Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The subacute toxic effects of dietary T-2 toxin were compared in young male Wistar rats, young male Swiss mice and juvenile Swiss mice. Purified T-2 toxin was fed in the diet at levels of 10 or 20 ppm for 2 or 4 weeks. Dose-related depressions in food consumption and weight gain consistently occurred in all animals fed T-2 toxin. Hyperkeratosis of the squamous gastric mucosa, atrophy of the thymus and thymus-dependent lymphoid tissues, and lymphopenia occurred in all animals exposed to T-2 toxin. These effects were most severe in juvenile mice, and least severe in rats. In addition, juvenile mice fed the 20-ppm level developed erythroid hypoplasia and became severely anemic by 4 weeks. These results demonstrate that dietary T-2 toxin at levels up to 20 ppm cause similar effects attributable to food refusal and alimentary irritation in both species. However, mice and rats were relatively resistant to hematopoietic suppression. Only the juvenile mice fed 20 ppm developed this potentially lethal toxic effect.
 ...
PMID:Comparative toxicity of dietary T-2 toxin in rats and mice. 718 2

Changes in hematopoietic and lymphoid tissues of young Swiss mice fed a balanced semipurified diet containing T-2 toxin (20 ppm) were examined after one, two, three, four or six weeks. During the first three weeks of exposure of T-2 toxin, lymphoid tissues, bone marrow and splenic red pulp became hypoplastic, resulting in anemia, lymphopenia and eosinopenia. Subsequently, during continued exposure to T-2 toxin, hematopoietic cells regenerated in bone marrow and splenic red pulp and became hyperplastic by six weeks. Granulopoiesis and thrombopoiesis resumed in advance of erythropoiesis. All lymphoid tissues remained atrophic throughout the six week trial. Mice exposed to T-2 toxin also developed perioral dermatitis and hyperkeratosis with ulceration of the mucosa of the esophageal region of the stomach. These results indicated that young mice were susceptible to both the irritant and the hematopoietic-suppressive toxic effects of dietary T-2 toxin. However, supression of hematopoiesis was transient and did not lead to hematopoietic failure.
 ...
PMID:Subacute toxicity of dietary T-2 toxin in mice: morphological and hematological effects. 740 92

The subacute toxic effects of dietary T-2 toxin (20 ppm) incorporated in semipurified diets of 8%, 12% or 16% protein, were examined in young Swiss mice after one, two, three and four weeks. Dietary T-2 toxin caused substantial reductions in growth and food consumptaion, the degrees of which were greatest in mice fed the diets of reduced protein content. T-2 toxin consistently caused similar degrees of nonregenerative anemia, lymphopenia, thymic atrophy and gastric hyperkeratosis irrespective of the dietary protein level. However, erythroid hypoplasia was temporary in mice fed T-2 toxin in the 16%-protein diet such that erythroid precursors regenerated in splenic and bone marrow and were hyperplastic after four weeks. Liver to body weight ratios of mice fed T-2 toxin in the 16%-and 12%-protein diets increased during the four week trial in comparison to control mice fed at a similar rate. These observations indicated that suppression of erythropoiesis in mice by dietary T-2 toxin was temporarty and that the interval before regeneration was prolonged by diets of reduced protein content.
 ...
PMID:Subacute toxicity of Dietary T-2 toxin in mice: influence of protein nutrition. 740 93

A total of 45 non-uremic dogs, with clinical signs indicating leishmaniosis, entered the study. Diagnosis was confirmed by indirect immunofluorescence assay (IFA) on serum and polymerase chain reaction (PCR) on bone marrow samples. The dogs were randomly allocated into Group A (n=37) that received allopurinol (10mg/kg B.W., per os, twice daily) for 4 consecutive months, and Group B (n=8) that were placebo-treated. Clinical signs were scored just before and at monthly intervals throughout the study period, in a blinded and independent fashion. Complete blood count, serum biochemistry profile, urinalysis, lymph node and bone marrow parasitology, IFA and enzyme-linked immunosorbent assay (ELISA) serology and bone marrow PCR were carried out at the beginning and at the end of the trial. A total of three Group A and one Group B dogs died of end stage kidney disease that developed during the trial. In Group A animals that endured the trial there was a significant improvement in the general body condition, conjunctivitis, peripheral lymphadenopathy, splenomegaly, masticatory muscle atrophy, ulcerative stomatitis, epistaxis, exfoliative dermatitis, cutaneous ulcerations, blepharitis and nasodigital hyperkeratosis. The same observation was made for anemia, lymphopenia, hyperproteinemia, hyperglobulinemia, hyperphosphatemia, increased alkaline phosphatase activity and the low albumin/globulin ratio. By contrast, no improvement of any kind was seen in Group B dogs. Lymph node and bone marrow parasite numbers were significantly decreased in Group A animals. In Group B, that occurred only in the lymph nodes. Apart from remission of clinical signs and restoration to normal of clinicopathological abnormalities, allopurinol did not eliminate Leishmania organisms, as the PCR result on bone marrow was still positive in all the dogs that finished the trial.
 ...
PMID:A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis. 1142 83

Codeine is used in a variety of pharmaceuticals including analgesics, sedatives, hypnotics, antiperistaltics, and antitussive agents. The National Cancer Institute and the Food and Drug Administration nominated codeine for study because it is a widely used drug and it is representative of the morphine class of compounds, for which chronic carcinogenicity studies had not been conducted. The oral route of administration was selected because it is the primary route of human exposure. Male and female F344/N rats and B6C3F1 mice were given codeine (99% pure) in feed for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 1,562, 3,125, 6,250, 12,500, or 25,000 ppm codeine in feed for 14 days, which resulted in daily doses of approximately 125, 250, 450, 650, or 750 mg codeine/kg body weight to males and 125, 250, 500, 700, or 300 mg/kg to females. One female exposed to 6,250 ppm, one male and three females exposed to 12,500 ppm, and all males and females exposed to 25,000 ppm died during the study. Final mean body weights and mean body weight gains of all exposed groups except 1,562 ppm females were significantly lower than those of the controls. No chemical-related gross lesions were observed in rats at necropsy. Thickening of the forestomach mucosa (hyperplasia and hyperkeratosis) and lymphoid depletion of the thymus in exposed males and females and testicular degeneration in exposed males, observed primarily in the 12,500 and 25,000 ppm groups, were associated with decreased survival and increased morbidity in these groups. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm codeine in feed for 14 days, which resulted in daily doses of approximately 150, 300, 600, 1,300, or 3,000 mg codeine/kg body weight to males and 200, 400, 750, 1,500, or 3,000 mg/kg to females. All mice survived to the end of the study. The final mean body weight of 3,125 ppm females was significantly greater than that of the controls; the final mean body weight of 12,500 ppm females and the mean body weight gains of 12,500 ppm males and females were significantly lower than those of the controls. Absolute and relative liver weights of 3,125, 6,250, and 12,500 ppm males and of 12,500 ppm females and the absolute and relative right kidney weights of 12,500 ppm males were significantly lower than those of the controls. No gross or histopathologic lesions were attributed to codeine exposure. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 390, 781, 1,562, 3,125, or 6,250 ppm codeine in feed for 13 weeks, which resulted in daily doses of approximately 25, 50, 100, 200, or 450 mg codeine/kg body weight to males and 25, 50, 100, 250, or 500 mg/kg to females. There were no chemical-related deaths during the study. Final mean body weights and mean body weight gains of all groups of exposed males and of females exposed to 1,562, 3,125, and 6,250 ppm were significantly lower than those of the controls. Feed consumption decreased with increasing exposure concentration during the first week of the study; however, by the end of the study, feed consumption by most exposed groups was similar to that by the controls. There were alterations of various hematology and clinical chemistry parameters at the end of the study. There was a mild dose-dependent lymphopenia in females receiving 1,562 ppm and above and in 6,250 ppm males. There also was a minimal to mild macrocytosis that occurred in all exposed groups of males and in females exposed to 781, 3,125, or 6,250 ppm. No significant differences between control and exposed rats were observed in sperm morphology or vaginal cytology parameters. Absolute and relative adrenal gland weights of exposed males and of 3,125 and 6,250 ppm females were significantly greater than those of the controls. Absolute and relative liver weights of exposed males werees were significantly lower than those of the controls. Relative thymus weights of 3,125 and 6,250 ppm males were significantly lower than that of the controls. No chemical-related gross or histopathologic lesions were observed in male or female rats. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 390, 781, 1,562, 3,125, or 6,250 ppm codeine in feed for 13 weeks, which resulted in daily doses of approximately 60, 120, 260, 460, or 1,000 mg codeine/kg body weight to males and 60, 130, 280, 530, or 1,200 mg/kg to females. Two male mice in the 3,125 ppm group died during week 7. All other mice survived to the end of the study. Final mean body weights of exposed males and females were similar to those of the controls. Feed consumption by exposed males and females was similar to that by the controls. Abnormal posture was observed in all exposed groups of males. There were no significant differences in hematology or urinalysis parameters in male or female mice. Minor, sporadic changes occurred in a few of the clinical chemistry parameters; they were not considered biologically significant. No significant differences in sperm morphology or vaginal cytology were attributed to codeine exposure. Absolute and relative kidney weights of 3,125 and 6,250 ppm males were lower than those of the controls. No chemical-related differences in organ weights were observed in females. No chemical-related gross or histopathologic lesions were observed in male or female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 400, 800, or 1,600 ppm codeine for up to 106 weeks, with 9 or 10 rats per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 15, 30, and 70 mg codeine/kg body weight to males and 15, 40, and 80 mg/kg to females. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of 400 ppm females was significantly greater than that of the controls; survival of all groups of exposed males and of 800 and 1,600 ppm females was similar to that of the controls. There was an exposure-related decrease in mean body weights of males and females. The final mean body weight of 1,600 ppm males was 88% that of the controls, and the final mean body weight of 1,600 ppm females was 89% that of the controls. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings were limited to ocular discharge in exposed males and females. Pathology Findings: Absolute and relative adrenal gland weights of 800 and 1,600 ppm males were significantly greater than those of the controls at 15 months. There were no increased incidences of neoplasms attributable to codeine exposure at any site. At 2 years, there were exposure-related decreases in the incidences of adrenal medulla hyperplasia in males and females. There was an exposure-related decrease in the incidence of benign pheochromocytomas in males, and the incidences in exposed males were significantly lower than that in the controls. In 1,600 ppm females the incidences of mammary gland fibroadenomas and of fibroadenomas or adenocarcinomas (combined) were significantly lower than those in the controls. The decreased incidences of benign pheochromocytomas in males and mammary gland neoplasms in females were considered to be related to codeine exposure. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 750, 1,500, or 3,000 ppm codeine for up to 106 weeks, with 9 or 10 mice per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 100, 200, or 400 mg codeine/kg body weight to males and females. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed males and females was similar to that of the controls. Mean body weights of 750 and 1,500 ppm males and females were similar to those of the controls throughout most of the study. Mean body weights of 3,000 ppm males and females were less than those of the controls from about week 13, and the final mean body weights of these groups were 86% and 82% those of the respective controls. Feed consumption by exposed groups was similar to that by the controls. Pathology Findings: There were no increased incidences of neoplasms attributable to codeine exposure at any site. At 15 months, the incidence of thyroid gland follicular cell hyperplasia in 3,000 ppm males was significantly greater than that of the controls, and this lesion was observed in 1,500 and 3,000 ppm females. At 2 years, the incidences of follicular cell hyperplasia in all exposed groups of mice were significantly greater than those in the controls, but there were no increases in thyroid gland follicular cell neoplasms. The incidence of centrilobular fatty change in the liver of 3,000 ppm males was significantly lower than that in the controls at 15 months, and the decreased incidence appeared to be related to exposure level. At 2 years, the incidences of eosinophilic foci, foci of fatty change, centrilobular cytomegaly, and centrilobular fatty change in 3,000 ppm males were lower than those in the controls. The incidence of hepatocellular adenomas and the incidence of hepatocellular adenomas or carcinomas (combined) in 3,000 ppm males and females were significantly lower than those in the controls; this was considered to be related to lower body weights in these groups. GENETIC TOXICOLOGY: Codeine phosphate was not mutagenic in any of four strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes. In cytogenetic tests with cultured Chinese hamster ovary cells, codeine phosphate induced dose-related increases in sister chromatid exchanges, with and without S9, only at concentration levels that caused cell cycle delay. No induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated with codeine phosphate, with or without S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of codeine in male or female F344/N rats exposed to 400, 800, or 1,600 ppm. There was no evidence of carcinogenic activity of codeine in male or female B6C3F1 mice exposed to 750, 1,500, or 3,000 ppm. Thyroid gland follicular cell hyperplasia was increased in exposed male and female mice. Decreased incidences of benign pheochromocytomas of the adrenal medulla in male rats and mammary gland fibroadenomas and fibroadenomas or adenocarcinomas (combined) in female rats were related to codeine exposure. Synonyms: 7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol; methylmorphine; 3-0-methylmorphine monohydrate; N-methylnorcodeine; morphine-3-methyl ether; morphine monomethyl ether Trade names: Codeinum, Codicept, Coducept, Metilmorfina
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Codeine (CAS No. 76-57-3) in F344 Rats and B6C3F1 Mice (Feed Studies). 1258 21