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)

A review of the clinical efficacy of four structurally distinct antidepressant drugs is presented. Their antidepressant activity can be rationalised within current pharmacological hypotheses of drug action, despite markedly different effects on "in vitro" testing. Fluoxetine, a specific serotonin re-uptake inhibitor, has proven safe, effective treatment for depressive illness and may have a role to play in the treatment of obsessive-compulsive disorder and panic attacks. While it has few of the anticholinergic side effects of the tricyclic antidepressants, nausea, tremor, headache, weight loss, nervousness and sweating are side effects most frequently reported. Minaprine, a compound with weak MAO inhibiting properties and effects on serotonergic receptors, has clinical efficacy in the treatment of depression based on several comparative studies. It is claimed that minaprine lacks anticholinergic and sedative properties. Moclobemide, a specific, reversible inhibitor of MAO-A, has been extensively evaluated in depressive illness. The major advantage of this agent over other irreversible, non-specific MAO inhibitors, is the significant attenuation of the so-called "cheese effect" with doses of tyramine likely to be encountered in foodstuffs. Rolipram, a phosphodiesterase inhibitor, represents a new approach to antidepressant treatment. Limited clinical data suggest that the drug may be an effective antidepressant with few side effects. The place of these agents in therapy is yet to be established.
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PMID:New pharmacological approaches to the management of depression: from theory to clinical practice. 158 Aug 88

A method is described for studying platelet function in human whole blood immediately after venepuncture in order to evaluate the antithrombotic potential of new pharmacological agents. In this method, platelet aggregation is quantified by measuring the fall in single platelet count, by using a whole blood platelet counter. We have investigated the platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 (reported to be Ca++ sensitisers and phosphodiesterase inhibitors), alone and in combination with dipyridamole. Venous blood was drawn directly into prewarmed (37 degrees C) plastic syringes containing anticoagulants (3.2% trisodium citrate solution) plus a platelet aggregation inhibitor. Spontaneous platelet aggregation (SPA) was studied by roller mixing aliquots of blood in the collecting syringes for 6 min at 37 degrees C. Collagen induced platelet aggregation was studied by incubating aliquots of blood with 1 microgram/ml collagen on a shaking water bath for 3 min. In the absence of an inhibitor, there was a 50% fall in single platelet count due to SPA and a 65% fall was induced by collagen. Both SPA and collagen induced aggregation responses were inhibited by pimobendan (0.5-10 microM) and UD CG 212 (0.5-10 microM), in a dose dependent manner. A combination of 10 microM dipyridamole with 2 microM pimobendan or UD CG 212 was markedly a more effective inhibitor of platelet aggregation than a high dose of either inhibitor alone. It is suggested that the present method is simple and rapid, with minimal sample processing, and therefore the results may be protected from serious artifacts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 in whole blood. 259 Sep 3

Extracellular adenosine 3',5'-cyclic monophosphate (cAMP) is required for cell-type-specific gene expression in developing Dictyostelium discoideum. We have developed a microassay for the expression of these genes, using antibodies directed against their protein products. To characterize the transduction mechanism, we have used in this assay cAMP analogues that preferentially activate either the cell-surface cAMP receptor or the internal cAMP-dependent protein kinase. N6-(aminohexyl) cAMP activates the Dictyostelium cAMP-dependent protein kinase but does not bind to the cell-surface cAMP receptor and does not cause cell-type-specific gene expression. 2'-Deoxy-cAMP does not activate the cAMP-dependent protein kinase but binds to the receptor and causes cell-type-specific gene expression. Cyclic AMP-induced accumulation of prestalk mRNA in shaking cultures still occurs in the presence of caffeine, which blocks the receptor-coupled activation of adenyl cyclase. This suggests that the extracellular cAMP induction of cell-type-specific gene expression in developing Dictyostelium cells is mediated by the cell-surface cAMP receptor and that activating adenyl cyclase by this receptor is not essential. Using the N6-(aminohexyl) cAMP to competitively inhibit phosphodiesterase, we show that 30 nM cAMP is sufficient to induce prestalk or prespore gene expression.
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PMID:cAMP induction of prespore and prestalk gene expression in Dictyostelium is mediated by the cell-surface cAMP receptor. 302 99

The efficacy of the selective adenosine cyclic 3',5'-monophosphate (cAMP) phosphodiesterase (PDE) inhibitor (+/-)-rolipram and its optical isomers (0.006 to 25 mg kg-1) in inducing characteristic behavioural changes like hypothermia, hypoactivity, forepaw shaking, grooming and head twitches in rats has been examined. (+)-Rolipram was found some 15 times less potent than the racemate suggesting a stereoselective interaction with a rat brain cAMP phosphodiesterase isoenzyme. Following their intracerebral administration, the stereoisomers also demonstrated their unusual potency ratio. These findings suggested that (+)-rolipram is a less potent neurotropic PDE inhibitor in-vivo than its (-)-enantiomer.
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PMID:Neurotropic effects of the optical isomers of the selective adenosine cyclic 3',5'-monophosphate phosphodiesterase inhibitor rolipram in rats in-vivo. 613 85

The significance of a characteristic symptomatology (hypothermia, hypoactivity, forepaw shaking, grooming, head twitches) as a potential in vivo correlate of enhanced availability of brain adenosine cyclic 3',5'-monophosphate (cAMP) was examined in rats following systemic administration of various doses of dibutyryladenosine cAMP (dBcAMP) or of the phosphodiesterase (PDE) inhibitors rolipram, Ro 20-1724, ICI 63-197, isobutylmethylxanthine (IBMX) theophylline, cartazolate, and papaverine. The various PDE inhibitors could be assigned to three groups according to the pattern of behavioral alterations they induced. Rolipram, Ro 20-1724, and ICI 63-197 (group 1) caused hypothermia, hypoactivity, forepaw shaking, grooming, and head twitches. All behavioral effects were mimicked by dBcAMP but not dBcGMP. The order of potency and effective dosage range to induce the behavioral alterations were, in descending order, rolipram (0.09-1453 mumol/kg IP), ICI 63-197 (0.48-119 mumol/kg IP), Ro 20-1724 (5.6-1438 mumol/kg IP), corresponding with the recently reported efficacy of the drugs to elevate rat brain cAMP in vivo. Comparatively high doses of the alkylxanthine PDE inhibitors IBMX and theophylline (group 2) caused hypothermia, forepaw shaking, grooming, and head twitches concomitantly with a decline of the motor stimulatory effect, suggesting enhanced availability of brain cAMP. The order of potency and the effective dosage range to induce the behavioral alterations were, in descending order, IBMX (28.1-113 mumol/kg IP) and theophylline (139-555 mumol/kg IP). The third group, papaverine (295-1179 mumol/kg IP) and cartazolate (21.5-345 mumol/kg IP), caused only hypothermia and hypoactivity. The differences in the behavioral pattern of the two latter groups of compounds in comparison with dBcAMP and the selective cAMP PDE inhibitors are discussed with regard to their additional interference with adenosine actions besides their nonselective PDE inhibitory action.
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PMID:Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3', 5'-monophosphate phosphodiesterase inhibitors. 618 75

The effect of the phosphodiesterase (PDE) inhibitors rolipram, Ro 20-1724 and isobutylmethylxanthine (IBMX) on motor behaviour and rectal temperature was studied in mice, rats and guinea pigs following intraperitoneal administration (0.39 to 25 mg/kg). The selective adenosine cyclic 3',5'-monophosphate (cAMP) PDE inhibitors rolipram and Ro 20-1724 in each species caused a dissimilar pattern of neurotropic effects: Hypothermia and hypokinesia in mice, hypothermia, hypokinesia and head twitches in rats, hypothermia, hyperkinesia and head twitches in guinea pigs. The head twitches were associated with forepaw shaking and increased grooming. Rolipram was the most potent compound in the three species. In guinea pigs it was less active than in rats or mice. Ro 20-1724 was approx. 15 to 30 times less potent in inducing the characteristic alterations in the various species. The alkylxanthine PDE inhibitor IBMX, 0.39 to 6.25 mg/kg, slightly stimulated the locomotor activity of mice and rats, most probably due to antagonism of central adenosine actions. IBMX, 6.25 to 25 mg/kg, caused a pattern of neurotropic effects identical to that produced by the selective cAMP PDE inhibitors, indicating the prevalence of the cAMP PDE inhibitory action over the adenosine antagonistic action at higher dosages. IBMX was approx. as potent as Ro 20-1724 in this respect. The species differences in the neurotropic responses to cAMP PDE inhibition in vivo presumably reflect similar differences in the extent of cAMP accumulation in brain tissue of the three species in vitro. Enhanced availability of brain cAMP in vivo in the various rodent species seems to be correlated with diverse patterns of more or less complex motor behavioural symptoms.
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PMID:Species differences in behavioural effects of rolipram and other adenosine cyclic 3H, 5H-monophosphate phosphodiesterase inhibitors. 619 Sep 91

Phosphorylated proteins may play an important role in regulating the metabolism or function of rod photoreceptors. In mammalian retinas, a photoreceptor protein of 33 000 (33K) molecular weight is phosphorylated in a cyclic nucleotide dependent manner in vitro. Since light initiates the activation of a photoreceptor-specific phosphodiesterase and a rapid reduction in guanosine cyclic 3',5'-phosphate concentration, phosphorylation of the 33K protein may be modulated by light in situ. In order to test this possibility, dark-adapted rat retinas were incubated for 30 min in the dark in phosphate-free Kreb's buffer containing [32P]orthophosphate. Following incubation, rod outer segments were detached by shaking, and the 32P-labeled rod outer segment proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, detected by autoradiography, and quantitated by densitometric scanning. The incorporation of radioactivity (32P) into the 33K protein was higher than into any other rod outer segment protein, and the amount of 32P-labeled 33K protein in the detached rod outer segments remained unchanged during 10 additional min of darkness. The addition of isobutylmethylxanthine to the incubation medium enhanced the incorporation of 32P into 33K protein to about 400% of the original level. Exposure of freshly detached rod outer segments to room light for 90 s decreased the amount of labeled 33K protein to 45% of its original level. The dephosphorylation of labeled 33K protein continued, reaching 12% of the original dark value 10 min after the previously illuminated sample was returned to darkness. Light initiated the phosphorylation of rhodopsin, and rhodopsin phosphorylation continued during the postillumination period of darkness.
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PMID:Light-induced dephosphorylation of a 33K protein in rod outer segments of rat retina. 620 20

We studied the effect of posture on the sympathoadrenal response to intravenous theophylline in six normal subjects. On three separate occasions they received an intravenous infusion of either theophylline (6 mg/kg) while supine, theophylline (6 mg/kg) while standing or saline as placebo while standing. With the subjects standing theophylline caused tremor, a peak heart rate of 99 +/- 6 beats/min, and an elevation of plasma cyclic AMP from 9.3 +/- 0.7 to 15.1 +/- 1.7 nmol/1 (mean +/- s.e. mean). There was a small, but significant, elevation of plasma adrenaline, noradrenaline and glucose. The elevation in plasma catecholamines was insufficient to explain either the sympathomimetic effects of theophylline or the rise in plasma cyclic AMP. Theophylline had little or no effect with the subjects supine. The mean peak theophylline concentration following infusion was significantly higher with the subjects upright than when supine (18.3 c.f. 12.4 mg/l, P less than 0.025). However, adequate plasma levels of theophylline were obtained in all subjects when lying or supine. Analysis of individual data suggests that differences in plasma levels of theophylline are unlikely to account for the increased effects seen on standing. The mechanism of action of theophylline cannot be explained by increased secretion of catecholamines alone. Theophylline appears to amplify the increased sympathetic activity associated with standing and this is probably by phosphodiesterase inhibition.
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PMID:The effect of posture on the sympathoadrenal response to theophylline infusion. 631 28

The drug UM 1046 (N-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazoc ine), administered to opiate-naive monkeys, produces certain behavioral responses resembling antagonist-precipitated morphine withdrawal (Swain and Seevers, 1975). In the present study, UM 1046 (5.6 mg/kg, i.v.), administered to naive rats, produced a syndrome that consisted primarily of retching, chewing, teeth chattering, shaking and abnormal postures. It was of interest to determine whether UM 1046 had an effect on noradrenergic neurons of the locus coeruleus (NE-LC) since increased activity of these cells has been reported to occur during antagonist-precipitated opiate withdrawal (Aghajanian, 1978) and after the administration of drugs that mimic this syndrome in normal animals. (i.e. methylxanthine phosphodiesterase inhibitors, Grant and Redmond, 1981). In the present study, UM 1046 (1.0-5.6 mg/kg, i.v.) caused a dose-dependent increase (of up to 200%) in the spontaneous discharge rate of noradrenergic neurons of the locus coeruleus in rats anesthetized with halothane. The time-course of this effect was similar to the time-course of the behavioral syndrome described above. Stimulation of central muscarinic receptors is integrally involved in the response to this drug since the effects of UM 1046 (5.6 mg/kg) were antagonized by scopolamine (0.5 mg/kg, i.v.), but not by methylscopolamine (1.0 mg/kg, i.v.). Unlike systemic administration, iontophoretic application of UM 1046 did not consistently increase the spontaneous discharge rate of these cells, indicating that the site of action of the drug may be outside the nucleus locus coeruleus. This study complements previous findings of increased activity in noradrenergic neurons of the locus coeruleus during withdrawal-like behavior. In addition, the results are compatible with others which suggest that a cholinergic link is essential for the withdrawal-like actions of the benzazocine.
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PMID:Activation of locus coeruleus neurons in the rat by a benzazocine derivative (UM 1046) that mimics opiate withdrawal. 668 52

The shaking pup, a canine mutant, carries a point mutation in the myelin proteolipid protein (PLP) gene that causes dysmyelination of the central nervous system (CNS) with resultant tremor, seizures, and other persistent neurological deficits. The developmental potential of glial cells in the shaking pup CNS and peripheral nervous system (PNS) was evaluated by quantitative analysis of the expression of several glial-specific genes. All of the myelin-associated genes demonstrated developmental patterns of expression similar to those observed in the controls, but at significantly reduced levels. Expression of the genes for the major CNS myelin proteins, PLP and the myelin basic protein, are most dramatically affected in the shaking pup, although reduced expression levels are observed for other oligodendrocyte-specific genes such as 2',3'-cyclic nucleotide 3'phosphodiesterase and glucose phosphate dehydrogenase. The pattern of gene expression in the shaking pup indicates that the oligodendrocytes experience an inhibition in development after the myelination program has begun. There appears to be little evidence for an astrocytic response to the dysmyelinating condition at the RNA level, but we present evidence for ectopic expression of P0 mRNA in the CNS. Expression of the P0 and PLP genes in the sciatic nerve appears to be normal, reinforcing previous reports that PNS myelination is unaffected by the mutation in the PLP gene.
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PMID:Molecular analysis of glial cell development in the canine 'shaking pup' mutant. 889 46


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