Monoamine Oxidase Type B Inhibitors Research Articles

Role of rasagiline in treating Parkinson’s disease: effect on disease progression

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson's disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off", and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.

Pharmacologic treatment of advanced Parkinson's disease: A meta-analysis of COMT inhibitors and MAO-B inhibitors

Objective To perform a meta-analysis of randomized placebo-controlled trials evaluating catechol- O-methyltransferase (COMT) inhibitors or monoamine oxidase type B (MAO-B) inhibitors in addition to levodopa versus levodopa alone for the treatment of advanced Parkinson's disease (PD). Methods A systematic literature search was performed between 1990 and October 2007. The primary outcome measures assessed were the reduction in scores of Unified Parkinson's Disease Rating Scale (UPDRS) total, activities of daily living (ADL) and motor scores from baseline. Other efficacy and safety endpoints were also evaluated. Results A total of 13 trials ( n = 3775 subjects) were included in the meta-analysis. As compared to placebo, COMT and MAO-B inhibitor use resulted in greater improvement in UPDRS total score (weighted mean difference [WMD] −2.13, 95%CI −0.46 to −0.20; and WMD −5.03, 95%CI −7.38 to −2.68) ADL scores (WMD −0.99, 95%CI −1.56 to −0.43; and WMD −1.48, 95%CI −2.13 to −0.83) and motor scores (WMD −1.50, 95%CI −2.70 to −0.30; and WMD −3.19, 95%CI −4.57 to −1.80) as well as increase in “on” time, reduction in “off” time and decreased need in levodopa dose compared to placebo. Incidences of dyskinesia were significantly higher with the COMT and MAO-B inhibitors compared to placebo. Conclusion The use of COMT or MAO-B inhibitors plus levodopa is superior to levodopa alone at reducing PD symptoms in patients with advanced PD. While combination therapies with COMT or MAO-B inhibitor plus levodopa seem especially useful amongst PD patients with wearing-off phenomenon, they are associated with more adverse events.

Assessment of MAO-B Occupancy in the Brain With PET and [11C]-L-Deprenyl-D2: A Dose-Finding Study With a Novel MAO-B Inhibitor, EVT 301

Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.

Monamine Oxidase Inhibitors

Monoamine oxidase type B (MAO-B) is the predominant isoform responsible for the metabolic breakdown of dopamine in the brain. Selective inhibition of brain MAO-B results in elevation of synaptosomal dopamine concentrations. Data have been reported regarding the selective MAO-B inhibitors, rasagiline and selegiline, for the symptomatic treatment of Parkinson disease (PD). Selegiline has demonstrated efficacy as monotherapy in patients with early PD (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study), but evidence of selegiline efficacy as adjunctive treatment in levodopa-treated PD patients with motor fluctuations is equivocal. A new formulation of selegiline (Zydis selegiline) has been evaluated in 2 small, placebo-controlled studies as adjunctive therapy to levodopa. The Zydis formulation allows pregastric absorption of selegiline, minimizing first-pass metabolism, and thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline is a selective, second-generation, irreversible MAO-B inhibitor, with at least 5 times the potency of selegiline in vitro and in animal models. Rasagiline has demonstrated efficacy in 1 large, randomized, double-blind, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) as initial monotherapy in patients with early PD, and in 2 large, controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off," Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily) as adjunctive treatment in levodopa-treated PD patients with motor fluctuations. Unlike selegiline, rasagiline is an aminoindan derivative with no amphetamine metabolites. A randomized clinical trial is underway to confirm preclinical and preliminary clinical data suggesting rasagiline has disease-modifying effects.

Community and Long-Term Care Management of Parkinson???s Disease in the Elderly

Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes.

Rasagiline: A second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson's disease.

The pharmacology, pharmacokinetics, clinical efficacy, and safety of rasagiline are reviewed. Rasagiline is a novel, investigational propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). Rasagiline demonstrates complete and selective inhibition of MAO-B and is at least five times more potent than selegiline. Unlike selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to the nonamphetamine compound aminoindan. Clinical studies have revealed that rasagiline is associated with improved outcomes in patients with early Parkinson's disease (PD) and also reduces "off" time in patients with moderate to advanced PD with motor fluctuations. Rasagiline is rapidly absorbed by the gastrointestinal tract and readily crosses the blood-brain barrier. The optimal therapeutic dosage is 0.5-1 mg administered orally once daily. Rasagiline appears to be well tolerated, although elderly patients may be more prone to treatment-emergent adverse cardiovascular and psychiatric effects. At the recommended therapeutic dosage of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, rasagiline has demonstrated neuroprotective properties in experimental laboratory models. The mechanisms whereby rasagiline exerts neuroprotective effects are multifactorial and include upregulation of cellular antioxidant activity and antiapoptotic factors. Rasagiline is an investigational selective and irreversible inhibitor of MAO-B that has demonstrated efficacy and safety for the treatment of PD. Whether rasagiline is associated with clinically significant neuroprotection is the subject of ongoing clinical trials.

Remarkable Effect of Selegiline (L-Deprenyl), a Selective Monoamine Oxidase Type-B Inhibitor, in a Patient With Severe Refractory Depression

A 34-year-old man presented with severe refractory depression. He had failed to respond to various antidepressants, augmentation therapy with lithium carbonate, and modified electroconvulsive therapy. Switching from amoxapine 150 mg/day to selegiline 7.5 mg/day, a selective monoamine oxidase type-B inhibitor, produced a dramatic reduction in hypobulia and lassitude, leading to a complete remission of all depressive symptoms. The patient reverted to his former position at work after an interval of approximately 3 years. Although the biologic basis of the antidepressant effect of selegiline in this patient is unknown, it is suggested that the enhancement of dopaminergic neurotransmission or elevation of brain-derived neurotrophic factor levels in the brain by administration of selegiline is involved in the recovery of this patient from severe refractory depression. This report indicates the antidepressant effect of selegiline in a refractory depressed patient.

Monoamine oxidase type B inhibitors reduce motor fluctuations, disability and the need for levodopa in people with early Parkinson's disease

QuestionAre monoamine oxidase type B inhibitors (MAOBIs) safe and effective for people with early Parkinson's disease?Study designSystematic review with meta-analysis.Main resultsSeventeen trials involving 3525 people with early Parkinson's disease met inclusion criteria (thirteen selegiline, three lazabemide and one rasagiline). All trials provided information on blinding and reported follow-up data. Treatment duration varied from 6 weeks to 10 years. MAOBIs did not significantly increase deaths compared with controls (20% with MAOBIs ν 21% with control; see results table). At 3 months, selegiline improved activities of daily living scores, motor scores and total scores compared with controls (improvement in activities of daily living score: 0.9, 95%CI 0.5 to 1.4; improvement in motor score: 1.8, 95%CI 0.8 to 2.7; improvement in total score: 2.7, 95%CI 1.4 to 4.1). People taking MAOBIs were less likely to need extra levodopa or develop motor complications than controls. However, MAOBIs did not reduce dyskinesia. Adverse effects were more common with MAOBIs, although there was no difference in study withdrawal between the two groups (see results table).Authors’ conclusionsMAOBIs reduce motor fluctuations, disability and the need for levodopa in people with early Parkinson's disease. There is no evidence that selegiline increases death compared with controls. MAOBIs appear to be safe and effective, but long-term studies are needed.

Carphology by Rajendra

The popularity of monoamine oxidase type B inhibitors (MAOIBs) in early Parkinson’s disease decreased after their use was found to be associated with increased mortality. But a recent meta-analysis of...

Alternatives to Levodopa in the Initial??Treatment of Early Parkinson???s Disease

Parkinson's disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD. Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly. Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations. Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly. Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.

MAO Inhibitors in Early Parkinson Disease

Monoamine oxidase type B inhibitors (MAOBIs), such as selegiline (Eldepryl and generics), have been used in both early and later Parkinson disease (PD)

Tolerability, Safety, Pharmacodynamics, and Pharmacokinetics of Rasagiline: A Potent, Selective, and Irreversible Monoamine Oxidase Type B Inhibitor

To investigate the tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline after once-daily oral administration of single or repeated doses. A randomized, double-blind, placebo-controlled, three-way, single-dose study and a randomized, double-blind, placebo-controlled, repeated-dose study. Clinical research center in France. Healthy male volunteers aged 18-40 years (12 in the single-dose study, 24 in the repeated-dose study). In the single-dose study, subjects received, in a randomized sequence, single doses of placebo, rasagiline 1 mg, and rasagiline 5 mg; or placebo, rasagiline 2 mg, and rasagiline 10 mg. Six subjects received an additional single dose of rasagiline 20 mg. There was a 2-week washout period between each dose. In the repeated-dose study, subjects were randomized to receive rasagiline 2 mg, 5 mg, or 10 mg, or placebo once/day for 10 days. To assess tolerability and safety, patients underwent physical examinations, vital sign measurements, 12-lead electrocardiograms, clinical laboratory testing, and bleeding time studies. To determine platelet monoamine oxidase type B (MAO-B) activity and rasagiline pharmacokinetics, blood and urine samples were taken. In the single-dose study, rasagiline 1-20 mg was well tolerated. Each dose significantly inhibited platelet MAO-B activity. In the repeated-dose study, all doses of rasagiline were well tolerated; almost full inhibition of platelet MAO-B activity was achieved with each rasagiline dose. Rasagiline is well tolerated at doses up to 20 mg once/day and is a potent inhibitor of platelet MAO-B in humans.

Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients

Objective To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinson's disease.Data sources Searches of the Cochrane Library, Medline, Embase, PubMed, and...

Deprenyl changes the expression of Trk-B and P75 NTR receptors in rat after sciatic nerve axotomy

During development many of neurons die by the phenomenon named programmed cell death or apoptosis and this reaction is regulated by neurotrophin (BDNF, NGF, NT3 and NT4/5). These neurotrophins bind to two different classes of transmembrane receptor proteins, the Trks and P75 NTR. Axotomy can induce apoptosis after birth and deprenyl is a an inhibitor of monoamineoxidase type-B and seems to act as a neuroprotective factor and reduces apoptosis after sciatic nerve axotomy. The aim of this research was to study the effect of deprenyl (2.5 mg/kg, i.p.) following axotomy in newborn rat and to study the changes in expression of Trk-B and P75 NTR by RT-PCR. The segment of L4-L6 was studied after sciatic nerve axotomy. This study was conducted on 2 groups, control (normal saline injection) and experimental (deprenyl injection) and each group was classified into 3 subgroups on the basis of the time of injection and axotomy. In all of the 6 subgroups, 4 hours after injection, they were sacrificed and the segments L4-L6 of spinal cord processed by RT-PCR. The results showed that deprenyl increases expression of Trk-B, but decreases expression of P75 NTR as compared to control group.

Reaction profiling of the MAO-B catalyzed oxidative deamination of amines in Alzheimer's disease

Monoamine oxidase type B (MAO-B) catalyzes the oxidative deamination of various endogenous and exogenous primary, secondary, and tertiary amines. During this reaction, reactive oxygen species (ROS) are produced which contribute to the oxidative stress in a biological system. Further, research has indicated that increased MAO-B levels and increased ROS production may lead to deposition of β-amyloid (Aβ) and act as contributing factors to the pathogenesis of Alzheimer's disease (AD). As such, irreversible MAO-B inhibitors like selegiline, which decrease the rate of MAO-B catalyzed oxidative deamination, and thus the production of ROS, may have therapeutic potential via neuroprotection. In the current study, molecular orbital calculations were performed using the complete basis set 4m (CBS-4m) theoretical framework employed within the gaussian 98 software to elucidate the full energetic and thermodynamic profile of the MAO-B catalyzed oxidative deamination reaction. Full geometry optimizations were performed on model compounds to reveal the energies (Δ E) and Gibbs Free Energies (Δ G) of the oxidative deamination reaction as a means to clarify the details of this paramount reaction and how it relates to AD and selegiline's therapeutic potential. Results reveal that the oxidative deamination reaction consists of three successive energy-consuming steps for all amines. Trends indicate that for all amines, as amine substitution increases: (1) energetic investments needed for steps 1 and 3 increase, (2) Δ E Reaction and Δ G Reaction values for the oxidative deamination reaction as a whole increase, (3) differences between Δ G Reaction and Δ E Reaction values increase, and (4) Δ G and Δ E values for step 2 of the reaction decrease. The second step of the MAO-B catalyzed reaction is the only step, where increased amine substitution correlates with decreased Δ E and Δ G values. Due to the fact that step two possesses the lowest investment of energy for tertiary and secondary amines but the highest investment of energy for primary amines, it can be postulated that MAO-B has preferred secondary and tertiary substrates. The fact that step 2 is the rate-limiting step relates to the notion that it modulates the potential to increase oxidative stress, and thus, must be tightly regulated to maintain oxidant and anti-oxidant homeostasis. Finally, in disease states such as AD, where increased MAO-B levels have been documented, it is possible that MAO-B mediated oxidative stress is a contributing factor to AD. Thus, MAO-B inhibition by drugs like selegiline will provide neuroprotective benefits and help to prevent AD pathogenesis.

Recent developments in the pharmacological treatment of Parkinson?s disease

Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.

7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP +) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N G-nitro- l-arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.

Cholinergic neurons with monoamine oxidase type B (MAOB)-activity in the laterodorsal tegmental nucleus of the mouse

No neurons in the laterodorsal tegmental nucleus (LDTg) show monoamine oxidase (MAO) activity in the rat or monkey. However, in our recent study, many LDTg neurons with MAO type B (MAOB)-activity were found in MAOA-deficient mice that were derived from C3H mouse line. In the present study, LDTg neurons with MAOB-activity were found not only in normal C3H mouse but also in BALB/C and C57BL/6 mouse lines: MAO histochemistry revealed LDTg neurons with MAO-activity even after pharmacological suppression of MAOA-activity with clorgyline, a specific MAOA inhibitor, but not after pharmacological suppression of MAOB-activity with deprenyl, a specific MAOB inhibitor. LDTg neurons with MAOB-activity also showed NADPH-diaphorase-activity, a marker of cholinergic neurons.

Safety of selegiline (deprenyl) in the treatment of Parkinson's disease.

Selegiline (deprenyl), a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B) is widely used in the treatment of Parkinson's disease. As the first MAO-B inhibitor approved for the treatment of Parkinson's disease, concerns were raised about the safety of the drug based on the adverse effect profiles of older, nonselective MAO inhibitors. Unlike the nonselective MAO inhibitors, selegiline does not significantly potentiate tyramine-induced hypertension (the 'cheese effect') at the dosages (5 to 10 mg daily) used for the treatment of Parkinson's disease. Selegiline has been well tolerated when given alone. The most frequent adverse events seen during monotherapy have been insomnia, nausea, benign cardiac arrhythmias, dizziness and headache. When combined with levodopa, selegiline can potentiate the typical adverse effects of levodopa, if the dose of levodopa is not reduced sufficiently. Thus, the most common adverse effects associated with this combination are nausea, dizziness, fatigue, constipation and insomnia. At the later stages of Parkinson's disease when fluctuations in disability occur, peak dose dyskinesias, psychiatric complications like hallucinations and insomnia, and orthostatic hypotension are further potentiated by selegiline. Mortality was recently reported to be increased when selegiline and levodopa were given together in comparison with treatment with levodopa alone, but a large meta-analysis of 5 long term studies and 4 separate studies did not support this conclusion. Selegiline seems to be generally well tolerated in combination with other drugs. However, when pethidine (meperidine) has been given to patients who are receiving selegiline therapy, severe adverse effects have been reported. Thus, the concomitant use of these drugs is not recommended. A low tyramine diet is recommended if selegiline is used together with nonselective MAO inhibitors or the selective, reversible MAO-A inhibitor, moclobemide. Several adverse effects have been reported when fluoxetine and selegiline have been used together. A recent survey revealed that the incidence of a true serotonin syndrome is, however, very low with this combination. Concomitant use of selegiline and other selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) like citalopram, which have generally less interactions than fluoxetine, seems to be well tolerated. Nevertheless, caution is advised when combining a SSRI or a tricyclic antidepressant and selegiline.

Desmethylselegiline, a Metabolite of Selegiline, Is an Irreversible Inhibitor of Monoamine Oxidase Type B in Humans

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.