reductions in body weight gain occurred in male rats administered 800 mg/kg, male mice administered 1,600 mg/kg, and female mice administered 800 or 1,600 mg/kg. All dose groups of male rats and all groups of female rats receiving 100 mg/kg or more showed significant increases in absolute and/or relative liver weights compared to control groups. This change was also seen in mice receiving 200 mg/kg and greater, except female mice in the 400 mg/kg group. No compound-related lesions occurred in rats or mice of either sex. Based on compound-related deaths and suppression of body weight gains observed at higher doses in the 13-week studies, doses of 0, 100, and 400 mg/kg were used for the 2-year studies in rats and mice. These doses were administered once daily, 5 days a week for up to 103 weeks to groups of 50 males or 50 females of each species. Body Weight and Survival in the 2-Year Studies: The mean body weight of high-dose female rats was 10% to 20% lower than that of controls throughout the studies. Mean body weights for all other dosed rats and for all dosed mice were similar to those of controls throughout the 2-year studies. Survival of high-dose male rats and high-dose and low-dose male mice was significantly lower than that of controls. Survival rates after 2 years were: male rats--control, 37/50; 100 mg/kg, 34/50; 400 mg/kg, 22/50; female rats--24/50; 35/50; 19/50; male mice--38/50; 23/50; 24/50; female mice--32/49; 32/49; 32/50. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: No chemical-related histopathologic toxic effects or increased incidence of tumors attributable to probenecid were observed in male or female rats receiving probenecid by corn oil gavage for up to 2 years. Mammary gland fibroadenomas and combined thyroid C-cell adenomas or carcinomas exhibited significant negative trends in female rats. These decreased tumor rates were associated with lower body weights. The incidence of adrenal medullary pheochromocytomas was significantly decreased in high-dose male rats. No compound-related increase in nonneoplastic lesions was observed in rats of either sex. No compound-related neoplastic effects were observed in male mice. In high-dose female mice, there were significant increases in the incidences of hepatocellular adenomas (3/48; 2/49; 14/49), but there was no corresponding increase in carcinomas (2/48; 2/49; 3/49). Treatment-related increased incidences of ovarian abscesses in female mice were causally related to Klebsiella species infection rather than directly related to chemical administration. Genetic Toxicology: Probenecid was not mutagenic in Salmonenot mutagenic in Salmonella typhimurium strain TA100, TA1535, TA1537, or TA98 with or without metabolic activation. In cytogenetic tests with Chinese hamster ovary cells, probenecid induced sister chromatid exchanges in the absence, but not in the presence of S9 activation. No induction of chromosomal aberrations was observed with or without S9. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas. Synonyms: 4-[(Dipropylamino)sulfonyl]benzoic acid; p-(dipropylsulfamoyl)benzoic acid; p-(dipropylsulfamyl)benzoic acid Trade Names: Benacen; Benemid; Benemide; Benn; Probalan; Probecid; Proben; Probenid; Robenecid; Uricocid
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PMID:NTP Toxicology and Carcinogenesis Studies of Probenecid (CAS No. 57-66-9) in F344/N Rats and B6C3F1 (Gavage Studies). 1263 64

Links between rheumatic manifestations and neoplasms are today an evidence. Certain syndromes have epidemiologic studies confirming strong association with malignancy, such as dermatomyositis and polymyositis, hyperthrophic osteoarthropathy and Lambert - Eaton myasthenic syndrome. These disorders may mimic idiopathic conditions, difficulting diagnosis. Besides that, longstanding rheumatic syndromes may, in their course, behave like premalignant conditions, as a result of their pathophysiology or drugs used in their treatment. The mechanisms whereby the neoplasm leads to rheumatic symptoms are: direct invasion of the musculoskeletal system, synovial reaction of justa-articular bony or capsular carcinomatous, secondary gout and paraneoplastic manifestations. Neoplasms constitute an important admission cause in Internal Medicine wards and rheumatic manifestations are common causes of Internal Medicine and Rheumatology appointments. The objective of the present work is to review the literature concerning rheumatic syndromes more frequently associated with malignancy, characterizing features that may suggest the presence of a hidden neoplasm as well as the potential diagnostic and prognostic value of their presence in malignant diseases.
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PMID:[Rheumatic manifestations and neoplasms]. 1733 43

The great apes (chimpanzees, bonobos, gorillas, and orangutans) are our closest relatives. Despite the many similarities, there are significant differences in aging among apes, including the human ape. Common to all are dental attrition, periodontitis, tooth loss, osteopenia, and arthritis, although gout is uniquely human and spondyloarthropathy is more prevalent in apes than humans. Humans are more prone to frailty, sarcopenia, osteoporosis, longevity past reproductive senescence, loss of brain volume, and Alzheimer dementia. Cerebral vascular disease occurs in both humans and apes. Cardiovascular disease mortality increases in aging humans and apes, but coronary atherosclerosis is the most significant type in humans. In captive apes, idiopathic myocardial fibrosis and cardiomyopathy predominate, with arteriosclerosis of intramural coronary arteries. Similar cardiac lesions are occasionally seen in wild apes. Vascular changes in heart and kidneys and aortic dissections in gorillas and bonobos suggest that hypertension may be involved in pathogenesis. Chronic kidney disease is common in elderly humans and some aging apes and is linked with cardiovascular disease in orangutans. Neoplasms common to aging humans and apes include uterine leiomyomas in chimpanzees, but other tumors of elderly humans, such as breast, prostate, lung, and colorectal cancers, are uncommon in apes. Among the apes, chimpanzees have been best studied in laboratory settings, and more comparative research is needed into the pathology of geriatric zoo-housed and wild apes. Increasing longevity of humans and apes makes understanding aging processes and diseases imperative for optimizing quality of life in all the ape species.
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PMID:Comparative Pathology of Aging Great Apes: Bonobos, Chimpanzees, Gorillas, and Orangutans. 2672 8