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

1. Samples of cerebrospinal fluid (c.s.f.) have been taken from the cisterna magna of unanaesthetized cats, whilst rectal temperature was recorded, during exposure of the animals to various ambient temperatures and during fever induced by pyrogen. The concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in samples of c.s.f. has been assayed. 2. Cats exposed to low ambient temperatures (-2 to +2 degrees C) for 3 h maintained body temperature by both behavioural and autonomic heat gain activity. Exposure of cats to high ambient temperatures (44 - 45 degrees C) for 3.5 h caused a rise in body temperatures of about 2.5 degrees C, despite behavioural and autonomic heat loss activity. Neither cold nor heat stress had a significant effect on c.s.f. cyclic AMP. 3. Fever induced by intravenous Shigella dysenteriae (2 and 20 mug/kg) was associated with a dose-related increase in the concentration of cyclic AMP in c.s.f. Paracetamol (75 mg/kg) injected I.P. before the onset of fever, suppressed the increase in both temperature and c.s.f. cyclic AMP in response to pyrogen. Paracetamol (50 and 100 mg/kg), injected after the onset of fever, caused a fall in temperature, which was not associated with a decrease in the concentration of cyclic AMP in c.s.f. 4. Fever induced in cats by intravenous Shigella dysenteriae (20 mug/kg) was associated with an increase in the concentration of cyclic AMP in plasma as well as in c.s.f. 5. The sodium salt of cyclic AMP (0.1-10 mg/kg) injected I.V. into unanaesthetized cats caused a dose-related hypothermia, which was associated with autonomic heat loss activity and a dose-related increase in the concentration of cyclic AMP in cisternal c.s.f., which was not mimicked by adenosine. 6. It is concluded that the raised concentrations of cyclic AMP in c.s.f., in response to pyrogen I.V., do not mediate fever in the cat and that the concentration of cyclic AMP in cisternal c.s.f. may be affected by changes in the plasma concentration of the nucleotide.
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PMID:Cyclic adenosine 3', 5'-monophosphate in cerebrospinal fluid during thermoregulation and fever. 19 Mar 83

1. Cholera enterotoxin was used to evaluate a possible role of endogenous cyclic AMP in production of hyperthermia. Injection of purified toxin (0.10-1.0 mug in 0.10 ml.) into the lateral cerebral ventricle of unanaesthetized cats caused dose-related hyperthermic responses. Heating the toxin for 40 min at 90 degrees C abolished its hyperthermic activity.2. Intraventricular administration of dibutyryl cyclic AMP (250-1000 mug) also caused hyperthermia which, however, was preceded by transient periods of hypothermia and/or excitation in about half of the tests.3. Paracetamol, indomethacin and sodium salicylate inhibited hyperthermic responses to cholera enterotoxin. Paracetamol and indomethacin also inhibited hyperthermia induced by dibutyryl cyclic AMP (sodium salicylate was not tested).4. It is likely that the hyperthermic effect of cholera enterotoxin in the cat is mediated via endogenous cyclic AMP and that the antipyretics inhibit this effect by an action subsequent to the increase in cyclic AMP.5. It is unlikely that prostaglandin-induced hyperthermia in the cat is mediated via cyclic AMP since these antipyretics do not inhibit this response to prostaglandin E(1).
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PMID:The hyperthermic effect of intracerebroventricular cholera enterotoxin in the unanaesthetized cat. 437 Oct 60

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.
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PMID:Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. 673 27

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

Ca2+ accumulates in the nucleus and DNA undergoes enzymatic cleavage into internucleosome-length fragments before acetaminophen and dimethylnitrosamine produce hepatic necrosis in vivo and toxic cell death in vitro. However, Ca(2+)-endonuclease fragmentation of DNA is characteristic of apoptosis, a type of cell death considered biochemically and functionally distinct from toxic cell death. The present studies investigate DNA fragmentation as a critical event in toxic cell death by testing whether the Ca(2+)-calmodulin antagonist chlorpromazine and the Ca2+ channel blocker verapamil prevent acetaminophen-induced hepatic necrosis by inhibiting Ca2+ deregulation and DNA damage. Acetaminophen overdose in mice produced accumulation of Ca2+ in the nucleus (358% of control) and fragmentation of DNA (250% of control) by 6 h, with peak release of ALT occurring at 12-24 h (38,000 U/l). Pretreatment with chlorpromazine prevented increases in nuclear Ca2+ and DNA fragmentation and nearly abolished biochemical evidence of toxic cell death. Verapamil pretreatment also decreased Ca2+ accumulation and DNA damage while attenuating liver injury. The Ca2+ antagonists did not protect against toxic cell death through hypothermia because neither produced the delay in toxicity that is customarily associated with hypothermia. Nor did chlorpromazine or verapamil protect through inhibiting acetaminophen bioactivation. Chlorpromazine failed to diminish glutathione depletion in whole liver and isolated nuclei. Verapamil (250 microM) also failed to alter glutathione depletion in whole liver and had no effect on acetaminophen-glutathione adduct formation by mouse liver microsomes and by cultured mouse hepatocytes. Collectively, these results support the hypothesis that Ca(2+)-induced DNA fragmentation plays a significant role in cell necrosis produced by acetaminophen and may contribute to toxic cell death caused by other alkylating hepatotoxins.
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PMID:Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. 846 87

Acetaminophen and idiosyncratic drug induced hepatotoxicity are the most commonly identified etiologies of acute liver failure in Western countries. Infectious complications and cerebral edema remain the leading causes of death. Moderate hypothermia and other medical interventions may improve cerebral edema in selected patients with acute liver failure. In addition, pilot studies suggest that recombinant factor VIIa infusions may allow for the safe placement of intracranial pressure monitoring devices in patients with cerebral edema and severe coagulopathy. Auxiliary liver transplantation and bioartificial liver devices offer the hope of temporary liver support for selected patients with a high likelihood of native liver regeneration. Prognostic survival models that include arterial lactate levels may improve our ability to identify acetaminophen overdose patients in urgent need of liver transplantation. The lower 1-year patient survival following liver transplantation for acute liver failure compared to chronic liver failure (60 vs 80%) is in part due to the emergent nature of surgery, concomitant vital organ failure, and the higher incidence of immunologically mediated graft dysfunction. Vaccination against hepatotrophic viruses and other public health measures designed to minimize the incidence of both intentional and non-intentional acetaminophen overdose may help reduce the future incidence of acute liver failure. In the meanwhile, it is recommended that acute liver failure patients be managed in experienced centers with ready access to liver transplantation to optimize outcomes in this rare but frequently fatal illness.
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PMID:Liver transplantation in acute liver failure. 1285 32

Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57/BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2 degrees C below normal) with a dose of 300 mg/kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E(2) concentrations in the brain. In cyclooxygenase (COX)-2(-/-) mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE(2) levels, whereas in COX-1(-/-) mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1(-/-) mice had approximately 70% lower levels of PGE(2) than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE(2) levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE(2) that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.
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PMID:Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. 1526 79

Paracetamol produces analgesia in the mouse writhing test through a central action which is paralleled by a reduction in brain PGE(2) concentrations. In contrast, diclofenac has a peripheral analgesic action in this test. Paracetamol-induced hypothermia is also accompanied by a reduction in brain PGE(2) concentrations in C57/Bl6 mice. This hypothermic effect of paracetamol was reduced in COX-1 but not in COX-2 gene-deleted mice. These results support the view that analgesia and hypothermia due to paracetamol are mediated by inhibition of a third COX isoenzyme (designated COX-3). In cultured mouse macrophages, COX-2 is induced by treatment with LPS or with high concentrations of diclofenac. Diclofenac-induced COX-2 is inhibited with low concentrations of paracetamol, whereas LPS-induced COX-2 is insensitive to paracetamol inhibition. The mechanisms of induction and possibly the functions of these two COX-2 enzymes are also different.
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PMID:COX-3 and the mechanism of action of paracetamol/acetaminophen. 1562 90

Acetaminophen (AC) reduces the core temperatures (T(c)) of febrile and non-febrile mice alike. Evidence has been adduced that the selectively AC-sensitive PGHS isoform, PGHS-1b (COX-3), mediates these effects. PGHS-1b, however, has no catalytic potency in mice. To resolve this contradiction, AC was injected intravenously (i.v.) into conscious PGHS-1 gene-sufficient (wild-type (WT)) and -deficient (PGHS-1(-/-)) mice 60 min before or after pyrogen-free saline (PFS) or E. coli LPS (10 microg/kg) i.v. T(c) was monitored continuously; brain and plasma PGE(2) levels were determined hourly. AC at <160 mg/kg did not affect T(c) when given before PFS or LPS; at 160 mg/kg, it caused a approximately 2.5 degrees C T(c) fall in 60 min. LPS given after AC (all doses) induced a approximately 1 degrees C fever, not different from that in AC-untreated mice. But this rise was insufficient to overcome the hypothermia of the 160 mg/kg-treated mice; their T(c) culminated 1 degrees C below baseline. LPS given before AC similarly elevated T(c) approximately 1 degrees C. This rise was reduced to baseline in 30 min by 80 mg AC/kg; T(c) rebounded to its febrile level over the next 30 min. At 160 mg/kg, AC reduced T(c) to 4 degrees C below baseline in 60 min, where it remained until the end of the experiment. WT and PGHS-1(-/-) mice responded similarly to all the treatments. The basal brain and plasma PGE(2) levels of PFS mice and the elevated plasma levels of LPS mice were unchanged by AC at 160 mg/kg; but the latter's brain levels were reduced at 1h, then recovered. Thus, AC could exert an anti-PGHS-2 effect when this enzyme is upregulated in the brain of febrile mice. The hypothermia it induces in non-febrile mice, therefore, is due to another mechanism. PGHS-1b is not involved in either case.
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PMID:Acetaminophen: antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant. 1808 54

The purpose of the present study was to compare the efficiency of small and standard volumes (1.5-20 and 7-10 ml/g of the myocardium, respectively) of Custodiol solution in myocardial ischemia lasting 2 and 4 hours. Experiments were carried out on 24 mongrel dogs weighing 22-36 kg under extracorporeal circulation (EC) with bicaval cannulation under moderate general hypothermia and balanced general intravenous anesthesia. According to the solution volume and cardioplegia (CP) duration, all the animals were divided into 4 groups: 1) 2-hour CP (standard volume); 2) 2-hour CP (small volume); 3) 4-hour CP (standard volume); 4) 4-hour CP (small volume); of them Groups 1 and 3 served as a control. Antegrade CP was accomplished by the conventional procedure. In Groups 1 and 3, the volume of Custodiol solution was 1000-2000 ml; in Groups 2 and 4, that was 300-600 ml depending on myocardial mass. In Groups 1 and 3, the mean duration of myocardial perfusion was 9.8+/-2.8 and 8.4+/-1.4 min, respectively; and in Groups 2 and 4, that was 4.2+/-0.7 and 4.5+/-1.4 min. Groups 3 and 4 animals received additional myocardial perfusion with Custodiol solution in a volume of 400-500 and 200-250 ml, respectively. The efficiency of myocardial protection was evaluated from the course of a reperfusion period (RP) and from central hemodynamic changes, the concentrations of glucose, lactate, malonic dialdehyde, medium-weight molecules, and blood gas and electrolyte composition of the coronary sinus. The studies were performed in stages: outcome, launch of blood flow (5-10 in); RP (30 min); complete loading (30 min); disconnection from an extracorporeal circulation apparatus. The experiment has indicated that the use of Custodiol solution in the standard volumes ensures an effective cardioplegic protection within 4 hours. Reductions in the volume and time of perfusion to the values characteristic of extracellular-type solutions cause a lower efficiency of this protection. Moreover, myocardial damage progresses as the duration of CP increases. The used Custodiol solution dose of 1.5-2.0 ml/g of the myocardium is apparent to be insufficient to set an ionic balance between cardioplegic solution and intracellular fluid, which reduces the duration of CP effect and the efficiency of myocardial protection. It may be assumed that lower perfusion volume lowers the efficiency of the buffer system of the solution and the metabolic effects of substrates. The authors consider that the decreased volume and time of perfusion of intracellular Custodial solution are unjustified and may result in the development of complications associated with inadequate cardioplegic myocardial protection.
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PMID:[Effect of perfusion volume of the Custodiol solution on the efficiency of cardioplegia in experiment]. 1910 31


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