Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N-carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported.
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PMID:Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans. 783 26

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.
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PMID:Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. 783 16

It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinson's disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2 1/2 months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinson's disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.
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PMID:Chronic treatment with levodopa and/or selegiline does not affect behavioral recovery induced by fetal ventral mesencephalic grafts in unilaterally 6-hydroxydopamine-lesioned rats. 786 55

Potentiation by 4-phenylpyridine (a MAO-B inhibitor) on the neuromuscular blocking action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in mouse phrenic nerve-diaphragm. MPTP blocked nerve-evoked twitches in a concentration (1-200 microM)-dependent manner. 4-Phenylpyridine, but not pargyline or tranylcypromine potentiated this inhibitory effect of MPTP. Pretreatment with 50 microM 4-phenylpyridine, reduced IC50 (concentration for 50% inhibition of twitch amplitude) values of MPTP from 53 to 18 microM and d-tubocurarine from 0.7 to 0.3 microM, respectively. 4-Phenylpyridine also enhanced the inhibitory action of MPTP and d-tubocurarine on acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm. The twitch inhibition induced by alpha-bungarotoxin and the specific binding of [125I]alpha-bungarotoxin to the mouse diaphragm were potentiated by 4-phenylpyridine but the inhibitory action of MPTP and d-tubocurarine on [125I]alpha-bungarotoxin binding were not significantly changed by pretreatment with 4-phenylpyridine. Electrophysiological studies revealed that the inhibitory actions of MPTP and d-tubocurarine on the amplitudes of m.e.p.ps and e.p.ps were augmented by 4-phenylpyridine. These indicate that 4-phenylpyridine enhanced the neuromuscular blocking action of the MPTP and d-tubocurarine at the postsynaptic nicotinic acetylcholine receptors. The implication of this finding is that the possible application of 4-phenylpyridine in the MPTP-induced Parkinson's disease is limited by its potentiation on the neuromuscular blocking action of MPTP.
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PMID:Potentiation of MPTP by 4-phenylpyridine on the neuromuscular blockade in mouse phrenic nerve-diaphragm. 790 91

Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of dopaminergic neurons in the brainstem. Recent studies suggest that several genes may have a role in determining individual susceptibility to this disease, and the degradative enzyme monoamine oxidase (MAO) has been implicated in the disease process. Wide differences in activity levels for both forms of this enzyme (MAO-A and MAO-B) exist in the human population, and levels of both are genetically determined. Here we have compared the frequency of haplotypes at the MAOA and MAOB loci on the X chromosome in 91 male patients with PD and 129 male controls. Alleles were marked using two restriction fragment length polymorphisms (RFLPs), a (GT)n repeat in the MAOA locus, and a (GT)n repeat in the MAOB locus. One particular haplotype marked by the RFLP's at MAOA was three times more frequent in patients with PD as compared with controls, and the overall distribution of these alleles was significantly different (p = 0.03) between these two groups. Another MAOA haplotype was about threefold more common in controls than in patients with PD (p = 0.005). No associations were observed between individual MAOB alleles and the disease state, but the frequency distribution for all alleles was significantly different in the two populations (p = 0.046). These findings support the idea that the MAO genes may be among the hereditary factors that influence susceptibility of individuals to PD.
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PMID:Hereditary variations in monoamine oxidase as a risk factor for Parkinson's disease. 791 37

Recent findings emphasize the significance of oxidative mechanisms, involving the activity of monoamine oxidase (MAO) and the formation of free radicals, in the pathogenesis of Parkinson's disease. The possible role of such mechanisms in the degeneration of neurones in the substantia nigra has led to clinical trials aimed at preventing or slowing the progressively disabling course of the disease. However, conclusive clinical evidence of a neuroprotective effect in PD is still lacking. In this paper, we discuss possible mechanisms by which selegiline manifests neuroprotective effects in experimental and clinical situations. Besides MAO-B inhibition, which above all explains the prevention of protoxin activation and substrate oxidation by MAO-B, selegiline appears to exhibit other mechanisms of action (induction of superoxide dismutase, stimulation of neurotrophic factor synthesis, antagonistic modulation of the polyamine binding site of the NMDA-receptor) which are independent of its action on MAO-B.
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PMID:Is selegiline neuroprotective in Parkinson's disease? 793 Dec 25

The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.
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PMID:Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP. 793 Dec 28

Recent data obtained in animals and in humans suggest that both MAO-A and MAO-B inhibitors present cognitive enhancing properties of possible interest in the treatment of cognitive disorders. In addition, the rational for using selegiline as a neuroprotector in Parkinson's disease may also be applicable in Alzheimer's disease in which a dramatic increase in the MAO-B activity has been reported. It seems then worthwhile to investigate the neuroprotective effect of MAOIs in humans and to assess, furthermore, the real therapeutical benefit of their cognitive enhancing properties.
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PMID:Monoamine oxidase inhibitors, cognitive functions and neurodegenerative diseases. 793 Dec 35

Ro 19-6327 (lazabemide, L), MDL 72974, selegiline, AGN 1135 and MDL 72145 were investigated for their MAO inhibitory effect in rat tissues in vitro. The selectivity of MAO-B inhibition of L, selegiline and MDL 72974 was also measured in vitro in human brain tissue as well as ex vivo in rat brain and liver after acute and subchronic administration. Of all compounds investigated L was the most selective for MAO-B inhibition under in vitro and ex vivo conditions. In volunteers, L completely but reversibly inhibited platelet MAO-B with a dose-dependent duration. Clinical trials with L are under way in both Alzheimer's and Parkinson's disease (PD).
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PMID:Lazabemide (Ro 19-6327), a reversible and highly sensitive MAO-B inhibitor: preclinical and clinical findings. 793 Dec 45

MDL 72974A, a new irreversible selective inhibitor of monoamine oxidase (MAO)-B which is not metabolized to amphetamine-like compounds, is currently being developed for the treatment of Parkinson's disease. In this double blind, placebo controlled randomized study 24 healthy volunteers (n = 6/dose) received single oral doses of placebo, 1, 12 or 24 mg of MDL 72974A qd over two weeks. Sensitivity to orally administered tyramine was determined under fasting conditions before and after drug administration and the doses of tyramine yielding a 30 mmHg increase of SBP (PD30) compared. The 2-fold increase of tyramine sensitivity at end of treatment seen at all MDL 72974A dose levels, however, is within the variability range of the tyramine pressor response. MDL 72974A selectively inhibits MAO-B at doses up to 24 mg orally and has a favourable safety profile.
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PMID:Pharmacodynamics of MDL 72974A: absence of effect on the pressor response to oral tyramine. 793 Dec 53


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