piperidines and budipine

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.

Topics: Amantadine; Excitatory Amino Acid Antagonists; Humans; Indans; Memantine; Monoamine Oxidase; Monoamine Oxidase Inhibitors; N-Methylaspartate; Parkinson Disease; Piperidines; Selegiline

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

The diagnosis of Parkinson's disease (PD) is clinical and is based on the identification of a combination of the cardinal motor signs of bradykinesia plus at least one of the following: rigidity, tremor or postural instability. There are many causes of parkinsonism such as drug induced parkinsonism, subcortical vascular disease, and multisystem atrophy. PD is a well characterised syndrome which represents only a part of the various causes of parkinsonism. A good response to dopaminergics is an important diagnostic criteria for PD. Pharmacotherapy for PD relies primarily on levodopa and dopamine agonists. Deep brain stimulation is increasingly used in the management of patients with severe dopa fluctuations and dyskinesias. Cholinesterase inhibitors are introduced for dementia in parkinsonism. Neuroprotective compounds, nerve growth factors such as GDNF and the implantation of dopaminergic cells are studied in clinical trials.

Topics: Aged; Amantadine; Antiparkinson Agents; Apomorphine; Botulinum Toxins; Catechols; Cholinesterase Inhibitors; Clinical Trials as Topic; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Enzyme Inhibitors; Ergot Alkaloids; Family Practice; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Piperidines

Several lines of evidence suggest that substitution of the dopaminergic striatal deficit only represents one important aspect of the treatment of Parkinson's disease (PD) because neurotransmitter systems other than the dopaminergic one also degenerate and aggravate parkinsonian motor, vegetative and cognitive symptoms. Thus, regulation and balance of altered non-dopaminergic neurotransmission could provide an additional benefit for parkinsonian patients (PP). Moreover, onset of motor complications, psychosis and loss of drug efficacy increasingly reduce parkinsonian quality of life in the course of long-term dopamine substitution. Indirect stimulation of the dopaminergic neurotransmission via non-dopaminergic systems is an upcoming interesting strategy to solve these problems. Treatment of L-dopa-associated dyskinesias represents a further important future task of non-dopaminergic drug therapy. NMDA antagonists are a promising therapeutic option but further trials are necessary to elucidate their efficacy. A further peripheral effect of L-dopa/dopa decarboxylase inhibitor (DDI) application is increased homocysteine synthesis with its putative hypothetical additional central impact on neurodegeneration and progression of PD. Long-term monitoring with subsequent therapeutic decrease of homocysteine levels with folic acid could result in substantial clinical benefits at reasonable costs for PP. Also, it could hypothetically influence altered dopaminergic and non-dopaminergic neurotransmission beside its impact on occurrence of vascular disease and altered striatal microvascularisation in PD. The interesting field of non-dopaminergic drug therapy is emerging and will hopefully lead to a better understanding of PD and subsequently improve drug therapy of parkinsonian symptoms, which do not respond to dopaminergic substitution or are long-term complications of dopamine substitution.

Topics: Adenosine; Adrenergic alpha-Antagonists; Body Weight; Cholinergic Antagonists; Homocysteine; Humans; Levodopa; Methionine; N-Methylaspartate; Parkinson Disease; Piperidines; Serotonin Receptor Agonists

The lipophilic t-butyl analog of 1-alkyl-4,4-diphenyl piperidine, budipine, possesses a polyvalent spectrum of mechanisms of action. Budipine experimentally increased the brain content of norepinephrine, serotonine, dopamine and histamine in reserpine treated rats. Budipine did not alter the receptor affinity of these neurotransmitters but antagonizes the effect of NMDA at its receptor binding site in vitro. Budipine reduced MPP+ toxicity in the nigrostriatal system of mice. This complex pharmacologic profile is not comparable to the one of convenient antiparkinsonian drugs. In clinical trials budipine reduced tremor, akinesia and rigidity. Budipine induced a relevant additional positive effect in patients with an optimal dopaminergic therapy based on levodopa and dopamine agonists, such as bromocriptine. Current available data suggest that the need for levodopa application in early stages of the disease may be postponed by budipine and that the long-term application of budipine may induce a levodopa-sparing effect.

Topics: Animals; Antiparkinson Agents; Clinical Trials as Topic; Humans; Parkinson Disease; Piperidines

Four major components of the mechanism of action have been identified for the antiparkinsonian drug budipine up to now. 1) The primary action of budipine is an indirect dopaminergic effect as shown by facilitation of dopamine (DA) release, inhibition of monoamine oxidase type B (MAO-B) and of DA (re) up-take and stimulation of aromatic L-amino acid decarboxylase (AADC), which in sum might be responsible for enhancing the endogenous dopaminergic activity. 2) Radioligand and functional studies at the N-methyl-D-aspartate (NMDA) type glutamate receptor characterize budipine as a low-affinity, uncompetitive antagonist with fast kinetics and moderate voltage-dependency at the phencyclidine (PCP) binding site, comparable to that observed with amantadine, thereby counteracting an increased excitatory glutamatergic activity. 3) The antimuscarinic action of budipine, verified by functional and binding studies at native muscarinic M1-M3 and human recombinant m1-m5 receptor subtypes in vitro, is up to 125-fold weaker than that of biperiden and corresponds to its approximately 100-fold lower potency to cause experimentally-induced peripheral antimuscarinic effects and explains only part of its high potency, which equals biperiden, to suppress cholinergically evoked tremor. 4) An additional inhibition of striatal gamma-aminobutyric acid (GABA) release by budipine may be beneficial to suppress an increased striatal GABAergic output activity. The contribution of other observed effects to the therapeutic action of budipine, i.e. weak stimulation of noradrenaline and serotonin release, binding to brain sigma1 receptors and blockade of histamine H1 receptors, is not yet clear. By means of these multiple mechanisms, budipine might correct the imbalance of striatal output pathways by restoring DA levels in the striatum, and positively influence the secondary changes in other transmitter systems (glutamate, acetylcholine, GABA) observed in Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Brain Chemistry; Humans; Neurotransmitter Agents; Piperidines; Receptors, Neurotransmitter

To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias.. Thirty-four PD patients had cabergoline up-titrated and their levodopa (L-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26).. Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean L-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious.. High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for L-dopa.

Topics: Adolescent; Adult; Aged; Amantadine; Antiparkinson Agents; Cabergoline; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Humans; Levodopa; Middle Aged; Nitriles; Parkinson Disease; Piperidines; Prospective Studies; Quality of Life; Selegiline; Severity of Illness Index; Treatment Outcome

Previous studies demonstrated the efficacy of budipine on motor symptoms of treated patients with Parkinson's disease (PD) with rating scales. However rating procedures may be subjective and variable. Therefore additional use of instrumental motor tests are helpful to reflect therapeutic benefits. Objective was to test the efficacy of 20 mg budipine (t.i.d.) in 51 previously untreated idiopathic PD patients in a monocenter, double-blind, placebo-controlled trial with a 2:1 randomisation over a three month interval. Budipine was not superior to placebo application. However a detailed analysis of rating results shows, that budipine but not placebo treated patients significantly improved. Budipine caused significant better outcomes of motor tests with execution of complex movements, but did not change results of tasks, which demand for simple motions. Placebo significantly improved dopamine sensitive motor test results. These outcomes may result from improved non dopaminergic neurotransmission due to budipine. Placebo caused better results of dopamine sensitive tests, since placebo may release endogenous dopamine.

Topics: Adult; Aged; Antiparkinson Agents; Basal Ganglia; Disability Evaluation; Dopamine; Double-Blind Method; Female; Humans; Male; Middle Aged; Movement; Neurologic Examination; Parkinson Disease; Piperidines; Placebo Effect; Synaptic Transmission; Treatment Outcome

The complex pharmacological profile of the antiparkinsonian drug budipine influences neurotransmission beyond the dopaminergic system. Previous studies have demonstrated the therapeutic efficacy of budipine on motor symptoms in insufficiently treated patients with Parkinson disease.. To demonstrate the efficacy of 20 mg of budipine, 3 times daily, in addition to a stable, prior, optimum-titrated dopaminergic substitution consisting of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine mesylate, and optional selegiline hydrochloride in 99 patients with idiopathic Parkinson disease in a multicenter, double-blind, placebo-controlled trial.. Budipine significantly (P<.001) decreased the Columbia University Rating Scale sum score (median, 15.0; 95% confidence interval, 11.3-17.0) compared with placebo (median, 4.3; 95% confidence interval, 3.0-7.5) at study end point. Budipine reduced Columbia University Rating Scale subscores for tremor, rigidity, and akinesia.. The additional application of budipine provides further therapeutic benefit in subjects with Parkinson disease receiving a stable, prior, optimum-titrated dopaminergic drug regimen because of the hypothetical positive impact of budipine on altered nondopaminergic neurotransmission in patients with Parkinson disease.

Topics: Adult; Aged; Antiparkinson Agents; Bromocriptine; Dopamine Agents; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines; Treatment Outcome

In a randomised double blind parallel-group study in three centers budipine, a diphenylpiperidin derivate, was compared to amantadine with respect to efficacy and safety in the monotherapy of mild to moderate Parkinson's disease (PD). From 53 patients of either sex 27 patients were randomised to 3 x 20 mg/d budipine and 26 patients to 3 x 100 mg/d amantadine. The duration of treatment was 4 weeks in 1 center (21 patients) and 12 weeks in the other 2 centers (32 patients). Safety was measured by vital signs, ECG, adverse event recording and clinical laboratory. Both drugs caused a clinically relevant and statistically significant (p < 0.001) improvement of Parkinsonian symptoms according to the Webster-Rating-Scale (WRS) as compared to pretreatment values. With respect to the total WRS score sum there was no difference between the groups (p > 0.05; n.s.), while budipine showed a significantly (p < 0.05) better effect on the main symptom tremor after 12 weeks. During amantadine treatment more adverse events were observed than after budipine intake. Two patients left the study prematurely, one in the amantadine group due to psychiatric adverse events and one in the budipine group because of insufficient efficacy.

Topics: Aged; Aged, 80 and over; Amantadine; Antiparkinson Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg single dose. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with ascending doses of orally given budipine. Time to maximum serum concentration (tmax) and terminal half-life (t1/2) were independent of the administered dose. As compared to the 10 mg single dose pharmacokinetics, the repeated oral administration of budipine 10 mg t.i.d. resulted in an increase in AUC of 11% and 93% for budipine and its metabolite p-OH-budipine, respectively. In clinical practice, a predictable response in proportion to the dose is to be expected.

Topics: Administration, Oral; Adult; Antiparkinson Agents; Area Under Curve; Cross-Over Studies; Dose-Response Relationship, Drug; Half-Life; Humans; Intestinal Absorption; Male; Metabolic Clearance Rate; Piperidines

Topics: Adult; Aged; Antiparkinson Agents; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; N-Methylaspartate; Parkinson Disease; Pilot Projects; Piperidines; Severity of Illness Index

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

Budipine, a new 4,4-diphenylpiperidine derivative, and placebo were administered three times daily to 31 patients with Parkinson's disease over a period of 12 weeks. All patients in the two treatment groups received levodopa (plus benserazide) at an optimum and constant dose for at least 2 months before the start of the study and throughout the trial. The additional administration of budipine (daily dose 60 mg) was excellently tolerated by 14 patients, while 2 patients left the study because of mental confusion at an early stage of the trial. The budipine group showed a 22% improvement on the Columbia Rating Scale (median score). Compared with the placebo group (4% improvement), there was a highly significant difference (P less than 0.01, one-tailed test). Of the three main symptoms of Parkinson's disease, the best effect was seen on tremor, and less pronounced effects on bradykinesia and rigidity. Owing to its long half-life (31 h) with little plasma level fluctuations, budipine appears to be an effective agent in the treatment of Parkinson's disease.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Benserazide; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines

Topics: Adult; Aged; Amantadine; Antiparkinson Agents; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Piperidines; Random Allocation

Parkinson's disease is a frequent neurodegenerative disease, which typically occurs in older age. With progression of the disease, therapeutic complications, such as dyskinesias and fluctuations in the response to medication are common. To embed the medication of Parkinson's disease into a complex treatment plan of a patient suffering from multimorbidity can be challenging.. Not only the cardinal motor symptoms have to be treated properly but also the non-motor symptoms e.g. depression, dementia, autonomic dysregulations and gastrointestinal disorders. Pharmacological treatment and their risks are presented.. Especially in older patients the symptoms need to be treated with regard to multimorbidity and the risks of polypharmacotherapy. The therapeutic strategy needs to be carefully planned in order to achieve a high quality of life and social interaction.

Topics: Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Cholinergic Antagonists; Dopamine Agonists; Female; Humans; Levodopa; Male; Monoamine Oxidase Inhibitors; Parkinson Disease; Piperidines

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.

Topics: Amantadine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Dopamine; Drug Interactions; Excitatory Amino Acid Antagonists; Extracellular Fluid; Frontal Lobe; Glutamic Acid; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Selective Serotonin Reuptake Inhibitors; Up-Regulation

1. Evidence has recently suggested that NMDA receptors may play a role in the aetiology and possible treatment of depression and that weak noncompetitive NMDA receptor antagonists such as amantadine can synergize with conventional antidepressants in a model of the illness. 2. To try to obtain a neurochemical rationale for these findings, we have studied the effects of acute and chronic administration of amantadine or the related drug budipine on cortical release of 5-hydroxytryptamine (5-HT) following the antidepressants reboxitine (REB), paroxetine (PAROX) and clomipramine (CLOM) in freely moving rats by using microdialysis. 3. Acute administration of amantadine (40 mg kg(-1)), budipine (10 mg kg(-1)), REB (10 mg kg(-1)), PAROX (10 mg kg(-1)) or CLOM (10 mg kg(-1)) all failed to significantly alter extracellular 5-HT in the cortex. However, when either amantadine or budipine was administered 30 min prior to any of the three antidepressants, a significant rise in 5-HT was observed. 4. For chronic studies, the effects of the drugs were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular 5-HT at any time point. The three antidepressant drugs all elicited a gradual increase in 5-HT, which became significant after 14 days and tended to plateau thereafter. When either amantadine (20 mg kg(-1)) or budipine (5 mg kg(-1)) was coadministered with any of the three antidepressants, two differences were seen compared with the effects of the antidepressants alone. Firstly, the time required for significant increases in cortical 5-HT was reduced with elevated levels now being observed by 7 days. Secondly, the absolute magnitude of the increase in extracellular 5-HT was markedly greater in these rats from day 7 until the end of the experiment. 5. If, as is widely considered, an increase in extracellular 5-HT represents a critical step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants as well as possibly enhance their efficacy.

Topics: Amantadine; Animals; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Clomipramine; Drug Synergism; Male; Microdialysis; Paroxetine; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Serotonin

Apoptosis is one essential step for neuronal death in the nigrostriatal region in patients with Parkinson's disease. Cytotoxic tumor necrosis factor-alpha (TNF-alpha) and the proinflammatory cytokine interleukin-6 (Il-6) provide a proapoptotic environment. We investigated the influence of the antiparkinsonian compound budipine on the release of TNF-alpha and Il-6 in peripheral blood mononuclear cells (PBMC) and on the degree of cisplatin induced apoptotic cell death in SH-SY 5Y human neuroblastoma cells. 10(-7), 10(-8), 10(-9) mol/l of budipine significantly reduced release of TNF-alpha and Il-6 in PBMC and decreased apoptotic cell death after 50 hours and 74 hours in the SH-SY 5Y cells. Our results suggest, that budipine administration provides an antiapoptotic environment and slows neuronal apoptotic and inflammatory mediated loss of neurons.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antiparkinson Agents; Apoptosis; Cell Line; Cell Line, Tumor; Humans; Interleukin-6; Piperidines; Sympathetic Nervous System; Tumor Necrosis Factor-alpha

To evaluate the antiepileptic and neuroprotective properties of topiramate (TPM) alone and with coadministration of the N-methyl-D-aspartate (NMDA)-receptor antagonist budipine in a rat model of refractory status epilepticus.. Male Sprague-Dawley rats had electrodes implanted into the perforant path and dentate granule cell layer of the hippocampus under halothane anesthesia. Approximately 1 week after surgery, the perforant path of each animal was electrically stimulated for 2 h to induce self-sustaining status epilepticus. Successfully stimulated rats were given intraperitoneally vehicle (n = 6), TPM (20-320 mg/kg; n = 28), budipine (10 mg/kg; n = 5), or budipine (10 mg/kg) and TPM (80 mg/kg; n = 6) 10 min after the end of the stimulation and monitored behaviorally and electroencephalographically for a further 3 h. The animals were killed 14 days later, and histopathology was assessed.. Neither budipine alone nor TPM at any dose terminated status epilepticus. Despite this, TPM resulted in various degrees of neuroprotection at doses between 40 and 320 mg/kg. Coadministration of budipine with TPM terminated the status epilepticus in all rats. This combination also significantly improved the behavioral profile and prevented status-induced cell death compared with control.. Budipine and TPM are an effective drug combination in stopping self-sustained status epilepticus, and TPM alone was neuroprotective, despite the continuation of seizure activity.

Topics: Animals; Anticonvulsants; Cell Death; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Electrodes, Implanted; Electroencephalography; Fructose; Humans; Male; Neurons; Neuroprotective Agents; Perforant Pathway; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Status Epilepticus; Topiramate

Budipine is a non-dopaminergic antiparkinsonian drug causing acquired forms of Long QT syndrome (aLQTS). As a consequence, the manufacturer has restricted the use of budipine in patients who exhibit additional risk factors for the development of "Torsades-de-Pointes" tachycardias (TdP). The molecular basis of this serious side effect has not been elucidated yet. Human ether-a-go-go related gene (HERG) channel block being the main cause of drug induced QT prolongation, we investigated the effect of budipine on the rapid component of the delayed-rectifier potassium current (I(K(r))) in guinea pig cardiomyocytes and on HERG potassium channels heterologously expressed in Xenopus oocytes. In guinea pig cardiomyocytes, budipine (10 microM) inhibited I(K(r)) by 86% but was without any effect on calcium currents. In Xenopus oocytes, HERG potassium channels were blocked by budipine with an IC(50) of 10.2 microM. Onset of block was fast and block was only slowly and incompletely reversible upon washout. Budipine blocked HERG channels in the open and inactivated state, but not in the closed states. The half-maximal activation voltage was slightly shifted towards more negative potentials. Steady-state inactivation of HERG was also influenced by budipine. Budipine block was neither voltage- nor frequency-dependent. In HERG channel mutants Y652A and F656A, drug affinity was reduced dramatically. Therefore, these two aromatic residues in the channel pore are likely to form a main part of the binding site for budipine. In summary, this is the first study that provides a molecular basis for the budipine-associated aLQTS observed in clinical practice. Furthermore, these findings underline the importance of the aromatic residues Y652 and F656 in the binding of lipophilic drugs to HERG channels.

Topics: Animals; Antiparkinson Agents; Binding Sites; Calcium Channels; Cation Transport Proteins; Ether-A-Go-Go Potassium Channels; Guinea Pigs; In Vitro Techniques; Long QT Syndrome; Myocytes, Cardiac; Oocytes; Patch-Clamp Techniques; Piperidines; Potassium Channels; Potassium Channels, Voltage-Gated; Time Factors; Xenopus laevis

The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on mu receptors.

Topics: Analgesics, Opioid; Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Discrimination Learning; Enzyme Inhibitors; Female; Hydrocodone; Hydromorphone; Macaca mulatta; Pain Measurement; Piperidines; Quinidine; Receptors, Opioid, mu

The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Uptake Inhibitors; alpha-Methyltyrosine; Animals; Antiparkinson Agents; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Levodopa; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Reserpine; Serotonin; Substantia Nigra; Tyrosine 3-Monooxygenase

The atypical antipsychotic drug olanzapine has been proposed for treatment of dopaminergic psychosis in Parkinson's disease (PD). We report on a 68-year-old patient who developed a severe akinetic-rigid extrapyramidal syndrome, accompanied by additional paranoid symptoms, following olanzapine treatment of optic hallucinosis in PD. Olanzapine may also induce clinically relevant extrapyramidal side effects in PD patients.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Drug Therapy, Combination; Hallucinations; Humans; Levodopa; Male; Olanzapine; Paranoid Disorders; Parkinson Disease; Piperidines; Pirenzepine; Selegiline; Severity of Illness Index

Topics: Antiparkinson Agents; Humans; Parkinson Disease; Piperidines

The NMDA receptor antagonistic effects of budipine were assessed using concentration- and patch-clamp techniques on cultured striatal, hippocampal, cortical and superior colliculus neurones. Inward current responses of striatal neurones to NMDA (200 microM) at -70 mV were antagonized by budipine in a concentration-dependent manner (50% inhibitory concentration (IC50) 59.4 +/- 10.7 microM, n = 17) with 24 times lower potency than memantine but similar potency to amantadine. In striatal neurones, budipine blocked outward currents at +70 mV with an IC50 of 827 microM, suggesting that the binding site is less deep in the channel (delta = 0.45) than for memantine. However, more detailed analysis of the fractional block by budipine 300 microM in hippocampal neurones gave a delta-value of 0.90, but revealed that 28% block is mediated at a voltage-independent site. This voltage-insensitive site was accessible in the absence of agonist. Budipine exhibited concentration-dependent open channel blocking kinetics (kappa(on) = 0.71 x 10(4) M(-1) s(-1)) whereas the fast offset rate was concentration-independent (kappa(off) = 0.63 s(-1)). Calculation of the ratio kappa(off)/kappa(on) revealed an apparent Kd value of 88.7 microM. Budipine, memantine and amantadine had similar effects against NMDA-induced currents in cultured hippocampal, cortical and superior colliculus neurones, although amantadine was somewhat more potent in cultured striatal neurones. The relevance of NMDA receptor antagonism to the anti-Parkinsonian effects of budipine remains to be established.

Topics: Amantadine; Animals; Antiparkinson Agents; Brain; Cells, Cultured; Cerebral Cortex; Embryo, Mammalian; Hippocampus; Memantine; Neostriatum; Neurons; Patch-Clamp Techniques; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Superior Colliculi

The present study examined the effects of the antiparkinsonian drug budipine on dopamine synthesis and release from L-DOPA in the substantia nigra of reserpine-treated rats. Budipine (at 100 microM, but not 10 microM) applied by reverse dialysis to the nigra caused a small and significant rise in dopamine recovery in normal rats, but not in rats pretreated with reserpine (4 mg/kg i.p. for 18 hours) and alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg i.p. for 1 hour to limit dopamine synthesis to L-DOPA). L-DOPA applied to the nigra by reverse dialysis in reserpine + alpha-MPT-treated rats, increased the recovery of dopamine when applied at 5 or 10 microM, but not at 2 microM. Coadministration of budipine (10 microM) significantly enhanced L-DOPA-induced dopamine (and DOPAC) release with 5 microM L-DOPA, but not with 2 or 10 microM L-DOPA. This potentiation was even more pronounced when the budipine concentration was raised to 100 microM (equivalent to approximately 10 microM extracellularly). Pretreating rats with budipine (5, 12.5, or 20 mg/kg i.p.) for 1 hour significantly raised the activity of the enzyme L-aromatic amino acid decarboxylase in the striata and nigras of intact rats, as well as in rats pretreated with reserpine alone (5 mg/kg i.p.), without altering tissue levels of dopamine or its metabolites. It is suggested that the beneficial effects of budipine, when used as an adjunct to L-DOPA therapy of Parkinson's disease, may be due to an increase in the bioconversion of L-DOPA with a consequent rise in synaptic dopamine. These actions of budipine may be related to its weak NMDA receptor antagonist property.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Methyltyrosine; Animals; Antiparkinson Agents; Aromatic-L-Amino-Acid Decarboxylases; Corpus Striatum; Dopamine; Drug Synergism; Kinetics; Levodopa; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Reserpine; Substantia Nigra; Time Factors

Humans that lack cytochrome P450 2D6 (CYP2D6) activity may have an altered risk of drug dependence or abuse because this enzyme is important in the metabolism of some drugs of abuse, including hydrocodone. In rats, hydrocodone conversion to hydromorphone is catalyzed by CYP2D1, the rat homolog of the human CYP2D6. To determine the impact of impaired hydromorphone formation on the behavioral effects of the parent compound, hydrocodone-induced analgesia and hyperactivity, hydrocodone discrimination and self-administration were examined in male Wistar rats, with or without pretreatment with CYP2D1 inhibitors (quinine and budipine). In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) produced a marked suppression in brain and plasma hydromorphone levels detected after the peripheral administration of hydrocodone, thus confirming that the doses used suppressed CYP2D1 activity. In contrast, CYP2D1 inhibition had no impact on the analgesic or discriminative stimulus effects of hydrocodone, nor did this type of manipulation alter hydrocodone self-administration. The effects of quinine on the locomotor activating effects of hydrocodone were subtle at best. Because inhibition of CYP2D1 in this rat strain is proposed to be a useful animal counterpart for studying the impact of CYP2D6 polymorphism in humans, these data suggest that differences in CYP2D6 phenotype will have limited influence on the drug response to hydrocodone after nonoral administration. This has recently been verified in a study showing that inhibition of hydrocodone biotransformation to hydromorphone does not affect measures of abuse liability. Therefore, hydrocodone's behavioral effects are most likely attributable to its own intrinsic effects at mu opioid receptors.

Topics: Animals; Behavior, Animal; Brain; Cytochrome P-450 CYP2D6 Inhibitors; Enzyme Inhibitors; Hydrocodone; Male; Piperidines; Quinine; Rats; Rats, Wistar; Self Administration

The nature of [3H] (1-[2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl) piperazine dihydrochloride) (GBR 12935) binding to human platelets was investigated. A common property of the inhibitors of this binding was their association with the cytochrome P-450 system. cis-Flupenthixol and (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl) piperazine dihydrochloride) (GBR 12909) biphasically inhibited the binding. The fraction of [3H]GBR 12935 binding that was inhibited by low concentrations of cis-flupenthixol was sensitive to protease treatment. [3H]GBR 12935 binding in this fraction was saturable and of high affinity (Kd 4.5 nM). The present results reveal that [3H]GBR 12935 binds to multiple sites in platelets and suggest that part of the binding is associated with cytochrome P-450IID6.

Topics: Antipsychotic Agents; Blood Platelets; Culture Techniques; Cytochrome P-450 Enzyme System; Dopamine Antagonists; Enzyme Inhibitors; Flupenthixol; Humans; Ligands; Lobeline; Piperazines; Piperidines; Quinidine

In rats, amphetamine (AMP) conversion to 4-OH-AMP is metabolized by CYP2D1, the rat equivalent of the human enzyme CYP2D6. To determine the impact of impaired AMP metabolism on its behavioural effects, AMP-induced hyperactivity, AMP discrimination and AMP self-administration were examined in male Wistar rats with or without pretreatment with the CYP2D1 inhibitors quinine and budipine. In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) increased the plasma area under the curve of AMP 4-fold and 3.6-fold respectively, and decreased the plasma levels of 4-OH-AMP, 3-fold and 8.6-fold, confirming that the doses used suppressed CYP2D1 activity. Both inhibitors prolonged AMP-induced hyperactivity (0.3 mg/kg) and prolonged the duration of AMP-appropriate responding for periods of up to 90 min post-AMP administration in a drug discrimination procedure. In rats given a preload dose of AMP (0.8 mg/kg) 3 h prior to the self-administration test session, CYP2D1 inhibition resulted in fewer AMP infusions being taken compared with rats receiving the AMP preload dose alone. These studies indicate that AMP is responsible for the behavioural effects seen in rats and that a rat phenocopy model of the human CYP2D6 deficiency state can be produced by CYP2D1 inhibitors.

Topics: Alcohol Oxidoreductases; Animals; Aryl Hydrocarbon Hydroxylases; Behavior, Animal; Central Nervous System Stimulants; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P450 Family 2; Dextroamphetamine; Discrimination, Psychological; Drug Interactions; Enzyme Inhibitors; Generalization, Stimulus; Male; Motor Activity; p-Hydroxyamphetamine; Piperidines; Quinine; Rats; Rats, Wistar; Self Administration

Budipine is a novel antiparkinsonian drug which is particularly beneficial in the treatment of parkinsonian tremor. The mechanism of action of budipine is not fully understood. To study whether budipine has dopaminergic activity in vivo, we used the 6-hydroxydopamine rotational model of Parkinson's disease. Budipine (0.78-12.5 mg/kg i.p.) did not induce ipsilateral or contralateral rotations, suggesting that it does not possess direct or indirect dopaminergic activity. This conclusion is further supported by the observation that budipine (10 mg/kg) i.v. did not facilitate striatal dopamine release measured in vivo by brain microdialysis. To investigatate possible antimuscarinic and N-methyl-D-aspartic acid (NMDA) antagonistic properties of budipine, we compared budipine with the antimuscarinic antiparkinsonian drug biperiden and the NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid (CPP). In receptor-binding assays, budipine inhibited thienylcyclohexylpiperidyl-3,4-[3H](n) ([I3H]TCP) (2.5 nM)-binding with an IC50 of 36 microM and [3H]3-quinuclidinol benzilate-binding with an IC50 of 1.1 microM. The respective values for biperiden were 170 and 0.053 microM. In line with these findings, budipine and CPP increased the threshold for NMDA-induced seizures in mice with an ED50 of 10.2 and 4.4 mg/kg, respectively, whereas biperiden was not effective. In 6-hydroxydopamine-lesioned rats, budipine (3.13-12.5 mg/kg) and CPP (0.1-0.39 mg/kg) increased the number of contralateral rotations induced by apomorphine, whereas biperiden was not effective. The present data suggest that budipine acts by blocking muscarinic and NMDA transmission while facilitation of dopaminergic transmission does not appear to contribute to its in vivo action. In comparison to biperiden, which has also antimuscarinic and NMDA receptor antagonistic properties, the anti-NMDA action of budipine is more prominent.

Topics: Animals; Antiparkinson Agents; Biperiden; Central Nervous System; Dopamine; Excitatory Amino Acid Antagonists; Male; Mice; Microdialysis; Muscarinic Antagonists; N-Methylaspartate; Neostriatum; Neurotransmitter Agents; Oxidopamine; Piperazines; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Rotation; Seizures; Stereotyped Behavior; Sympatholytics

We have estimated the affinity of the antiparkinsonian drug budipine to the PCP binding site of the NMDA receptor and to sigma 1 binding sites in membranes from postmortem human brain frontal cortex. The affinity of budipine to both binding sites is in a concentration range that may be reached under therapeutic conditions (Ki-values of about 12 and 2 microM at the PCP and sigma 1 binding site, respectively). Interactions with NMDA receptors as well as sigma 1 binding sites may contribute to the antiparkinsonian effects of budipine.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Autopsy; Female; Frontal Lobe; Humans; Male; Middle Aged; Piperidines; Radioligand Assay; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

N-Methyl-D-aspartate- (NMDA-) evoked [3H]acetylcholine release in rabbit caudate nucleus slices was inhibited by the antiparkinsonian drugs budipine (1-tert-butyl-4,4-diphenylpiperidine) and biperiden (1-bicyclo[2.2.1.]hept-5-en-2-yl-1-phenyl-3-piperidino propanol) yielding functional Ki values of 4.6 and 8.8 microM. In contrast to the competitive antagonist 2-amino-5-phosphonopentaonate, budipine and biperidene significantly reduced both the apparent KD and the Emax value of NMDA. Moreover, they displaced [3H]MK-801 specifically bound to membranes of the same tissue, although with low affinity (IC50: 38 and 92 microM). It is concluded that budipine and biperiden are use-dependent (uncompetitive) antagonists at the NMDA receptor, binding to the receptor-linked ion channel, but probably not to the MK-801 binding site. NMDA antagonism may contribute to the antiparkinsonian effects of budipine.

Topics: Acetylcholine; Animals; Antiparkinson Agents; Binding, Competitive; Biperiden; Caudate Nucleus; Dizocilpine Maleate; In Vitro Techniques; Piperidines; Rabbits; Receptors, N-Methyl-D-Aspartate; Software

The effects of the antiparkinsonian drugs budipine and biperiden on spontaneous and electrically evoked release of dopamine (DA), acetylcholine (ACh), GABA or noradrenaline (NA) were studied in caudate nucleus or cortex slices, respectively, of the rabbit brain. Whereas both drugs (1-10 microM) strongly increased spontaneous [3H]outflow in caudate nucleus slices preincubated with [3H]DA, budipine inhibited but biperiden facilitated the evoked DA release. In the presence of the DA-reuptake inhibitor nomifensine, a significant part of the budipine-induced basal [3H] outflow consisted of unmetabolized DA. Synaptosomal high-affinity uptake of [3H]DA was only weakly affected by budipine and biperiden (IC50 values, 11 and 9 microM, respectively). Budipine enhanced also basal [3H]outflow from cortex slices prelabeled with [3H]NA, however this outflow consisted mainly of NA metabolites even in the presence of cocaine. The evoked release of [3H]ACh in rabbit caudate nucleus slices preincubated with [3H] choline was almost unaffected by budipine but enhanced by biperiden in the absence of further drugs. In the presence of nomifensine, however, budipine inhibited, but biperiden still enhanced, the evoked ACh release. Moreover, both drugs showed antimuscarinic properties in the presence of the ACh esterase inhibitor physostigmine, i.e., they facilitated the evoked ACh release, exhibiting pA2 values of about 6.9 (budipine) and 8.3 (biperiden). Addition of the D2 receptor antagonist domperidone diminished all inhibitory effects of budipine on the evoked ACh release. The evoked overflow of [3H] in caudate nucleus slices preincubated with [3H]GABA was reduced by both budipine and biperiden. It is concluded that both anticholinergic and indirect dopaminomimetic properties contribute to the antiparkinsonian effects of budipine, whereas biperiden exhibits mainly anticholinergic effects. Moreover, both drugs might disinhibit GABA controlled neurons in the central nervous system.

Topics: Acetylcholine; Animals; Antiparkinson Agents; Caudate Nucleus; Cerebral Cortex; Dopamine; Dopamine Agents; gamma-Aminobutyric Acid; In Vitro Techniques; Neurotransmitter Agents; Norepinephrine; Parasympatholytics; Piperidines; Rabbits; Receptors, GABA-A; Sympathomimetics

Budipine (1-t-butyl-4,4-diphenylpiperidine) is a novel antiparkinsonian agent. Its clinical efficacy has been proven in double-blind placebo-controlled trials. The mechanism of action of budipine, however, is unknown. Budipine selectively increased the threshold of N-methyl-D-aspartate (NMDA)-induced seizures in mice. Similar to known specific NMDA antagonist, budipine depressed polysynaptic spinal reflexes in mice, but had no consistent effect on spinal monosynaptic reflexes. In receptor binding experiments, budipine displaced thienylcyclohexylpiperidyl-3,4-[3H]-(n) ([3H]-TCP) from its binding site with an IC50 of 36 microM suggesting that budopine acts as a non-competitive NMDA antagonist with moderate receptor affinity. It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity. Our findings are additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease (PD).

Topics: Amino Acids; Anesthesia; Animals; Antiparkinson Agents; Binding, Competitive; Brain Chemistry; H-Reflex; In Vitro Techniques; Male; Mice; N-Methylaspartate; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Reflex; Reflex, Monosynaptic; Seizures; Spinal Cord

Rats were stereotactically implanted with electrodes into four brain areas (frontal cortex, hippocampus, striatum, and reticular formation) to allow registration of intracerebral field potentials. Connection of the electrodes to a microplug fixed to the skull of the animals allowed wireless transmission of the signals using a four-channel telemetric device. The potentials were subjected to a frequency analysis in real time, the power spectra obtained were segmented according to previous experience. Even in the low-dose range, budipine affected the power within these frequency bands: at 2 mg/kg i.p. in the hippocampus, at 4 mg/kg in the frontal cortex also. Power increases, observed mainly in the alpha-1 and beta-2 bands, became decreases in several bands when the dosage was raised to 8 mg/kg. Further power decreases, especially in the alpha-1 and beta-1 range, were observed after 12 mg/kg of budipine. It is notable that the reticular formation was affected only at the high dosage. The muscarinic anticholinergics biperiden and scopolamine provoked a pattern of electric brain activity changes which were to some extent similar to those obtained with the low dose of budipine, in terms of power increases the delta, alpha-1 and beta-2 frequencies in the hippocampus and frontal cortex. In the striatum and reticular formation, however, they were essentially different. Here the anticholinergics differed not only from budipine, but also from each other: biperiden caused decreases in theta and alpha-2 power comparable to the action of 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol, a dopamine D1-agonist. Scopolamine, in contrast, displayed the familiar pattern of delta and alpha-1 increases in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antiparkinson Agents; Electroencephalography; Male; Parasympatholytics; Piperidines; Rats; Rats, Inbred F344; Telemetry

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys nigrostriatal dopaminergic pathways and thereby produces a syndrome similar to Parkinson's disease. MPTP is oxidized by monoamine oxidase B (MAO B) to the 1-methyl-4-phenylpyridinium ion (MPP+), which is taken up in dopaminergic neurons through the dopamine (DA) uptake system, where it develops its toxic effect. Our observations show a new aspect of the MPP+ mode of action, in which deprenyl in mice has a partially protective effect against MPP+. Furthermore budipine, a therapeutic agent for Parkinsonism, is also able to partially prevent MPP+ toxicity. A MAO B-inhibitory component of budipine, as shown in receptor binding studies previously, could contribute to this effect. Comparable experiments with nomifensine do not exclude the possibility of budipine as an effect as a DA uptake inhibitor. An unexplained after effect of budipine leads to a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels five weeks after the last administration.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Brain; Catecholamines; Caudate Nucleus; Dose-Response Relationship, Drug; Drug Interactions; Female; Injections, Intraventricular; Male; Monoamine Oxidase Inhibitors; Movement Disorders; Nomifensine; Phenethylamines; Piperidines; Pyridinium Compounds; Selegiline; Serotonin

Topics: Adolescent; Adult; Chronic Disease; Cluster Headache; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Vascular Headaches

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin which produces degeneration of the nigrostriatal bundles in the central nervous system of man and animals. In these areas of the brain are concentrated the receptor binding sites for [3H]MPTP. 1-Alkyl-4, 4-diphenylpiperidines displace [3H]MPTP from these binding sites with Ki values in the micromolar range. The t-butyl analogue in this class of substances, budipine, is a novel therapeutic agent for Parkinsonism whose mechanism has not yet been fully clarified. The affinity of budipine for the MPTP receptor binding site was determined as a Ki value of 2.2 microM. Other 4, 4-diphenylpiperidine derivatives such as 1-methyl-4, 4-diphenylpiperidine and 1-i-propyl-4, 4-diphenylpiperidine have substantially lower affinities. Monoamine oxidase inhibitors such as deprenyl, pargyline and harmaline have affinities to the MPTP receptors which parallel their affinity for the B type of monoamine oxidase (MAO B). This supports the theory that the MPTP receptor binding sites is identical with membrane bound MAO B.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Animals; Brain; Male; Neurotoxins; Piperidines; Pyridines; Pyridinium Compounds; Radioligand Assay; Rats; Rats, Inbred Lew; Receptors, Cholinergic; Synaptosomes

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson syndrome in humans and in monkeys. In the rat, treatment with MPTP for a month resulted in permanently reduced dopamine and serotonin levels in the caudate nucleus. However, if the rats were pretreated with budipine, no MPTP-induced reduction in the dopamine and serotonin levels in the caudate nucleus was observed although one month recovery and observation time had elapsed between the last budipine injection and decapitation. It is surmised that budipine antagonises the neurotoxic effect of MPTP.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Dopamine; Drug Interactions; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Piperidines; Pyridines; Rats; Rats, Inbred Strains; Serotonin

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Binding, Competitive; Humans; Parkinson Disease, Secondary; Piperidines; Pyridines; Rats; Receptors, Drug

Topics: Antiparkinson Agents; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines

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

The in vitro uptake and release of 14C-5-hydroxy-tryptamine (14C-5-HT) by human blood platelets was examined, which were used in this study as a simple model for serotonergic nerve endings. Experimental conditions allowed measurement of initial velocity of uptake and excluded possible (re)uptake of recently liberated 14C-5-HT in the release studies. The effects of two new antiparkinson drugs, 1-isopropyl-4,4-diphenylpiperdine (prodipine) and its 1-tert-butyl analogue (budipine), on the two opposite transport processes of serotonin were investigated. Prodipine and budipine inhibit the uptake of 14C-5-HT by human blood platelets in a dose-dependent manner. Inhibition of uptake by both drugs is non-competitive; Ki values are 1.1X10(-4) mol/l for prodipine and 9X10(-5) mol/l for budipine, with prodipine additionally showing an effect on Km of serotonin for uptake system. Both substances liberate recently accumulated 14C-5-HT from the platelets. Stimulation of this process is dose-dependent, budipine proving more active than prodipine, both drugs being 5.4 and 4.1 times stronger than amantadine. The observed effects of prodipine and budipine on uptake and release of 14C-5-HT by isolated blood platelets are discussed in the light of other pharmacological activities and the antiparkinson efficacy of these drugs.

Topics: Adult; Antiparkinson Agents; Blood Platelets; Female; Humans; In Vitro Techniques; Kinetics; Male; Piperidines; Serotonin