Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurements of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chest and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on a weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.
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PMID:Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. 234 2

In a plant producing vinyl chloride by the emulsion method 200 workers who were exposed to vinyl chloride for 1 to 25 yr (mean 14), 58 (i.e. 29%) were free of complaints and nervous disturbances. An astheno-autonomic syndrome was found in 54 (i.e. 27%) and in 88 (i.e. 44%) in combination with positive neurological findings, i.e. pyramidal syndromes (in 52), cerebellar disturbances (in 38), trigeminal neuropathy (in 24) and extrapyramidal symptoms (in 3), in various combinations - pyramidal + cerebellar in 12, trigeminal + pyramidal in 7, trigeminal + cerebellar in 5. Headaches (48%), nervousness (26%), decrease in physical strength (16%), loss of memory (14%), sleeping disturbances and somnolence were the most frequent complaints. Scleroderma-like skin changes were found in ten subjects, but only six of them had any neurological disturbances. Occupational exposure to vinyl chloride was lower in workers without neurological findings. Frequency of the arterial hypertension was the same in both groups, whereas acroparesthesias, Raynaud's syndrome, and increased gamma GTP serum activity were significantly more frequent in workers with neurological disturbances. Sixty-two per cent of the neurologically positive group and only 24% of the negative group reported euphoric or narcotic states after exposure. This probably indicates episodic exposures to high concentrations of vinyl chloride. This difference points to a possibility that neurological disturbances may be related to short exposures to peak concentrations. The neurological injury may be both a direct neurotoxic effect of vinyl chloride and secondary to vascular disorders.
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PMID:Vinyl chloride disease-neurological disturbances. 662 5

Benzamide riboside (BR), a synthetic C-nucleoside, acts as a strong growth inhibitor of cancer cells in vitro and in vivo. BR, like TR and related nucleoside prodrugs, act by anabolism to NAD analogs. These analogs selectively inhibit IMPDH, leading to depletion of cellular GTP, growth cessation, and cell differentiation. To date only preclinical studies have been carried out. However, in tiazofurin (TR), a related drug, phase I/II clinical trials have been conducted in patients with acute leukemia and shown to be a very promising agent with a response rate of 85% in 26 patients in one of the trials. Tiazofurin is now undergoing phase III clinical trials as a result. Dose limiting toxicity of tiazofurin was headache, somnolence and nausea with no myelosuppression noted. By contrast, BR showed skeletal muscle toxicity, hepatotoxicity and myelosuppression in preclinical data. Skeletal muscle toxicity was noted in the paraspinal muscles and may represent dose-limiting toxicity. Since BR does exhibit myelosuppression, the most common chemotherapy-related side effect in humans, careful judgment is warranted should BR be included in multidrug regimens, although BR's potent cytotoxicity to tumor cells in preclinical models still makes it a promising drug.
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PMID:Toxicity and efficacy of benzamide riboside in cancer chemotherapy models. 1196 43

Cortex Mori Radicis is a traditional Chinese herbal medicine which has a long history of use for the treatment of headaches, cough, edema and diabetes. However, its function and mode of action within nervous system remain largely unclear. In the present study, we have attempted to determine the effects of Cortex Mori Radicis Extract (CMRE) on neuronal differentiation. Here, we reported that CMRE induces the neurite outgrowth in pheochromocytoma PC12 cells and primary cortical neuron. Following the generation of neurite outgrowth, extracellular Ca(2+) influx was inhibited and intracellular Ca(2+) decreased. In addition, CMRE induced the extracellular signal-regulated kinase 1/2 (ERK1/2) activation and also stimulated the Rap1-GTP expression, which is closely linked to neuritogenesis. Moreover, the neurite outgrowth induced by CMRE was antagonized to a marked degree by suppressing activation of p-ERK1/2 with the specific ERK1/2 inhibitor (PD98059), suggesting the involvement of Rap1-GTP and ERK1/2 in CMRE-induced neurite outgrowth. Taken together, these results demonstrate that CMRE induces neurite outgrowth of PC12 cells through Rap1-ERK signaling pathway via inhibiting Ca(2+) influx, and provide a novel insight into the manner in which CMRE participates in neuritogenesis.
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PMID:Cortex Mori Radicis Extract induces neurite outgrowth in PC12 cells activating ERK signaling pathway via inhibiting Ca(2+) influx. 2613 Oct 75

Individuals with an inactive acetaldehyde dehydrogenase 2 have an. elevated level of serum acetaldehyde after drinking alcohol, and this may cause an alcohol flushing response with symptoms such as facial flushing, tachycardia, headache, and nausea. Recent studies have suggested that the flushing response influences the association between alcohol consumption and various health-related outcomes. In the present study, we investigated the impact of the flushing response on the relationship between alcohol consumption and serum y -GTP levels in Japanese drinkers. We conducted a cross-sectional study of 521 Japanese drinkers (260 men and 261 'vomen) to examine the impact of the alcohol flushing response on the relationship between alcohol consumption and serum y -GTP levels. The subjects were divided into three groups according to the amount .of daily alcohol consumption. (low, <20 g; moderate, 20-39 g;. and high, >40 g). Multiple adjustments were performed with linear regression models to examine the association between daily alcohol consumption and serum y-GTP levels, adjusting for potential con- founders including the flushing response. We found that the proportion of flushers was significantly lower in the high alcohol consumption group than in the low consumption group. The results of a multivariable analysis showed that,serum y -GTP levels were significantly higher in the moderate and high consumption groups than in the low consumption group after. adjusting for all potential confounders other than the flushing response. In addition, the association between serum y -GTP levels and alcohol consumption was unchanged after adjusting for the presence of the flushing response. In conclusion, serum y -GTP levels increased with increasing alcohol-consumption regardless of the flushing response. Screening for heavy drinkers using serum y-GTP levels was very important to prevent alcohol-related diseases or health problems in health examination.
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PMID:Impact of Flushing Response on the Relationship between Alcohol Consumption and Gamma-glutamyl Transpeptidase: the KOBE study. 3048 Sep 3