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M. S. Starr - One of the best experts on this subject based on the ideXlab platform.
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Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent.
Neuroscience, 2000Co-Authors: A. Fisher, Christopher S. Biggs, O. Eradiri, M. S. StarrAbstract:Abstract The comparative effects of l -3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25–200 mg/kg) dose-dependently inhibited the activity of aromatic l -amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs Budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25–50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100–200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 μM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator Budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25–100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or Budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas Budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D 2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D 1 >D 2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.
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Microdialysis study of the effects of the antiparkinsonian drug Budipine on L-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum.
Synapse (New York N.Y.), 1999Co-Authors: C. S. Biggs, M. S. StarrAbstract: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.
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Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase
Amino Acids, 1998Co-Authors: A. Fisher, C. S. Biggs, M. S. StarrAbstract:This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30–60 min later and AADC activity assayed in the substantia nigra pars reticulate (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, Budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase.
Amino acids, 1998Co-Authors: A. Fisher, C. S. Biggs, M. S. StarrAbstract:This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, Budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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The antiparkinsonian drug Budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra.
Synapse (New York N.Y.), 1998Co-Authors: C. S. Biggs, A. Fisher, M. S. StarrAbstract: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.
Thomas Klockgether - One of the best experts on this subject based on the ideXlab platform.
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Budipine provides additional benefit in patients with Parkinson disease receiving a stable optimum dopaminergic drug regimen.
Archives of neurology, 2002Co-Authors: Horst Przuntek, Thomas Klockgether, Stefan Bittkau, Harald Bliesath, Ulrich Büttner, G. Fuchs, Joachim Glass, Harald Haller, Peter H. Kraus, Lutz LachenmayerAbstract:Background 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. Objective 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. Results Budipine significantly ( P Conclusion 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.
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tremorlytic activity of Budipine in parkinson s disease
Clinical Neuropharmacology, 1999Co-Authors: Sybille Spieker, Thomas Klockgether, S Breit, J DichgansAbstract: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.
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Tremorlytic activity of Budipine in Parkinson’s disease
Journal of neural transmission. Supplementum, 1999Co-Authors: Sybille Spieker, Thomas Klockgether, S Breit, Johannes DichgansAbstract: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.
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Effects of the antiparkinsonian drug Budipine on central neurotransmitter systems
European journal of pharmacology, 1996Co-Authors: Thomas Klockgether, Ullrich Wüllner, Joachim P. Steinbach, Vibke Petersen, Lechoslaw Turski, Peter-andreas LöschmannAbstract: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.
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Tremorlytic activity of Budipine : a quantitative study with long-term tremor recordings
Clinical neuropharmacology, 1995Co-Authors: Sybille Spieker, Thomas Klockgether, Peter-andreas Löschmann, C. Jentgens, A. Boose, Johannes DichgansAbstract: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.
Peter Spielmanns - One of the best experts on this subject based on the ideXlab platform.
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Budipine is a low affinity n methyl d aspartate receptor antagonist patch clamp studies in cultured striatal hippocampal cortical and superior colliculus neurones
Neuropharmacology, 1998Co-Authors: Chris G. Parsons, Sabine Hartmann, Peter SpielmannsAbstract: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.
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Budipine is a low affinity, N-methyl-d-aspartate receptor antagonist: patch clamp studies in cultured striatal, hippocampal, cortical and superior colliculus neurones
Neuropharmacology, 1998Co-Authors: Chris G. Parsons, Sabine Hartmann, Peter SpielmannsAbstract: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 μM) at −70 mV were antagonized by Budipine in a concentration-dependent manner (50% inhibitory concentration (IC50) 59.4±10.7 μM, 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 μM, suggesting that the binding site is less deep in the channel (δ=0.45) than for memantine. However, more detailed analysis of the fractional block by Budipine 300 μM in hippocampal neurones gave a δ-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 (κon=0.71∗104 M−1 s−1) whereas the fast offset rate was concentration-independent (κoff=0.63 s−1). Calculation of the ratio κoff/κon revealed an apparent Kd value of 88.7 μM. 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.
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antagonist
1998Co-Authors: Chris G. Parsons, Sabine Hartmann, Peter SpielmannsAbstract:Budipine is a low affinity, N-methyl-D-aspartate recepto
Horst Przuntek - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of Budipine and placebo in untreated patients with Parkinson’s disease
Journal of Neural Transmission, 2005Co-Authors: Th. Müller, W. Kuhn, Horst PrzuntekAbstract: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.
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Efficacy of Budipine and placebo in untreated patients with Parkinson's disease.
Journal of neural transmission (Vienna Austria : 1996), 2004Co-Authors: T. Müller, W. Kuhn, Horst PrzuntekAbstract: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.
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Budipine provides additional benefit in patients with Parkinson disease receiving a stable optimum dopaminergic drug regimen.
Archives of neurology, 2002Co-Authors: Horst Przuntek, Thomas Klockgether, Stefan Bittkau, Harald Bliesath, Ulrich Büttner, G. Fuchs, Joachim Glass, Harald Haller, Peter H. Kraus, Lutz LachenmayerAbstract:Background 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. Objective 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. Results Budipine significantly ( P Conclusion 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.
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Non-dopaminergic therapy in Parkinson’s disease
Journal of Neurology, 2000Co-Authors: Horst PrzuntekAbstract:Parkinson’s disease no longer seems to be a disease entity caused by only one pathogenetic factor. The facile characterization of Parkinson’s disease as a more or less isolated disorder of the dopaminergic system proves to be an unacceptable oversimplification of the pathology of the disease. Characteristically, not all dopaminergic systems of the central nervous system are involved in the degenerative process. In addition to the nigrostriatal dopaminergic pathway, parts of the glutamatergic, cholinergic, tryptaminergic, noradrenergic, adrenergic, serotonergic, and peptidergic neurons show serious cytoskeletal damage. In the light of these findings, drugs influencing these transmitter systems should be useful in the treatment of parkinsonian symptoms. For this reason, non-dopaminergic drugs are gaining more and more importance. Besides the theoretically interesting adenosine A2 receptor antagonists, Budipine, a polyvalent potent new antiparkinsonian drug, has been tested in clinical studies. Budipine is a potent non-dopaminergic antiparkinsonian drug with pharmacological effects that are not comparable to those of conventional drugs applied in Parkinsonian pharmacotherapy. Budipine experimentally increased the brain content of noradrenaline, dopamine, serotonin, and histamine. The dopamine, serotonin, noradrenaline, gamma aminobutyric acid (GABA), and endorphine receptor affinities were not altered, but N-methyl-D-aspartate (NMDA) and sigma receptor affinities were increased as shown by in vivo and in vitro trials with Budipine. MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP^+ antagonistic effects have also been demonstrated. Budipine also shows neuroprotective as well as symptomatic antiparkinsonian effects. In two randomized, double-blind, multicenter, placebo-controlled studies, relevant therapeutic effects have been observed in previously untreated, so-called “de-novo” parkinsonian patients and in subjects in later stages of the disease. Budipine significantly reduces akinesia, rigidity, and tremor. Optimal effects of Budipine can be seen 4–6 weeks after starting treatment with this substance. Budipine can be added to all available antiparkinsonian drugs. An open, prospective, long-term study of 2532 patients with Parkinson’s disease (Study BY701/01A) confirmed the favorable safety and tolerability profiles of Budipine.
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Clinical efficacy of Budipine in Parkinson’s disease
Journal of neural transmission. Supplementum, 1999Co-Authors: Horst Przuntek, Th. MüllerAbstract: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 positve 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.
A. Fisher - One of the best experts on this subject based on the ideXlab platform.
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Synergism between Topiramate and Budipine in Refractory Status Epilepticus in the Rat
Epilepsia, 2004Co-Authors: A. Fisher, Xiaolan Wang, Hannah R. Cock, Maria Thom, Philip N. Patsalos, Matthew C. WalkerAbstract:Purpose: 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.Methods: Male Sprague-Dawley rats had electrodes implanted into the perforant path and dentate granule cell layer of the hippocampus under halothane anesthesia. Approximately I 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.Results: 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. Conclusions: 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.
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Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent.
Neuroscience, 2000Co-Authors: A. Fisher, Christopher S. Biggs, O. Eradiri, M. S. StarrAbstract:Abstract The comparative effects of l -3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25–200 mg/kg) dose-dependently inhibited the activity of aromatic l -amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs Budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25–50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100–200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 μM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator Budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25–100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or Budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas Budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D 2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D 1 >D 2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.
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Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase
Amino Acids, 1998Co-Authors: A. Fisher, C. S. Biggs, M. S. StarrAbstract:This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30–60 min later and AADC activity assayed in the substantia nigra pars reticulate (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, Budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase.
Amino acids, 1998Co-Authors: A. Fisher, C. S. Biggs, M. S. StarrAbstract:This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, Budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.
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The antiparkinsonian drug Budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra.
Synapse (New York N.Y.), 1998Co-Authors: C. S. Biggs, A. Fisher, M. S. StarrAbstract: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.
