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)

The intraperitoneal administration of sodium salicylate, L-tryptophan, and tyrosine resulted in significant hypothermia when rats were exposed to a 4degree C ambient temperature. Salicylate and tryptophan increased plasma levels of nonprotein-bound tryptophan while total and bound tryptophan were reduced in salicylate-treated rats. Tryptophan concentrations were unaffected by tyrosine administration. Concomitant with increases in free plasma tryptophan, there occurred significant rises in brain levels of tryptophan in both groups of rats, while brain tyrosine levels were increased in those rats receiving tyrosine. Similarly, significant increments in hypothalamic serotonin levels in rats receiving salicylate or L-tryptophan and increases in hypothalamic norepinephrine in tyrosine-treated rats seem to reflect the increased availability of tryptophan and tyrosine for monamine synthesis. However, alternative mechanisms of hypothermiaseem to be operative since oxygen consumption studies demonstrate dissimilar results for tryptophan and salicylate administration.
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PMID:Salicylate, tryptophan, and tyrosine hypothermia. 113 May 45

The antipyretic activity of alpha-methyl--4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) was studied in rats with comparable hyperthermia after s.c. injection of brewer's yeast. The lowest dose effectively reducing fever is 5 mg/kg and restoration of normal body temperature is obtained with 40 mg/kg. Hypothermia is not observed even after treatment with 160 mg/kg. The ED50 (with confidence limits), which reduces fever below 39 degrees C in 50% of the animals, at the time of peak hyperthermia is 10.0 (6.6--15.2) mg/kg. ED50's of simultaneously studied reference compounds are 5.7 (3.9--8.3) mg/kg for indometacin, 38 (24--61) mg/kg for tolmetin, 76 (47--121) mg/kg for phenylburazone and 113 (75--170) mg/kg for acetyl-salicylic acid. Two to four times higher doses of these compounds restore normal body temperature but further increase of the dose induces hypothermia, which is particularly pronounced for acetyl-salicylic acid and phenylbutazone. Suprofen is a potent antipyretic agent, devoid of hypothermic activity even at 32 times the lowest effective dose.
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PMID:The antipyretic effect of suprofen in rats with yeast-induced fever. 124 33

The effects on body temperature of intracerebroventricular and intraperitoneal sodium salicylate were evaluated in anesthetized and nonanesthetized, nonrestrained rats. Also, the effects of various neurotransmitter receptor blocking drugs were evaluated on salicylate-induced hypothermia of nonanesthetized animals. Sodium salicylate, 150-350 mg/kg induced a dose-related hypothermia of unanesthetized animals. However, in anesthetized animals, marked hyperthermia was observed. In unanesthetized, unrestrained rats, intracerebroventricular administration of 1.0 mg/h salicylate caused greater hypothermia than peripheral administration of salicylate, 350 mg/kg. Salicylate hypothermia was unaffected by para-chlorophenylalanine, cyproheptadine, or naloxone, and was only partially inhibited by pimozide. These results strongly suggest a potent direct action of salicylate within the central nervous system to induce hypothermia, and suggest possible involvement of dopaminergic neurons in this process.
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PMID:Central and peripheral actions of salicylate in altering nonpyrogenic thermoregulation of rats. 288 3

To study the transport system of propranolol (PL), a basic drug, in the blood-brain barrier, the uptake of PL into isolated bovine brain microvessels was investigated. The uptake of PL was a concentrative one via saturable process (Km = 42.5 microM) that was decreased by hypothermia (Q10 = 2.2), but not by metabolic inhibitors (2,4-dinitrophenol, KCN, ouabain). Although basic drugs such as quinidine and imipramine decreased both the initial rate of uptake and the steady-state cell-to-medium concentration ratio (C/M) of PL, acidic drugs (phenobarbital, salicylic acid) did not affect them. These results suggest that PL is taken up by the endothelial cells of the isolated brain microvessels by facilitated diffusion which is specific for basic drugs and then binds to certain binding sites in the cells.
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PMID:Uptake of propranolol by microvessels isolated from bovine brain. 343 Mar 39

To characterize the transport system of cimetidine, an organic cation, in the blood-cerebrospinal fluid barrier, the accumulation of cimetidine by the isolated rat choroid plexus was examined. Accumulation of cimetidine was against a concentration gradient via a saturable process (Km = 53 microM, Vmax = 12 nmol/ml/min) that was inhibited by sulfhydryl reagents (p-hydroxymercuribenzoate), metabolic inhibitors (KCN and 2,4-dinitrophenol) and hypothermia (Q10 = 4.5), but did not require inward Na+ gradient. Organic cations such as 1N-methylnicotinamide, tetraethylammonium, choline, histamine and creatinine did not affect the accumulation of cimetidine at the concentration of 1 mM. Cimetidine did not affect the accumulation of tetraethylammonium. More lipophilic cations such as quinidine and quinine inhibited not only the accumulation of cimetidine but also that of an organic anion, benzylpenicillin, although the inhibitory mechanisms are not known. One millimolar of organic anions, such as 5-hydroxyindoleacetic acid, p-aminohippuric acid, homovanillic acid, salicylic acid and benzylpenicillin, inhibited the accumulation of cimetidine. Furthermore, the accumulation of organic anions (benzylpenicillin and salicylic acid) showed saturability and was inhibited by cimetidine. Cimetidine and the organic anions thus showed a mutual inhibition. Oligopeptides also inhibited the accumulation of cimetidine. These findings suggested that cimetidine transport in the choroid plexus is via carrier-mediated active transport process, but does not require inward Na+ gradient. This transport is inhibited by several compounds with different properties like oligopeptides, lipophilic cations and organic anions, although the inhibitory mechanism is not known.
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PMID:Transport of cimetidine by the rat choroid plexus in vitro. 379 52

The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. 783 34

1. Administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine. 2. MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg(-1) (3 h apart) producing a 70% loss. 3. Pretreatment 30 min before each MDMA dose with either of the N-methyl-D-aspartate antagonists AR-R15896AR (20, 5, 5 mg kg(-1)) or MK-801 (0.5 mg kg(-1)x3) failed to provide neuroprotection. 4. Pretreatment with clomethiazole (50 mg kg(-1)x3) was similarly ineffective in protecting against MDMA-induced dopamine loss. 5. The free radical trapping compound PBN (150 mg kg(-1)x3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature. 6. Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg(-1)x3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg(-1)x3) and AR-R17477AR (5 mg kg(-1)x3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia. 7. MDMA (20 mg kg(-1)) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue-damaging peroxynitrites.
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PMID:A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') on dopamine neurones in mouse brain. 1173 48