Safety comparisons among monoamine oxidase inhibitors against Parkinson's disease using FDA adverse event reporting system.

Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson's disease (PD). Selegiline, rasagiline, and safinamide are widely used as MAO-B inhibitors worldwide. Although these drugs inhibit MAO-B, there are pharmacological and chemical differences, such as the inhibitory activity, the non-dopaminergic properties in safinamide, and the amphetamine-like structure in selegiline. MAO-B inhibitors may differ in adverse events (AEs). However, differences in actual practical clinics are not fully investigated. A retrospective study was conducted using FAERS, the largest database of spontaneous adverse events. AE signals for MAO-B inhibitors, including selegiline, rasagiline, and safinamide, were detected using the reporting odds ratio method and compared. Hypocomplementemia, hepatic cyst, hepatic function abnormal, liver disorder and cholangitis were detected for selegiline as drug-specific signals. The amphetamine effect was not confirmed for any of the three MAO-B inhibitors. The tyramine reaction was detected as an AE signal only for rasagiline. Moreover, the REM sleep behavior disorder was not detected as an AE signal for safinamide, suggesting that non-dopaminergic effects might be beneficial. Considering the differences in AEs for MAO-B inhibitors will assist with the appropriate PD medication.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.

Orthostatic hypotension: a non-motor complication assessment in 82 patients with idiopathic Parkinson's disease in Phramongkutklao Hospital.

OBJECTIVE: Parkinson's disease (PD) is one of the neurogenic etiologies of orthostatic hypotension, a non-motor symptoms complex, that tends to be under-recognized and under-treated leading to a major cause of disability for PD patients. This complication is associated with one or recurrent falls causing mortality and morbidity. To the authors' knowledge, there is no study about this condition in Thai PD population. The authors therefore aimed to determine the frequency, clinical and risk factors of orthostatic hypotension in PD patients treated in Phramongkutklao Hospital. MATERIAL AND METHOD: The authors enrolled consecutive patients with idiopathic PD over a 10-month period. Supine and standing blood pressure (BP) were measured sequentially as the standard techniques. Orthostatic hypotension (OH) was diagnosed if there was a reduction in systolic or diastolic BP of at least 20 or 10 mmHg respectively within 3 minutes after standing. The authors analyzed for the frequency of this condition as well as determined the risk factors between the OH and non-OH groups. RESULTS: The number of patients enrolled was 82 with the mean age of 69 years. The median duration of PD was 4 years. Eighty-five percent were in Hoehn & Yahr stage 1-3. Thirty-three patients (40.2%) had orthostatic hypotension and 70% of them were asymptomatic. By univariate and multivariate analysis, the risk factors for this condition were the longer duration of PD diagnosis, the more advanced staging and the use of selegiline. CONCLUSIONS: The frequency of orthostatic hypotension among the present PD was 40.2%. The longer duration of disease, the more advanced stage of Parkinson's disease and selegiline usage were the factors associated with this non-motor condition.

A double-blind, placebo-controlled, randomized clinical trial of oral selegiline hydrochloride for smoking cessation in nicotine-dependent cigarette smokers.

AIM: The primary aim of this study was to determine the safety and efficacy of the monoamine oxidase-B (MAO-B) inhibitor selegiline hydrochloride (SEL, l-Deprenyl; Eldepryl) as an aid for smoking cessation in cigarette smokers. METHODS: One hundred and one nicotine-dependent adult cigarette smokers without current psychiatric or substance use disorders participated in this 8-week randomized, double-blind, placebo-controlled trial. Participants received either SEL (5mg bid, n=51) or placebo (PLO, n=50), in combination with brief (<10 min) manualized smoking cessation counseling. The main smoking outcome measures were 7-day point prevalence abstinence at end of trial (EOT), 4-week continuous smoking abstinence at end of trial (CA), and 7-day point prevalence abstinence at 6-month follow-up (6MFU). Abstinence was determined by an absence of self-reported cigarette smoking and biochemically verified by expired breath carbon monoxide and plasma cotinine levels. RESULTS: Rates of smoking abstinence did not differ by medication group (EOT: SEL=16%, PLO=20%, p=0.57; CA: SEL=14%, PLO=18%, p=0.56; 6MFU: SEL=12%, PLO=16%, p=0.54). Adverse events were modest and comparable between medication groups. Participants receiving SEL were more likely than those receiving PLO to report dry mouth (25.5% versus 8.2%, p<0.05). CONCLUSIONS: Our results suggest that SEL was safe and well-tolerated by adult cigarette smokers, but did not improve smoking abstinence rates compared to PLO.

Community and long-term care management of Parkinson's disease in the elderly: focus on monoamine oxidase type B inhibitors.

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.

Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of 'off' episodes in patients with Parkinson's disease.

OBJECTIVE: Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility ('off' episodes) between doses. This study assessed adjunctive Zelapar (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety. METHODS: This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5 mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25 mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings. RESULTS: This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6 h) for patients previously given selegiline ODT, 6.0% (1.2 h) for those switched from placebo, and 8.1% (1.4 h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation. CONCLUSIONS: Long-term selegiline ODT 2.5 mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.

Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs.

Drug abuse and human immunodeficiency virus (HIV) infection seem to cause cumulative damage in the central nervous system (CNS). Elevated extracellular dopamine is thought to be a prime mediator of the reinforcing effects of addictive substances. To investigate the possible role of increased dopamine availability in the pathogenesis of HIV dementia, simian immunodeficiency virus (SIV)-infected monkeys were treated with dopaminergic drugs (selegiline or L-DOPA). Both substances increased intracerebral SIV expression, combined with aggravation of infection-related neuropathology and ultrastructural alterations of dendrites in dopaminergic areas (spongiform polioencephalopathy) in asymptomatic animals. Moreover, this treatment resulted in enhanced TNF-alpha expression in the brains of SIV-infected animals. These findings indicate a synergistic interaction between dopamine and SIV infection on microglia activation, leading to increased viral replication and production of neurotoxic substances. Our results suggest that increased dopamine availability through dopaminergic medication or addictive substances may potentiate HIV dementia.

Selegiline: a second look. Six years later: too risky in Parkinson's disease.

(1) The reference treatment for Parkinson's disease is levodopa plus a peripheral dopadecarboxylase inhibitor (benserazide or carbidopa). (2) In 1996, selegiline, a type B MAOI marketed in France since 1988, saw its indications extended to cover single-agent therapy of early-stage Parkinson's disease, and in combination with levodopa, before onset of complications of levodopa therapy. The initial clinical file failed to show that selegiline had any benefit in these indications. (3) Now, in 2002, new data from trials involving hundreds of untreated patients show that selegiline postpones the need for levodopa therapy for a few months but fails to substantially alter the progression of Parkinson's disease. (4) A clinical trial and a retrospective epidemiological study of patients with advanced Parkinson's disease showed excess mortality on selegiline. (5) The side effects of selegiline are similar to those of other antiparkinsonian drugs and amphetamine. Notable side effects include cardiovascular problems (postural hypotension, atrial fibrillation and arterial hypertension). (6) Selegiline can cause a serotoninergic syndrome and arterial hypertension, so must not be combined with pethidine, tramadol, bupropion, sumatriptan, zolmitriptan or naratriptan. Concurrent treatment with serotonin reuptake inhibitor antidepressants should also be avoided. (7) Given the only moderate effects of selegiline in Parkinson's disease, and the possibility of a slight increase in mortality, there is no justification for prescribing this medication in patients with Parkinson's disease. (8) Whatever the stage of Parkinson's disease, there is no justification for starting patients on selegiline. Patients who are already taking selegiline should only continue to take it if they feel a clear benefit and are free from risk factors for early mortality, especially cardiovascular disease.

[Serotonin syndrome: report of a fatal case and review of the literature]. / Síndrome serotoninérgico: presentación de un caso de evolución letal y revisión de la literatura.

We report here the case of a patient with fluoxetine and selegiline induced serotonin syndrome, which presented as encephalopathy, generalized myoclonias, fever, stiffness and sweating, complicated with acute renal failure, rhabdomyolysis and disseminated intravascular coagulation findings. The patient died 6 days after admission. This syndrome is discussed, with an analysis of its causes, pathophysiology and therapy. A special emphasis is placed on the clinical issues and differential diagnosis with the malignant neuroleptic syndrome and other clinical entities with which it could be mistaken. General recommendations are provided to avoid this poorly characterized syndrome that, as in our patient, may have a fatal outcome.

Medical treatment of canine pituitary-dependent hyperadrenocorticism (Cushing's disease).

Pituitary-dependent hyperadrenocorticism (Cushing's disease) is a relatively common endocrine disorder of middle- to old-age dogs. Three treatments commonly used in the management of pituitary-dependent Cushing's disease in dogs include mitotane, ketoconazole, and L-deprenyl. These medications are associated with the potential of different side effects and expense, but all can produce satisfactory results in dogs with this disease. The choice of treatment for a given dog depends on the severity of the dog's disease, as well as clinician and client preferences. This article reviews the indications and adverse effects associated with each of these three drugs, as well as the treatment protocols commonly used in treating dogs with hyperadrenocorticism.

Neurorescuing effects of the GAPDH ligand CGP 3466B.

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.

Single-blind, placebo phase-in trial of two escalating doses of selegiline in the chronic fatigue syndrome.

AIM: To perform a clinical trial of selegiline in 25 patients with chronic fatigue syndrome (CFS) where patients were told they would receive placebo or active agent at different times during the 6-week trial. We chose selegiline, a specific monoamine oxidase (MAO) B receptor inhibitor, because a prior trial of lowdose phenelzine, a nonspecific MAO inhibitor, showed a small but significant therapeutic effect. METHODS: Questionnaires comprised of 19 tests of mood, fatigue, functional status and symptom severity were collected at the start and end of the trial as well as 2 weeks after its start. The trial was done in three 2-week blocks: in the first, 2 placebo pills were given per day; in the next, one 5-mg tablet of agent and one placebo were given per day, and in the last, a 5-mg tablet of agent was given twice a day. The plan was to compare the changes in the 19 tests during the placebo phase to those found in the active treatment phase in 19 patients completing the trial. FINDINGS: Significant improvement in 3 variables-tension/anxiety, vigor and sexual relations-was found. A significant pattern of improvement compared to worsening was found for the 19 self-report vehicles during active treatment as compared with placebo treatment. Evidence for an antidepressant effect of the drug was not found. CONCLUSIONS: Selegiline has a small but significant therapeutic effect in CFS which appears independent of an antidepressant effect.

Cortisol is higher in parkinsonism and associated with gait deficit.

INTRODUCTION: We propose an active pathogenic mechanism, involving circulating cortisol, in parkinsonism. MATERIALS AND METHODS: Serum cortisol was measured in 96 subjects with idiopathic parkinsonism, 170 without, and in 17 spouses and 36 siblings of elderly sufferers with double the number of controls, all obeying inclusion/exclusion criteria. RESULTS: Cortisol, adjusted for sampling time, was greater (17%, on average, P<0.001) in parkinsonians, but not in relatives. The central cortisol lowering effect of anti-muscarinics was seen (P=0.025). Selegiline may attenuate the disease, and parkinsonism is less frequent in tobacco smokers. Selegiline was associated with a lower cortisol (P=0.03): chronic smoking appeared (P=0.08) to be, irrespective of parkinsonism. Bowel stasis has been implicated in the pathogenesis: cortisol was higher in parkinsonians requiring laxatives (P=0.05). In controls, cortisol was lower, the longer the stride (P=0.02): in parkinsonians, this relationship was numerically reversed. A similar (P=0.01) group performance interaction was seen for deterioration, over 4 years, in gait. CONCLUSION: Cortisol is doing harm or mirroring something which is. A common pathway for neuronal protection/rescue emerges.

Monoamine oxidase inhibitors and cardiac anesthesia revisited.

There are well-recognized adverse interactions between the monoamine oxidase inhibitors and anesthetic drugs, particularly narcotics. Patients having cardiopulmonary bypass procedures are commonly anesthetized using high-dose narcotic techniques. We describe an uneventful perioperative course in a parkinsonian patient who required urgent coronary artery bypass graft surgery while he was taking selegiline, a selective inhibitor of monoamine oxidase type B.

Retrospective study of selegiline-antidepressant drug interactions and a review of the literature.

Selegiline is a selective monoamine oxidase inhibitor used in the treatment of Parkinson's disease. It is estimated that approximately one-half of Parkinsonian patients will develop depression requiring antidepressant drug treatment. Recently, selegiline's package insert was revised to reflect the potential risk of adverse effects when it is used in combination with selective serotonin reuptake inhibitors and tricyclic antidepressants. The objective of our study is to assess the safety of combining selegiline with antidepressants. A retrospective chart review was performed on all 28 patients with Parkinson's disease receiving selegiline and antidepressants concurrently to identify possible drug interactions. Compliance was assessed according to prescription refill records. Suspected adverse reactions with combination therapy were documented. There was a total of 40 selegiline-antidepressant drug combinations involving tricyclic antidepressants (n = 25), selective serotonin reuptake inhibitors (n = 7), trazodone (n = 5), and bupropion (n = 3). One patient receiving fluoxetine developed a reaction consistent with the serotonin syndrome; however, it was never documented as such. No other selegiline drug interactions were found. Adverse effects noted were typical of antidepressant monotherapy. Although no selegiline drug interactions were documented in our study, the concurrent administration of selegiline and selective serotonin reuptake inhibitors should be avoided because of literature-reported interactions. We believe that bupropion, tricyclic antidepressants, and trazodone are reasonable choices in combination with selegiline, although tricyclic antidepressants and trazodone may be reserved as second-line treatments.

The pharmacology of B-type selective monoamine oxidase inhibitors; milestones in (-)-deprenyl research.

(-)-deprenyl cannot be considered as a simple, selective inhibitor of MAO-B. It increases the dopaminergic tone in the central nervous system by a complex mechanism. The MAO-B inhibition could result in a potentiation of the effect and the reduction of the dose of L-dopa, including the restoration of the sensitivity to L-dopa treatment, when the response to the drug has already been diminished or lost. Pre-treatment with (-)-deprenyl prevent the effect of neurotoxins like MPTP, 6-hydroxydopamine, DSP-4, AF64A by inhibiting the conversion of the pretoxin to toxin, or by inhibiting the neuronal reuptake mechanisms, or the combination of the two processes. However, other effects of the inhibitor cannot be ruled out. (-)-deprenyl, but not its (+)-enantiomer, proved to be a potent inhibitor of programmed cell death (apoptosis) of PC12 cells and that of human melanoma cells, in a concentration which does not induce MAO-B inhibition. The activity of MAO-B increases with age and the age related changes led to an overproduction of neurotoxic agents. The inhibition of the enzyme activity can play a preventive role against neurodegenerative brain disorders. The most widely used MAO-B inhibitor in the therapy is (-)-deprenyl and it lacks the "cheese reaction". The complex mechanism for the lack of the former effect is not fully known.

Pseudo-phaeochromocytoma after multiple drug interactions involving the selective monoamine oxidase inhibitor selegiline.

A patient presented with paroxysmal hypertension and typical clinical features of phaeochromocytoma, but with a normal adrenal computed tomographic scan and much higher plasma noradrenaline than adrenaline concentrations. Urinary vanillylmandelic acid concentrations were only moderately elevated. This syndrome probably arose as a consequence of an interaction between the monoamine oxidase inhibitor selegiline, the sympathomimetic agent ephedrine, and a tricyclic antidepressant. The mechanism of the interaction is thought to be related to increased sympathetic release of noradrenaline by ephedrine, inhibition of catabolism by selegiline, and inhibition of reuptake of noradrenaline by the tricyclic. Although newer selective monoamine oxidase inhibitors are considered to be safer than earlier non-selective inhibitors, they can also contribute to drug interactions mimicking phaeochromocytoma.