Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Acetyl, N-propionyl, and N-pivaloyl derivatives of taurine were synthesized by applying a modified Schotten-Bauman method starting from taurine and using the corresponding acid chloride or acid anhydride for direct acylation reactions. The central nervous system actions of these lipid soluble taurine derivatives, which were presumed to pass the blood-brain barrier, were studied and compared to those of taurine in mice. A large dose (15 mmol/kg) of intraperitoneally administered taurine lengthened the pentobarbitone induced sleep by 30%. N-Pivaloyltaurine was 45 times more potent but not more effective than taurine. Neither N-acetyl- nor N-propionyltaurine lengthened the pentobarbitone induced sleep in doses up to 3 mmol/kg. Intraperitoneally administered N-pivaloyltaurine depressed the locomotor activity in a smaller dose and for a longer period than taurine. However, when administered intracerebroventricularly neither N-acetyl- nor N-pivaloyltaurine altered the locomotor activity in three times larger dose than in which taurine clearly depressed it. Intraperitoneally administered N-pivaloyltaurine decreased the rectal temperature slightly more than taurine, whereas intracerebroventricularly administered taurine was clearly more potent in inducing hypothermia than its acyl derivatives. Intraperitoneally administered N-pivaloyltaurine was about three times more potent than taurine in increasing the striatal concentration of dopamine. Intraperitoneally administered N-pivaloyltaurine only in a very large dose (3 X 15 mmol/kg) slightly and transiently increased the cerebral taurine concentration. Carboxylesterase inhibition by bis-p-nitrophenyl phosphate (BNPP) did not modify this increase. Furthermore, BNPP pretreatment modified neither the hypothermic nor the striatal dopamine concentration elevating effects of N-pivaloyltaurine. Our results suggest that N-pivaloyltaurine possesses taurine-like pharmacological actions. It is not converted to taurine to produce these actions. When administered intracerebroventricularly it is less potent than taurine. However, when administered intraperitoneally it is more potent than taurine because it seems to pass the blood-brain-barrier more easily than taurine. Thus N-pivaloyltaurine could be used to study the behavioural and other central nervous system actions of taurine.
 ...
PMID:Comparison of central nervous system actions of taurine and N-pivaloyltaurine. 406 Oct 94

Death and toxicity after cocaine use do not correlate with cocaine blood levels. One explanation for this observation is that cocaine abusers may posses one or more of the 58 possible known mutations in the butyrylcholinesterase gene (BCHE). Butyrylcholinesterase (BChE) serves as the primary cocaine hydrolase producing a nontoxic product ecgonine methyl ester. A reduction in endogenous levels of BChE may result in increased metabolism by hepatic carboxylesterase to produce norcocaine, a toxic product. Humans have carboxylesterase in tissues but not in plasma, whereas wild-type mice have significant amounts of carboxylesterase in tissues and plasma. Knockout mice with no plasma carboxylesterase were created to eliminate the contribution of plasma carboxylesterase in cocaine hydrolysis, thereby simulating human enzyme levels. This study tested the hypothesis that reductions in BChE such as those in humans with BChE mutations contribute to increased toxicity after cocaine use. Carboxylesterase and BChE double knockout mice, models for humans with BChE deficiency, were challenged with a nonlethal dose of 100 mg/kg (-)-cocaine. Carboxylesterase/BChE double knockout mice demonstrated toxic signs significantly longer than did wild-type and carboxylesterase knockout mice. The carboxylesterase/BChE-deficient mice took approximately 2.5 times as long to recover from cocaine toxicities, including the following: hypothermia, hyperactivity, stereotypical behavior, ocular effects, and dorsiflexion of the tail. The carboxylesterase/BChE double knockout mouse model demonstrates the importance of endogenous BChE for protection against cocaine toxicity and provides an in vivo system for studying drug sensitivity of humans who carry a BChE mutation.
 ...
PMID:Prolonged toxic effects after cocaine challenge in butyrylcholinesterase/plasma carboxylesterase double knockout mice: a model for butyrylcholinesterase-deficient humans. 2154 Mar 57