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Margaret G. Filbert Jeffry S. Forster Sorabe Phann Gerald P. H. Ballough 《Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid》1998,33(1):1-14
Turnover of [3H]phosphoinositides (PI) was examined in brain slices from the hippocampus of rats undergoing soman-induced seizure activity. Hydrolysis of PI was determined by measuring the accumulation of [3H]inositol-1-phosphate (IP1). Incubation of hippocampal slices in the presence of carbachol or norepinephrine (NE) increased PI hydrolysis. Stimulated hydrolysis by NE, but not carbachol was significantly reduced in slices from soman-challenged rats undergoing convulsive activity. NE-stimulated PI hydrolysis was not reduced in slices from animals exposed to soman that did not exhibit convulsive activity. In rats surviving for 24 h, the response to NE was not different from control rats. In control slices, NE-stimulated hydrolysis of PI was potentiated by GABA. No potentiation by GABA was seen in slices from animals undergoing seizures. Uptake and incorporation ofmyo-[2-3H]inositol into phospholipids was reduced in slices from rats undergoing convulsions. Reduced IP1 production appeared to be owing, in part, to decreased synthesis of inositol lipids. These observations suggest that during soman-induced seizure activity, there is an apparent decrease in the response of the PI second messenger system to NE stimulation, and that this may contribute to the severity and duration of convulsions and brain damage resulting from exposure to soman and other anticholinesterase compounds. 相似文献
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Margaret G. Filbert Leland W. Dochterman Catherine D. Smith Jeffry S. Forster Sorabe Phann Frank J. Cann 《Drug development research》1993,30(1):45-53
The effect of intravenous mannitol on soman-induced neuropathology and cardio-myopathy was studied in rats. Soman, an organophosphorus agent, irreversibly inhibits total body acetylcholinesterase and induces a cholinototoxic syndrome in rats which results in the development of sezures, brain damage, and degenerative cardiomyopathy. The severity of the cardiomyopathy parallels the severity of the neuropathology. When mannitol at a dose of 1.5 g/kg was administered at the onset of sezures and followed by a second dose 5 h later, there was a significant increase in 24 h survival. Moreover, the severity of brain lesions was reduced in the piriform cortex, thalamus, amygdala, and the caudate putamen. The same treatment schedule also provided almost complete protection against the concomitant development of degenerative cardiomyopathy. The finding that the mannitol treatments reduced both the severity of the neuropathology and the degenerative cardiomyopathy reinforces the concept of a possible central neurogenic mechanism for the development of the cardiomyopathy. These results suggest that mannitol may be useful to reduce the severity of sezure-related neuropathology and to provide additional protection to other vital organs which may be secondarily susceptible to neurogenically mediatd pathologic change, such as the heart in rats which develop cardiomyopathy following soman-induced seizures. © 1993 wiley-Liss, Inc. 相似文献
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Jessica Manning Pattaraporn Vanachayangkul Chanthap Lon Michele Spring Mary So Darapiseth Sea Youry Se Sok Somethy Sut-Thang Phann Soklyda Chann Sabaithip Sriwichai Nillawan Buathong Worachet Kuntawunginn Mashamon Mitprasat Raveewan Siripokasupkul Paktiya Teja-Isavadharm Eugene Soh Ans Timmermans Charlotte Lanteri Jaranit Kaewkungwal Montida Auayporn Douglas Tang Char Meng Chour Satharath Prom Mark Haigney Louis Cantilena David Saunders 《Antimicrobial agents and chemotherapy》2014,58(10):6056-6067
Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia''s formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. .) NCT01624337相似文献
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