piperidines and Tremor

It is generally accepted that patients with a tremor-dominant type of idiopathic Parkinson's disease progress more slowly than the ones with the rigid-akinetic type. On the other hand successful treatment of Parkinsonian tremor is a challenge. German neurologists use anticholinergics, budipine, beta-blockers, clozapine, dopaminergic substances and for most severe cases deep brain stimulation. Budipine is an enigma because its main mode of action is still unknown, although it is mostly listed under glutamate antagonists. There is however no other anti-Parkinsonian drug available with such a broad spectrum of action as shown for budipine. Budipine has been studied in open and double-blind studies as monotherapy and adjunct therapy. In both instances the drug showed beneficial effects to the patients. It may well be that the non-dopaminergic mode of action of budipine is helpful even for patients who are on stable medication. When 3 years ago reports on budipine-induced prolongation of the QT interval in the ECG emerged larger trials were stopped and nowadays there are strict rules on how to use budipine. Nonetheless, budipine in our hands is a most useful and safe drug to treat tremor and other main symptoms of Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Humans; Parkinson Disease; Piperidines; Tremor

Topics: Amiodarone; Angina Pectoris; Benzofurans; Cerebrospinal Fluid Proteins; Electromyography; Humans; Inclusion Bodies; Lipid Metabolism; Microscopy, Electron; Movement Disorders; Muscles; Nervous System Diseases; Paresthesia; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Pigments, Biological; Piperidines; Polyradiculoneuropathy; Schwann Cells; Skin; Tremor

Topics: Absorption; Administration, Oral; Aerosols; Albuterol; Animals; Asthma; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Half-Life; Hemodynamics; Humans; In Vitro Techniques; Injections, Intravenous; Isoproterenol; Kinetics; Muscle Contraction; Myocardial Contraction; Organ Specificity; Piperidines; Terbutaline; Tremor

In order to objectively quantify the tremorlytic activity of budipine in Parkinson's disease (PD) we performed longterm tremor recordings in a subset of patients enrolled in two clinical trials. Eleven PD patients with marked tremor participating in an open-label study underwent longterm recording before and during medication. Nine patients completed the study. Tremor occurrence was reduced from 52 +/- 18.6% to 34.7 +/- 19.3% (p < 0.05); tremor intensity decreased from 15.3 +/- 4.8 (SNR) to 11.3 +/- 4.8 (p < 0.01). UPDRS tremor subscores were also significantly improved. Fourteen patients who enrolled in a multicenter, double-blind, placebo-controlled study underwent longterm tremor analysis in addition to the Columbia University Rating Scale (CURS). Tremor occurrence was improved in the budipine group (n = 7) from 24.7 +/- 15.5% to 14.8 +/- 14.5% (p < 0.05). Tremor intensity decreased from 9.1 +/- 2.5 (SNR) to 7.2 +/- 1.6. However, the latter result was statistically not significant, probably due to the small patient number. In the placebo-group (n = 7) there was no reduction of tremor occurrence or of tremor intensity. The CURS sum score was improved from 5.7 to 3.0 in the budipine group, whereas there was only a smaller improvement in the placebo group (from 7.1 to 5.5). These data suggest that budipine is an effective tremorlytic agent in PD, which may be used as an alternative to anticholinergics.

Topics: Aged; Antiparkinson Agents; Double-Blind Method; Electromyography; Female; Humans; Levodopa; Male; Parkinson Disease; Piperidines; Tremor

The tremorlytic activity of the novel antiparkinson agent budipine was quantified in an open trial. Eleven patients with Parkinson's disease (PD) were treated with individual doses of budipine added to stable conventional antiparkinsonian medication. Tremor activity was measured using long-term electromyogram (EMG) recordings. Tremor intensity was reduced by 25%, tremor occurrence by 34%, and conventional "Unified Parkinson's Disease Rating Scale" (UPDRS) scores improved by 20% with this medication. There were two dropouts because of side effects. One dropout appeared not to be related to budipine. Apart from those, the drug was well tolerated by all patients. We conclude that budipine is an effective and well-tolerated tremorlytic drug and that the method of long-term EMG recording is suitable for tremor quantification in clinical studies.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Electromyography; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Piperidines; Time Factors; Tremor

Topics: Absorption; Administration, Oral; Aerosols; Albuterol; Animals; Asthma; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Half-Life; Hemodynamics; Humans; In Vitro Techniques; Injections, Intravenous; Isoproterenol; Kinetics; Muscle Contraction; Myocardial Contraction; Organ Specificity; Piperidines; Terbutaline; Tremor

The bronchodilating efficacy and the degree of beta2-selectivity of rimiterol, salbutamol and isoprenaline were determined in seven asthmatic patients. Rimiterol, 0.5 (high dose) and 0.05 mug/kg/min (low dose), salbutamol, 0.3 and 0.03 mug/kg/min, isoprenaline, 0.05 and 0.005 mug/kg/min, and placebo were administered by a single intravenous injection over 6 minutes in a double-blind trial. Airway resistance, heart rate, blood pressure and skeletal muscle tremor were measured before and at various times for 2 hours after each injection. The high doses of rimiterol (37%), salbutamol (37%) and isoprenaline (32%) produced immediate and effective bronchodilatation. The duration of action of rimiterol and isoprenaline was similar and shorter than that of salbutamol. For these ventilatory responses there were heart rate increases of 32, 20 and 40 beats/min for rimiterol, salbutamol and isoprenaline, respectively. The three drugs produced similar increases in pulse pressure and tremor. Dose-responses were obtained for each drug with all parameters measured and significant differences at various times found. Isoprenaline was approximately 8 and 5 times as potent as rimiterol and salbutamol, respectively, in bronchodilator action, when equimolar doses were compared. Similarly, isoprenaline was approximately 16 and 12 times as potent in increasing the heart rate as rimiterol and salbutamol, respectively. For an equal bronchodilator action, isoprenaline increased the heart rate 2 and 2.5 times more than rimiterol and salbutamol, respectively. Rimiterol is an effective, short-acting bronchodilator, with similar beta2-selectivity to salbutamol, when administered intravenously to asthmatic patients. The relative potencies and degrees of beta2-selectivity of these drugs depend partly on their route of administration.

Topics: Adrenergic beta-Agonists; Adult; Albuterol; Asthma; Blood Pressure; Bronchi; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Forced Expiratory Volume; Heart Rate; Humans; Isoproterenol; Male; Middle Aged; Piperidines; Placebos; Tremor; Vital Capacity

Topics: Aggression; Analysis of Variance; Arrhythmias, Cardiac; Basal Ganglia Diseases; Benzoates; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Handwriting; Humans; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Statistics as Topic; Tranquilizing Agents; Tremor

Topics: Adolescent; Adult; Antipsychotic Agents; Catatonia; Chlorpromazine; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Injections; Male; Methotrimeprazine; Middle Aged; Palmitic Acids; Pilot Projects; Piperidines; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Sulfonamides; Time Factors; Tremor

Topics: Animals; Barbiturates; Humans; Mice; Parasympatholytics; Parkinson Disease, Postencephalitic; Piperidines; Tremor; Tremorine

Although the behavioral effects of acute and chronic exposure to cannabinoids have been extensively studied in mice, spontaneous withdrawal following exposure to cannabinoids has not been well characterized in this species. To address this issue, different groups of mice were treated for 5 days with saline, 20-36 mg/kg/day of the CB partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), or 0.06-0.1 mg/kg/day of the CB high-efficacy agonist AM2389. Initial studies assessed changes in observable behavior (paw tremors) that were scored from the recordings taken at 4 or 24 h after the last injection. Subsequently, radiotelemetry was used to continuously measure body temperature and locomotor activity before (baseline), during, and after the 5-day dosing regimens. Results show that increases in paw tremors occurred following 5-day exposure to AM2389 or Δ9-THC. In telemetry studies, acute AM2389 or THC decreased both temperature and activity. Rapid tolerance occurred to the hypothermic effects of the cannabinoids, whereas locomotor activity continued to be suppressed following each drug injection. In contrast, increases in locomotor activity were evident 12-72 h after discontinuing daily injections of either 0.06 or 0.1 mg/kg/day AM2389. Increases in locomotor activity were also noted in mice treated daily with 30 or 36, but not 20 mg/kg/day Δ9-THC; these effects were smaller and appeared later than effects seen in AM2389-treated mice. These results indicate that the discontinuation of daily treatment with a CB high-efficacy agonist will yield evidence of spontaneous withdrawal that may reflect prior dependence, and that the degree of cannabinoid dependence may vary in relation to the dose or efficacy of the agonist injected daily.

Topics: Animals; Cannabinoids; Dronabinol; Mice; Piperidines; Pyrazoles; Rimonabant; Tremor

Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A2A-CB1-D2 heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A2A-CB1-D2 receptor heteromers in the striatum of both naïve and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion, and assessed how receptor heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A2A-CB1-D2 receptor heteromers are present in the striatum of both naïve and HPD-rats. However, behavioral results indicated that the combined administration of A2A (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A2A receptor antagonist alone. These behavioral results prompted identification of heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the heteromer is lost following acute or chronic treatment with L-DOPA.

Topics: Adenosine A2 Receptor Antagonists; Animals; Antiparkinson Agents; Cannabinoid Receptor Antagonists; Cholinesterase Inhibitors; Corpus Striatum; Disease Models, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Functional Laterality; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Piperidines; Protein Binding; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Rimonabant; Tacrine; Time Factors; Tremor

Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C(max) of galantamine and prolonged t(1/2) (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

Topics: Aging; Animals; Biological Availability; Brain; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Dose-Response Relationship, Drug; Galantamine; Half-Life; Hypothermia; Indans; Male; Metabolic Clearance Rate; Piperidines; Random Allocation; Rats; Rats, Inbred Strains; Receptor, Muscarinic M2; Salivation; Tacrine; Tears; Tremor

Increasing evidence suggests that marijuana abstinence leads to clinically significant withdrawal symptoms in humans. In mouse models, following chronic treatment with delta9-tetrahydrocannabinol (THC), administration of the selective cannabinoid CB1 receptor antagonist SR141716 (rimonabant) elicited varying behavioral responses, depending on mouse strain and dosing regimen. In the present study, C57BL/6 mice were injected s.c. with THC (25 mg/kg) or vehicle twice daily for 4.5 days. SR141716 (15 mg/kg) was administrated i.p. 4 h following the last THC treatment. During a 2-h observation period immediately following the SR141716 challenge, the total locomotor, ambulatory and stereotypic activities of THC-treated mice were 4.1, 3.3, and 3.8 times those of vehicle-treated mice, respectively. The number of paw tremors elicited in THC-treated mice was 111+/-11 during the 45 min immediately following SR141716, whereas only 1.1+/-0.4 was associated with vehicle-treated animals. In contrast, the number of scratching bouts was higher in vehicle-treated (182+/-20) vs THC-treated (17+/-4) mice. The present study is the first to demonstrate hyperlocomotion as an explicit sign of THC abstinence in mice. Together with paw tremors, the two unambiguous withdrawal signs may permit highly quantitative investigation of THC abstinence in C57BL/6 mice and may facilitate investigation of the mechanisms involved via both pharmacological and genetic manipulations, and ultimately potential treatments for cannabis dependence.

Topics: Analysis of Variance; Animals; Dronabinol; Dyskinesia, Drug-Induced; Forelimb; Locomotion; Male; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Psychotropic Drugs; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome; Tremor

A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease.

Topics: Animals; Data Interpretation, Statistical; Dopamine Agents; Dyskinesia, Drug-Induced; Jaw; Levodopa; Macaca fascicularis; Male; MPTP Poisoning; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Tremor; Urea

Topics: Aged; Donepezil; Female; Humans; Indans; Jaw; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Tremor

(1) Three cholinesterase inhibitors are marketed in France for the treatment of Alzheimer's disease: donepezil, galantamine and rivastigmine. Tremor and dystonia are known adverse effects of cholinesterase inhibitors. (2) In patients with Parkinson's disease who have cognitive disorders, or in patients with Lewy body dementia, exacerbations of parkinsonism and tremor have been observed during treatment with cholinesterase inhibitors at normal doses. The disorders were reversible on withdrawal of the cholinesterase inhibitor. (3) Withdrawal of cholinesterase inhibitors should be considered if gait disorders, falls or parkinsonism occur or worsen during treatment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Dystonia; France; Galantamine; Humans; Indans; Lewy Body Disease; Parkinson Disease; Phenylcarbamates; Piperidines; Tremor

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Topics: Aged; Antidepressive Agents, Second-Generation; Ataxia; Atrophy; Brain; Cyclohexanols; Dementia; Dominance, Cerebral; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Carrier Screening; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Mood Disorders; Neurologic Examination; Neuropsychological Tests; Nootropic Agents; Piperidines; Tremor; Trinucleotide Repeats; Venlafaxine Hydrochloride

A patient with Parkinson's disease refused both anti-Parkinson medication and general anaesthesia. Low dose remifentanil infusion suppressed her otherwise severe tremor, and the operation was performed uneventfully under local anaesthesia.

Topics: Aged; Anesthesia, Local; Anesthetics, Intravenous; Cataract Extraction; Female; Humans; Infusions, Intravenous; Parkinson Disease; Piperidines; Remifentanil; Tremor

We evaluated the pharmacological profiles of (2R)-N-[1-(6- aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide(compound A), which is a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity. Compound A inhibited [(3)H]NMS binding to cloned human muscarinic m1, m2, m3, m4, and m5 receptors expressed in Chinese hamster ovary cells with K(i) values (nM) of 1.5, 540, 2.8, 15, and 7.7, respectively. In isolated rat tissues, compound A inhibited carbachol-induced responses with 540-fold selectivity for trachea (K(B) = 1.2 nM) over atria (K(B) = 650 nM). In in vivo rat assays, compound A inhibited acetylcholine-induced bronchoconstriction and bradycardia with intravenous ED(50) values of 0.022 mg/kg and >/=10 mg/kg, respectively. Furthermore, in dogs, compound A (0.1-1 mg/kg p.o.) dose dependently shifted the methacholine concentration-respiratory resistance curves. In mice, compound A (10 mg/kg i.v.) did not inhibit oxotremorine-induced tremor. The brain/plasma ratio (K(p)) of compound A (3 mg/kg i.v.) was 0.13 in rats; this K(p) was less than that of scopolamine (1.7) and darifenacin (0.24). The inhibition of compound A (3 mg/kg i.v.) on ex vivo binding in rat cerebral cortex was almost similar to that of NMS. These findings demonstrate that compound A has high selectivity for M(3) receptors over M(2) receptors, displays a potent, oral M(3) antagonistic activity without inhibition of central muscarinic receptors because of low brain penetration. It is well known that central muscarinic antagonists may have diverse CNS effects, and M(2) receptors regulate cardiac pacing and act as autoreceptors in the lung and bladder. Thus, compound A may have fewer cardiac or CNS side effects than nonselective compounds.

Topics: Animals; Benzeneacetamides; Brain; Bronchoconstriction; Heart Atria; Heart Rate; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Muscarinic Antagonists; Muscle, Smooth; Muscle, Smooth, Vascular; Piperidines; Pirenzepine; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptors, Muscarinic; Trachea; Tremor; Vas Deferens

Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.

Topics: Animals; Camphanes; Cannabinoids; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spasm; Tremor

There are now several acetylcholinesterase inhibitors in clinical use for the treatment of Alzheimer's disease, however, no systematic comparative studies of their central and peripheral cholinergic mediated effects in rats appear to have been reported. The present study investigated the dose-response characteristics of donepezil, tacrine, rivastigmine and metrifonate in inducing tremor, lacrimation, salivation and hypothermia and the duration of action of these compounds in Lister hooded rats. Data obtained were compared with the clinical observations on these drugs. Three doses of each compound were given orally to establish a dose-response curve for each behaviour, Tremor and lacrimation were scored, salivation was measured by weighing swabs applied to the mouth area and hypothermia was measured with a rectal probe. ED50 values were calculated for tremor. Using a just sub-maximal tremorigenic dose, the duration of response was examined. All four compounds produced dose-dependent increases in tremor and hypothermia. Only tacrine also produced marked salivation and lacrimation. The order of potency (ED50 value in micromol/kg) was rivastigmine (3.7), donepezil (18.0), tacrine (37.5), metrifonate (470). Tremor following tacrine (150 micromol/kg) and donepezil (20 micromol/kg) was prolonged (> 6 h) with a similar hypothermic response. The duration of these responses following metrifonate (777 micromol/kg) and rivastigmine (12.5 micromol/kg) did not exceed 3 h. Tacrine had poor selectivity for central (tremor) versus peripheral (salivation/lacrimation) effects compared to the other compounds. Donepezil also had a sustained duration of action. The data are consistent with clinical results and indicate that simple in-vivo models may assist in the selection of acetylcholinesterase inhibitors with a suitable response profile for use in the symptomatic treatment of Alzheimer's disease.

Topics: Animals; Body Temperature; Carbamates; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Hypothermia; Indans; Lacrimal Apparatus; Male; Phenylcarbamates; Piperidines; Rats; Rivastigmine; Saliva; Tacrine; Tremor; Trichlorfon

1. The involvement of the N-methyl-D-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3. The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally within 8 h of injection. 4. Pretreatment of the mice with dizocilpine (0.3 mg kg-1, i.p.) resulted in antagonism of the first phase of spermine-induced effects, but a higher dose (0.3 mg kg-1, (x2), i.p.) was necessary to inhibit the second phase effects. 5. Whereas the glutamate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (D-CPP) (10, 20 mg kg-1, i.p.), the glycine antagonist 7-chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg-1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6. Co-administration of ifenprodil with either D-CPP or 7-chlorokynurenate resulted in a dose-dependent antagonism of the development of the second phase of spermine-induced effects. 7. It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.

Topics: Animals; Brain; Cerebral Ventricles; Dizocilpine Maleate; Female; Kynurenic Acid; Mice; Neuroprotective Agents; Piperazines; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Tremor

Topics: Adult; Antipsychotic Agents; Female; Humans; Isoxazoles; Neuroleptic Malignant Syndrome; Piperidines; Primidone; Psychotic Disorders; Risperidone; Tremor

Cisapride, a substituted piperidinyl benzamide that is chemically related to metoclopramide, is a prokinetic agent that facilitates motility of the gastrointestinal tract (1). The mechanism by which cisapride exerts its actions is not clear. It enhances acetylcholine release in the myenteric plexus of the gut, and evidence exists that it has an agonistic action on a serotonin receptor, probably the 5-HT4 receptor (2). The drug is well tolerated, and no central nervous system side effects have been reported. We describe two patients with parkinsonism who experienced aggravation of tremor while on therapy with cisapride.

Topics: Aged; Anti-Ulcer Agents; Cisapride; Female; Humans; Parkinson Disease, Secondary; Piperidines; Tremor

The study attempted to verify whether activation of locus coeruleus neurons by alpha 2 antagonists might improve parkinsonian signs. Treatment with the racemic alpha 2 antagonist R 47 243 of a monkey with MPTP-induced parkinsonian signs normalized blink rate, reduced resting tremor, and improved several other parkinsonian signs. In a second experiment, the (-)-isomer R 62 651 produced a gradual change in tremor which was the inverse of the mannner in which tremor had become installed as the result of progression earlier upon the MPTP challenge. It is proposed that further research be conducted to determine whether alpha 2 antagonists may beneficially influence the progression of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adrenergic alpha-Antagonists; Animals; Blinking; Locus Coeruleus; Macaca fascicularis; Neurons; Parkinson Disease, Secondary; Piperidines; Thiazoles; Tremor

The effects of levocabastine (R 50 547; CAS 79516-68-0) on the central nervous system were studied in comparison with those of diphenhydramine, ketotifen and azelastine. At high doses, levocabastine caused a decrease in locomotor activity, prolongation of thiopental-induced sleep, depression of acetic acid-induced writhing in mice and inhibition of active avoidance response in rats, but these adverse effects were much less potent than those seen in diphenhydramine, ketotifen and azelastine. Oxotremorine-induced tremor and salivation in mice were delayed after extremely high dosage of levocabastine; however, these were much less effective than those seen after diphenhydramine and ketotifen. Levocabastine did not affect the tonic extensor seizure induced by maximal electroshock in mice which is different from that of diphenhydramine. In EEG analysis, levocabastine at a dose of 20 mg/kg caused no significant changes in the EEG recorded from the frontal cortex, occipital cortex, hippocampus and amygdala in rats with chronic electrodes.

Topics: Acetates; Animals; Avoidance Learning; Central Nervous System; Electroencephalography; Histamine H1 Antagonists; Male; Mice; Mice, Inbred Strains; Motor Activity; Oxotremorine; Pain; Piperidines; Rats; Rats, Inbred Strains; Salivation; Sleep; Thiopental; Tremor

The severity of anaemic decerebrate rigidity was quantitatively determined by measuring the frequency of electromyographic potentials in the rat. Some oxazolidinones markedly reduced the severity of this decerebrate rigidity in a dose-dependent manner, (4S,5R)-4-(2-methylpropyl)-3- [3-(perhydroazepin-1-yl)propyl]-5-phenyl-1,3-oxazolidin-2-on e (MLV-6976) being the most potent. In addition to the oxazolidinones, an aminoalcohol derivative, (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino )hexan-1-ol (MLV-5860) also reduced the rat decerebrate rigidity. In the oxazolidinone series, the optical isomers with absolute configuration (S) at the 4-position were more potent than the corresponding (4R)-isomers, while there was no significant difference in their LD50 values. Normal rats and mice receiving MLV-6976 at doses which reduced decerebrate rigidity showed no behavioural changes, impairment of motor coordination only appearing at extremely high doses. MLV-6976 and its derivatives did not affect spinal reflex potentials in cats. MLV-6976 reduced the severity of harmaline-induced tremor in mice in a dose-dependent manner, but slightly augmented tremorine-induced tremor. The frequency of the spike discharges induced by iontophoretically applied glutamate was reduced by MLV-6976 in a dose-dependent manner in rat cortical neurones. The amplitude of miniature endplate potentials of the rat diaphragm was decreased by MLV-6976 only at concentrations greater than 0.1 mM. It is concluded that MLV-6976 acts on the brainstem or/and higher levels of the brain rather than on the spinal cord or the peripheral nervous system to reduce the excessive activities of the nervous system.

Topics: Animals; Azepines; Decerebrate State; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Motor Endplate; Muscle Relaxants, Central; Muscle Rigidity; Neurons; Oxazoles; Oxazolidinones; Piperidines; Rats; Rats, Inbred Strains; Reflex; Tremor

Daily injection of triiodothyronine (T3) for 3 consecutive days dose dependently enhanced 1-5-HTP (4 mg/kg)-induced head twitches in mice. This effect was blocked by 1-penbutolol. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of clenbuterol but not indalpine to potentiate the response to 1-5-HTP. Likewise, the effects of T3 were more pronounced on the desipramine- or maprotiline-induced potentiation of head-twitches than on the action of citalopram or clomipramine. These data suggest that the increased responsiveness to 1-5-HTP caused by T3 involves an indirect (noradrenalin-mediated) rather than a direct effect on serotonergic processes.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Clenbuterol; Dose-Response Relationship, Drug; Drug Synergism; Head; Male; Mice; Movement; Piperidines; Tremor; Triiodothyronine

1-Alkyl-4,4-diphenylpiperidines 5-23 are accessible in a simple manner and with attractive yields by regioselective reaction of piperidine derivatives like 1, 2, 3 or particularly 3-aroyl-4-aryl-4-hydroxypiperidines 4, which can be varied widely at the nitrogen atom, with benzene under Friedel-Crafts conditions. The physico-chemical parameters, which are important for the transport and the distribution of a drug in a living system, are discussed for the 1-tert-butyl derivative 13 (budipine) (pKa, partition coefficient P, saturation concentration Cs, surface activity, protein binding). Rapid absorption of this drug in man is indicated by the size of the permeability coefficient PM of the passive transport through artificial phospholipid collodium membranes as well as the invasion curves calculated from PM. According to pharmacological screening tests, most of the compounds of this class show marked antagonistic activity against experimentally generated pathological states in mice (tremorine and reserpine antagonism) which suggest their potential use in the therapy of Parkinson's disease. 13 has been selected for detailed investigations. Structure-activity analyses did not readily demonstrate the presence of a relationship between the type of alkyl substituent at the piperidine nitrogen atom and the pharmacological screening results obtained.

Topics: Animals; Chemical Phenomena; Chemistry, Physical; Drug Evaluation, Preclinical; Lethal Dose 50; Magnetic Resonance Spectroscopy; Mice; Permeability; Piperidines; Reserpine; Salivation; Structure-Activity Relationship; Tremor

Budipine is a new 1-tertiary-butyl-diphenylpiperidine derivative with primarily central action. In animal experiments involving different pathological models, a pharmacological profile is found suggesting that budipine has therapeutic potential as antiparkinson drug. Besides a mild centrally stimulatory effect in the unprovoked animal, strong antagonistic effects are observed on tremorine- or N-carbamoyl-2-(2,6-dichlorophenyl)-acetamidine-hydrochloride (LON-954) induced tremor, and on cataleptic states elicited by haloperidol, reserpine, tetrabenazine and perphenazine. Attempts are made to elucidate tha mechanism of action in comparison with conventional clinical anti-parkinson drugs. The anticholinergic activity of budipine is too weak to explain its effectiveness. Direct dopamine receptor stimulation was excluded, but not the release of dopamine or reuptake inhibition. No clear influence was detectable on noradrenergic neurons either peripherally or centrally. An influence of serotoninergic mechanisms by way of reuptake inhibition and release, however, appears feasible. Peripheral effects are minimal. The possible advantages of budipine in the treatment of Parkinson's disease are discussed in comparison to the drugs used in therapy today.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Biogenic Amines; Central Nervous System; Electroencephalography; Mice; Peripheral Nerves; Piperidines; Rats; Rats, Inbred Strains; Tremor

Topics: Aged; Basal Ganglia Diseases; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Thioxanthenes; Tremor

Topics: Adult; Aged; Antiparkinson Agents; Basal Ganglia Diseases; Female; Humans; Male; Methods; Middle Aged; Parasympatholytics; Piperidines; Psychometrics; Tremor; Xanthenes

Topics: Adult; Aged; Benzocycloheptenes; Dihydroxyphenylalanine; Ergolines; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Promethazine; Thiophenes; Tremor; Trihexyphenidyl

Topics: 1-Propanol; Adolescent; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Biperiden; Catatonia; Delayed-Action Preparations; Extrapyramidal Tracts; Humans; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: 1-Propanol; Adjustment Disorders; Adult; Aged; Antidepressive Agents; Antiparkinson Agents; Anxiety Disorders; Basal Ganglia Diseases; Biperiden; Bipolar Disorder; Delayed-Action Preparations; Depression; Depressive Disorder, Major; Female; Humans; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: 1-Propanol; Animals; Central Nervous System; Ileum; Mice; Organ Culture Techniques; Parasympatholytics; Parkinson Disease; Peripheral Nerves; Piperidines; Rats; Stereoisomerism; Stomach; Synaptic Transmission; Tremor; Trihexyphenidyl

Topics: Adrenergic beta-Antagonists; Amino Alcohols; Animals; Dihydroxyphenylalanine; Drug Combinations; Hydrazines; Isoproterenol; Male; Mice; Parasympatholytics; Phenethylamines; Piperidines; Propranolol; Stereoisomerism; Sympatholytics; Tranylcypromine; Tremor; Tremorine

Topics: Acetylcholine; Animals; Chemistry, Organic; Cyclohexanes; Guinea Pigs; Ileum; In Vitro Techniques; Injections, Intraperitoneal; Methylamines; Mice; Muscle Contraction; Organic Chemistry Phenomena; Phenylacetates; Piperidines; Pupil; Pyrrolidinones; Salivation; Stereoisomerism; Structure-Activity Relationship; Tremor

Topics: Androstanes; Animals; Cats; Gallamine Triethiodide; Hexamethonium Compounds; Muscle Contraction; Neostigmine; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents; Piperidines; Quaternary Ammonium Compounds; Tremor; Tubocurarine

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Autistic Disorder; Autonomic Nervous System; Catatonia; Female; Hallucinations; Humans; Hypnotics and Sedatives; Liver Function Tests; Male; Mental Disorders; Nausea; Neurotic Disorders; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Schizophrenia; Sleep Wake Disorders; Stimulation, Chemical; Sweating; Tremor; Vascular Diseases; Vomiting

Topics: Amphetamine; Animals; Antidepressive Agents; Catecholamines; Central Nervous System; Ephedrine; Male; Mice; Pentylenetetrazole; Piperidines; Seizures; Sensory Receptor Cells; Sympathomimetics; Time Factors; Tremor

Topics: Anesthesia; Animals; Anticonvulsants; Arousal; Behavior, Animal; Cats; Central Nervous System; Dogs; Electroencephalography; Emetics; Evoked Potentials; Female; Hypnotics and Sedatives; Male; Mice; Piperazines; Piperidines; Pyrrolidines; Rats; Tremor

Topics: Humans; Parasympatholytics; Parkinson Disease; Piperidines; Tremor

Topics: Adult; Aged; Chemical Phenomena; Chemistry; Drug Synergism; Female; Humans; Male; Middle Aged; Muscles; Parkinson Disease; Piperidines; Propranolol; Tremor

Topics: Animals; Animals, Newborn; Anticonvulsants; Atropine; Benactyzine; Diphenhydramine; Electromyography; Guaifenesin; Mice; Muscles; Neurons; Parasympatholytics; Phenobarbital; Piperidines; Propiophenones; Scopolamine; Spinal Cord; Strychnine; Tremor; Trihexyphenidyl

Topics: Acetylcholine; Alkaloids; Anesthesia; Animals; Arteries; Avoidance Learning; Behavior, Animal; Blood Pressure; Dogs; Electric Stimulation; Epinephrine; Male; Mice; Piperidines; Rabbits; Rats; Tremor

Topics: Adult; Animals; Dogs; Electrocardiography; Humans; Hypertension, Pulmonary; Piperidines; Pulmonary Heart Disease; Pyrazoles; Tremor

Topics: Central Nervous System; Chemistry, Pharmaceutical; Mice; Pharmacology; Pharmacy; Piperidines; Research; Seizures; Toxicology; Tremor