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In two trials, we have studied the effectiveness and tolerability of L-deprenyl, a selective MAO B inhibitor, in the treatment of end of dose akinesia in patients with Parkinson's disease. The first trial was designed as an open controlled trial. In the L-deprenyl phase, an improvement in fluctuations in motor function as well as an overall reduction in the sum score of Webster's rating scale from 12.5 to 8.9 was observed, which almost returned to baseline during the placebo phase. The second trial was designed as a randomized trial comparing L-deprenyl therapy with a low-dose bromocriptine regimen. Both therapeutic approaches yielded the same results with respect to fluctuations; the CURS sum score dropped from 37 to 26. As regards tolerability, however, L-deprenyl was superior to bromocriptine.
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Proper treatment of tremor in any clinical setting depends on correct diagnosis. Essential, or familial, tremor is symptomatic with movement and involves the limbs, head and voice. Parkinson's disease tremor occurs at rest, involves the jaw and limbs and is associated with bradykinesia, rigidity and falling. Parkinson's disease is treated with a number of medications, but levodopa, a dopamine precursor, is considered most effective. Other therapies in the early stages of Parkinson's disease may include neuroprotective agents, dopamine agonists, dopamine reuptake inhibitors, anticholinergics and/or amantadine. Polypharmacy is often necessary to minimize or avoid drug side effects.
A new strategy has been developed for synthesizing positron emission tomography (PET) radiotracers using [11C]methyl iodide. This strategy relies on the ability of organic co-solvents to cluster within mixtures of supercritical fluids resulting in localized regions of high density which can serve as microscopic pockets for reaction. We've shown that acetonitrile will cluster about dilute solutes when mixtures of this co-solvent with carbon dioxide are forced to behave as a homogeneous fluid at the critical point. We applied this strategy in a systematic investigation of the conditions for optimized reaction between methyl iodide and L-alpha-methyl-N-2-propynyl phenethylamine (nordeprenyl) to yield L-deprenyl. Variables such as temperature, ultraviolet light exposure, co-solvent concentration, system pressure, and methyl iodide concentration were explored. The synthesis of radioactive [11C]-L-deprenyl using no-carrier-added concentrations of [11C]methyl iodide was also tested. Results showed that greater than 90% radiochemical yield of the desired product could be attained using 40 times less labeling substrate than in conventional PET tracer syntheses.
Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes.
An attempt was made to establish a decision algorithm for the treatment of idiopathic Parkinson's disease at various stages and in different subgroups such as akinetic-rigid or tremor dominance type. We suggest treating young patients with selegiline and a dopamine agonist. In the tremor dominance type we use either budipine or a dopamine agonist. Due to levodopa-induced dyskinesia, we try to avoid levodopa in the early stages of the disease and use it only later in more advanced situations in a combination therapy with dopamine agonists. Since IPS is not only based upon dopamine deficiency but also on resulting glutamatergic overstimulation, we advocate the use of a glutamate antagonist such as amantadine or budipine. Catechol-O-methyl inhibitors are very helpful when wearing-off occurs. Anticholinergics are only used in the early stages of tremor-dominant IPS because we fear enhancing the risk of dementia.
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Recent human PET studies with the monoamine oxidase B (MAO B) tracer [11C]L-deprenyl show that the rapid rate of radiotracer trapping relative to transport reduces the sensitivity of the tracer in regions of high MAO B concentration. This study investigates the use of deuterium substituted L-deprenyl ([11C]L-deprenyl-D2) to reduce the rate of trapping in tissue and to improve sensitivity.
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The speed and amplitude of repetitive finger movement were lower in early PD patients than in healthy controls. Early PD patients also had a progressive decrement of movement amplitude (sequence effect). Patients with advanced PD had lower speed, amplitude and movement regularity during finger tapping in comparison to early PD and healthy controls but no sequence effect. In early PD, selegiline improved both the movement speed and amplitude though it did not influence the sequence effect.
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Monoamine oxidase (MAO) inhibitors are effective antidepressants whose use is limited because of unwanted side effects and the possibility of a tyramine-induced hypertensive crisis (cheese reaction). (-)-Deprenyl (the official nonproprietary name for this substance is selegiline), a selective MAO type B inhibitor, may be safer and have fewer side effects, but its antidepressant efficacy is uncertain. A double-blind placebo-controlled study was carried out in depressed outpatients who were treated with (-)-deprenyl in an MAO type B selective dose range and at a higher nonselective dose range. (-)-Deprenyl did not have a statistically significant antidepressant effect after three weeks of treatment at doses of 10 mg/d. However, after six weeks and at higher doses (averaging about 30 mg/d for the second three weeks), (-)-deprenyl was superior to placebo in antidepressant effect with a positive response rate of 50% vs 13.6% and with a 41% reduction in the Hamilton Depression Rating Scale mean score vs 10% in the placebo-treated group. No hypertensive crises were seen. The rate of occurrence of side effects with (-)-deprenyl was no greater than with placebo. It was concluded that (-)-deprenyl is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of nonselective MAO inhibitors.
Patient-reported data can be a valuable, adjunctive tool in helping physicians assess the quality-of-life and functional changes in patients with Parkinson's disease (PD). We analyzed and evaluated the largest PD patient-reported database (PROPATHtrade mark) relative to prescribing habits and changes in reported outcomes by therapy. Our analysis included 1436 patients, followed for 1 yr, who completed a series of questionnaires assessing medication therapy, daily activity scores adapted from the Unified Parkinson's Disease Rating Scale (UPDRS), global disease visual analogue scale, and health resources consumption. Our results indicated that physicians are prescribing Eldepryl(R) with increased frequency in patients with early and mild PD. Patients receiving Eldepryl alone or in combination with Sinemet(R) reported better outcomes than those receiving Sinemet monotherapy. There was a great deal of variability in the reported utilization of healthcare resources by patients in the PROPATH program and, thus, no statistical differences were noted for patients treated with different regimens. We conclude that the adjunctive use of longitudinal patient self-reported data programs such as PROPATH can help assess and improve overall patient outcomes. Future controlled studies should be conducted to further evaluate the roles of alternative therapies and patient-reported data in improving quality-of-life and outcomes for PD patients.
To study the long-term effects of selegiline in monotherapy and in combination with levodopa in the early phase of Parkinson disease (PD).
This case broadens the characterization of BTP to include levodopa-responsive PD.
Production of hydrogen peroxide as a by-product of the breakdown of catecholamines by the enzyme monoamine oxidase (MAO) has been hypothesized to contribute to the increased proclivity of dopaminergic neurons for oxidative injury. We established clonal dopaminergic PC12 cell lines which have elevated MAO activity levels resulting from transgenic expression of the B isoform of the enzyme. Both MAO-A and MAO-B have relatively equivalent affinities for dopamine, and since PC12 primarily express the A and not the B form of the enzyme, this allowed us to distinguish the transgenic MAO activity in these cells from endogenous using the MAO-B specific substrate PEA. Elevation of MAO activity levels in the MAO-B+ cells resulted in higher levels of both free radicals and free radical damage compared with controls. In addition, increased MAO-B levels within PC12 cells caused a dose-dependent increase in sensitivity to the toxin MPTP. Our data suggests that oxidation of catecholamines by MAO can contribute to free radical damage in catecholaminergic neurons and that the low MAO-B activity levels found endogenously in these cells likely accounts for their relative resistance to MPTP toxicity.
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A wide variety of drugs is available for treating Parkinson's disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.
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The effects of unspecific doses of the irreversible monoamine oxidase inhibitor selegiline on alpha-tocopherol, alpha-tocopherolquinone, ubiquinol and ubiquinone were studied in frontal cortex, hippocampus and striatum of male C57BL/6 mice 4 h and 96 h after a single or six injections of selegiline (100 mg/kg body weight, i.p.), respectively. Inhibition of monoamine oxidase was confirmed by activity measurements of its isoforms A and B in brain stem nuclei and striatum as well as by determination of striatal levels of dopamine and its major metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. In general, levels of alpha-tocopherol were not altered and levels of alpha-tocopherolquinone were below the detection limit. However, 96 h following selegiline, levels of ubiquinols 9 and 10 were significantly increased, whereas levels of ubiquinones 9 and 10 concomitantly decreased in the striatum. Concentrations of ubiquinols and ubiquinones in frontal cortex and hippocampus were unchanged 96 h following selegiline. These data suggest that selegiline affects the striatal redox ratio of ubiquinol to ubiquinone which is important for cellular antioxidant defense and mitochondrial electron transfer.
Clinical evidence suggests that deprenyl may slow progression of Parkinson's disease, although mechanisms underlying this putative neuroprotective action remain poorly understood. To address this issue, we studied deprenyl in 12 parkinsonian patients using a single-blind, placebo-controlled, crossover design. After 1 month, deprenyl (10 mg/d) decreased the optimal levodopa requirement by 24% (oral) and 16% (intravenous). Levodopa-induced dyskinesias were prolonged by 430%, and antiparkinsonian action by 44%. Mood improved by 47%. One month after withdrawing deprenyl, effects on dyskinesias and mood had yet to return to baseline. There was no change in activities of circulating glutathione peroxidase, glutathione reductase, glutathione transferase, superoxide dismutase, and catalase, nor in levels of lipid peroxide and vitamin E. Deprenyl also failed to modify CSF levels of total glutathione and activities of glutathione peroxidase or superoxide dismutase. These effects on levodopa pharmacodynamics and mood complicate the interpretation of available investigations of deprenyl's neuroprotective action and increase the risk of adverse effects of levodopa.
Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the 'wearing off' phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson's disease. In 2 well conducted trials of 6 months' duration and smaller short term studies, treatment with entacapone (200 mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily 'on' time and decreases in 'off' time. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores concurred with changes in 'on' and 'off' times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials. Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug's ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation.
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Surface populations of Astyanax mexicanus, living in rivers like their common ancestors, school, while several, independently derived cave populations of the same species have lost schooling behavior.
There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B (MAOB) inhibitors. They have been studied for their potential disease-modifying effects in Parkinson's disease (PD) for over 20 years in various clinical trials. This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD. Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug. Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles, some of which may be insurmountable.
The noradrenaline (NA), dopamine (DA) and serotonin (5HT) reuptake inhibitory potency of deprenyl, the highly selective and irreversible inhibitor of MAO-B, methamphetamine enantiomers, and some other MAO inhibitors (clorgyline, J-508, J-511, J-512, J-516, LK-63, U-1424, 2-HxMP) was compared. In vitro hypothalamic NA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)- J-508 and (+)-deprenyl (IC50: 0.35, 3.5, 17.0 and 17.8 mumol/l, respectively), and U-1424, J-512, J-516, LK-63 and 2-Hx-MP showed IC50 > 1000 mumol/l. Striatal DA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)-, and (-)-deprenyl and clorgyline with IC50 of 0.6, 42.0, 24.0, 98.6 and 27.0 mumol/l, respectively, however the other compounds were ineffective. Hippocampal 5HT reuptake was slightly inhibited by clorgyline (IC50 205.0 mumol/l), while the other MAO-inhibitors were devoid of potency. Data suggest that potency and selectivity of MAO inhibition and reuptake inhibition are independent features of the compounds, and metabolism of deprenyl results in increased noradrenaline and dopamine reuptake inhibition.
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There was a 59% difference ( P=0.14) in the area under the serum concentration-time curve (AUC) of selegiline during the HRT compared with the placebo phase, but only a little or no concomitant reduction in the AUC of desmethylselegiline (-7%, P=0.071) or metamphetamine (2%, P=0.614) was observed. Maximum plasma concentration (C(max)) of selegiline was not changed, but a small, statistically significant, reduction in the C(max) of desmethylselegiline (-17%, P=0.03) was seen during the HRT phase. The C(max) of methamphetamine was slightly but not significantly reduced (-5%, P=0.06). The unchanged AUC ratios of desmethylselegiline/selegiline and metamphetamine/selegiline indicate that the primary metabolism of selegiline was not affected by HRT. All study treatments were well tolerated.
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A significant negative correlation was obtained between DED slope values and GM density in the parahippocampus in PIB-positive (PIB + ve) MCI patients (p = 0.025) (prodromal AD). Furthermore, in exploratory analyses, a positive correlation was observed between PIB-PET retention and DED binding in AD patients (p = 0.014), and a negative correlation was observed between PIB retention and CSF Aβ42 levels in MCI patients (p = 0.021), while the GM density and CSF total tau levels were negatively correlated in both PIB + ve MCI (p = 0.002) and MCI patients (p = 0.001). No significant correlation was observed with FDG-PET and with any of the other PET, MRI, or CSF biomarkers.
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A sensitive assay for human plasma BzAO, involving the conversion of 14C-benzylamine to 14C-benzaldehyde, was developed. MPTP and several of its analogues were found to be competitive inhibitors of the enzyme. Ki values for the MPTP analogues in the presence of human plasma BzAO were determined. The analogues had a different rank order of inhibition of human plasma BzAO compared with the rank order of inhibition of bovine plasma BzAO found previously. MPTP and 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), which are potent nigrostriatal toxins, were weak inhibitors of human plasma BzAO.
Private health insurance plays a large role in the U.S. health system, including for many individuals with depression. Private insurers have been actively trying to influence pharmaceutical utilization and costs, particularly for newer and costlier medications. The approaches that insurers use may have important effects on patients' access to antidepressant medications.
Parkinson's disease affects mainly the elderly population and is characterized by tremor, bradykinesia, rigidity and postural abnormalities. As the disease progresses, drug therapy is inevitable and the strategies used aim to correct the imbalance of neurotransmitters in the CNS. Antimuscarinic drugs counteract the excessive effects of acetylcholine while levodopa, dopamine agonists, selegiline and amantadine supplement or enhance the effects of dopamine. Although initially effective, these therapies are not without problems which include tolerance and long-term effects. This article aims to augment the reader's knowledge of the disease and the drug therapies available, including their place in therapy and their potential side-effects.
There was no evidence that those agents had proper efficacy in treating the antipsychotic-induced sexual dysfunction. An algorithm for managing sexual dysfunction induced by antipsychotics is suggested as a support for clinical decisions. Since the outcome from schizophrenia treatment is strongly related to compliance with the antipsychotics, prevention of sexual dysfunction is better than its treatment, since there is a scarcity of data available regarding the efficacy of intervention to deal with these problems.
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The aging process demonstrates gradual and spontaneous changes, resulting in maturation through childhood, puberty and young adulthood, and then decline through middle and late age. However, animals and humans are capable of reaching the extreme limit of life span characteristic for the species with a very efficient network of antiaging mechanisms. Among them, neuroendocrine-immune interactions play a pivotal role. The loss of the capacity of the organism in remodeling the neuroendocrine-immune response leads to the appearance of age-associated pathologies. We herein report some substances which can be proposed as new antiaging strategies because of their capacity to remodel some biological functions in old animals and humans. These substances are: L-deprenyl, leptin, ghrelin, carnosine and NO donors. Their role as possible antiaging strategies in healthy people in relation to neuroendocrine-immune responses and zinc ion bioavailability is reported and discussed.
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Significant binding affinity of ursolic acid was seen with MAO-A, which indicated its potential role in other neurological disorders, for example, Alzheimer's disease and Parkinson disease besides depression.