Non-selective MAO Inhibitors Research Articles

Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi’s) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

Novel isoxazole derivatives as potential antiparkinson agents: synthesis, evaluation of monoamine oxidase inhibitory activity and docking studies

Selective monoamine oxidase B inhibitors are potential drug candidates for the treatment of Parkinson’s disease. A series of phenyl substituted isoxazole carbohydrazides was designed by structural modification of isocarboxazid, a nonselective MAO inhibitor and evaluated as inhibitors of MAO-A and MAO-B. The compounds were not able to inhibit MAO-A significantly, but most of the compounds exhibited potent inhibitory activity against MAO-B. The enzyme kinetic study of the most active compounds 5d, 5-phenyl-N′-(1-(p-tolyl)ethylidene)isoxazole-3-carbohydrazide and 5g, N′-(1-(3,4-dimethoxyphenyl)ethylidene)-5-phenylisoxazole-3-carbohydrazide displayed reversible and competitive MAO-B inhibition. In molecular modeling studies, compounds 5d and 5g exhibited strong binding affinity on MAO-B active site. The administration of compounds 5d and 5g exhibited prevention of MPTP-induced Parkinsonism as indicated by footprint analysis and horizontal wire tests. Further optimization studies are essential to exploit their potential for MAO-B associated neurodegenerative pathologies.

Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson's disease.

The era of MAO-B inhibitors dates back more than 50years. It began with Kálmán Magyar's outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called 'cheese effect'. Since MAO-B is involved mainly in the degradation of dopamine, the inhibitors lack any antidepressant effect; however, they became first-line medications for the therapy of Parkinson's disease based on their dopamine-sparing activity. Extensive studies with selegiline indicated its complex pharmacological activity profile with MAO-B-independent mechanisms involved. Some of these beneficial effects, such as neuroprotective and antiapoptotic properties, were connected to its propargylamine structure. The second MAO-B inhibitor approved for the treatment of Parkinson's disease, rasagiline also possesses this structural element and shows similar pharmacological characteristics. The preclinical studies performed with selegiline and rasagiline are summarized in this review.

New trends in the neurobiology and pharmacology of affective disorders

Although depression is a common disorder that is often resistant to pharmacotherapy, its pathophysiology has remained elusive. Since the early 1950s, when the first antidepressants were introduced, i.e., the non-selective MAO inhibitors and tricyclic drugs, a number of hypotheses describing ethiopathogenesis of depression and antidepressant drug action have been formulated. The Institute of Pharmacology, the Polish Academy of Sciences has performed experimental and clinical research focused on the pathophysiology of depression and the mechanisms of action of antidepressant drugs for over 40 years. Our results from this period have significantly contributed to understanding the complex mechanisms of antidepressant drug actions and new pathways that underpin the pathophysiology of depression. Most of these theories are based on the finding that the chronic administration of antidepressants leads to adaptive changes in pre- and post-synaptic monoaminergic and glutamatergic neurotransmission as well as to alterations in gene transcription and immune-inflammatory and neurotrophic factors, resulting in neuroplastic changes in the brain. Taking into account the functional interdependence of the neuronal, hormonal and immunologic systems, we propose neurodevelopmental and neuroimmune theories for affective disorders. Moreover, commonalities have been documented for the pathomechanisms of depression and neurodegenerative and metabolic disorders as well as drug dependence. The aim of this special issue is to briefly present the major research contributions and the new research directions of the Institute of Pharmacology, the Polish Academy of Sciences with respect to the neurobiology of affective disorders and the mechanisms of action of marketed and new putative antidepressant drugs.

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine β-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 μM, and 43.9 μM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 μM, and 42.5 μM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 μM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 μM and this value was higher than that of deprenyl (0.046 μM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 μM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.

Anxiety-like behavior and cognitive flexibility in adult rats perinatally exposed to increased serotonin concentrations

Serotonin (5-hydroxytryptamine, 5HT) is a biologically active amine that regulates the development of 5HT neurons and target tissues during neurogenesis, while later it assumes the function of a neurotransmitter. Serotonin mediates many essential behaviors common to all mammals, and is held responsible for anxiety-like behavior and cognitive rigidity. Proper serotonin levels, controlled through 5HT synthesis and metabolism, are crucial for normal brain development. In this study we investigated anxiety-like behavior and cognitive flexibility in adult animals after exposing their developing brains to increased 5HT concentrations. Wistar rats were treated subcutaneously from gestational day 12 to post-natal day 21 with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25mg/kg), a non-selective MAO inhibitor tranylcypromine (TCP, 2mg/kg), or saline. After reaching adulthood, animals were tested for anxiety-like behavior (exploratory behavior, thigmotactic behavior, social contact, and reaction to stressful stimulus) and cognitive flexibility (ability for reversal learning). Results of the behavioral studies corresponded with our previous neurochemical findings. Treatment with 5HTP, which has induced mild reduction in cortical 5HT concentrations, caused reduction in only one aspect of anxiety-like behavior (increased exploratory activity). Treatment with TCP, which lead to drastic reduction in 5HT concentration/function, resulted in a highly anxiolytic phenotype (reduced thigmotaxis, reaction to stress, and social anxiety) with improved cognitive flexibility. Although further neurochemical, anatomical and gene-expression studies are needed to elucidate the mechanisms underlying the observed behavior, we hope that our results will contribute to the understanding of the role of serotonin in anxiety-like behavior and cognitive rigidity.

Pharmacologic Safety Concerns in Parkinson's Disease: Facts and Insights

ABSTRACTKnowledge and insight of pharmacologic safety issues and drug interactions are important for medical management of Parkinson's disease (PD). This review will discuss several topics, including apomorphine safety and interactions, impulsivity and excessive daytime somnolence associated with dopamine agonists (DAs), tolcapone hepatotoxicity, and monoamine oxidase type-B (MAO-B) inhibitor drug interactions. Initiation of apomorphine requires antiemetic prophylaxis to minimize nausea and orthostatic hypotension. Centrally acting antidopaminergic antiemetics will worsen parkinsonism and block the therapeutic effects of apomorphine and should be avoided. Additionally, serotonin 5-HT3 receptor antagonist antiemetics should be avoided on the basis of limited clinical data suggesting lack of efficacy for apomorphine-induced nausea. Dopamine-agonist-induced impulsivity and daytime somnolence are not uncommon. When severe, these effects can be disabling and unsafe. Tolcapone-induced hepatotoxicity has been significantly minimized with routine monitoring of liver enzymes, especially during the initial 6 months of therapy. Early detection of abnormal results will allow tolcapone discontinuation before progression to fulminant hepatotoxicity. In patients treated with selective MAO-B inhibitors, the risk of serotonin toxicity (ST) due to a concomitant serotonergic agent (e.g., antidepressants, dextromethorphan, serotonergic analgesics) or hypertensive crisis due to dietary tyramine or sympathomimetic amines appears to be minimal and is based on isolated case reports and overgeneralizations from nonselective MAO inhibitor pharmacology. Concerns about ST or hypertensive crisis should not preclude or restrict clinicians from using MAO-B inhibitors in patients with PD.

The effects of the perinatal treatment with 5-hydroxytryptophan or tranylcypromine on the peripheral and central serotonin homeostasis in adult rats

Serotonin (5HT) is a biologically active amine present in mammals in the brain and the peripheral tissues. Autism is a neurodevelopmental disorder in which 5HT homeostasis is disturbed both centrally and peripherally, but the relationship between the 5HT disturbances in the two compartments is not understood. In an attempt to explore the relationship between the disturbed peripheral 5HT homeostasis and central 5HT functioning, we exposed the developing rat brain to increased 5HT concentrations, by treatment of rats with subcutaneous injections of the immediate 5HT precursor 5-hydroxy-l-tryptophan (5HTP, 25mg/kg), or the non-selective MAO inhibitor tranylcypromine (TCP, 2mg/kg), during the period of the most intensive development of 5HT neurons – from gestational day 13 to post-natal day 21. The effects of the mentioned treatments on peripheral and central 5HT levels were then studied in adult rats. Platelet and plasma 5HT concentrations (measured by ELISA), as well as cortical and midbrain 5HT, tryptophan and 5-hydroxyindoleacetic acid levels (measured by HPLC) were determined in twelve 5HTP treated and eight TCP treated rats, and compared with the values measured in 10 control, saline treated rats. Treatment with 5HTP significantly raised peripheral but not central 5HT concentrations. At adult age, peripheral 5HT homeostasis was re-established, while modest decrease in 5HT concentration was observed in frontal cortex, presumably due to hyperserotonemia-induced loss of 5HT terminals during brain development. Treatment with TCP induced significant 5HT elevations in both compartments. At adult age, permanent changes in 5HT homeostasis were observed, both peripherally (as hyperserotonemia) and centrally (as altered 5HT metabolism with decreased 5HT concentrations). Further studies are planned in order to explore the nature of the different disturbances of 5HT homeostasis induced by the two compounds, and their results are expected to shed some light on the role of hyperserotonemia in autism.

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine

Monoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of beta-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of beta-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose beta-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased beta-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in beta-phenylethylamine.

Perinatal treatment

Abstract Serotonin (5-hydroxytryptamine, 5HT) regulates the development of 5HT neurons and target tissues during neurogenesis, while later it assumes the function of a neurotransmitter. Alterations in serotonin neurotransmission are indicated as biological substrates in several neuropsychiatric disorders, including autism. The most consistent 5HT-related finding in autistic disorder is hyperserotonemia, but the mechanism of its development and its relation to central 5HT dysfunction are still unclear. In an attempt to pharmacologically induce hyperserotonemia during the period of most intensive development of 5HT neurons, and to later investigate its effects on central 5HT functions, we have treated rats from gestational day 13 until postnatal day 21 with 2 mg/kg of the nonselective irreversible MAO inhibitor tranylcypromine (TCP). The control group received saline in the same manner. TCP treated rats displayed a long-lasting significant increase in platelet 5HT concentrations compared to the control rats. The TCP treated group had smaller litters, significantly lower pup survival rate, and slower weight gain during the post-weaning free-feeding period than the control group. Pups from the TCP group returned to their dams significantly slower than the control pups suggesting lower separation anxiety. Our results indicate that the perinatal treatment of rats with tranylcypromine has induced both, disregulation of the peripheral 5HT homeostasis and disturbances in central 5HT physiology in pups and young rats. The extent of the changes in the central serotonergic compartment in adult rats will be explored in our further studies.

Effects of tyramine administration in Parkinson's disease patients treated with selective MAO‐B inhibitor rasagiline

Rasagiline is a novel, potent, and selective MAO-B inhibitor shown to be effective for Parkinson's disease. Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. To test safety, tyramine challenges (50-75 mg) were performed in 72 rasagiline-treated and 38 placebo-treated Parkinson's disease (PD) patients at the end of two double-blind placebo-controlled trials of rasagiline. An abnormal pressor response was prespecified as three consecutive measurements of systolic blood pressure (BP) increases of >or= 30 mm Hg and/or bradycardia of < 40 beats/min. In the first study involving 55 patients with early PD on rasagiline monotherapy, no patients randomized to rasagiline (1 mg/2 mg; n = 38) or placebo (n = 17) developed systolic BP (SBP) or heart rate changes indicative of a tyramine reaction. In the second trial involving 55 levodopa-treated patients, 3 of 22 subjects on rasagiline 0.5 mg/day and 1 of 21 subjects on placebo developed asymptomatic, self-limiting SBP elevations >or= 30 mm Hg on three measurements. No subject on 1 mg/day rasagiline (0/12) experienced significant BP or heart rate changes following tyramine ingestion. These data demonstrate that rasagiline 0.5 to 2 mg daily is not associated with clinically significant tyramine reactions and can be used as monotherapy or adjunct to levodopa in PD patients without specific dietary tyramine restriction.

Selegiline in the Treatment of Negative Symptoms of Schizophrenia

Key words: Selegiline; schizophrenia; negative symptoms; neurotherapeutics; clinical trial. Introduction and Overview One of the great successes of modern psychiatry was the introduction of antipsychotic drugs over 50 years ago (Ayd & Blackwell, 1970). The impressive effectiveness of these agents in relieving florid positive symptoms of schizophrenia has permitted a whole population of formerly institutionalized patients to live in the community. Unfortunately, this great benefit has not been matched by the effect of antipsychotic drugs on the negative symptoms of schizophrenia, which so limit the daily function of these patients, and classical neuroleptics often worsened these symptoms. More recently, atypical antipsychotics have shown improved properties in this regard, but negative symptoms remain the least medication-responsive features of chronic schizophrenia. The impoverishment of emotion and initiative that underlie negative symptoms resemble symptoms affecting patients with Parkinson's disease, as well as the pseudo-parkinsonian effects of first-generation antipsychotics, and has been hypothesized to reflect specific deficits in the functioning of dopaminergic pathways (Bermanzohn & Siris, 1992; Davis et al ., 1991). Selegiline (formerly 1-depreny1) is a dopamine enhancing antiparkinsonian drug (Knoll, 1983), which acts as a selective monoamine oxidase type B (MAO-B) inhibitor without the clinical toxicities that have limited the use of non-selective MAO inhibitors (MAOIs) in psychiatry. The potential of selegiline to alleviate some of the parkinsonian-like emotional deficits of schizo-phrenics has led to a series of investigations of its use as a specific remedy for negative symptoms over the past 15 years.

Inhibition of MAO‐A Activity Enhances Behavioural Activity of Rats Assessed Using Water Maze and Open Arena Tasks

To determine if the inhibition of MAO-A and/or MAO-B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, 1-deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), 1-deprenyl (0.25 mg/kg) and pargyline (I or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days: I trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO-A inhibitor), 1-deprenyl (MAO-B inhibitor) and pargyline (non-selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, 1-deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO-A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO-A or MAO-B, either alone or combined, does not facilitate spatial learning in adult rats.

Undesirable Blood Pressure Changes Under Naturalistic Treatment with Moclobemide, a Reversible MAO-A Inhibitor - Results of the Drug Utilization Observation Studies

Blood pressure decrease, associated with postural hypotension, as well as spontaneous hypertension are considered to be typical side-effects of conventional, irreversible and nonselective MAO (A+B) inhibitors. The new generation of reversible MAO-A inhibitors is, however, expected to have negligible cardiovascular effects and low propensity to induce either blood pressure increases or decreases. But, the true incidence of such changes is largely unknown since observation studies, specifically assessing the frequency of blood pressure changes, in unselected population of patients treated in the practice, are lacking.

Pharmacology and subcellular distribution of [ [formula omitted]]rilmenidine binding sites in rat brain

We have previously reported that in rat brain membranes, [ 3 H ]rilmenidine, in addition to labelling α 2-adrenoceptors and the I 2B-subtype of imidazoline receptor binding site (I 2B-RBS), may label an additional I-RBS population, distinct from previously classified I 1-RBS and I 2-RBS. In this study, using crude or fractionated rat brain membranes we examined the possible association of [ 3 H ]rilmenidine-labelled I-RBS with the A- and B-isoforms of monoamine oxidase (MAO) by studying the inhibition of [ 3 H ]rilmenidine binding by a number of MAO inhibitors; and comparing the maximal binding density ( B max) and subcellular distribution of [ 3 H ]rilmenidine binding sites with that of MAO-A and MAO-B catalytic sites labelled by [ 3 H ]RO41-1049 and [ 3 H ]RO19-6327 and I 2-RBS labelled by [ 3 H ]2-BFI. Inhibition of [ 3 H ]rilmenidine binding by all MAO inhibitors tested produced very shallow curves (slope 0.29–0.56). Clorgyline and moclobemide (selective MAO-A inhibitors) displayed moderate affinities (60–140 nM), while pargyline (non-selective MAO-inhibitor), RO41-1049 (selective MAO-A inhibitor) and RO19-6327 (selective MAO-B inhibitor) exhibited very low affinities (>2 μM) for 50–75% of [ 3 H ]rilmenidine-labelled I-RBS in crude brain membranes and even lower affinity for the remaining binding. Under identical buffer conditions, the B max of [ 3 H ]rilmenidine-labelled I-RBS (1.45±0.14 pmol/mg protein) was considerably lower than those of MAO-A (13.10±0.15 pmol/mg) and MAO-B (10.35±0.50 pmol/mg) sites. These results suggest that [ 3 H ]rilmenidine does not interact directly with the active catalytic site of either MAO enzyme and could at best only associate with a subpopulation of MAO molecules. Binding studies on five fractions of rat cortex homogenates—nuclear (N), heavy (M) and light (L) mitochondrial, microsomal non-mitochondrial (P), and soluble cytosolic (S) fractions—revealed that 45% of total [ 3 H ]rilmenidine binding was present in the P fraction cf. 20 and 23% in the M and L fractions, in contrast to [ 3 H ]RO19-6327 and [ 3 H ]2-BFI which bound 11–13% in the P fraction and 36–38% and 35–44% in the M and L fractions, respectively. Binding of all ligands in the N fraction was 6–15% of total. These studies reveal that [ 3 H ]rilmenidine-labelled I-RBS, unlike the I 2-RBS, are not predominantly associated with mitochondrial fractions containing the MAO enzymes (and cytochrome oxidase activity), but appear to be distributed in both the mitochondrial and plasma membrane fractions in rat cerebral cortex.

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.

Role of selegiline in combination therapy of Parkinson's disease.

Selegiline (earlier called deprenyl) is an irreversible inhibitor of monoamine oxidase type B (MAO-B). The inhibition is based on a covalent, irreversible bond formed between the propargyl group of selegiline and the flavin part of MAO. [1] In low doses (0.25 mg/kg subcutaneously in rats and 10 mg daily in humans) selegiline is a potent and selective inhibitor of MAO-B. [2,3] MAO-B inhibition can be easily tested in humans by measuring the MAO activity of platelets, as about 95% of MAO activity in platelets is of type B. [4] Because of its selectivity it is free of the cheese effect, i.e., increase of blood pressure after food rich in tyramine, which is a substrate for MAO-A. [5,6] In rodents selegiline does not have marked effects on the concentrations of the main catecholamines, dopamine or noradrenaline, because MAO-A is the predominant form of MAO in rodent brain. [7] In primate brain MAO-B is the predominant form with regard to degradation of dopamine, and therefore selegiline causes an increase of dopamine and decrease of 3,4-dihydroxyphenylacetic acid (DOPAC) in caudate in monkey brain. [8] In parkinsonian rat models, such as the 6-hydroxy dopamine (6-OHDA) model in which substantia nigra has been unilaterally destroyed with the toxin, selegiline enhances the effect of levodopa. [9-11] Nonselective MAO inhibitors had earlier been reported to cause some benefit but unacceptable adverse events in the treatment of Parkinson's disease (PD), [12,13] and therefore it was logical to test selegiline in this disease. The early findings by Birkmayer et al. [14] showed that selegiline potentiated the efficacy of levodopa in the treatment of PD patients and was well tolerated. This preliminary finding was followed by a number of trials assessing selegiline therapy in PD. The studies first concentrated on the use of selegiline in advanced PD, i.e., patients with …

A 61-Year-Old Man With Parkinson's Disease-Reply

In Reply. —Dr Hayes' points regarding the potential interaction between selegiline and SSRIs are worthy of consideration. It was not my intent to minimize the seriousness of the serotonin reaction, merely to represent that this reaction has primarily been described with the combination of an SSRI and nonselective MAO inhibitors. In contrast, this reaction is rare with drugs that selectively inhibit only the MAO-B isoform such as selegiline. Somerset Pharmaceuticals, the distributors of selegiline in the United States, have only 48 reports of possible serotonin interactions on file despite the many thousands of patients who have received selegiline in combination with antidepressants during the 10 years the drug has been approved for use in the United States. 1 Parkinson Study Group investigators report a serotoninlike syndrome in only 11 (0.24%) of 4568 patients taking selegiline with an antidepressant and only 2 (0.04%) of these were deemed to be serious. 2 It is

Interaction of MAO inhibitors and dietary tyramine: A new experimental model in the conscious rat

The aim of this study was to assess a new model for tyramine-induced pressor effects in the rat. The predictivity of the test is improved by simulating the real clinical situations where tyramine is ingested with food and beverages containing the amine. The pressor effect was investigated after oral administration of tyramine in a feed preparation or in a water solution by continuously recording blood pressure just above the aorta junction via a left-carotid catheter. The response was quantified by measurement of peak systolic blood pressure and as the percentage of tyramine-sensitive rats (TSR) in which the maximal pressor response to the amine was higher than 30 mm Hg (clinical risk threshold). Tyramine elicited, after oral administration (by gavage), a statistically significant dose-dependent increase in blood pressure from the dose of 10 mg kg in solution (i.e., 23 ± 3 mm Hg, N = 36) and 40 mg kg in feed preparation (i.e., 20 ± 2 mm Hg, N = 26). Almost all rats showed a systolic blood pressor increase higher than 30 mm Hg after oral administration of tyramine at a dose of 80 mg kg p.o. in solution (TSR = 96%). Administration of tyramine in food (80 mg kg ) significantly delayed the time of the peak blood pressure (13 ± 2 min instead of 7 ± 0.5 min in solution, p < .001). Under these conditions, the tyramine threshold dose of TYR 30 (dose inducing an average response equivalent to the clinical risk threshold) was 14 mg kg p.o. in solution and 67 mg kg p.o. in feed preparation, respectively. Thus, as has been observed in man, the dose-effect curve for tyramine is shifted to the right when given mixed with food to the rat. The efficacy ratio of the two tyramine vehicles defined on the basis of the TYR30 ratio is 4.8. Then, this methodology supplies a higher range of doses of tyramine without significant pressor effect (doses below 40 mg kg p.o. versus doses below 10 mg kg p.o. with tyramine in solution), a necessary condition to study the interaction between MAOI's and oral tyramine. To validate our model, phenelzine (48 mg kg ), a nonselective and irreversible MAO inhibitor, and toloxatone (75 mg kg ), a reversible MAO-A inhibitor, were administered orally 60 and 30 minutes respectively before the dietary tyramine (4–32 mg kg ). Under these conditions, phenelzine produced a very marked potentiation of the tyramine pressor effect that was characterized by a TYR30 dose of 7 mg kg , whereas, as expected, a new generation reversible MAO-A inhibitor, such as toloxatone, induced a much weaker potentiation (TYR30 of 19 mg kg ). It is concluded that the described model provides a sensitive method for the evaluation of the interaction between MAOI's and oral tyramine.