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Open Access Journal of Pharmaceutical Research ISSN: 2574-7797 MEDWIN PUBLISHERS Committed to Create Value for Researchers

Review on Novel Inhibitors: A Clinician’s Guide

Patil AJ and Suryawanshi MR* Mini Review Department of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Poona College of Volume 5 Issue 2 Pharmacy, India Received Date: March 04, 2021

Published Date: June 02, 2021 Mugdha R Suryawanshi, Department of Pharmaceutical Chemistry, *Corresponding author: DOI: 10.23880/oajpr-16000240 Poona College of Pharmacy, Bharati Vidyapeeth Deemed to be University, Pune 411038, India, Tel: 9011032733; Email: [email protected]

Abstract

The purpose of this review is to provide information on the mechanisms of action, , therapeutic effectiveness,

safety, and tolerability of four novel : , , , and . In spite of the initial pharmacological interest, monoamine oxidase (MAO) inhibitors are used in clinics for their effects and in the treatment of Parkinson’s syndrome due to proven neuroprotective effects. Patients with a lack of efficacy or tolerability for some monoamine oxidase inhibitors may benefit from the option of a new one monoamine oxidase inhibitors with various mechanism of actions. In the selection of newer monoamine oxidase inhibitors, these drugs may be an alternative. The simple deficiency of in the brain does not cause depression, but rather a complex interplay of different , planincluding of treatment, some regions the ambiguity of the brain of include the underlying serotonin, neurobiological , process should and be . considered. The novel monoamine oxidase inhibitors described above exert their therapeutic advantages by acting on multiple neurotransmitters. When formulating a

Keywords:

Depression; Monoamine Oxidase Inhibitors; Pirlindol; Safinamide; Selegiline; Toloxatone Introduction and Background upgrade either noradrenergic or serotonergic systems, or both. Shockingly, these derivatives block cholinergic, Major Depressive Disorder (MDD) may be a major public histaminergic, and alpha-1-adrenergic receptors sites, communicate with various different prescriptions occupational, and social functioning. The prevalence rates and realize various unfortunate reactions. There forhealth depression concern arewith estimated significant to impairment be around 3.2%in psychological, in patients without concurrent physical illnesses and 9.3% to 23.0% in haswith been their significant use, and seconddebate aboutbecause the many use of have MAO questioned inhibitors, for disability around the world and is estimated to be firsttheir becauseeffectiveness of the as periodic opposed hypertensive to the crises antidepressants associated patients with chronic conditions. It is the fourth explanation affects around 300 million individuals no matter gender, be used refractory to other types of treatment in depressed ethnicity,the second geographical leading explanation location, and for sociodisability economic in 2020. status, It Patients(TCAs) [2]. [3]. Clinical theory indicates that MAO inhibitors can contributing to the general global burden of disease [1].

Early antidepressant e.g. all the synthesized balanced formative methodologies. Most as of now presented analogs at a portion of 20 mg/kg IP showed anticonvulsant antidepressantsAll these more are up tomonoamine date mixes arebased the consequencesand tweaking of monoamine activity. It must be emphasized, however, that these newer antidepressants are far from the ideal ones, also activity. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are compelling because they

Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide Pharm Res 2 Open Access Journal of Pharmaceutical Research resulting in undesirable side effects and requiring 2-6 weeks hydrazine []), or via receptor type selectivity of treatment to produce a therapeutic effect. Furthermore, (reversible or irreversible). It used to be later shown that selective(MAO-A, blockadeMAO-B, orof both),MAO- or properly also as offered their reversibilitycomparable beenapproximately the development 30% of of the potential population novel doessystems not of respondactivity pastto current the monoaminergic therapies. A significantneural connection. new improvement The results has of A alone recent novel developmental approaches have suggested that therapeutic benefits in contrast to inhibition of each MAO-A and MAO-B [2]. , noradrenaline, and serotonin are (substance P and corticotrophin-releasing factor) receptors Dopaminedeaminated and through MAO-A use receptors, both isoforms. whereas This benzylamine encouraged andmodulation the intracellular of N-methyl-D-aspartate messenger system (NMDA), may provide neuropeptide entirely and B-phenylethylamine are substrates for MAO-B receptors. new set of potential therapeutic targets. Thus, chemically Therethe rummage are few around more up for to each date reversible treatment and choices selective including, MAO-A inhibitor for depression and MAO-B for Parkinson’s disease. notwithstandingnew classes of antidepressants the preliminary must pharmacological be explored in orderinterest to with stimulant activities through various neurochemical aretreat used such in patients. medical Monoamine institution oxidasefor their (MAO) antidepressant inhibitors, activitiespirindole,, [6]. safinamide This review toloxatone article may furthermore, guide the selegilineclinicians impact and in the management of parkinson symptoms, about the clinical components including the system of activity, pharmacokinetics, clinical viability, and wellbeing tolerability of these agents is emerged from large-scale and and bearableness. The creators additionally give a rundown due to the mounted neuroprotective action. Efficacy and antidepressants. The randomized controlled trials (RCTs) randomized scientific trials [4,5]. either by andof proof open-label based trials examinations are the main with basis respect of this toreview the fresherarticle. means of chemical structure (e.g., hydrazine versus non- Historically, MAOIs had been categorized

Figure 1: Synthesis and of Dopamine by MAO A and MAO B:

The hydroxylase (TH) catalyzes the conversion of tyrosine to levodopa (l-DOPA), which is then decarboxylated by dopa decarboxylase (DDC) to release dopamine. dopamineIntraneuronal levels, monoamine but prolonged oxidase therapy A (MAOA), with asthese well medications as glial and astrocyteimproves MAOAdopamine and MAOB,production, metabolize probably dopamine. due to enhanced Selective endogenousMAOA and MAOB brain antagonistsamines or receptor (selegiline, regulation , [7]. and safinamide, for example) have little impact on steady-state striatal

Pirindole reversible inhibitor which has been developed and islate widely 1960s used [8]. as an It antidepressantis a monoamine in Russia. oxidase A (RIMA) is 8-methyl-1H-pyrazino [3,2,1-jk]-carbazole HCl) is structurally and pharmacologically related to it [9]. a tetracyclicPirlindole compound hydrochloride that was (2,3,3a,4,5,6-hexahydro- synthesized in the

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 3 Open Access Journal of Pharmaceutical Research

Structure intervals of at least 6 hrs over 8 days, the kinetic parameters ofexcretion. the plasma After levels repeated did dosingnot account of 75 mgfor pirlindoleaccumulation t.i.d. orat enzyme induction by the unchanged compound. The binding to human plasma proteins was 95–97% [12].

Clinical use

RCTs in adults at a dose range of 75-300 mg. Pirlindole appears Figure 2: Pirlindole. as a Thesafe efficacymedication of pirlindole relative to for tricyclic MDD wasantidepressants established inand 9

Mechanism of Action of activity with the cardiovascular system and low ability tononselective amplify the MAO effects inhibitors of tyramine due to and its noradrenalinerelatively low degreestrain. Mechanism of action of This double-blind randomized -controlled study clearly shows the effectiveness and safety of pirlindole in the treatment of major depression [13]. In comparison to critical pirlindole consists of inhibiting monoamine oxidase depressive symptoms in the pirlindole group, cognitive A selectively and reversibly. It also depressive factors predominate in the group dopaminergicexerts an inhibitory and cholinergic effect on systems. of It noradrenaline has only a slight and potential5-hydroxytrypt-. for amplifying Itthe haspressure no effect effect of tyramine in the in addition to core symptoms [14,15]. No specific and be based on a ‘cheese effect [10]. statistically meaningful differences were identified with and noradrenaline, which makes one expect that it would not withregard amitripytline to the therapeutic versus efficacy pirlindole in depressive or in comparison syndromes with of Dosage and Administration a nosologically different classification, either in comparison the potential for the treatment of unipolar (single or Pirlindole is used in doses of 150–450 mg/day, with 225 and pirlindole [16]. This confirms mg/day being the most common dose (given as 75mg three and pirlindole [17]. This four week, double- times daily) and it is administered by oral route [11]. blind,chronic placebo episodes) controlled and bipolar study disorder indicates with that RIMAs, pirindole such (75 as

Pharmacokinetics weeks,b.i.d) could short-and be well long-term tolerated administration and beneficial of treatmentpirlindole did for syndrome [18]. In an open-label trial of 52 90 percent relative . The presumption of rapid Pirlindole was almost fully absorbed, with approximately thesenot alter trials platelet including and plasma the participants MAO-B activity, sample indicating size, duration, a lack apparent plasma clearance (450–1000 1/h). The primary doses,of inhibition and age of ranges MAO-B [19,10]. Table 1 summarizes the features of coursebiotransformation of removal of of pirlindole the metabolites was confirmed in man by was the renalhigh

Dose range Studies Design Groups (n) Duration Age (years) (mg) Pirindole (50 mg/day)=5 (75 mg/day)= 10 RCT 21 days 25-65 100-375 H, et al. [13] Schwarz A, Schwarz Pirindole (75 mg 3 times / day ) =52 Lehmann E, Kinzler (375 mg/day)= 1(Flex) Pir = 225 Des = RCT 3 wks >18 E, et al. (1985) [14] 50-150 day)=59 (2x 25 mg/day -3 x 50/ 1.Pirindole (a.m.:150 mg and Noon:75mg) 1.Pir: 27-67 1. Pir = 75-150 1) 6 wks (F) 21-49 (M) Schapperle O, noon:50mg) =40 =40 Amitriptyline (a.m.:100 mg and Eckmann F, et al. RCT 2. Pir: AMT= 50-100 (1985) [17] 2. Pirindole (50 mg t.i.d/day ) = 40 20-60 2.Pir = 50 IMP 2) 3 wks Imipramine (75 mg t.i.d/day ) = 40 IMP: = 75 18-56

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 4 Open Access Journal of Pharmaceutical Research

Pirindole 300 mg /day =10 Pir 300 Renfordt Ernst [16] RCT 28 days

Pirindole (300 mg/day)=49 RCT Amitriptyline 200 mg/day =10 42 days 44-57 AMT75-300 200 S, et al. (1996) [15] Placebo=49 De Wilde JE, Geerts Pir (150-300 mg / day ) = 52 Pir = 150-300 RCT 42 days 18-65 et al. (1996) [18] Moc (300-600 mg / day )=59 Moc = 300-600 Tanghe’ A, gee S, JS, Pirindole (75 mg b.i.d)= 45

RCT 4 wks 39.8± 8.8 75-150 et al. (1998) [19] Pirindole (75 mg b.i.d)= 33 Ginsberg F, Joos E, Placebo =44 [SA]

Bruhwyler et al. Pir (150-500 mg/day)=1330 32 OLT Placebo =28 [EA] - 150-500 (1997) [10] PMS months Table 1: Summary of demographic characteristics, dose ranges, and duration of studies of Pirlindole.

Disorder, Moc: Moclobemide, OLT: Open-label trial, Pir: Pirlindole, PMS: Post marketing survey, RCT: Randomized controlled AMT: Amitriptyline, Des: Desipramine, EA: Efficacy analysis Flex: Flexible dose, IMP: imipramine MDD: Major Depressive trial, RIMA: Reversible inhibitor , SA: Safety Analysis. Studies Clinical outcomes Pirlindole appears as a safe relative to tricyclic antidepressants and non- et al. (1975) [13] Schwarz JA, Schwarz H, Lehmann E, Kinzler E, et Pirlindole appears as a safe medicationselective MAO relative inhibitors to tricyclic antidepressants and non- al. (1985) [14]

Schapperle O, Eckmann In both trials, pirlindole, amitriptylineselective or imipramine MAO inhibitors showed no phenomena of intolerance, F, et al. (1985) [17]

no significant side effects or irregular laboratory parameters. al. (1996) [15] to placebo. The tolerability of pirlindole was nice and did not vary substantially from placebo. De Wilde JE, Geerts S, et The higher efficacy of pirlindole was apparent and statistically important relative No difference in the care outcomes in any of the assessment methodsused (1997) [18] Tanghe A, Gee SJ, et al. Bruhwyler J, Monseu MJ, Long-term(HDRS, administration HARS and substantially MADRS) in the decreased pirindole plasma and moclobemide norepinephrine groups. and serotonin et al. (1997) [10] .

uptake concentrations and improved [3H]-yohimbine binding site expression (1998)[19] Ginsberg F, Joos E, et al. Pirindole (75 b.i.d) could be a fibromyalgia syndrome treatment that is well tolerated Table 2: Summary of clinical outcomes of studies of Pirlindole. and beneficial.

MAOIs: Monoamine oxidase inhibitors, HDRS: Hamilton Depression Rating Scale, HARS: Hamilton Anxiety Rating Scale, MADRS: Montgomery-AsbergSafety and Tolerability Depression Rating Scale. is close to that of placebo on sensorimotor output related tohas driving a favourable a motor tolerability vehicle, asprofile. pirlindole The effect tends of to pirlindole have an trials have shown the antidepressant effectiveness and protection A number of pirlindole of placebo are and supported active comparator by several controlled years of long-termactivating administration profile rather due than to a its sedating unique antidepressantand reversible profile. No tyramine or ‘cheese’ effect is likely after short or deleteriousclinical experience effects ofon depression cardiovascular care. Itdynamics. has also beenPirlindole seen Pirlindole is validated by available evidence as a safe and recently in the treatment of fibromyalgia syndrome with no MAOA inhibition and relatively short removal half-life.

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 5 Open Access Journal of Pharmaceutical Research successful therapeutic choice for the management of

[21].mild hepatic impairment, not exceeding 50 mg once daily; depressionPregnancy and fibromyalgia syndrome [20]. contraindicate in patients with extreme hepatic impairment Pharmacokinetics There is little research on the use of pirlindole in pregnancy and lactation, and pirlindole administration recommended for the care of children < 12 years of age [20]. Safinamide is absorbed easily, with a bioavailability in these cases is not recommended. Also, pirlindole is not of 95%, and a demonstrated time to maximum plasma Safinamide concentration of 1.8–2.8 hours. It has extensive extravascular metabolismdistribution andwith is a regulated volume of by distribution amidase enzymes of approximately producing 165 L. Safinamide does not undergo extensive first-pass during ‘off’ episodes as an add-on treatment for Parkinson’s disease;Safinamide it has several (INN; modes brand of name action, Xadago) including is amonoamine drug used safinamide acid and other metabolites. Safinamide is mediated by (CYP) 3A4 isoenzymes. 2015, in March 2017, in the United States and in January boundSafinamide to plasma acid, while protein not and clinically is mainly significant, removed also in binds the 2019oxidase in CanadaB inhibition. [21]. It was approved in Europe in February formto OAT3 of (Organicits metabolites Anion Transporter by the kidneys 3). It is (about88 % to76%), 90% with a half-life of 20 to 30 hours of removal. About 1.5% Structure: of

safinamide is considered to be excreted in faeces. After oral administration of 50 mg to 300 mg, safinamide exhibitsClinical linear Use pharmacokinetics [22].

Five placebo controlled RCTs have been re- viewed for the safety and efficacy of - safinamide. The addition- of safinamide may provide an alternative approach to rais ing the dose of DA, thereby reducing the risk of side effects as- Figure 3: matelysociated 30 with to 60 DA, minutes such as a ICDs.day in The ‘ontime’ key clinical without benefits affecting of safinamidedyskinesia (involuntary at 24 weeks movements)were an improvement and a comparable of approxi de- Safinamide. crease in ‘off time’ relative to placebo [23]. This effect was Mechanism of Action still observed in a follow-up period of 2 years [24-26]. In le-

vodopa treated patients, safinamide was a safe and effective thusThe it reduces antiparkinson the degradation mechanism of dopamine. of safinamide It blocks is the via andfirst adjunctpatients therapy. undergoing It strengthened other concomitant 4/5 cardiac symptoms releasereversible of inhibitionglutamate of and selective the brain’s MAO-B, dopamine as a mesylate reuptake. salt, therapiesof PD, thus [27]. supporting In an open-label, moderate andrandomized, non-mild two-period, fluctuators - the clinical relevance of this for PD is unclear [22]. Safinamide also blocks channels of sodium and calcium, but two-sequence cross-over study, safinamide can be admin Dosage and Administration istered along with powerful inhibitors of CYP3A4 without dose modification requirement [28]. Findings of open label Begin with 50 mg orally administered once daily at trials, clearly support the clinical utility of safinamide as an- the same time of day; the dose may be increased to 100 marisesefficient thelevodopa features adjunctive of these trialstherapy including of 50 and the 100 participants mg / day mg once daily after two weeks, depending on individual sampleonce daily size, in duration,patients with doses, fluctuating and age PDranges. [29]. TableTable 43 sum- need and tolerability. Hepatic impairment: in patients with

marises the clinical finding s of those studies.

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 6 Open Access Journal of Pharmaceutical Research

Age Dose range Studies Design Groups (n) Duration (years) (mg)

Fabrizio S, et al. (2011) RCT 24 wks 30-80 100-200 [23] Safinamide 100 mg/day=90 vs placebo = 90 Safinamide 200 mg/day=89 Borgohain, et al. 2014a RCT 24 wks 30-80 50-100 (study 016) [24] placebo. n=669 Borgohain, et al. 2014b Safinamide 50 mg or 100 mg daily vs RCT 18 months 30-80 50-100 (study 018) [25] placebo. n=669 Safinamide 50 mg or 100 mg daily vs Kenney, et al. (2016) RCT 24 wks 61.9 50-100 Jost, Wolfgang H placebo = 275 n=549 (SETTLE study) [26] Safinamide 50 mg or 100 mg daily= 274 Vs Cattneo, et al. (2016) RCT 24 wks 30-80 50-100 (SETTLE study) [27] Safinamidemg/day 50 mg =43 or vs 100 Placebo mg daily= = 46 487 vs placebo = 484, Adjunct with levodopa 100 Sonja Krosser, et al. Saf=100 OLT 6 days 18-45 (2007) [28] Ketconazole 200mg (b.i.d.) Keto=200-400 Safinamide 100 mg daily= 14 Tsuboi Y, Hattori N, OLT 52 wks >30 50 (2020) [29] Yamamoto A, et al. safinamide 50 mg /day.=227 Table 3:

Summary of demographic characteristics, dose ranges, and duration of studies of Safinamide. CYP3A4: cytochrome 450 3A4; DA: dopamine ICDs: impulse control disorders; Keto: ; PD: Parkinson’s disease; OLT: Open-label trial; RCT: Randomized controlled trial; Saf: safinamide. Studies Clinical outcomes

Fabrizio S, et al. (2011)[23] at an early stage of PD and needs further study. Adding safinamide to a safe DA dose enhances motor symptoms Borgohain, et al. (2014) (study Mean daily change from baseline to week 24 without troublesome on time. 016)[24] (recorded in patient’s diary) Borgohain, et al. 2014b (study 018) [25] Alteration of the mean total DRS score over time. (2016) Mean daily change from baseline to week 24 without troublesome dyskinesia on time. Jost, Wolfgang H Kenney, et al. (recorded in patient’s diary) (SETTLE study) [26] Cattneo, et al. (2016) levodopa and strengthenedSafinamide was 4/5 a safeof the and cardinal effective symptoms first adjunct of PD therapy thus supporting in patients moderate treated with and (SETTLE study)[27]

Therapeutic steady state concentrations of the potent nonmild fluctuators and other concomitant dopaminergic therapy patients. Sonja Krosser, et al. (2012)[28]

ketoconazole inhibitor CYP3A4 do not alter the characteristics of safinamide exposure. effective in improving ON-time and et al. (2020) [29] Safinamide was safe, well tolerated, and Tsuboi Y, Hattori N, Yamamoto A, other symptoms of PD at 52 weeks as an adjunctive treatment for levodopa. Table 4:

Summary of clinical outcomes of studies of safinamide. DA: Dopamine; DRS: Dyskinesia Rating Scale; PD: Parkinson’s disease; RCT: Randomised Controlled Trial.

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 7 Open Access Journal of Pharmaceutical Research

Safety and Tolerability reuptake of these neurotransmitters in the CNS, resulting in increased levels at the synaptic cleft of the biologically active Randomized, double-blind, placebo- monoamines. Selegiline shows selective B-type monoamine controlled trials have identified Parkinson’s disease is the loss of dopamine containing symptoms of PD. The change in thesymptoms safety was and substantialefficacy of neuronsoxidase (MAO-B)in the midbrain inhibition substantia at lower nigra doses. and Thethe resulting cause of andsafinamide lasted for as atan least alternative two years for withoutthe treatment the worsening of motor of dyskinesia. For patients who are not receptive to other deficiency of dopamine throughout the striatum. The selective inhibition of MAO is therefore required for the treatment of andpharmacotherapy rasagiline, which choices show for PD,dyskinesia safinamide as a is secondary worthy of isParkinson’s not the desired disease, result because when using MAO-B selegiline mainly to metabolizes treat MDD. effect.formal Dyskinesia,consideration. falls, Unlike and thenausea MAO-B are inhibitors the most selegilinecommon dopamine [31]. In comparison, selective inhibition of MAO-B mechanism, for selegiline when used as a treatment for 100 mg at a rate of 2 % or higher versus placebo [22]. MDD.Inhibition The ofmonoamine both MAO-A hypothesis and MAO-B of depressionis used as an suggests effective a Hypertensionindigestion,adverse effects recorded in hypersensitivity clinical trials of safinamidereactions, fundamental physiological basis for depression as a decrease in central nervous system serotonin, nor epinephrine, side effects [21]. and dopamine levels [32]. Since elevated levels of these drowsiness, , anxiety and hallucinati-ons are some three monoamines are often the intended consequence Pregnancy subtypes is preferred. Selegiline Pre-treatment Could protect The advantages and risks of the drug in pregnant women of treating MDD, non-inhibitory inhibition of both MAO or women of childbearing age are due to the lack of human such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurons from various neurotoxins, Tetrahydropyridine, commencing treatment, this demographic must be weighed. evidence testing foetal risk when safinamide is used. Prior to (MPTP), N-(2-chloroethyl)-N-ethyl- 6-hydroxy dopamine; milk on breastfed infants is uncertain [22]. which2-DSP-4 damages bromo to benzyldopaminergic, amine, cholinergic, methyl-acetoxyethyl-2- adrenergic, Likewise, the occurrence and effect of safinamide in breast andChloroethylamine sertoninergic andneurons, 5,6-dihydroxy each [33]. serotoninSelegiline (AF64A),can also Selegiline so it can be used for depression treatment. Deprenyl/Selegiline (DEP), developed by Joseph Knoll in inhibit monoamine oxidase type A (MAO-A) at higher doses, Dosage and Administration the 1960s, registered as the first selective inhibitor of B-type Selegiline (deprenyl) is a potent inhibitor of type B depressivemonoamine disorder; oxidase (MAO-B)and used in as more an anti-agingthan 60 countries drug [29]. to treat Parkinson’s disease. Alzheimer’s disease is a major used in Parkinson’s disease patients. Selegiline 5 mg orally twicecerebral daily, monoamine with breakfast oxidase and at at the noon, dosage is prescribed (10mg /day) in Selegiline is the first irreversible, highly potent inhibitor of care of patients with Parkinson’s disease. Higher dosages StructureMA0 without ‘cheese effect’ [30]. are no more effective than 10 mg / day, and it may be appropriate to limit all tyramine containing food and indirect sympathomimetic drugs above this dosage [34].

Pharmacokinetics

due to presystemic clearance in the gut and ). The majorSelegiline plasma undergoes metabolites significant are metabolismN-desmethylselegiline, (presumably L-mephetamine and L-meth- . Only Figure 4: Selegiline. no known absolute bioavailability of selegiline after oral Mechanism of Action N-methylselegiline is an active MAO-B inhibitor. There is concentrations of these metabolites are 4 to almost 20 times greaterdose. After than athat single of normal oral doseselegiline of 10 plasma mg, the concentration peak plasma [1 ng/mL] [34]. However, single oral dose studies don’t predict serotoninSelegiline and is dopamine.an irreversible Blocking monoamine enzyme oxidase prevents inhibitor the multiple dose kinetics. The peak plasma level of selegiline (MAO), an enzyme which catabolizes norepinephrine,

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 8 Open Access Journal of Pharmaceutical Research at a steady state is 4-fold which was obtained after a single weeks, transdermal selegiline (20 mg applied once daily via a dose. The concentrations of metabolites increase to a lesser 20 cm2 patch) was a successful and well-tolerated treatment for adult outpatients with major depressions [37]. The taken with food, the bioavailability of selegiline is increased 3 early combination of selegiline and levodopa proved clearly degree, by an average of 2 folds seen after a single dose. When superior to mono- therapy with levodopa in most case of an open label trial, the replacement of orally disintegrating ofto systemic4-fold. The selegiline level of systemicclearance selegiline are valid. exposure The mean at half-life a given selegiline (ODS) with decreasing doses of dopamine ofdose selegiline varies significantlyremoval after between a single oralindividuals. dose is 2 Nohours. estimates Under stable conditions the half-life elimination increases to 10 hrs (EDS), pedal oedema, hallucinations and impulse control [35]. ( DAs) significantly reduced excessive daytime sleepiness Selegiline ODT on a long term 2.5 mg /day was successful, Clinical use healthydisorders(ICDs) and well withouttolerated sacrificing in Parkinson’s effectiveness disease patients [38-41].

5 summarises the features of these trials including the several adult RCTs and open-label trials. Selegiline provides participantsexperiencing sample episodes size, off duration, levodopa doses, therapy and age [42]. ranges. Table positiveThe effectsefficacy at of all selegiline levels of for PD PD and has helps been the identified patient toin

Table 6 summarises the clinical findings of those studies. obtain longer benefitsfrom levodopa treatment [36]. For 6 Age Dose range Studies Design Groups (n) Duration (years) (mg) Selegiline 10 mg/day=27 3 wks Myllya, et al. (1992) [36] RCT 2,4,8,12 __ 10 Placebo=25 months Transdermal Selegiline 20 mg/day in RCT 6 wks 41-44 20 20 cm2 Patch= 89 Alexander Bodkin J, et al. [37] Placebo=88 Selegiline 5 mg= 61 vs Przunztek H, Conrad B, RCT Placebo=55, 5 yrs __ 5 Dichgans J, et al. (1999) [38] as adjunt to Levodopa=116 Selegiline vs Placebo as adjunt to Levodopa Larsen JP, Boas J, Erdal JE, et al. RCT 5 yrs 35-75 10 (1999) [39] 10 mg/day =163 Placebo as adjunt to Levodopa Selegiline 10 mg/day =71 Palhagen S, Heinonen EH, RCT Placebo =69 7 yrs __ 10 Hagglund J, et al. (2006) [40]

Lyons KE. Friedman JH, etal. Orally disintegrating Selegiline OLT As adjunt to Levodopa 12 wks -90 1.25-2.5 (2010) [41] 1.25-2.5 mg/day =60 Lewa MF, Rajesh pahwab, et al. OLT selegiline ODT 2.5 mg = 254 12 months __ 2.5 (2007) [42] Table 5: Summery of demographic characteristic, dose ranges, and duration of studies of Selegiline. OLT: Open-label trial; RCT: Randomized controlled trial; ODT: Oral disintegrating Selegiline.

Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 9 Open Access Journal of Pharmaceutical Research

Studies Clinical outcomes Sel appears to delay the levodopa therapy’s long-term problems and allow Myllya, et al. (1992) [36]

parkinsonian patients to maintain the benefits of levodopa therapy longer

PrzunztekAlexander H, BodkinConrad J,B, et Dichgans al. [37] J, The selegiline transdermal system was superior to placebo on all measures of efficacy et al. (1999) [38] for 50% increase in levodopa dose in the selegiline group Sel shows symptomatic benefit as adjunct to levodopa. About twice longer time to need Larsen JP, Boas J, Erdal JE, et al. effect. Less deterioration of the disease within the selegiline group after 5 years. (1999) [39] Symptomatic benefit as adjunct to madopar and Sel Possible disease-modifying Palhagen S, Heino- nen EH, Improved motor scores after 5 years in the selegiline group with 19 % lower After 1 month of washout, benefit was maintained Hagglund J, et al. (2006) [40] levodopa dose. Lyons KE, Friedman JH, et al. (2010) [41] from 2.3 to 0.5 mg and from 11.2 to 2.9 mg for Immediate release. The addition of ODS permitted a reduction in the mean daily dose of Lewa MF, Rajesh pahwab, et al. (2007) [42] episodes off levodopa therapy Sel ODT 2.5 mg was effective for in Parkinson’s disease patients experiencing Table 6: Summary of clinical outcomes of studies of Selegiline. Sel: Selegiline; ODT: Oral disintegrating Selegiline.

Safety and Tolerability Toloxatone

1960s. Overall, the number of patients participating in reportedSelegiline clinical has trials been investigating on clinical the experience effectiveness since and the Animal studies failed to disclose evidence of safety of selegiline in Parkinson’s disease is more than atteratogenicity. doses greater Atthan high clinically multiples utilized of [44]. human doses and 4000. Since selegiline is well tolerated as monotherapy in Developmental toxicity, reproductive toxicity was observed the early phase of the disease, adverse effects are moderate, Structure and mainly dopaminergic. In conjunction with levodopa, selegiline can potentiate the dopaminergic adverse effects (dizziness, , , , O hallucination, and insomnia) caused by levodopa, but these O adverse effects can typically be controlled by decreasing OH levodopa dosages. One recent study suggested an increase N in mortality associated with the combination of selegiline and levodopa compared to levodopa only therapy, but ten other studies did not support this result. Therefore, it is possible that selegiline does not increase mortality, and the Figure 5:Toloxatone In general, when administered in combination with other drugs,earlier selegiline findings werewas relatively the result well of studytolerated. design However, problems. we should avoid the combination of and selegiline. Mechanism of Action selegiline, as these combinations have produced some severe adverseCaution shouldeffects [43].be taken when combining SSRIs or TCAs with This drug is a type-A (also known as RIMA) monoamine Pregnancy metabolismoxidase reversible of serotonin inhibitor. and catecholamines, In norepinephrinergic allowing andthe synapticserotonergic cleft neurons, to increase MAO-A circulation. can be Traditionalfound and regulates monoamine the

and thus, side effects, medication interactions, and food Animal studies failed to disclose evidence of interactionsoxidase inhibitors occur as irreversibly much as 2-3 inhibit weeks monoamine after discontinuing oxidase atteratogenicity. doses greater Atthan high clinically multiples utilized of [44]. human doses and Developmental toxicity, reproductive toxicity was observed toloxatone [46].

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Dosage and Administration Clinical Use

the morning, 200 mg in the middle of the day and 400 mg in the evening)The dose by of oraltoloxatone administration was 1000 [45]. mg on day 1 (400 mg in Both moclobemide and toloxatone inhibit norepinephrine and dopamine deamination significantly. Pharmacokinetics The MAO inhibiting effect of moclobemide is greater than betoloxatone. administered Together without with thephysiologic risk of inducingdoses of tyramine,a substantial the risenew inreversible systolic andblood selective pressure MAOA [45,48]. inhibitor In patients toloxatone treated can absorbed. The peak plasma levels at 30 min after dosing are with moclobemide, depressive retardation is signifycantly also Followingshown to be oral fast administration, absorption. The toloxatonefecal elimination is readily (7% of the dose in one subject), may be due to either incomplete of moclobemide treatment is improving sleep. The present studybetter hasthan shownwith toloxatone that there [49]. was Most only important a slight advantagemetabolic

hasabsorption been found or biliary that this . metabolite Toloxatone may also is metabolized be present inextensively. the human In humanbrain and urine, contribute a phenolic to derivativethe pharmacological of the drug interaction between amitriptyline and toloxatone, with a effect of the drug [47]. thesemarginal trials increase including in the the AMT/NT participants ratio sample due to size,an increase duration, in doses,the plasma and AMTage ranges level [50]. [51]. Table Table 7 summarises8 summarises the the features clinical of

findings of those studies. Dose range Studies Design Groups (n) Duration Age (years) (mg) Male= 20-29 Tol =1000 Berlin I, Zimmer R, et al. (1990) RCT Moclobemide 150 mg/day=12 1 month Female= [45] Toloxatone 1000mg/day=12 Moc=150 Placebo 59-77 Male= 20-29 Tol =1000 Dingemanse J, Berlin I, Payan C, et RCT Moclobemide 150 mg/day=12 1 month Female= al. (1992) [48] Toloxatone 1000mg/day=12 Moc=150 Placebo 59-77

Provost J, Funck‐ Brentano C, Toloxatone 600 mg/day Rovei, et al. (1992) [49] RCT ToloxatonePlacebo 1200 mg/day 2 wks __ Tyr=100-800 Tyramine100-800 mg/ day

Tol =1000 Lemoine P, Mirabaud C, et al. =133 RCT Toloxatone 1000 mg/day 28 days >18 (1992) [50] Moclobemide 450 mg/day Moc=450 =135 Tol= 600 RCT 2 wks 24-69 Toloxatone 600 mg/day=17 =17 Vandel S, Bertschy G, et al. (1992) Amitriptyline 125 mg/day Table 7: Amt= 125

Summery of demographic characteristic, dose ranges, and duration of studies of Toloxatone. AMT: Amitriptyline; Moc: Moclobemide; OLT: Open-label trial; RCT: Randomized controlled trial; ODT: Oral disintegrating Toloxatone; Tol: Toloxatone; Tyr: Tyramine.

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Studies Clinical outcomes Berlin I, Zimmer R, et al. (1990) [45] function, alertness, subjective emotions or sleep characteristics. Neither moclobemide nor toloxatone altered the subjects’ memory Dingemanse J, Berlin I, Payan C, et al. (1992) [48] function, alertness, subjective emotions or sleep characteristics Neither moclobemide nor toloxatone altered the subjects’ memory Jean‐Claude P, ‐C Funck Together with physiologic doses of tyramine, the new reversible and Brentano, Christian, et al. (1992) [49] inducing a substantial rise in systolic blood pressure. selective MAOA inhibitor toloxatone can be administered without the risk of Lemoine P, Mirabaud C, et al. (1992) [50] Moclobemide was found to be as effective as toloxatone, but with the benefits of improved sleep patterns and decreased anxiety. (1992) [51] A small pharmacokinetic interaction between Vandel S, Bertschy G, et al. toloxatone and amitriptyline (AMT), with a slight increase in plasma AMT / NT () Table 8: ratio: 0.68 before and 0.78 after toloxatone. Summary of clinical outcomes of studies of toloxatone. MAO-A:Safety Monoamine and Tolerability oxidase Inhibitor-A; AMT: Amitriptyline; NT: nortriptyline. the treatment of unipolar (single or chronic episodes) and (RIMA) reversible inhibitor and confirms the potential for patients in the community found global tolerance to be good pirlindole. Short-and long-term administration of pirlindole Toloxatone was well tolerated. Over 80 percent of with RIMAs, such as moclobemide and course of treatment. Somatic complaints are more common, or very good, and this level increased significantly during the itsdid antiparkinsonnot alter platelet mechanism and plasma is via MAO-B reversible activity, inhibition indicating of a lack of inhibition of MAO-B. Safinamide is another drug, suchPregnancy as anxiety [52]. selective MAO-B. The addition of safinamide may provide an alternative approach to raising the dose of DA, thereby reducing the risk of side effects associated with DA, such DiscussionToloxatone is contraindicated in pregnancy and lactation. as ICDs. Selegiline is the first irreversible, highly potent forInhibitor selegiline of MA0 when without used as ‘cheese a treatment effect’. Inhibition for MDD. ofHigher both In recent years, the incidence of depression has dosagesMAO-A andare no MAO-B more effective is used than as an 10 effectivemg / day, mechanism, and it may be appropriate to limit all tyramine containing food and many effective antidepressants are available, only 30 percent indirect sympathomimetic drugs above this dosage. The ofincreased patients due take to increasedpsychotropic depression medicines awareness. as prescribed While early combination of selegiline and levodopa proved clearly

therapeutic effects for many weeks, and the lack of response indue some to thepatients prevalence to conventional of AEs, antidepressants. the absence of SSRI, significant NRIs, inhibitor.superior toTogether monotherapy with physiologic with levodopa. doses of Toloxatone tyramine, isthe a , and . This paper reviews related type-A (also known as RIMA) monoamine oxidase reversible papers in order to provide a detailed description of several be administered without the risk of inducing a substantial risenew inreversible systolic blood and selective pressure. MAO-A inhibitor toloxatone can

inhibitorsnovel inhibitors used ofas monoamine agents for oxidase,the treatment including of pirlindol,disease, Conclusion safinamide, selegiline and toloxatone. The study of MAO-B

ageingAlzheimer’s of the disease, population. and neurological For the treatment disorders of isdepression currently refractory to other types of treatment in depressed patients. andof significant new psychological concern, potentially conditions, due many to the medications progressive Clinical theory indicates that MAO inhibitors can be used

treatment of MDD. This review helps to represent treatment serotoninIn the selection in the brain of newer does not monoamine cause depression, oxidase inhibitors,but rather alternativeswith MAO-An from inhibitory which both activity clinicians are used and in their the firstpatients line these drugs may be an alternative. The simple deficiency of some regions of the brain include serotonin, norepinephrine, a complex interplay of different neurotransmitters, including have difficulties choosing at the present moment. Pirlindole is a tetracyclic compound act as is a monoamine oxidase A dopamine, and histamine. The novel monoamine oxidase Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240. 12 Open Access Journal of Pharmaceutical Research

13.

ainhibitors plan of described treatment, above the exert ambiguity their therapeutic of the advantagesunderlying PatientsJA Schwarz, with Depressive Schwarz H, Syndrome. Kalhammer Psychiatry R Dosage the State and neurobiologicalby acting on multiple process neurotransmitters. should be considered When .Research formulating on Efficacy of the Antidepressant Pirlindole in 15 Female In: the use of novel antidepressants in human subjects is limited 14. of the Art pp: 271-272. differences and other novel characteristics of these new Depressive Inpatients pp: 321-322. drugs.and further studies are warranted to reveal significant Germany W. 150 Mg Desipramine In The Treatment Of 15.

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Patil AJ and Suryawanshi MR. Review on Novel Monoamine Oxidase Inhibitors: A Clinician’s Guide. Copyright© Patil AJ and Suryawanshi MR. Pharm Res 2021, 5(2): 000240.