UMLS:C0004134 - FACTA Search

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Query: UMLS:C0004134 (ataxia)
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A mitochondrial half-type ATP-binding cassette (ABC) protein, ABC7, plays a role in iron homeostasis in mitochondria, and defects in human ABC7 were shown to be responsible for the inherited disease X-linked sideroblastic anemia/ataxia. We examined the role of ABC7 in the biosynthesis of heme in erythroid cells where hemoglobin is a major product of iron-containing compounds. RNA blots showed that the amount of ABC7 mRNA in dimethylsulfoxide (Me(2)SO)-treated mouse erythroleukemia (MEL) cells increased markedly in parallel with the induction of the mRNA expression of ferrochelatase, the last enzyme in the pathway to synthesize heme. The transfection of the antisense oligonucleotide to mouse ABC7 mRNA into Me(2)SO-treated MEL cells led to a decrease of heme production, as compared with sense oligonucleotide-transfected cells. ABC7 protein was shown to be colocalized with ferrochelatase in mitochondria, as assessed by immunostaining. Furthermore, in vitro and in vivo pull-down assays revealed that ABC7 protein is interacted with the carboxy-terminal region containing the iron-sulfur cluster of ferrochelatase. The transient expression of ABC7 in mouse embryo liver BNL-CL2 cells resulted in an increase in the activity and level of ferrochelatase and thioredoxin, a cytosolic protein containing iron-sulfur. These increases were also observed in MEL cells stably expressing ABC7. When ABC7 transfectants were treated with Me(2)SO, an increase in cellular heme concomitant with a marked induction of the expression of ferrochelatase was observed. The extent of these increases was 3-fold greater than in control cells. The results indicated that ABC7 positively regulates not only the expression of extramitochondrial thioredoxin but also that of an intramitochondrial iron-sulfur-containing protein, ferrochelatase. Then, the expression of ABC7 contributes to the production of heme during the differentiation of erythroid cells.
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PMID:Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase. 1248 Jul 5

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan
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PMID:NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1257 87

p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an intermediate in the manufacture of pesticides, dyes, and industrial solvents. Groups of male and female F344/N rats and B6C3F1 mice were exposed to p-nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for toxicity and carcinogenicity studies. Genetic toxicology studies were conducted in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary cells, and in studies of erythrocyte micronucleus formation in mice in the 13-week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. All rats survived until the end of the study. Male and female rats given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000, 20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%, and 65% that of the controls. There were no clinical findings that were characteristic of organ-specific toxicity. Absolute and relative spleen weights were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm. There were decreases in erythrocyte count and hemoglobin and hematocrit values and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin concentration that were most pronounced in the 20,000 and 40,000 ppm groups. Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000 ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of the thymus in males and atrophy of the ovary, bone marrow, and thymus in females. 14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. Three males and two females given 40,000 ppm died during the study. All other animals survived until the end of the study. Male mice given 20,000 and 40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of 20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were significantly lower than those of the controls. There were no clinical findings related to organ-specific toxicity although lethargy and ataxia were observed in 40,000 ppm mice. Relative liver weights were significantly increased in 20,000 and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000 ppm females were reduced. No significant differences in hematology parameters occurred in exposed mice. Testicular degeneration was observed in three 20,000 ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in 40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660 mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived until the end of the study. Mean body weight gains and final mean body weights were significantly less than those of the controls in 2,500, 5,000, and 10,000 ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings related to organ-specific toxicity. Differences in spleen weights and hematology parameters characteristic of regenerative anemia were observed in males and females, primarily in groups given 10,000 ppm. The absolute and relative spleen weights were significantly increased in 10,000 ppm males and females and the relative spleen weights were significantly increased in 5,000 ppm males hts were significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz bodies, and reticulocyte counts were increased and erythrocyte counts, hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females. Congestion, pigmentation, and accumulation of macrophages in the spleen and pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males. Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A yellowish brown pigment (hemosiderin) in the spleen and kidney was associated with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p-nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or 20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460, 970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the study, except one 1,250 ppm female that was killed accidentally. Final mean body weights and mean body weight gains of all exposed males and of 5,000, 10,000, and 20,000 ppm females were significantly lower than those of the controls. No clinical findings or differences in organ weights or histopathology related to organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500 ppm males were similar to that of the controls. Two-year survival of 5,000 ppm males was marginally greater than that of the controls and was attributed in part to a decrease in the severity of nephropathy and a decrease in the incidence of mononuclear cell leukemia. Survival of exposed females was similar to that of the controls. Mean body weights of 5,000 ppm males were 2&percnt; to 8&percnt; lower than those of the controls through week 80. Final mean body weights of exposed males were similar to that of the controls. Mean body weights of 5,000 ppm females were 2&percnt; to 9&percnt; lower than those of the controls during the first year of the study and were 10&percnt; to 16&percnt; lower during the second year of the study. Final mean body weights of exposed females were 97&percnt; (1,250 ppm), 92&percnt; (2;500 ppm), and 84&percnt; (5,000 ppm) that of the controls. Feed consumption by exposed males and females was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 50, 100, or 210 mg/kg body weight per day to males and 60, 125, or 250 mg/kg per day to females. There were no clinical findings attributable to organ-specific toxicity. Pathology Findings: There were increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The incidences of clitoral gland adenoma or carcinoma (combined) in the exposed groups (29&percnt; to 31&percnt;) exceeded the historical control mean incidence (11&percnt;) and range (2&percnt; to 21&percnt;) in female F344/N rats in recent 2-year NTP feed studies. The increased incidences of clitoral gland neoplasms were considered to be some evidence of carcinogenic activity in female rats exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral gland in exposed females were marginally lower than that of the controls (10/50, 6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of nephropathy in male rats. Male rat kidneys were examined using both single and step-section analyses, and the incidences of renal tubule neoplasms were not statistically greater than those of the controls. Mild hyaline droplet accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in the 13-week study, but this effect was not severe enough to lead to a chemical-related neoplastic response in the 2-year study as has been observed with other chemicals. At the 15-month interim evaluation, hematologic parameters characteristic of a mild regenerative anemia and significant differences in spleen weights were noted in 5,000 ppm females. These differences included decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen weights, and hemosiderin accumulation in splenic macrophages. At 2 years, significant decreases in the incidences of mononuclear cell leukemia were observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50, 26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this decrease is unknown, decreases in the incidence of mononuclear cell leukemia have also been observed in 2year studies with other amine/nitro compounds. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice were similar to those of the controls. Mean body weights of 5,000 ppm males were 6&percnt; to 12&percnt; lower than those of the controls after week 17, and mean body weights of 5,000 ppm females were 12&percnt; to 24&percnt; lower than those of the controls after week 16. The final mean body weight of 5,000 ppm females was 19&percnt; less than that of the controls; final mean body weights of males were similar to that of the controls. Feed consumption by exposed mice was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of organ-specific toxicity. No chemical-related effects on hematology parameters were noted at the 15-month interim evaluation. Pathology Findings: There were no increases or decreases in neoplasms in male or female mice that were considered to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, results of both tests were negative. In vivo, no increase in micronuclei was observed in peripheral blood erythrocytes of male or female mice administered p-nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of p-nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female F344/N rats based on increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in the incidences of mononuclear cell leukemia in exposed male and female rats. p-Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4-Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p-carboxynitrobenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 21

Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weiody weights, and treatment-related liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of 0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300 mg/kg died. The mean body weight gain and final mean body weight of surviving male mice that received 300 mg/kg were significantly lower than those of the controls. No clinical signs of toxicity were observed. Male and female mice receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin. The absolute and relative liver weights of males and females that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular hypertrophy was observed in male and female mice receiving 300 mg/kg. The high dose selected for the 2-year study was 200 mg/kg, which was just below the level at which mortality and liver lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered coumarin in corn oil by gavage at doses of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: None of the male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg, 2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats was primarily attributed to chemical-related exacerbation of spontaneously occurring renal disease. Final mean body weights of female rats that received 100 mg/kg and all dosed groups of male rats were lower than those of the controls. There were no clinical signs of toxicity in rats, other than nonspecific signs relating to debilitation as a result of renal or other spontaneous disease. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values for one or more hematologic parameters including mean erythrocyte volume, mean erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in 100 mg/kg rats were significantly lower than those of controls. Activated partial thromboplastin times were also significantly lower in 50 and 100 mg/kg males, while platelet counts were significantly higher. Activities of alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100 mg/kg male and 100 mg/kg female rats were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: The principal lesions associated with the administration of coumarin to rats for up to 2 years occurred in the liver, kidney, and forestomach. While the hepatic lesions were seen in all groups of males, they occurred only in the 50 and 100 mg/kg females. The lesions consisted of a spectrum of changes including hepatocellular necrosis, fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia. The incidences of hepatocellular neoplasms were not increased in dosed rats. There was a chemical-related increase in the average severity of nephropathy in all groups of dosed male and female rats. There were corresponding increased incidences of parathyroid gland hyperplasia in all groups of dosed males, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, a low incidence of renal adenomas was seen in all groups of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50; 50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation of step sections identified additional individuals with renal tubule focal hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49) and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in the dosed groups. The incidences of forestomach ulcers in all groups of dosed male rats and in 100 mg/kg female rats were significantly greater than those of the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle during the 15-month recovery period. Similarly, a group of 30 male rats received 100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil during the 9-month recovery period. A group of 20 vehicle control male rats were necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. While chemical-related hepatic lesions were seen at both the 9- and 15-month interim evaluations, the incidences and severities of these lesions following the recovery period were generally similar to controls. Thus, the hepatic lesions produced by 9 or 15 months of exposure were reversible. In contrast to the liver lesions, the severity of nephropathy in male rats following the recovery period was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This is not unexpected, since nephropathy is a progressive degenerative disease that naturally increases in severity with age. The incidence of renal tubule hyperplasia in the 15-month stop-exposure group (dosed for 15 months followed by the recovery period) and the incidence of renal tubule adenoma in the 9-month stop-exposure group were significantly greater than those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or 200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the controls (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg, 37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg male and female mice were lower than those of controls throughout much of the study. There were no clinical findings related to chemical administration. Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200 mg/kg females were significantly lower than those of the controls. Blood platelet counts of 200 mg/kg males and females were significantly higher than those of controls. There were no biologically significant differences in enzyme activities between dosed and control mice. Pathology Findings: The principal toxic lesions associated with the administration of coumarin to mice occurred in the liver. The incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg females were significantly greater than those of controls. The incidences of syncytial alteration in all male dose groups and in 200 mg/kg females were also significantly greater than controls. The incidences of eosinophilic foci, a putative preneoplastic lesion, and of hepatocellular adenoma were significantly greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with low incidences in the dosed females, but none occurred in the controls. The overall incidence of hepatocellular neoplasms (benign and malignant combined) in the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51; 200 mg/kg, 13/50) exceeds the range in historical controls (range 2&percnt;-34&percnt;; 129/898, 14.4&percnt;) from recent NTP studies. The reason for a lack of liver response in 200 mg/kg female mice is not known, but may be due in part to the decrease in body weight. While the incidences of eosinophilic foci were marginally greater in dosed male mice, the incidences of hepatocellular neoplasms were similar among the dosed and control groups. The incidences of alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and female mice than in the controls. Further, the incidence of alveolar/bronchiolar carcinoma in 200 mg/kg females was also significantly greater than in controls. The overall incidence of pulmonary neoplasms (benign and malignant combined) in the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49, 27/51) exceeds the range in historical controls (males: range 6&percnt;-28&percnt;; 166/900, 18.4&percnt;; females: range 0&percnt;-14&percnt;; 58/899, 6.5&percnt;) from recent NTP studies. The incidence of squamous cell papilloma of the forestomach in 50 mg/kg males was greater than that of the controls (2/50, 8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male mice from recent NTP studies (range 0&percnt;-14&percnt;; 27/902, 3.0&percnt;). The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence did not exceed the NTP historical range (27/901, 3&percnt;; range, 0&percnt;-10&percnt;). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal aberrations in the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated either as adults by feeding or injection, or as larvae by feeding. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male and female B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H-benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone, kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka bean camphor
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PMID:NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 89

The aim of this study was to evaluate the efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy. One hundred and thirty anemic pregnant women were studied. Inclusion criteria were iron-deficiency type of anemia, and hemoglobin levels below of 11.5, 10.9 and 10.3 g/dl for the three trimesters of pregnancy, respectively. Twenty-five women who presented pregnancy-related complications were excluded during treatment. The remaining 105 were treated with 1600-mg iron protein succinylate per os daily for a period of four months. A group of anemia-related clinical signs and symptoms, and hematological parameters were recorded at the beginning of treatment, as well as two and four months later. They included epidermis and mucosal paleness, skin and nail lesions, glossitis, heart pulse, sickness, anorexia, apathy, ataxia, polypnea, insomnia, nervousness, paresthesias and other neurological symptoms; the hematological parameters included Hgb, hct, RBCs, WBCs, MCV, MCH, MCHC, PLTs, serum Fe and ferritin. Possible side or adverse effects were considered during treatment. The majority of symptoms and signs of anemia were gradually improved. There was a statistically significant increase in the means of Hgb, hct, WBCs, MCV, MCH, PLTs and serum ferritin (p < 0.05). Anemia was effectively treated in 100/105 (95.2%) women, but not in five patients (4.8%) who displayed poor compliance to the therapeutic protocol. There were transient and mild side-effects in seven (6.6%) treated women, namely diarrhea, epigastralgia, vomiting, and nausea, which however, did not necessitate discontinuation of the therapeutic protocol. Iron protein succinylate is an effective and well tolerated treatment of iron-deficiency anemia in pregnancy.
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PMID:The efficacy and tolerability of iron protein succinylate in the treatment of iron-deficiency anemia in pregnancy. 1610 96

We report a 60-year-old man with a 6-year history of tremor in his hands. He noted the onset of short of breath and gait disturbance in 1994; both of these symptoms were slowly progressive. Then recently he developed fever two months prior to the present admission. He was admitted to the rheumatology department of our hospital and neurological consultation was asked on December 13, 2000. On neurologic examination, he showed Gottron sign and fine crackle in both lungs. Pertinent neurological findings were bilateral dysmetria in finger-to-nose and heel-to-knee tests and a broad-based gait. In addition, he showed intention tremor in upper extremities more on the left. Romberg sign was positive. Deep tendon reflexes were decreased. Vibratory sensation was reduced at the wrists. The patient's hemoglobin was 11.1 g/dl, with a mean corpuscular volume of 92.0 fl. Vitamin B12 level was 190 (reference range, >230 pg/ml). Serum lactic acid, pyruvic acid and ceruloplasmin were slightly elevated. Chest X-ray showed interstitial pneumonia. Muscle biopsy showed grouping of small angular fiber. Brain MRI showed diffuse atrophy of the cerebral cortex and the cerebellum hemisphere. Thalamotomy did not improve his tremor. He was admitted again in November 2001. General worsening of his neurological findings was observed. IL2-receptor was markedly elevated. Serum anti-Hu, Yo and Ri antibodies were negative. An anaplastic carcinoma was found in his jejunum. He died from respiratory failure in February 2002. He was discussed in a neurological CPC and the chief discussant arrived at a conclusion that the patient had paraneoplastic syndrome. Other diagnosis entertained included MERRF, GSS, Ramsay Hunt syndrome, subacute combined degeneration, spinocerebellar degeneration. Majority of the participants thought that paraneoplastic syndrome was most likely. Post-mortem examination revealed poorly differentiated carcinoma in the small intestine. Myeline pallor was noted in the posterior and the lateral columns in the thoracic spine. Neuronal cell loss was observed in the Purkinje cell and granular cell layer in the cerebellum. Sural nerve demonstrated loss of myelinated fibers and grouping of small fibers. Neuropathological findings were consistent with Friedreich ataxia; nevertheless, no mutation was reported in frataxin in Japan. The neuropathologist concluded that neuropathological diagnosis was a spinocerebellar ataxia with neuropathological similarities to Friedreich ataxia.
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PMID:[A 60-year-old man with intention tremor as an initial symptom followed by cerebellar ataxia, peripheral neuropathy and dementia]. 1614 16

There is accumulated evidence that cortical reorganization plays an important role in motor recovery after supratentorial stroke. However neural mechanisms underlying functional recovery of ataxia after infratentorial stroke remain unclear. We investigated cortical activations during ataxic gait in patients with infratentorial stroke to test the hypothesis that cerebral cortices were involved in compensatory mechanisms for ataxic gait. Twelve patients with infratentorial stroke (mean duration+/-S.D. from the onset: 88.3+/-44.8 days) and 11 age-matched healthy subjects participated in this study. All patients had predominant ataxia without severe hemiparesis. We measured cortical activation as assessed by task-related increase of oxygenated hemoglobin during gait on a treadmill using functional near-infrared spectroscopy. Task consisted of three repetitions of gait period alternated with rest period. In controls, cortical activations in the lateral and medial prefrontal cortex during the acceleration phase tended to be attenuated during the steady phase of the gait period while these activations were sustained throughout the gait period in ataxic patients. Repeated measures ANOVA for cortical activation revealed significant interactions (p<0.005) between phase (acceleration/steady) and group (control/stroke) in the medial and lateral prefrontal regions. These results suggest that sustained prefrontal activation during ataxic gait might be relevant to compensatory mechanisms for ataxic gait after infratentorial stroke.
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PMID:Sustained prefrontal activation during ataxic gait: a compensatory mechanism for ataxic stroke? 1768 49

Obatoclax mesylate is a small molecule pan-Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells. Obatoclax was administered to patients with advanced CLL at doses ranging from 3.5 to 14 mg/m(2) as a 1-hour infusion and from 20 to 40 mg/m(2) as a 3-hour infusion every 3 weeks. Twenty-six patients received a total of 74 cycles. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and associated with the infusion. The maximum tolerated dose (MTD) was 28 mg/m(2) over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts. Circulating lymphocyte counts were reduced in 18 of 26 patients with a median reduction of 24%. Overall, the maximum plasma concentration (C(max)) and area under the curve (AUC) values of obatoclax were dose proportional. Activation of Bax and Bak was demonstrated in peripheral blood mononuclear cells, and induction of apoptosis was related to overall obatoclax exposure, as monitored by the plasma concentration of oligonucleosomal DNA/histone complexes. Obatoclax mesylate has biologic activity and modest single-agent activity in heavily pretreated patients with advanced CLL. Further evaluation in less heavily pretreated patients and in combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964.
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PMID:Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. 1893 44

A caracal (Caracal caracal) was bitten on the lower lip by a southern Pacific rattlesnake (Crotalus viridis helleri) and quickly developed progressive, severe soft tissue swelling and bruising of this site. Initial laboratory results revealed prolonged clotting times within the first hour of envenomation, followed by signs of vasculitis and anemia. The caracal was successfully treated with intravenous crystalloids, four vials of polyvalent crotalidae antivenom, and transfusions of bovine hemoglobin glutamer-200 (Oxyglobin) and fresh whole blood. The progressive soft tissue swelling and bruising halted and the coagulation parameters improved after administration of antivenom; however, the caracal continued to show neurologic dysfunction, including depression, weakness, muscle fasciculations, anisocoria, and ataxia. Administration of an additional vial of antivenom 72 hr after envenomation quickly corrected the weakness and muscle fasciculations, whereas the anisocoria and mild ataxia persisted for another 24 hr. The caracal remains clinically normal 3 yr after the envenomation.
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PMID:Successful treatment of a southern Pacific rattlesnake (Crotalus viridis helleri) bite in a caracal (Caracal caracal). 1956 91

Spontaneous cerebellar hemorrhage (SCH) represents approximately 10% of all intracerebral hemorrhage (ICH) and is an important clinical problem of which little is known. This study stereotaxically infused collagenase (type VII) into the deep cerebellar paramedian white matter, which corresponds to the most common clinical injury region. Measures of hemostasis (brain water, hemoglobin assay, Evans blue, collagen-IV, ZO-1, and MMP-2 and MMP-9) and neurodeficit were quantified 24 hours later (Experiment 1). Long-term functional outcomes were measured over 30 days using the ataxia scale (modified Luciani), open field, wire suspension, beam balance, and inclined plane (Experiment 2). Neurocognitive ability was assessed on the third week using the rotarod (motor learning), T maze (working memory), and water maze (spatial learning and memory) (Experiment 3), followed by a histopathological analysis 1 week later (Experiment 4). Stereotaxic collagenase infusion caused dose-dependent elevations in brain edema, neurodeficit, hematoma volume, and blood-brain barrier rupture, while physiological variables remained stable. Most functional outcomes normalized by the third week, while neurocognitive testing showed deficits parallel to the cystic-cavitary lesion at 30 days. All animals survived until sacrifice, and obstructive hydrocephalus did not develop. These results suggest that the model can generate important translational information about this subtype of ICH and could be used for future investigations of therapeutic mechanisms after cerebellar hemorrhage.
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PMID:Characterization of the brain injury, neurobehavioral profiles, and histopathology in a rat model of cerebellar hemorrhage. 2119 29

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