Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tremorogenic properties of a series of benzylimidoylurea derivatives are described. The most potent member, N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954), produces a reproducible, dose-dependent rest tremor in the mouse with oral doses of 5-100 mg/kg which is also seen in other species (rat, cat, dog, rabbit). The tremor is of constant frequency, rapid onset and short duration. It is not accompanied by akinesia, muscle ridigity, antinociceptive activity, parasympathomimetic effects or marked hypothermia and in these respects differs from tremor produced by oxotremorine. Pretreatment with a microsomal enzyme inhibitor had no effect on the tremor. An LD50 of 165 mg/kg p.o. was calculated in the mouse. After repeated administration both acute and chronic tolerance developed to the tremorogenic effects of LON-954. Evidence for a central site of action is presented, since the tremor could be reproduced following injection of small quantities (50-100 microgram) into the cerebral ventricles of the mouse. Furthermore, the use of spinal, decorticate and and decerebrate rats indicated that although tremor is not of cortical origin, it arises in an area rostral to the inferior colliculi. The mechanism underlying the tremor appears to involve dopaminergic pathways, since the action of LON-954 was antagonised by L-dopa and apomorphine and potentiated by pimozide. Atropine and carbachol were without effect. It is suggested that LON-954 could be used as an alternative to oxotremorine for the detection of anti-Parkinson drugs, particularly those exerting their effects through dopaminergic mechanisms.
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PMID:The pharmacology of N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride (LON-954) a new tremorogenic agent. 58 44

Carbaryl (50-200 mg/kg, p.o.) produced dose-dependent tremors and inhibition of striatal AChE activity. A dose-dependent elevation of striatal 5-HT and 5-HIAA levels was also observed with carbaryl but at the higher doses (100-200 mg/kg p.o.). L-Trp or 5-HTP or haloperidol potentiated the carbaryl-induced tremors. Further, 5-HTP or haloperidol, when administered (i) alone, reduced the ED50 value and increased the duration of carbaryl-induced tremors without affecting the maximum tremorogenic response of rats and (ii) together, did not change any of these measures significantly. Atropine (acetylcholine antagonist) completely blocked the tremors produced by carbaryl in the absence or presence of 5-HTP or haloperidol. Methysergide (5-HT antagonist) and bromocriptine (DA agonist) antagonised the potentiating effect of 5-HTP and haloperidol, respectively, on the carbaryl-induced tremors. Furthermore, bromocriptine antagonised the potentiating effect of 5-HTP on the carbaryl-induced tremor but, methysergide failed to achieve this antagonism in presence of haloperidol. These results indicate that carbaryl-induced tremors primarily involve the activation of central cholinoceptors and that the serotonergic potentiation of carbaryl-induced tremors is possibly mediated through the dopaminergic disinhibition of cholinergic neurons.
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PMID:Interaction of central serotonin and dopamine in the regulation of carbaryl-induced tremor. 169 44

The purported alpha 2-adrenergic agonist clonidine was found to inhibit rest tremor at doses of 0.023-0.1 mg/kg in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of parkinsonism. The effect was dose dependent, but sedation and reduced mobility were observed. Atropine at doses of 0.1-1 mg/kg also reduced tremor in a dose-dependent fashion, but side-effects in the form of agitation, dilated pupils, and dry mouth were seen. When the two drugs were combined, however, we saw a significant potentiation of the antitremor effect. We could even abolish tremor with doses of atropine and clonidine that by themselves were without effect. The side-effects were almost eliminated by the combination.
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PMID:Effect of clonidine and atropine on rest tremor in the MPTP monkey model of parkinsonism. 191 2

The enantiomers of the oxotremorine analog N-[4-(2-chloromethylpyrrolidine)-2-butynyl]-2-pyrrolidone (BM 130) were synthesized. The LD50 values of (+)- and (-)-BM 130 in mice (i.v.) were 10.4 +/- 1.4 and 13.5 +/- 1.9 mumol/kg, respectively. Atropine and N-methylatropine poorly protected against the lethal effects, suggesting that they were nonmuscarinic in nature. When administered i.v. to mice, (+)- and (-)-BM 130 were equipotent in producing peripheral and central muscarinic effects. ED50 values were 1.3 to 1.4, 2.8 to 3.2 and 0.20 to 0.26 mumol/kg, respectively, for salivation, tremor and analgesia (tail-flick assay). After i.p. injection, tremor was not observed and analgesic potency was reduced more than 10-fold compared to the i.v. route. The aziridinium ions [(+)- and (-)-BM 130A], formed by spontaneous cyclization of (+)- and (-)-BM 130, were virtually equipotent in eliciting contractions of the isolated guinea pig ileum and in causing salivation in mice. Their LD50 values in mice (i.v.) were 1.1 +/- 0.2 and 2.1 +/- 0.3 mumol/kg, respectively. The enantiomers of BM 130A had similar affinity for muscarinic receptors in the rat cerebral cortex as measured by competitive inhibition of (-)-[3H]N-methylscopolamine binding at 0 degrees C. The rate constants for alkylation of muscarinic receptors, obtained at 37 degrees C by measuring the decline in (-)-[3H]-3-quinuclidinyl benzilate binding to cortical homogenates that had been treated with various concentrations of (+)- and (-)-BM 130A for 20, 45 or 90 min, differed significantly for the two enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic actions and receptor binding of the enantiomers of BM 130, an alkylating analog of oxotremorine. 270 31

Propranolol in low doses antagonized and in higher doses facilitated oxotremorine-induced tremor (Oxo-tremor) in mice. Atropine blocked Oxo-tremor, an effect that was reversed by propranolol. Atropine pretreatment also antagonized the potentiating effect of propranolol on Oxo-tremor. Propranolol inhibited mice brain cholinesterase at doses which enhanced Oxo-tremor. Timolol and sotalol produced a dose-dependent antagonism of Oxo-tremor, whereas practolol failed to produce a similar effect. None of these three agents produced any significant enhancement of Oxo-tremor. These results suggest the involvement of a peripheral mechanism for the antagonism and a central cholinergic mechanism for the facilitation of Oxo-tremor by propranolol.
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PMID:Cholinergic involvement in the modulation of oxotremorine-tremor in mice by propranolol. 286 35

Alaproclate (10-60 mg/kg) injected i.p. into male mice potentiated and prolonged the oxotremorine and physostigmine-induced tremor in a dose-dependent manner. Atropine completely blocked the tremor caused by oxotremorine or physostigmine both in the presence and absence of alaproclate. Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate. Biochemical studies indicated that the above effects cannot be explained by assuming that alaproclate a) acts as a cholinergic agonist, b) inhibits the acetylcholine esterase, c) interferes with choline uptake or acetylcholine synthesis, or d) directly potentiates the release of acetylcholine. In ligand binding studies alaproclate was found to be a weak competitive inhibitor of muscarinic antagonist binding to membranes from the rat cerebral cortex, rat striatum, human cerebral cortex and human striatum. (Ki approximately 28-40 microM in all four tissues). The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the muscarinic cholinergic receptors.
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PMID:In vivo and in vitro studies on the potentiation of muscarinic receptor stimulation by alaproclate, a selective 5-HT uptake blocker. 298 30

Atropine, a postsynaptic muscarinic antagonist, and clonidine, a presynaptic inhibitor of acetylcholine release, protect mice from the lethal effects of soman, a potent and irreversible cholinesterase inhibitor. The purpose of this study was to determine the effects of atropine (6 mg/kg) and clonidine (0.2 mg/kg) on soman-induced lethality and behavioral changes in the rat. Soman produced a dose-dependent increase in lethality over a narrow concentration range (50-200 micrograms/kg, SC). Soman produced time- and dose-dependent increases in tremor, salivation, hind limb extension, convulsions and chewing behaviors, as well as decreases in three normal stereotyped behaviors, sniffing, locomotion and rearing. Atropine and clonidine were equally effective at limiting soman-induced lethality and behavioral changes. The protective effects of clonidine and atropine were synergistic, even though clonidine antagonizes some of the stereotyped behaviors elicited by atropine. Simultaneous pretreatment with clonidine and atropine completely eliminated the lethality and behavioral changes produced by injection of 200 micrograms/kg soman.
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PMID:Behavioral effects of toxic doses of soman, an organophosphate cholinesterase inhibitor, in the rat: protection afforded by clonidine. 336 26

The mycotoxins cyclopiazonic acid (CPA) and ergotamine, and the neurotransmitter serotonin all have the beta-aminoethylindole moiety in common. These compounds enhanced the peristaltic movements of the jejunum, ileum and estrous uterus and produced broncho-constriction in vitro. Atropine and cyproheptadine were able to counter the CPA-induced peristaltic movements of the ileum and jejunum. L-epinephrine was able to stop the contractions induced by CPA on both estrous and pregnant rat uteri. Unlike chlorpromazine, CPA did not block the inotropic effects of dopamine, epinephrine and serotonin in vas deferens. This indicated that the previously reported toxic effects of CPA (hypothermia, catalepsy, hypokinesia, tremor) which resembled the effects of anti-psychotic drugs (chlorpromazine, reserpine) probably were not due to the blocking of the neurotransmitter-receptors. In contrast to ergotamine, which decreased the inotropic effects of serotonin on the uterus, CPA had no anti-serotonin effects. The uterotonic effect of CPA (similar to that of ergotamine) suggested that CPA also might have an adverse effect on the reproductive function of humans and animals consuming CPA-contaminated foods.
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PMID:Effects of cyclopiazonic acid on the contractility of organs with smooth muscles, and on frog ventricles. 348 54

The ability of various treatments to prevent peripheral parasympathetic actions, central effects and lethality of the muscarinic agonist oxotremorine was studied in rats. The percentage of animals exhibiting effects of oxotremorine was dose and time dependent. The ED50 for producing lacrimation, salivation, tremor, convulsions and death was 2.5, 1.3, 1.6, 3.2 and 8.3 mg/kg i.p., respectively. Pretreatment with 5 mg/kg of atropine completely prevented all observable effects of oxotremorine at doses of 5 mg/kg and below. Doses of oxotremorine in excess of 5 mg/kg produced tremor, generalized clonic convulsions and death that could not be prevented by atropine when given at up to 160 mg/kg; lacrimation and salivation were not present in atropine-treated rats. In the presence of 40 mg/kg of atropine, ED50 values for oxotremorine were shifted more than 12-fold for lacrimation, salivation and tremor, whereas convulsions and death were maximally altered by a factor of 2. Scopolamine, benactyzine and benztropine were also incapable of completely preventing tremor, convulsions and death induced by 10 or 15 mg/kg of oxotremorine. Atropine methyl nitrate had effects comparable to atropine sulfate on lacrimation, salivation and lethality induced by oxotremorine (10 or 15 mg/kg) but had no effect on tremor or convulsions. A similar profile of atropine-insensitive effects was produced by pilocarpine and arecoline. Doses of diazepam 4 times higher (4 mg/kg) than necessary to prevent tonic-clonic convulsions induced by pentylenetetrazol were ineffective against tremor, convulsions or death produced by oxotremorine (10 or 15 mg/kg) unless given in conjunction with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nonmuscarinic neurotoxicity of oxotremorine. 357 94

The effect on behavior of eight anticholinergic agents: atropine, scopolamine, trihexyphenidyl, biperiden, homatropine, eucatropine, hexocyclium and propantheline, injected into the cerebral ventricle (ICV) of the cat was investigated and compared. The anticholinergic agents evoked: (1) psychomotor stimulation such as miaowing, loud calling, restlessness, impelling locomotion, jumping, vacant staring, apprehension and loss of interest of the surroundings; (2) aggression, hissing, threat, attack, defense, fighting with paws and flight; (3) autonomic responses including mydriasis, tachypnea, dyspnea, licking, vomiting, salivation, micturition and defection; and (4) motor phenomena comprising scratching, ataxia, rigidity, tremor, weakness with adynamia or myoclonic jerks. Convulsions appeared only after ICV injections of atropine and homatropine. The most characteristic behavioral effect of anticholinergic agents was psychomotor stimulation accompanied by mild aggressive responses. The only exception was propantheline which caused a muscular weakness and adynamia. Atropine and scopolamine alone induced a dose-dependent impelling locomotion as well as fighting behavior. Carbachol and eserine injected intracerebroventricularly reversed the locomotion autonomic and motor phenomena produced by anticholinergic agents administered similarly. It is suggested that anticholinergic agents acting as partial agonists, can produce their behavioral effects through central cholinoceptive sites.
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PMID:Comparative behavioral effects of anticholinergic agents in cats: psychomotor stimulation and aggression. 370 93


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