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The first paper on the beneficial effect of selegiline in the treatment of Parkinson's disease was published 17 years ago. In the first ten years several clinical studies were conducted world-wide to prove its efficacy as an adjuvant to the basic 1-dopa therapy. Although the design, duration and number of treated patients were different, the overall results were mainly uniform. The patients treated with 1-dopa selegiline combination showed marked improvement in disability, increasing duration of 1-dopa effect and marked lessening of dose-related fluctuations were seen, compared to those treated with 1-dopa alone. It became also generally evident that selegiline allows a 10-30% decrease in 1-dopa dose. The investigations in which selegiline has been used as monotherapy have been triggered by some purely clinical experience and by the discovery of pathobiochemical mechanisms of MPTP toxicity which causes fairly similar clinical picture to Parkinson's disease and can be successfully prevented by selegiline. The newly diagnosed parkinsonian patients treated with selegiline alone showed marked improvement in their clinical state. Beside the actual clinical effect on disability, selegiline slowed down the progression of Parkinson's disease. The latter fact has been proven in the largest clinical trial ever done with selegiline (DATATOP). Selegiline monotherapy can delay the need for 1-dopa substitution by around one year or longer. Based on the continuously growing clinical experiences it became widely accepted that selegiline is the drug of choice as initial treatment for newly diagnosed parkinsonian patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Recently, some case-control studies and case reports have shown an association between solvent exposure and parkinsonisms. We present a 55-year-old male parkinsonian patient with chronic exposure to n-hexane for 17 years. The results of neurophysiological (electromyography, evoked potentials), neuroradiological (MRI) and neuropsychological tests performed on the patient suggest a role of this solvent at the level of the central nervous system. Biological susceptibility to neurotoxic compounds is discussed briefly.
The experiences of a six years' follow-up study with L-Deprenyl are summarized. L-Deprenyl may be effective in influencing the very early Parkinsonian symptoms but usually levodopa derivates must be given in addition. In the course of substitution therapy L-Deprenyl successfully replaces about 30% of levodopa administered to optimally treated patients. Concerning the "on-off" phenomena L-Deprenyl seems to be beneficial in the mild forms of "end-of-dose deterioration".
The activities of MAO-A, MAO-B and the semicarbazide-sensitive amine oxidase (SSAO) were determined in bovine lens, retina, optic nerve, iris and epithelium. No activities were detected in lens but the SSAO activity was found to be rather evenly distributed in the other tissues. The SSAO activities determined with 1 microM benzylamine were about half those determined for MAO-B. MAO-A activity, measured with 5-HT as substrate, was considerably greater than those of MAO-B and SSAO, determined with 2-phenylethylamine and benzylamine, respectively, in all the eye tissues.
STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.
Seligiline, a monoamine oxidase inhibitor, has been previously approved by the US FDA for adjunctive treatment of Parkinson's disease. At present, it has been found to be effective in a transdermal system when administered daily in the treatment of major depressive disorder. The minimum dosage of 6 mg/24 h was effective in two trials; this dosage did not require any dietary precautions. Higher doses of 9 mg/24 h and 12 mg/24 h may also not require restrictions, however, current data is insufficient. Furthermore, a randomized 52-week prevention study found significant benefits for continuance of this treatment. There are several types of safety data available. First, there have been no reports of hypertensive crisis in any patient receiving selegiline via this transdermal system at any of the three doses. Tyramine challenge studies have found a comfortable cushion of safety at selegiline doses of 6 mg/24 h. Other side effects include a slightly higher rate of orthostatic hypotension, insomnia and, most frequently, application site reactions. There are no significant effects on weight or sexual side effects. In terms of drug interactions, carbamazepine was found to significantly increase seligiline levels (however, carbamazepine should be contraindicated). Direct sympathomimetics may be safe, but indirect ones are thought to put the patient at risk. Finally, due to risk of serotonin syndrome, other medications contraindicated include: selective serotonin re-uptake inhibitors, serotonin-noradrenaline re-uptake inhibitors and multiple analgesics - in particular meperidine. To prevent toxic drug interactions at initiation of seligiline transdermal system therapy, all mediactions that are at risk should be completely stopped a minimum of 4-5 times their respective half-lifes for full elimination. This is generally a time period of 1 week. Upon stopping treatment with selegiline, 2 weeks should pass prior to beginning any medication at risk for drug interactions.
This study, an open trial, was aimed at assessing the efficacy of selegiline in the treatment of mild camptocormia in PD patients.
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Autoxidation of dopamine or L-DOPA (3,4-dihydroxyphenylalanine) generates reactive oxygen species (ROS), i.e., hydrogen peroxide, superoxide, and hydroxyl radical, which are potentially cytotoxic. Increased formation of ROS has been proposed to be involved in the pathogenesis of many human diseases, including Parkinson's disease. Several reports suggest that R(-)-deprenyl (an MAO-B inhibitor and anti-Parkinsonian drug) may directly or indirectly exert antioxidant effects and thus protect neurons. We have assessed the toxic effects of dopamine and L-DOPA toward catecholaminergic neuroblastoma SH-SY5Y cells and whether R(-)-deprenyl and several structurally related compounds possess antioxidant effects in this system. The results show that both dopamine and L-DOPA are quite cytotoxic toward SH-SY5Y cells. R(-)-deprenyl rather than reducing this dopamine-induced toxicity actually enhances it. Structural analogues of R(-)-deprenyl, such as 4-methyldeprenyl, (-)-methylamphetamine, and clorgyline, exhibited similar effects. Some different MAO-B inhibitors, namely, the aliphatic N-methylpropargylamines, e.g., (+/-)-M-2-PP [N-(2-pentyl)-N-methylpropargylamine] and N-[2-hexyl]-N-methylpropargylamine, which can also protect and rescue neurons in several in vivo and in vitro models, did not exacerbate the cytotoxicity of dopamine. Neither R(-)-deprenyl nor (+/-)-M-2-PP affected the L-DOPA-induced cytotoxicity toward SH-SY5Y cells.
We evaluated 16 (15 men, 1 woman) autopsy-verified progressive supranuclear palsy (PSP) cases during 31 years (1969-2000) for clinical diagnosis and the course of the disease. The onset was gait difficulty or postural instability in 9 (56.3%), general motor slowing in 3 (18.8%), and tremor in 2. One case had onset with cognitive decline and 1 as hemidystonia. Four cases had supranuclear ophthalmoplegia (SNO) at the first assessment and were diagnosed as PSP. By last assessment, PSP diagnosis was made in 4 additional cases, but in 8 (50%) who never manifested ophthalmoplegia (mean 9.8 years after onset), PSP diagnosis was not made. Other manifestations included bulbar symptoms in 13 (81.3%), and cognitive impairment in 10 (62.5%) during the course of illness. Fifteen cases received levodopa, amantadine, anticholinergics, dopamine agonists, and selegiline in different combinations with symptomatic benefit in 9 of 15 (60%). Five had some improvement on levodopa alone and 3 showed more improvement when a dopamine agonist was added to levodopa. In general, the benefit was minimal and occurred only early in the course of illness. The mean age at onset was 63.7 (range, 53-85) years. Mean duration at PSP diagnosis was 4.8 (range, 2-11) years. Mean survival was 8.6 (range, 3-24) years and mean age at death was 72.3 (range, 60-89) years. When the different diagnostic criteria recommended in the literature were used, the accuracy of clinical diagnosis did not improve substantially.
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Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Aβ, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.
Although antidepressant medications are commonly used to treat depression in Parkinson's disease (PD), little information is available regarding their safety and efficacy in this condition. Sertraline is a relatively selective serotonin reuptake inhibitor with some dopamine reuptake inhibitor activity. It has a favorable tolerability profile, especially in the elderly. We undertook an open-label pilot evaluation of the safety and efficacy of sertraline to treat depression in PD. A total of 15 patients with PD and depression participated in the study. Sertraline was introduced at a daily dose of 25 mg for 1 week and then increased to 50 mg/day. Patients underwent evaluation at baseline and at a final visit approximately 7 weeks later. Sertraline was generally well tolerated, but five patients experienced side effects, and two discontinued medication. Patients taking selegiline experienced more adverse effects. Beck Depression Inventory scores improved significantly (mean +/- SE = 16.0 +/- 2.0 vs 11.7 +/- 1.9, p = 0.03), and Unified Parkinson's Disease Rating Scale and energy-level scores were unchanged. These results suggest that sertraline may be a useful treatment for depression in PD. As substantial placebo effects can occur in studies of PD and depression, placebo-controlled, double-blind studies are warranted.
We previously reported that the optimal dosage of (-)deprenyl to increase superoxide dismutase (SOD) activities in striatum in rats differs 10 fold between young male and female rats (1). Furthermore, in female rats the optimal dosage increased with age (1). In the present study in order to clarify how the optimal dosage of this effect changes with age in male rats, we examined the effects of four different dosages of deprenyl on SOD enzyme activities in striatum and several other tissues in old (28-29-month-old) male Fischer 344 (F-344) rats. Continuous s.c. infusion of deprenyl for 3 wks increased activities of SOD and catalase (CAT) in striatum, substantia nigra and cortical regions but not in hippocampus, cerebellum or the liver. The dose of 0.5 mg/kg/day was found to be most effective, while higher (1.0, 2.0 mg/kg/day) or lower (0.1 mg/kg/day) dosages were less effective. This value of 0.5 mg/kg/day was 4 fold lower than the dosage of 2.0 mg/kg/day which was most effective in increasing SOD and CAT activities in young (5-7 month old) male rats of the same strain (1,2). The decline of the optimal dosage with age found in male rats is best explained by a possible decline with age in the hepatic microsomal monooxygenase enzyme activities that are involved with the metabolism of deprenyl. In view of the large differences in the optimal dosages shown among different sexes and ages of rats, future studies regarding the unique effect of this drug in prolonging the life span of rats must be carefully investigated with the caution in mind that the optimal dosage for the life prolonging effect may well differ depending on sex, age and possibly strain and species of animal model used.
Selective inhibition of the "false" proliferative signals via targeting tyrosine kinases resulting in the induction of apoptosis by depletion of the "survival factors" is one of the most studied and widely accepted concepts of modern chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors and tested these compounds for apoptosis induction. Some of the tyrosine kinase inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various tumor cell cultures. The somatostatin analogue oligopeptide TT-232, which indirectly inhibits tyrosine kinases, exerted a dose-dependent apoptosis-inducing effect. The tumor growth-inhibitory effect of TT-232 and some tyrosine kinase inhibitors has also been proven by in vivo experiments, using human tumor xenografts. On the other hand, a dose-dependent pro- or anti-apoptotic activity of (-)-deprenyl has been shown in melanoma cell cultures, the lower doses inhibiting and the higher doses inducing apoptosis. Various metabolites of (-)-deprenyl are responsible for these actions. The effect of (-)-deprenyl is connected with depolarization of mitochondrial membranes. The kinase inhibitors act on the growth factor receptor signaling pathways (survival factor pathways) and initiate the caspase cascade. The key enzyme for the action of both pro-apoptotic and anti-apoptotic compounds is caspase 3.
A total of 1504 patients with PD (471 with R+ATD; 511 with R; and 525 with ATD) were enrolled from 37 sites. In the R+ATD and ATD groups, selective serotonin reuptake inhibitors (SSRIs) were most frequently used (74.5% and 77%, respectively). In the R+ATD and ATD groups, mean duration of antidepressant use (tricyclic, SSRI, and other) were 50.5-53.5 weeks and 51.7-80.9 weeks, respectively. Overall, 195 patients (13%) from all three groups had one or more hospitalization/ED visits. No cases of STS were identified in any group.
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Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), clorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I-birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H-GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age.
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We searched the Cochrane Tobacco Addiction Group trials register which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycLIT, and other reviews and meeting abstracts, in September 2001.
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Rasagiline, a new drug developed to treat Parkinson's disease, is known to inhibit monoamine oxidase B. However, its metabolite R-(-)-aminoindan does not show this kind of activity. The present series of in vitro experiments using the rat hippocampal slice preparation deals with effects of both compounds on the pyramidal cell response after electric stimulation of the Schaffer Collaterals in comparison to selegiline, another MAO B inhibitor.
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We conclude that pre-existing cardiovascular autonomic dysfunction should be investigated and taken into account when deciding which combination therapy to choose in the treatment of parkinsonian patients.
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A battery of neuropsychological tests and clinical rating scales.
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Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats.
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Chiral separation of deprenyl-N-oxide isomers is presented using capillary electrophoresis in the presence of various cyclodextrin (CD) derivatives. This recently identified metabolite of R-(-)-deprenyl may possess desirable pharmacological activities. The effect of the cavity size and the substituents of the CD are examined on the enantiomer resolution of the compound having an asymmetric center on a heteroatom. The importance of hydrophilic or hydrogen bonding interaction, as well as the position of the interacting groups is demonstrated. Outstanding selectivity and resolution values are achieved using the chargeable carboxymethyl-beta-CD. 2-Hydroxypropyl-beta-CD is also suitable for the enantiomer separation of the analyte. Native beta-CD and carboxyethyl-beta-CD provide only poor enantioselectivity, whereas heptakis-(2,6-di-O-methyl)-beta-CD is capable of separating only the diastereomers. No chiral resolution can be observed in the presence of gamma-CD.
A 52 year old fully medicated physician with juvenile onset Parkinsonism experienced 4 years ago severe "on-off" fluctuations in motor disability and debilitating speech impairment with severe stuttering which occurred predominantly during "on-off" periods. His speech impairment improved 20%-30% when sertraline (75 mg/day), a serotonin reuptake inhibitor, was added to his dopaminergic medications which included levodopa, amantadine, selegiline and pergolide mesylate. A more dramatic and consistent improvement in his speech occurred over the past 4 years during which time the patient received, on a fairly regular basis, weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Recurrence of speech impairment was observed on several occasions when regular treatments with EMFs were temporarily discontinued. These findings demonstrate that AC pulsed applications of picotesla flux density EMFs may offer a nonpharmacologic approach to the management of speech disturbances in Parkinsonism. Furthermore, this case implicates cerebral serotonergic deficiency in the pathogenesis of Parkinsonian speech impairment which affects more than 50% of patients. It is believed that pulsed applications of EMFs improved this patient's speech impairment through the facilitation of serotonergic transmission which may have occurred in part through a synergistic interaction with sertraline.
The inhibition by chlorgyline and deprenyl of deamination of tyramine, i. e. substrate of two forms of monoamine oxidase (MAO) A and B, by fragments of rat liver mitochondrial membrane and the effects of competitive reversible inhibitors of the MAO activity, e. g. 4-ethylpyridine, benzyl alcohol, O-benzyl-hydroxylamine and 2-oxyquinoline, on this process were studied. It was shown that all the inhibitors used sharply increase the inhibiting effect of chlorgyline on tyramine deamination, the degree of the stimulating effect being the same irrespective of whether the inhibitors are added to the samples before or after a 30-min preincubation of chlorgyline with the enzyme at 23 degrees, i. e. after the onset of irreversible inhibition. The stimulating effect is due to the independent action of two inhibitors on the two different sites of the MAO active center: chlorgyline--on the isoalloxazine ring of FAD, that of 4-ethylpyridine, benzyl alcohol, O-benzylhydroxylamine, 2-oxyquinoline, respectively, on the hydrophobic region involved in tyramine binding. In similar experiments with deprenyl all the competitive inhibitors used, when added to the samples after a 30-min incubation of the inhibitor with the enzyme at 23 degrees, remove the inhibiting effect of deprenyl on tyramine deamination. The decrease of the inhibiting effect of deprenyl is indicative of an existence of competitive interactions between deprenyl and the above-mentioned compounds and of the reversible inhibition by deprenyl of tyramine deamination under the given experimental conditions. The data obtained revealed the differences in the type and mechanism of action of chlorgyline and deprenyl on tyramine deamination and showed that these inhibitors act on different sites of the MAO active center, responsible for tyramine oxidation. Chlorgyline blocks primarily the "flavin moiety" of the MAO molecule, essential for the catalytic act, while the effect of deprenyl is directed to the hydrophobic part of the enzyme active center essential for the enzyme binding to tyramine. In this case the irreversible inhibiting effect is achieved at a slower rate and the reversibility of tyramine oxidation by deprenyl is maintained for a longer period of time than the chlorgyline inhibition of deamination of this amine.
Male rats were given daily injections of 200 micrograms/kg l-thyroxine, s.c., for a period of 10 days. Monoamine oxidase (MAO) activities in the heart, lung and liver mitochondria decreased rapidly to about 50% those of the control rats with 5-HT and beta-phenylethylamine (beta-PEA) as substrates on the first day. After that, heart MAO activity increased gradually and exceeded the control value after 10 days with 5-HT as the substrate. The level of liver MAO activity was maintained at about 50-70% during the same period of administration with 5-HT as the substrate. The thyroxine treated rats showed no marked change in brain MAO activity. In vitro, l-thyroxine and its metabolites had no discriminative actions on MAO activities in these organs of rats. The heart, lung and liver MAO have unaltered Km values for 5-HT and beta-PEA, but decreases in the Vmax for both substrates were observed between the control and l-thyroxine-treated rats. Addition of the brain, heart and liver cytosol fractions from l-thyroxine treated rats caused MAO activities of heart mitochondria to decrease with 5-HT as a substrate and caused them to increase with beta-PEA as a substrate. MAO activities in liver also were inhibited by adding all the cytosols when beta-PEA was the substrate, but on the contrary, lung MAO activities were increased when 5-HT was the substrate. These results indicate the possible presence of multiple modulators of MAO in the cytosol fractions of l-thyroxine treated rats.
The extraction of lipids from rat liver mitochondrial membranes by 2-butanone treatment inhibited the activity of membrane-bound monoamine oxidase -A but not -B. For the -B form, the apparent Michaelis constants of the enzyme towards oxygen and the maximum molecular turnover numbers obtained when beta-phenethylamine and benzylamine were used as substrates were not significantly changed by the lipid-depletion procedure, but the values of the Michaelis constant towards benzylamine was significantly increased after lipid-depletion. The differential sensitivity of beta-phenethylamine and benzylamine oxidation to inhibition by Tris-HCl was not changed after lipid-depletion. The results are consistent with the hypothesis that the mitochondrial membrane lipids, while essential for the activity of the -A form of the enzyme in rat liver, play a more subtle modulatory role in the activity of the -B form.