UMLS:C0020672 - FACTA Search

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Query: UMLS:C0020672 (hypothermia)
17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of 10 male and 10 female rats were dosed orally with 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-tetrachlorobenzene (TCB) at levels that ranged from 200 to 4000 mg/kg, and were observed clinically for 14 d. LD50 values for 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-TCB were found to be 1470, 3105, and 2297 mg/kg, respectively, in male rats. In females, the LD50 values were found to be 1167 and 1727 mg/kg for 1,2,3,4- and 1,2,3,5-TCB, respectively. Clinical signs of toxicity included depression, flaccid muscle tone, prostration, piloerection, loose stool, hypothermia, dacryorrhea, coma, and death. In a subacute study, groups of 10 males and 10 females were fed diets containing 0, 0.5, 5.0, 50, or 500 ppm 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-TCB for 28 d. No deaths or clinical signs of toxicity were observed, and neither growth rate nor food consumption was affected. At 500 ppm, 1,2,4,5- but not 1,2,3,4- or 1,2,3,5-TCB caused a significant increase in the liver weight and serum cholesterol of male and female rats. Hepatic microsomal aniline hydroxylase and ethoxyresorufin deethylase were induced by 500 ppm 1,2,4,5-TCB. Hepatic microsomal aminopyrine demethylase activity was increased by the administration of this compound at 50 ppm and higher in males and at 500 ppm in the females. Rats fed 1,2,3,4- and 1,2,3,5-TCB at 500 ppm also showed a significant increase in aminopyrine demethylase activity. Moderate to severe histological changes were found in the liver, thyroid, kidney, and lungs of rats fed 500 ppm 1,2,4,5-TCB. Histological changes in the tissues produced by the administration of the 1,2,3,4- and 1,2,3,5-isomer were mild even at the highest dose levels. Tissue residue data showed that 1,2,4,5-TCB accumulated at much higher levels than the other two isomers. The results suggest that the position of chlorine substitution can affect the tissue accumulation and toxicity of chlorinated benzenes in rats.
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PMID:Comparative toxicity of 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-tetrachlorobenzene in the rat: results of acute and subacute studies. 662 Apr 5

In rats, lisuride, either administered systemically or intracerebroventricularly induced a dose-related hypothermia. This effect was selectively antagonized by blockade of DA receptors in the CNS but not by inhibition of catecholamine synthesis or blockade of serotoninergic receptors. Also a blocker of "peripheral" DA receptors failed to antagonize the hypothermic effect of lisuride in rats. Induction of rat liver microsomal drug-metabolizing enzymes by phenobarbital counteracted lisuride-induced hypothermia. In rabbits lisuride induced a hyperthermic response which was sensitive to both pimozide and metergoline pretreatment. These findings indicate that stimulation of brain DA receptors involved in thermoregulation is responsible for the changes in body temperature indiced by lisuride in rats and rabbits and that these effects are caused by the drug itself and do not require previous biotransformation into an active metabolite.
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PMID:Effects of lisuride on body temperature of rats and rabbits: relation to microsomal biotransformation and dopaminergic receptor stimulation. 677 96

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.
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PMID:Acetaminophen toxicity in fed and fasted mice. 680 76

Propranolol and verapamil are cardioactive drugs which may be useful during surgical procedures involving hypothermic cardiopulmonary bypass. Previous in vivo studies have shown that the pharmacokinetics of propranolol are altered by hypothermia, and that clearance of the drug is significantly reduced by lowered body temperature. Since both propranolol and verapamil are eliminated largely by hepatic metabolic activity, the effect of hypothermia on the ability of the liver to metabolize both drugs was studied in vitro with rat hepatic microsome preparations. Known quantities of the drugs were added after preincubation of microsomes at 37 degrees C (normothermia) or 26 degrees C (hypothermia), and the amount of drug substrate remaining after an additional incubation period was measured. Hypothermic microsomes metabolized significantly less of each drug at all substrate concentrations studies (p less than 0.001). Double-reciprocal plots showed similar results for experiments with both propranolol and verapamil: the extrapolated Vmax was the same for both temperature conditions, but the Km values were significantly increased by hypothermia (p less than 0.001), indicating reduced affinity for drug substrate by the microsomal enzymes. These in vitro studies show that hepatic metabolic elimination of both propranolol and verapamil is decreased by hypothermia.
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PMID:Effect of hypothermia on drug metabolism. In vitro studies with propranolol and verapamil. 738 93

The oxidative metabolism of cannabidiol (CBD) at the 8,9-double bond was examined. 8R,9-Epoxy-CBD was identified by GC-MS as a new metabolite of CBD produced by hepatic microsomal fractions of guinea pigs, rats and mice. The reaction required NADPH as a cofactor and molecular oxygen. The optimal pH for the reaction was 7.4-8.0. The 8R,9-epoxy-CBD forming activity was highest in guinea pigs, followed by mice and rats in the presence of 3,3,3-trichloropropene-1,2-oxide (TCPO), an inhibitor of epoxide hydrolase. The activity was significantly suppressed by SKF 525-A, alpha-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol (6 beta-CH2OH-delta 9-TCH) and 8,9-dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6 beta-CH2OH-delta 9-THC was markedly increased in the presence of TCPO with a concomitant decrease in the formation of 8,9-dihydro-8,9-dihydroxy-CBD in all animal species examined. Furthermore, 6 beta-CH2OH-delta 9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6 beta-CH2OH-delta 9-THC exhibited THC-like pharmacological effects, catalepsy, analgesia, pentobarbital-induced sleep prolongation and hypothermia in mice, although these effects were less marked than those of delta 9-THC. This study presents the first example of the biotransformation of CBD to a delta 9-THC derivative which exhibits some pharmacological effects.
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PMID:In vitro metabolic formation of a new metabolite, 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice. 828 29

The objective of this study was to investigate the effects of single and repeated administration of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)] on behaviour, energy metabolism and biotransformation. Single intraperitoneal administration to male Sprague-Dawley rats of CP-55,940 (0.4 mg/kg), induced a behavioural response characterized by 'splayed hind limbs', antinociception, hypothermia and a decrease in locomotor activity. Brain and liver mitochondria of the CP-55,940-treated rats exhibited an increase in respiration and no changes in ADP/O and citrate synthase specific activity. Repeated intraperitoneal administration of CP-55,940 (0.4 mg/kg, 11 days) induced behavioural tolerance, disappearance of the increase in the mitochondrial oxygen consumption as well as an increase in the monooxygenase activities and the content of liver microsomal cytochrome P450. Some hepatic metabolizing enzymes of the cytosolic glutathione-centre system were also affected. Previous studies had indicated that the tolerance after chronic administration of CP-55,940 could be due to down-regulation of brain cannabinoid receptors. The present findings demonstrate that the behavioural tolerance occurs together with modified biotransformation activities.
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PMID:Chronic cannabinoid, CP-55,940, administration alters biotransformation in the rat. 890 24

Anandamide (N-arachidonoylethanolamine) and six fatty acid ethanolamides were synthesized and their pharmacological effects in mice were assessed using catalepsy, hypothermia and pentobarbital-induced sleep prolongation as indices. The effects of phenylmethylsulfonyl fluoride (PMSF) pretreatment on anandamide effects were also evaluated and discussed in relation to inhibition of anandamide amidohydrolase in mouse brain and liver. The cataleptogenic effect of anandamide (ED50=6.0 mg/kg, i.v.) was 4 to 6 times more active than those of N-oleoyl- (ED50=26.5 mg/kg, i.v.) and N-linoleoylethanolamine (ED50=37.5 mg/kg, i.v.), although the peak time in the effect was observed within 1 min after i.v. administration. None of the saturated fatty acid ethanolamides (N-myristoyl-, N-palmitoyl-, N-stearoyl- and N-arachidoylethanolamine) showed a positive response in the cataleptogenic effect even at a dose up to 40 mg/kg i.v. Anandamide, N-linoleoyl-, N-oleoyl- and N-myristoylethanolamine (10 mg/kg, i.v.) produced a significant hypothermia (0.19 to 0.59 degrees C) at 5 to 15 min after administration. The duration of the effects of these ethanolamides was also relatively short. Anandamide, N-linoleoyl-, N-oleoyl- and N-palmitoylethanolamine (5 or 10 mg/kg, i.v.) significantly prolonged pentobarbital-induced sleeping time by 148-207% of control sleeping time. The cataleptogenic effect of anandamide was markedly potentiated by pretreatment of mice with PMSF (100 mg/kg, i.p.). The ED50 (mg/kg, i.v.) of anandamide was 0.48 (0.24-0.96) in PMSF-pretreated mice. The pretreatment of mice with PMSF significantly decreased the metabolic clearance rate of anandamide in microsomal fractions of liver and brain. Thus, the Vmax/Km values of brain and hepatic microsomes were 26 and 10%, respectively, as compared with those of control mice. The present study demonstrated that anandamide and N-acylethanolamines of unsaturated fatty acids exhibited cannabinoid-like effects in mice, and that anandamide amidohydrolase has an important role in the pharmacological effects of anandamide in vivo.
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PMID:Pharmacological effects in mice of anandamide and its related fatty acid ethanolamides, and enhancement of cataleptogenic effect of anandamide by phenylmethylsulfonyl fluoride. 1032 55

Stearoyl-CoA desaturase (SCD) is a microsomal enzyme involved in the biosynthesis of oleate and palmitoleate. Mice with a targeted disruption of the SCD1 isoform (SCD1-/-) exhibit reduced adiposity and increased energy expenditure. To address whether the energy expenditure is attributable to increased thermogenesis, we investigated the effect of SCD1 deficiency on basal and cold-induced thermogenesis. SCD1-/- mice have increased expression of uncoupling proteins in brown adipose tissue (BAT) relative to controls. The beta3-adrenergic receptor (beta3-AR) expression was increased and the phosphorylation of cAMP response element binding protein and the protein level of peroxisome proliferator-activated receptor-gamma coactivator-1alpha were increased in the SCD1-/- mice. Both lipolysis and fatty acid oxidation were increased in the SCD1-/- mice. When exposed to 4 degrees C, SCD1-/- mice showed hypothermia, hypoglycemia, and depleted liver glycogen. High levels of dietary oleate partially compensated for the hypothermia and rescued plasma glucose and liver glycogen. These results suggest that SCD1 deficiency stimulates basal thermogenesis through the upregulation of the beta3-AR-mediated pathway and a subsequent increase in lipolysis and fatty acid oxidation in BAT. The hypothermia and hypoglycemia in cold-exposed SCD1-/- mice and the compensatory recovery by oleate indicate an important role of SCD1 gene expression in thermoregulation.
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PMID:Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment. 1521 Aug 43

Therapeutic hypothermia may alter the required dosage of analgesics and sedatives, but no data are available on the effects of mild hypothermia on plasma fentanyl concentration during continuous, long-term administration. We therefore assessed in a porcine model the effect of prolonged hypothermia on plasma fentanyl concentration during 33 h of continuous fentanyl administration. Seven female piglets (weight: 11.8 +/- 1.1 kg) were anesthetized by IV fentanyl (15 microg . kg(-1) . h(-1)) and midazolam (1.0 mg . kg(-1) . h(-1)). After preparation and stabilization (12 h), the animals were cooled to a core temperature of 31.6 degrees +/- 0.2 degrees C for 6 h and were then rewarmed and kept normothermic at 37.7 degrees +/- 0.3 degrees C for 6 more hours. Plasma fentanyl concentrations were measured by radioimmunoassay, cardiac index by thermodilution, and blood flows of the kidney, spleen, pancreas, stomach, gut, and hepatic artery by a colored microspheres technique. Furthermore, in an additional 4 pigs, temperature dependency of hepatic microsomal cytochrome P450 3A4 (CYP3A4) was determined in vitro by ethylmorphine N-demethylation. Plasma fentanyl concentration increased by 25% +/- 11% (P < 0.05) during hypothermia and remained increased for at least 6 h after rewarming. Hypothermia reduced the cardiac index (41% +/- 15%, P < 0.05), as well as all organ blood flows except the hepatic artery. A strong temperature dependency of CYP3A4 was found (P < 0.01). Mild hypothermia induced a distribution and/or elimination-dependent increase in plasma fentanyl concentration which remained increased for several hours after rewarming. Consequently, a prolonged increase of the plasma fentanyl concentration should be anticipated for appropriate control of the analgesia/sedatives during and early after therapeutic hypothermia.
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PMID:The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. 1578 13

Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Over the past decade, the rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. Remarkable progress has been achieved. It has been established that the same inflammatory agent can induce either fever or hypothermia, depending on several factors. It has also been established that experimental fevers are generally polyphasic, and that different mechanisms underlie different febrile phases. Signaling mechanisms of the most common pyrogen used, bacterial lipopolysaccharide (LPS), have been found to involve the Toll-like receptor 4. The roles of cytokines (such as interleukins-1beta and 6 and tumor necrosis factor-alpha) have been further detailed, and new early mediators (e.g., complement factor 5a and platelet-activating factor) have been proposed. Our understanding of how peripheral inflammatory messengers cross the blood-brain barrier (BBB) has changed. The view that the organum vasculosum of the lamina terminalis is the major port of entry for pyrogenic cytokines has lost its dominant position. The vagal theory has emerged and then fallen. Consensus has been reached that the BBB is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, upstream signaling molecules (e.g., pro-inflammatory cytokines) are switched to a downstream mediator, prostaglandin (PG) E2. An indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located. The rapid progress in our understanding of how thermoeffectors are controlled has revealed the inadequacy of set point-based definitions of thermoregulatory responses. New definitions (offered in this review) are based on the idea of balance of active and passive processes and use the term balance point. Inflammatory signaling and thermoeffector pathways involved in fever and hypothermia are modulated by neuropeptides and peptide hormones. Roles for several "new" peptides (e.g., leptin and orexins) have been proposed. Roles for several "old" peptides (e.g., arginine vasopressin, angiotensin II, and cholecystokinin) have been detailed or revised. New pharmacological tools to treat fevers (i.e., selective inhibitors of COX-2) have been rapidly introduced into clinical practice, but have not become magic bullets and appeared to have severe side effects. Several new targets for antipyretic therapy, including mPGES-1, have been identified.
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PMID:Fever and hypothermia in systemic inflammation: recent discoveries and revisions. 1597 Apr 87

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