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To examine the effectiveness of transdermal selegiline for producing cigarette smoking abstinence.
A 74-year-old patient with idiopathic Parkinson's disease was evaluated for unintended sleep episodes that occurred after long-term treatment with 400 mg/day of L-dopa. Overnight sleep studies and multiple sleep latency testing were carried out under double-blind administration of either L-dopa or placebo. Mean sleep latency with L-dopa was 7 minutes, in contrast to a normal value of 19 minutes, 25 seconds with placebo. The authors' results suggest that L-dopa may cause daytime somnolence in some patients with Parkinson's disease.
A series of 1-methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (3a-k and 4a-u) were designed, synthesized, and evaluated for their inhibitory efficacy towards the two hMAO isoforms. Most of the derivatives were found to be potent and selective hMAO-B inhibitors. In particular, derivative 3g showed greater hMAO-B affinity than selective inhibitor selegiline coupled with high selectivity index (SI=145). The most selective hMAO-B inhibitor was the 3-methyl analogue 3f with an SI higher than 909.
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L-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase type B, but also exerts several effects on dopamine and noradrenaline systems independent of monoamine oxidase type B inhibition. Thanks to these properties, L-deprenyl has gained wide acceptance in the therapy of Parkinson's disease by using L-deprenyl both with levodopa and alone. Furthermore, L-deprenyl improves the performance of patients with Alzheimer's disease. Epilepsy, particularly temporal lobe epilepsy with complex-partial seizures, is often associated with disturbances of cognitive function and behavior, and it has been suggested that a drug combining cognition-enhancing and antiepileptic activity would be of benefit in the treatment of epileptic patients. This prompted us to study if L-deprenyl exerts anticonvulsant efficacy in amygdala-kindled rats, i.e., a useful model of complex-partial seizures in humans. In addition to anticonvulsant activity, i.e., effects on already developed seizures, we determined whether L-deprenyl exhibits antiepileptogenic properties, i.e., suppressive effects on development of kindling. In all experiments, behavioral alterations of the rats in response to L-deprenyl were monitored closely. In order to assess the role of active metabolites in the anticonvulsant and behavioral effects of L-deprenyl in the kindling model, the D-enantiomer of deprenyl, which is metabolized to more potent compounds (D-amphetamine and D-methamphetamine) than the L-enantiomer, was used for comparison. In fully kindled rats, L-deprenyl potently increased the threshold for focal afterdischarges. The most marked increase in afterdischarge threshold (up to 250% above control) was seen after a dose of 10 mg/kg, whereas the D-enantiomer was ineffective at this dosage.(ABSTRACT TRUNCATED AT 250 WORDS)
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1. Single oral doses (100, 200 and 300 mg) of moclobemide, a reversible inhibitor of monoamine oxidase (MAO) with predominant effects on the A-type of the enzyme, were administered to eight young, healthy male volunteers in a double-blind, random-order, placebo-controlled study. The investigation was thereafter continued in an open fashion by administering a single 10 mg dose of the MAO-B inhibitor deprenyl to the same subjects. 2. Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, as evidenced by up to 40% decreases in the urinary excretion of deaminated catecholamine metabolites, corresponding increases in the excretion of non-deaminated, methylated metabolites, and up to 79% average decreases in the plasma concentration of 3,4-dihydroxyphenylglycol (DHPG), a deaminated metabolite of noradrenaline (NA), and up to 75% average decreases in the plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a deaminated metabolite of dopamine. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) was only slightly reduced. In contrast, deprenyl, in a dose which almost totally inhibited MAO-B activity in blood platelets, did not appreciably affect the plasma concentrations of DHPG or DOPAC. 3. Due to the rapid, reversible, dose-dependent and MAO-A specific effect of moclobemide on plasma concentrations of DHPG, it is suggested that DHPG in plasma may be a useful indicator of the magnitude and duration of MAO-A inhibition in man. 4. Sympatho-adrenal function at rest was not significantly altered by moclobemide, as judged by unchanged plasma catecholamine concentrations and stable blood pressure and heart rate recordings. 5. Monoamine oxidase type B activity in blood platelets was slightly (less than 30%) and transiently inhibited after moclobemide. 6. The secretion of prolactin was dose-dependently stimulated by moclobemide, whereas the plasma concentrations of growth hormone (hGH) and cortisol remained unchanged.
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We investigated the effects of rivastigmine (a cholinesterase inhibitor) and selegiline ((-)deprenyl, an irreversible inhibitor of monoamineoxidase-B), alone and in combination, on brain acetylcholinesterase (AChE), (Na(+), K(+))-, Mg(2+)-ATPase activities, total antioxidant status (TAS), and learning performance, after long-term drug administration in aged male rats. The possible relationship between the biochemical and behavioral parameters was evaluated.
Dopaminergic drugs, the gold standard for motor symptoms, are known to affect cognitive function in Parkinson's disease (PD) patients.
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Despite the well-documented selectivity of rasagiline, the manufacturer recommends virtually all of the dietary (vis-à-vis tyramine) and drug restrictions of the nonselective MAO inhibitors. Although useful, selective MAO-B inhibitors have a limited role in Parkinson's disease. Of greater interest is the potential neuroprotective effect of rasagiline and its major metabolite, 1(R)-aminoindan, which may have great utility in a wide variety of neurodegenerative disorders of aging. In addition, bifunctional molecules combining selective MAO-B inhibition (based on the active moiety of rasagiline) with acetylcholinesterase inhibition or iron chelation may eventually be useful in Alzheimer's disease.
Cell viability was assessed by detecting the leakage of lactate dehydrogenase (LDH) into the medium. Apoptosis rate was measured by flow cytometry. Caspase-3-like activity was measured by fluorescence assay using the probe Ac-DEVD-AMC. The level of intracellular hydrogen peroxide and other peroxides in PC12 cells were quantified by loading cells with 2'-7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) in fluorescence assay. Lactic acid was measured spectrophotometrically. The DA levels in PC12 cells were determined by HPLC-ECD.
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DATATOP is a double-blind, multi-center, placebo-controlled clinical trial aimed at slowing the decline of patients who are in the early stages of Parkinson's disease (PD). The specific aim is to determine whether or not chronic administration of deprenyl 10 mg per day and/or tocopherol 2000 IU per day to early, otherwise untreated PD patients will prolong the time until levodopa therapy is required to treat emerging disability. Deprenyl and tocopherol exert antioxidative effects through separate but complementary mechanisms of action. A 2 X 2 factorial design allocates eligible subjects to one of four treatment groups: 1) deprenyl alone, 2) tocopherol alone, 3) deprenyl plus tocopherol, or 4) placebo. Eligible subjects include early PD patients (illness duration less than 5 years and in stages I and II), aged 30 to 79, who are not taking or requiring any anti-PD medications. The major response variable is the time period from randomization until the blinded investigator judges levodopa necessary to treat emerging parkinsonian disability. Randomization is stratified to ensure that treatment assignments are balanced for each blinded investigator. Cerebrospinal fluid is sampled just prior to randomization and one month after washout of experimental medications in order to help distinguish between symptomatic and protective effects of interventions. Based on pilot studies it is estimated that approximately 85% of untreated PD patients will require levodopa within two years and a total sample size of 800 subjects will provide a 95% likelihood for detecting a 10% "survival" difference between experimental medications and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
Selegiline is prepared in a three-step synthesis starting from phenylacetone and methylamine. Its possible impurities may be the (+)-isomer and compounds formed in side reactions. The syntheses of selegiline's metabolites are also described.
Although Sinemet CR is more costly, it may be more cost-effective in patients with motor fluctuations. Some patients may be able to reduce adjunctive medications.
Long-term use of selegiline was safe and well tolerated in this HIV cohort of HIV with cognitive impairment. Cognitive improvement may be delayed in neuroprotective trials, suggesting that trials longer than 6 months may be necessary to assess the efficacy of putative neuroprotective agents.
Selegiline, the R-enantiomer of deprenyl, is used in the treatment of Parkinson's disease. Bupropion, an antidepressant, often used to treat patients in conjunction with selegiline, is metabolized primarily by CYP2B6. The effect of selegiline on the enzymatic activity of human cytochrome CYP2B6 in a reconstituted system and its effect on the metabolism of bupropion were examined. Selegiline was found to be a mechanism-based inactivator of the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation (7-EFC) activity of CYP2B6 as well as bupropion metabolism. The inactivations were time-, concentration-, and NADPH-dependent and were characterized by K(I) values of 0.14 and 0.6 μM, k(inact) values of 0.022 and 0.029 min⁻¹, and t(½) values of 31.5 and 24 min, respectively. In standard inhibition assays, selegiline increased the K(m) of CYP2B6 for bupropion from 10 to 92 μM and decreased the k(cat) by ∼50%. The reduced carbon-monoxide difference spectrum revealed over a 50% loss in the cytochrome P450 spectrum in the inactivated sample, with no loss in heme, and there was ∼70% loss in enzyme activity. Trapping of the reactive metabolite using GSH led to the identification of a GSH-selegiline conjugate with a m/z 528 that could be explained by hydroxylation of selegiline followed by the addition of glutathione to the propargyl moiety after oxygenation to form the ketene intermediate. Liquid chromatography-tandem mass spectrometry analysis of the labeled protein following digestion with trypsin revealed the peptide ⁶⁴DVFTVHLGPR⁷³ as the peptide modified by the reactive metabolite of selegiline and the site of adduct formation is Asp64.
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Parkinson's disease is a complicated disease state that affects patients' quality of life. The first monoamine oxidase (MAO-B) inhibitor for PD, selegiline (Eldepryl), was approved by the Food and Drug Administration (FDA) in 1996, and rasagiline (Azilect) received FDA approval in 2006. At first, pharmacists may assume that rasagiline is just another me-too drug. There are three areas in which the two medications differ from each other: MAO type A inhibitors are found in high concentrations in the intestines, and MAO type B inhibitors are found mostly in the brain. If MAO-A inhibition occurs, the body cannot protect itself from exogenous amines such as tyramine. The absorbed tyramine can cause hypertensive crisis, also known as the cheese reaction. Selegiline's capsule product labeling includes a bolded warning that it "should not be used at daily doses exceeding 10 mg per day because of the risks associated with non-selective inhibition of MAO." It also says, "the selectivity of selegiline for MAO B may not be absolute, even at the recommended daily dose." The fact that rasagiline has the same effect has been challenged by two main-stream studies. Selegiline is a propargyl amphetamine derivative that undergoes extensive first-pass metabolism to L-methamphetamine and L-amphetamine. Rasagiline's major metabolite is amioindan, which has no amphetaminelike properties. Selegiline has been reviewed looking for neuroprotection, but studies have been unable to come to a definite positive neuroprotection conclusion. Proponents of rasagiline's neuroprotective effects also point to clinical studies in humans that demonstrate delayed and reduced need for future use of levodopa. In summary, selegiline and rasagiline look more and more like distant cousins instead of twins.
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Fluctuations in performance in levodopa-treated Parkinsonians pose frequent and difficult problems of managment. Controlled trials with two recently introduced drugs, bromocriptine and L-deprenyl, have been performed in an attempt to clarify their use in Parkinsonian oscillations. Bromocriptine, partially substituted for levodopa, was helpful in 4 of 6 patients with early morning dystonia, but did not benefit 9 patients with end-of-dose deterioration and 5 patients with "on-off changes. L-Deprenyl 10mg daily gave substantial benefit to 19 of 39 patients with end-of-dose deterioration, but to only 1 of 10 patients with "on-off' phenomena. Neither L-deprenyl nor bromocriptine helped patients disabled by freezing episodes or levodopa-induced involuntary movements.
Stress can affect the brain and lead to depression; however, the molecular pathogenesis is unclear. An association between stress and stress-induced hypersecretion of glucocorticoids occurs during stress. Dexamethasone (a synthetic glucocorticoid steroid) has been reported to induce apoptosis and increase the activity of monoamine oxidase (MAO) (Youdim et al. 1989). MAO is an enzyme for the degradation of aminergic neurotransmitters; dopamine, noradrenaline and serotonin and dietary amines and MAO inhibitors are classical antidepressant drugs. In this study, we have compared the ability of rasagiline (Azilect) and its main metabolite, R-aminoindan with selegiline (Deprenyl) in prevention of dexamethasone-induced brain cell death employing human neuroblastoma SH-SY5Y cells and glioblastoma 1242-MG cells. Dexamethasone reduced cell viability as measured by MTT test, but rasagiline, selegiline, and 1-R-aminoindan could significantly prevent dexamethasone-induced brain cell death. Among three drugs, rasagiline had the highest neuroprotective effect. Furthermore, the inhibitory effects of these drugs on MAO B catalytic activity and on apoptotic DNA damage (TUNEL staining) were examined. Rasagiline exhibited highest inhibition on MAO B enzymatic activity and prevention on DNA damage as compared to selegiline and 1-R-aminoindan. In summary, the greater neuroprotective effect of rasagiline may be associated with the combination of the parent drug and its metabolite 1-R-aminoindan.
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Levodopa remains the gold standard of medications. New drugs include recently introduced dopamine agonists like ropinorole and pramipexole, and COMT inhibitors. The role of selegiline in neuroprotection remains controversial. Dopamine agonist monotherapy may delay the onset of motor fluctuations. Levodopa may be associated with the earlier onset of motor complications such as dyskinesias, and it may be preferable to delay its use in younger patients. In older patients, especially those with significant disability, levodopa use should not be delayed. Surgical therapies such as pallidotomy, bilateral subthalamic deep brain stimulation and foetal transplantation can be considered for those who fail medical therapy. Molecular science techniques including gene therapy, neurotrophic factors, stem cell technology form the next frontier of Parkinson's research.
1. The metabolism of selegiline (SG) has been studied by investigating the time-course of urinary excretion of SG and its metabolites using high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS) in combination with solid-phase extraction. 2. The excretion profiles of SG and its four major metabolites, selegiline-N-oxide (SGO), N-desmethylselegiline (DM-SG), methamphetamine (MA) and amphetamine (AP), were investigated in six healthy volunteers after oral administrations of SG hydrochloride in a single dose of 2.5 or 7.5mg, and a repeat twice-daily dose of 5.0 mg day(-1) (for 3 days). 3. The cumulative amount of SGO excreted within approximately the first 8-12h was comparable with MA, and the amount in the first 72 h was 2.0-7.8 times larger (2.8-13.2% of the dose) than that of DM-SG. 4. These results demonstrate that SGO can be used in place of DM-SG, which is known to be a main specific metabolite of SG, as a new indicator for the discrimination of SG use compared with MA abuse.
14C-Deprenyl binding to serum proteins has been investigated using equilibrium dialysis and gel chromatography. Experiments in the equilibrium dialysis cells were performed both for binding of deprenyl to the serum proteins and the dissociation of the previously serum bound deprenyl. Comparative investigations were made with substance E, this reference compound showed reversible binding contrary to deprenyl that remained partially irreversibly bound to the serum proteins even in such conditions when substance E became totally released.
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The blockade of spinal glycine receptors with intrathecal (i.t.) strychnine (STR) produces reversible, segmentally localized allodynia in the rat. The purpose of this study was: (1) to investigate the effect of the anticonvulsant agent, milacemide, a glycine pro-drug on STR-allodynia; (2) to compare this effect with that of milacemide on normal nociception (without STR); and (3) to determine the sensitivity of the anti-allodynic effect of milacemide to pretreatment with selective monoamine oxidase (MAO)-A (clorgyline) and MAO-B (L-deprenyl) inhibitors. Male Sprague-Dawley rats, fitted with chronic i.t. catheters, were lightly anesthetized with urethane. Hair deflection (HD) evoked maximum changes in blood pressure and heart rate were recorded from left carotid artery, and cortical electroencephalographic (EEG) activity was continuously monitored using subdermal needle electrodes before and after i.t. STR (40 microg). Rats were pretreated with a single intravenous (i.v.) injection of milacemide (100-600 mg/kg), 1 h before i.t. STR. To sustain the allodynic state, STR was injected every hour for up to 4 h. HD was applied to the affected dermatomes (2 min duration) using a cotton-tipped applicator at 5-min intervals for the duration of the STR effect. Normally innocuous HD elicited a marked increase in mean arterial blood pressure and heart rate, an immediate motor responses, and desynchronisation of EEG when applied to the cutaneous dermatomes affected by i.t. STR. Milacemide (100-600 mg/kg, i.v.) dose-dependently inhibited the heart rate and pressor responses (ED50 = 398 mg/kg; 95%CI = 196-873) and the motor responses (ED50 = 404 mg/kg; 95%CI = 275-727). Maximum inhibition was observed approximately 2 h after i.v. injection. The duration of action ranged from 3 h (400 mg/kg) to 4 h (600 mg/kg). Milacemide had no effect on the percent synchrony in the EEG. At the time of maximum inhibition of STR-allodynia (2 h post-infusion), responses evoked by noxious pinch were unaffected by milacemide. Pretreatment with L-deprenyl (3 mg/kg, i.p.), but not clorgyline (10 mg/kg, i.p.) significantly blocked the anti-allodynic effect of milacemide (600 mg/kg i.v). These data indicate that i.v. milacemide significantly attenuates the allodynia arising from spinal glycine receptor blockade, and are consistent with: (1) the selective modulation of low threshold afferent input by STR-sensitive, glycine interneurons in the rat spinal cord; and (2) the pharmacological actions of milacemide as a glycine pro-drug.
The cerebrovascular actions of phenylethylamine, an amine that has been implicated in the pathogenesis of migraine, were investigated in 16 anesthetized baboons. The influence of monoaminergic blocking agents and of a specific inhibitor of monoamine oxidase upon the cerebral circulatory and metabolic actions of phenylethylamine were examined. The reductions in cerebral blood flow (28 percent) and cerebral oxygen consumption (31 percent) that accompany the intracarotid administration of phenylethylamine (2 X 10(-6) moles per kilogram per minute) were unaffected by the prior administration of either phenoxybenzamine (1.5 mg per kilogram, IV) or pimozide (0.5 mg per kilogram, IV). The administration of phenoxybenzamine and pimozide per se did not significantly disturb cerebral blood flow or oxygen consumption. The ability of migraine patients to oxidatively deaminate phenylethylamine is reduced at the time of their attacks. In the present experiments, the administration of the monoamine oxidase type B inhibitor, deprenyl (1 mg per kilogram, IV), did not effect significant changes in cerebral blood flow or cerebral oxygen consumption. However, following deprenyl, the administration of phenylethylamine (4 X 10(-8) moles per kilogram per minute), a concentration which was without effect in normal animals, significantly reduced cerebral blood flow. Some of the possible mechanisms influencing the sensitivity of the cerebral circulation to phenylethylamine, and their relationship to migraine, are considered.
At the end of the 2-year period, 33% of patients had been institutionalized. The NHP patients did not differ at baseline from the not-NHP patients in gender, age, caregiver status, duration of illness, CDR sum of boxes, BDRS, or dependence level. The NHP patients had a lower baseline Mini-Mental State Examination score and a slightly worse BRSD total score. Patients reaching CDR3 were eight times more likely to be institutionalized than those who remained at CDR2. The change scores on all four dementia severity measures were strongly associated with NHP; the change score on the BRSD and its subscales were not. On the other hand, adverse events that included a behavioral disturbance, especially agitation, were associated with NHP.
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Idiopathic Parkinson's disease may derive from the action of an environmental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like compound. Monoamine oxidase (MAO) B converts MPTP to an actual neurotoxin, 1-methyl-4-phenylpyridinium (MPP+) whilst prior administration of an MAO B inhibitor, (-)deprenyl, prevents the conversion. There is preliminary evidence that this drug can interrupt the pathological process in Parkinson's disease and prolong life expectancy. Thus, markers should be sought to identify the premorbid parkinsonian condition, prior to long-term (-)deprenyl treatment. Possibly approaches are by monitoring putative overactivity of the dopamine degrading enzymes, phenolsulphotransferase and MAO B, narrowing the field down further by PET-scan after administering a positron-emitting dopa analogue, 6-18F-labelled dopa.
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This article reviews the current status of therapy with acetylcholine-enhancing compounds in the management of patients with Alzheimer's disease. The focus is on pivotal articles investigating the role of cholinergic augmentation strategies, including precursor loading and acetylcholinesterase (AChE) inhibitors, in the management of cognitive and noncognitive symptoms of Alzheimer's disease. Precursor loading strategies have been for the most part unimpressive. By contrast, studies with AChE inhibitors--tacrine and donepezil--have been promising. For patients in whom hepatotoxicity and gastrointestinal side effects were not problematic, tacrine improves cognitive performance and selected secondary psychiatric symptoms and significantly delays nursing home placement. Donepezil, recently approved for use in mild to moderate Alzheimer's disease, appears to be less toxic and better tolerated than tacrine. It improves performance on cognitive testing and, in one preliminary investigation, demonstrated a sustained drug effect over several years. Therapy with AChE inhibitors provides modest significant symptomatic improvement in patients with mild to moderate Alzheimer's disease.
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Postulated cytoprotective action of (-)-deprenyl (D), (-)-desmethyl-deprenyl (DD) and (-)-deprenyl-N-oxide (DNO) on L-buthionine-(S,R)-sulfoximine (BSO) toxicity was investigated using in vitro cultures of serum-deprived A-2058 melanoma cells. BSO (10 microM/l) decreased viable cell number and mitotic rate, while increased the apoptotic index. D and both of its metabolites, given together with BSO in the concentration of 50 microM/l, mitigated cell loss and decreased the apoptotic ratio. DD was the most effective compound in decreasing apoptotic activity, while DNO stabilized the cell number on control level and increasing the ratio of mitotic cells above the only serum-deprived control. Surveillance on mitochondrial membrane stability and antioxidant properties may play an important role in these processes.
Baseline expectancies were not associated with abstinence outcomes; however, expectancies changed over time with changes in smoking, and the greatest changes were seen with smoking abstinence. Information about the relationship between smoking beliefs and behaviors may be used to enhance or tailor smoking cessation treatments.
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Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study.
Dopaminergic drug treatment is persistently reduced and simplified following chronic STN-DBS for up to 3 years.