improving l -dopa therapy: the development of enzyme inhibitors

Improving L-dopa Therapy: The Development of Enzyme Inhibitors

Oscar S. Gershanik, MD*

Institute of Neuroscience, Favaloro Foundation University Hospital, Solis 461, Buenos Aires, Argentina

ABSTRACT: The introduction of levodopa pro-duced a monumental change in the treatment of Parkin-son’s disease (PD). Limitations in its bioavailability andtolerability led to the search for drugs that couldimprove its pharmacokinetics and safety profile. Dopa-decarboxylase inhibitors were the first such drugs thatwere developed, and their use in combination withL-dopa has become standard practice. Increasingknowledge on the metabolism of L-dopa allowed theidentification of additional targets for intervention in anattempt to improve the symptomatic efficacy of L-dopa.Monoamineoxidase inhibitors, enhancing the centralbioavailability of dopamine by blocking its metabolism,

were the next step, and despite controversies regardingtheir efficacy, they have remained as valuable adjunctsto L-dopa in the treatment of PD. More recently, theintroduction of potent, selective catechol-O-methyltransferase inhibitors have found their place in the ther-apeutic armamentarium of PD and are prescribed incombination with L-dopa to prolong the duration of itsaction. VC 2014 International Parkinson and MovementDisorder Society

Key Words: levodopa; dopa-decarboxylase inhibi-tors; monoamineoxidase inhibitors; catechol-O-methyltransferase inhibitors; pharmacokinetics

Soon after the introduction of levodopa as therational therapeutic approach for the treatment of Par-kinson’s disease (PD), it became evident that the druggiven alone had several limitations, including its verylimited bioavailability, the need for a very slow titra-tion period to achieve a significant symptomatic effect,and the frequent occurrence of adverse events (AEs).The metabolic conversion of levodopa to dopamine(DA) at the peripheral level accounted for most ofthese limitations.1,2

Increasing knowledge of the pharmacokinetics andmetabolism of L-dopa, both in the periphery and atthe central level, allowed the identification of potentialtargets for pharmacological manipulation. L-dopadecarboxylation in the periphery was initially identi-

fied as the first major obstacle responsible for thedrug-limited bioavailability and its poor tolerability,leading to the development of drugs capable of inhibi-ting the activity of dopa decarboxylase (DDC) in theperiphery, thus increasing the amount of drug reach-ing the brain and dramatically improving its safetyprofile and tolerability.1,2 The introduction of bothbenserazide and carbidopa made a significant impactin this regard, and to this day, L-dopa is alwaysadministered in combination with dopa decarboxylaseinhibitors (DDCIs).2

Almost in parallel to the development of DDCIs,early attempts were made to potentiate the centraleffects of L-dopa by preventing the degradation of DAby central monoamine oxidase (MAO) with the use ofnonselective inhibitors of the enzyme catalyzing theconversion of dopamine to dihydroxyphenyl aceticacid (DOPAC) within the brain.2 However, sideeffects (“cheese effect”) associated with the nonselec-tive type A plus B MAO inhibitors available then pre-vented further use of these drugs. The development ofselective MAO-B inhibitors (MAOIs), however, rein-troduced the concept of MAO inhibition into the ther-apy of PD and led to the development of selegilineand, more recently, rasagiline as safe drugs to be usedalone or in combination with L-dopa plus DDCIs inthe treatment of PD.3

------------------------------------------------------------This article was published online on 21 October 2014. An error was sub-sequently identified. This notice is included in the online and print ver-sions to indicate that both have been corrected on 27 October 2014.

*Correspondence to: Dr. Oscar S. Gershanik, Institute of Neuroscience,Favaloro Foundation University Hospital, Solis 461, Av. Belgrano 1746,C1078AAI Buenos Aires, Argentina; E-mail: [email protected]

Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the online ver-sion of this article.

Received: 5 August 2014; Revised: 5 September 2014; Accepted: 11September 2014

Published online 00 Month 2014 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.26050

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Patients under chronic treatment with L-dopa plusDDCIs sooner or later developed fluctuations in theirtherapeutic response, the most common of which isthe “wearing-off” effect, manifested by a progressiveshortening of the duration of the effect of each dose ofL-dopa. The wearing-off effect is related to the shortplasma half-life of the drug, a progressive loss of thebuffering capacity of the system resulting fromincreased DA cell loss, lack of presynaptic regulatorymechanisms, and, probably, additional pharmacody-namic factors.4 To further prevent the peripheralmetabolism of L-dopa, and therefore increase its bioa-vailability, with the idea of increasing the duration ofits therapeutic effect, catechol-O-methyl transferase(COMT) inhibitors (COMTIs) were more recentlyintroduced.1,2 Metabolism of L-dopa by COMT is thesecond important degradation pathway leading to theconversion of L-dopa to 3-O-methyl dopa (3OMD).2

Tolcapone was the first of this new generation ofenzyme inhibitors to be introduced as add-on therapyto L-dopa, although, unfortunately, because of theappearance of liver toxicity, it was withdrawn fromthe market after a few years in most countries or itsused allowed under strict liver function monitoring.5,6

Other COMTIs were being developed in parallel, andentacapone, a drug devoid of liver toxicity, reachedthe market shortly thereafter.2,5 Entacapone alone asadd-on therapy or used in a single triple-combinationtablet including L-dopa/carbidopa/entacapone is theonly COMTI presently available for routine clinicaluse.5,7

Overview of L-dopa Parmacokineticsand Metabolism

To better understand the targets upon which enzy-matic inhibitors exert their actions, it is necessary tomake a brief review of the pharmacokinetics andmetabolism of L-dopa and DA.

The absorption of L-dopa takes place mainly in theproximal portion of the small intestine, through asaturable L-neutral amino acid transport system, shar-ing it with other large amino acids (tryptophan, phe-nylalanine, tyrosine, threonine, leucine, isoleucine,methionine, histidine, valine, and cysteine).8,9 Withincreasing doses of L-dopa, there is a more than pro-portional increase in the plasma concentration of thedrug, probably as a result of saturation of the aminoacid decarboxylation pathway at the level of the gas-trointestinal tract.9 When L-dopa is given orally,there is almost complete absorption of the drug, andonly 2% is eliminated unmodified in the feces; how-ever, only approximately 30% of an oral dose of L-dopa, given alone, reaches the systemic circulationintact.9 Because of an extensive first-pass metabolismand rapid plasma clearing by decarboxylation to DA

at the intestinal level and in the liver, only 1% of anoral dose of L-dopa enters the brain unmodified.8-10

There are other barriers preventing the influx ofL-dopa into the brain, including high levels of activ-ity of L-aromatic amino acid decarboxylase (AAAD)in the vascular endothelium, and possible uptake byerythrocytes, where the drug can be metabolized to3OMD within red cells.8 DA, the product of decar-boxylation of L-dopa, is a charged species that thetransport mechanism cannot carry into the brain.8

This is a very effective mechanism that prevents thepassage through the blood–brain barrier (BBB) intothe brain of a large proportion of L-dopa. AAADactivity at the vascular endothelium is also a satura-ble process, whereby excess of unmetabolized L-dopais thus capable of entering the brain.8

A second important pathway in the peripheralmetabolism of L-dopa is O-methylation through theactions of the enzyme, COMT, that converts L-dopainto 3OMD.1 COMT is present both systemically,mainly in the liver, and in the brain, where a majorproportion of L-dopa is metabolized to 3OMD.9 Bloodlevels of 3OMD slowly rise in the periphery afterL-dopa administration, with brain accumulation lag-ging behind. Maximal levels of this metabolite in thebrain are reached approximately 1 hour after peakplasma L-dopa levels are achieved after an oral dose.The half-life of 3OMD is approximately 15 hours,therefore explaining its significant accumulation anddelayed clearance in comparison with its shorter-livedparent compound.9 3OMD does not undergo furthermetabolism. There is much speculation as to whetherthe presence of high plasma levels of 3OMD maycompete for the passage of L-dopa into the brain.5,8-10

Exogenously administered L-dopa may still be decar-boxylated within the brain despite massive loss of DAcells in PD. In addition to the remaining DA termi-nals, there is a significant number of L-amino aciddecarboxylase (AADC)-containing cells at the striatallevel, including serotonin and noradrenalin neurons,intrinsic striatal DA neurons, and glial cells, allowingDA to reach available postsynaptic DA receptors.2

DA generated from exogenously administeredL-dopa is further metabolized in the brain by MAO-Band COMT. After being released into the synapticcleft by presynaptic dopaminergic neurons (DAergic),DA can be recycled after reuptake by DAergic neuronsor be degraded after uptake by glial cells.11 WithinDAergic neurons, DA can follow two different path-ways: sequestration into the synaptic storage vesiclesby the vesicular monoamine transport system, whilethe fraction that remains free in the cytosol undergoesoxidative deamination by MAO and, through an inter-mediate enzymatic step, is converted to DOPAC.8,11

DA present in the synaptic cleft can be taken up bysurrounding glial cells, where it is converted by

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COMT and MAO to homovanillic acid (HVA). BothDOPAC and HVA are the major metabolites of DAexcreted in the urine (Fig. 1).8,11

Peripheral Decarboxylase Inhibitors

Overview

DDC was identified in 1938 and was later recognizedas being one of the major enzymatic pathways neces-sary for the conversion of L-dopa to DA at the systemiclevel.1 In 1967, Bartholini et al. pointed out the avail-ability of drugs capable of blocking the activity of theenzyme in the periphery without themselves crossingthe BBB and concluded that such drugs could beexpected to potentiate the therapeutic action of L-dopain several ways.12 This concept led the way to the pro-posal of the combined use of L-dopa with DDCIs, basedon the pharmacological principle that this combinationwould reduce the degradation of L-dopa to DA in theperipheral compartment and, consequently, increasethe amount of DA available to the brain among otherbeneficial effect.13 Reducing the peripheral degradationof L-dopa would not only increase the bioavailability of

the drug, thus allowing more drug to reach the brainunmodified, but it would also reduce the dosagerequirement and shorten the titration period, while atthe same time minimizing AEs resulting from peripheralconversion of L-dopa to DA.1

DDC was first identified in mammalian kidney tissueas an essential catalytic step in epinephrine biosynthe-sis. Today we know that the reaction specificity of theenzyme is broader, given that, in addition to decar-boxylating L-dopa to DA, it participates in the conver-sion of L-5-hydroxytryptophan to serotonin and,much less efficiently, in the catalytic metabolism ofother aromatic amino acids, such as p-tyrosine, trypto-phan, and phenylalanine, to the corresponding amines(trace aromatic amines).14 Given that its role in mono-amine metabolism is more extensive than originallythought, DDC is also designated, more correctly, asAADC. Its major role is to supply organisms withessential neurotransmitters. AADC uses pyridoxalphosphate (PP; vitamin B6) as a cofactor and catalyzesthe decarboxylation of several aromatic L-amino acids,such as L-dopa, L-tyrosine, L-tryptophane, and L-histi-dine.8,14 DDC is not considered to be the rate-limitingstep in the synthesis of physiologically active

FIG. 1. Peripheral and central metabolism of L-DOPA.

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catecholamines or indoleamines; however, it becomesrate limiting in several pathological states related toabnormal dopamine production, such as PD.14 Inmammals, the enzyme is widely distributed in neuro-nal and non-neuronal tissues. Its presence in neuronalcells is consistent with its activity in neurotransmittersynthesis, whereas its abundance in other tissues, forexample, the kidney, where the enzyme is highlyexpressed, is less clearly explained. The presence ofthe enzyme in non-neuronal tissues is the main reasonwhy L-dopa given alone is readily degraded in theperiphery, thus preventing the drug from reaching thebrain in sufficient amounts for its conversion to DA atthe central level.8,14

As mentioned above, the search for an inhibitor ofDDC started soon after the introduction of L-dopa asthe rational therapy for PD, with the provision that, tobe a therapeutically effective DDC inhibitor, it shouldnot be able to cross the BBB.1,8,14 They should primar-ily block L-dopa metabolism in the periphery, therebyreducing the rate of the first-pass metabolism and slow-ing the plasma clearance of L-dopa.8,14

Carbidopa and benserazide were the molecules thatwere developed to be used in association with L-dopa.Their chemistry is based on a hydrazine group thatforms a hydrazone derivative with PP, thus blocking itand inactivating the enzyme. Thus, a greater amountof L-dopa could reach the brain, where it could betransformed to DA more effectively, therefore increas-ing the therapeutic efficacy of the drug.1,8,14

The introduction of DDCIs resulted in a 10-foldincrease in central nervous system L-dopa availability. Itwas also demonstrated that, when administered with aDDCI, the peripheral half-life of L-dopa is prolonged toapproximately 90 minutes and the required L-dopa doseis reduced by 60% to 80%. Moreover, reduced periph-eral decarboxylation of L-dopa to DA was able todiminish the characteristic peripheral side effects of DA(i.e., nausea, vomiting, and anorexia), making the drugsafer for its use in clinical practice.1,8,10

Carbidopa

Carbidopa [(—)-L-a-hydrazino-a-methyl-b-(3,4-dihy-droxybenzene) propanoic acid monohydrate] (MK-486) is a noncompetitive DDCI (http://www.drug-bank.ca/ drugs/DB00190) developed and patented byMerck in West Point, Pennsylvania, in 1962. Workcarried out by Victor Lotti at Merck and others latershowed that the use of the L-form of carbidopa, signif-icantly reduced the effective therapeutic dose of L-dopa, and that treatment with this drug before L-dopaadministration in parkinsonian patients was able toincrease the plasma concentration of dopa and con-comitantly decreased both plasma DA and its majoracid metabolite, HVA, suggesting that carbidopa wasindeed an effective inhibitor of DDC in humans.13

The combination of L-carbidopa and L-dopa was mar-keted in 1975 under the brand name of Sinemet andhas been in clinical use since then.15,16

Several seminal scientific articles published in theearly 1970s provided evidence on the advantages ofthe combination of L-dopa/carbidopa over the adminis-tration of L-dopa alone, in terms of efficacy or toler-ability.12,17,18 One of the pioneering studies was thatof Calne et al., in which the effects of L-dopa werecompared with a combination of L-dopa plus carbi-dopa in 21 PD patients. Both regimens were adminis-tered in maximum tolerated dosage in a double-blind,crossover study. Because there were no validatedassessment scales at the time, an ad-hoc designed scalewas used, including items of functional impairmentand disability, as well as physical signs, which werearbitrarily graded from 0 to 4. Although no significantbenefits were observed, in terms of reduction of symp-tomatology or functional impairment, the combinationshowed significantly better tolerability (reduced nauseaand vomiting), allowing for a faster titration period,and reduced the dosage requirement of L-dopa by22%. Patients on the combination showed increaseddyskinesia, compared to L-dopa alone.12 A few yearslater, Marsden et al. carried out a long-term study (1year) on 40 PD patients that were assigned to receivethe combination of L-dopa/carbidopa or L-dopa andplacebo. Results were similar to the previous study,although in these cases, aside from the benefitsobserved in reduced titration period, better tolerability,and L-dopa dose reduction, the patients on the combi-nation showed a slightly better clinical response, but atthe expense of increased abnormal involuntary move-ments.17 In a subsequent double-blind study comparingthe effects of carbidopa and L-dopa combined in a sin-gle tablet with L-dopa alone in 50 PD patients, Lieber-mann et al. reported that, after 6 months of treatment,patients receiving the combination showed a statisti-cally significant improvement over baseline in totalscore, rigidity, and tremor. In addition, 40% of thepatients treated with L-dopa/carbidopa showed obviousclinical improvement (a greater than 50% reduction intheir total score) over treatment with L-dopa alone.Nausea, vomiting, and anorexia developed in 56% ofpatients on L-dopa, but in only 27% of patients on thecombination. However, abnormal involuntary move-ments, observed in 48% of patients on L-dopa, werepresent in 77% of patients on L-dopa/carbidopa. Theinvestigators concluded that, despite the increase inabnormal involuntary movements, L-dopa/carbidopawas more effective than L-dopa alone.18

Benserazide

Benserazide [(RS)22-amino-3-hydroxy-N0-(2,3,4-tri-hydroxybenzyl) propanehydrazide] (Ro 4-4602) is areversible, peripheral DDCI, developed by Roche

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http://www.drugbank.ca/

http://www.drugbank.ca/

through the work of Da Prada and first tested clini-cally by Birkmayer in 1969, demonstrating the possi-bility of improving the therapeutic profile of L-dopaby prolonging its efficacy and providing better toler-ability.1,19 An interesting story that reflects the contro-versies existing at the time DDCIs were firstintroduced involved Alfred Pletscher (chief pharmacol-ogist at Roche) and Birkmayer. The former actuallygave benserazide to Birkmayer to test the validity ofhis report about the efficacy of L-dopa—assuming thatif L-dopa acted through production of DA, blockingDDC with benserazide would abolish its clinicaleffects. Birkmayer found just the opposite, but hisfindings were received initially with a lot of skepti-cism; however, his observations on the L-dopa effectspurred further research in Pletscher’s laboratory,leading to the discovery that benserazide did not passthe BBB, and it was indeed effective as a peripheralDDCI.20 The combination of L-dopa/benserazide wasfirst marketed in Europe in 1975 under the brandname Madopar. Several studies evaluating the efficacyof the L-dopa/benserazide combination in a 4:1 ratio(200 mg/50 mg) were published in the mid-1970s.The study by Rinne et al. compared patients treatedwith L-dopa alone or with the DDCI combination in acontrolled, double-blind, clinical, multicenter trial on94 patients with PD.21 During the 4 months of assess-ment, the combined treatment proved superior to L-dopa on several accounts. Nausea and vomitingoccurred with statistically significant less severity andfrequency. Clinical improvement, as measured by theWebster rating scale, occurred sooner and was alto-gether greater. Both treatment schedules were no dif-ferent with regard to other side effects, in particular,involuntary movements and reduction in supine bloodpressure. Safety parameters, such as liver function,renal function, and hematological parameters, werenot significantly influenced by both formulations.21

There have been a few studies comparing the effi-cacy and safety and tolerability of the two combina-tions L-dopa/benserazide versus L-dopa/carbidopa. Atriple-blind, controlled, multicenter study carried outin Scandinavia in 1976 compared the efficacy and tol-erability of both combinations in de novo patientswho were randomly assigned to receive either formu-lation.22 There was no significant difference in thedegree of improvement obtained with either combina-tion. Safety parameters were equal, as well as toler-ability, with the exception of dyskinesias that weremore frequently observed with the L-dopa/carbidopapreparation, perhaps related to the higher dosesachieved with this formulation.22 In a double-blind,crossover trial, Rinne and Molsa compared the twocombinations using doses that produced equivalentplasma levels and found no differences in symptomaticefficacy or frequency of dyskinesias, although nausea

and vomiting occurred more often with the 10:1 ratiopreparation of L-dopa/carbidopa, attributed to anincomplete inhibition of peripheral DDC.23

MAO Inhibitors

Overview

MAO is a mitochondrial enzyme involved in theoxidative deamination of several monoamines, includ-ing 5-hydroxytryptamine (5-HT; or serotonin), hista-mine, and the catecholamines, DA, noradrenaline, andadrenaline. This enzyme is present in most mammaliantissues under two isoforms (MAO-A and MAO-B).DA is oxidized by both isoenzymes; however MAO-Bis the predominant type in the human brain.3,11

MAO inhibitors were first introduced for the treat-ment of depression almost 50 years ago. All availableMAOIs in the early days of L-dopa therapy were non-selective A plus B. Thus, in the very few attempts atcombining these drugs to potentiate the effects of L-dopa, results were limited by the appearance of AEssuch as hypertensive crises attributed to dietary intakeof food rich in tyramine, such as cheese and other fer-mented or preserved foods, which caused an increasein blood pressure through peripheral vasoactive mech-anisms (thus the designation of the “cheese effect”),which required severe dietary restrictions in patientsreceiving non selective MAOIs.3 Development of selec-tive MAO-B (MAOBIs) inhibitors, through the workof Knoll on selegiline, revitalized the original idea ofMAO inhibition as a potential way of improving L-dopa therapy.24 More recently, rasagiline, a new selec-tive MAOBI, was developed specifically for its use inPD.25 In addition to their original indication as adju-vant therapy to L-dopa, both selegiline and rasagilinewere explored as potential disease-modifying therapies(DATATOP and ADAGIO studies) on the basis oftheir putative neuroprotective effects (inhibition ofoxidative stress and other potentially neurotrophicmechanisms).26,27 The results of these studies will notbe discussed here because they exceed the scope of thetopic under analysis.

Selegiline (Deprenyl)

Selegiline (phenylisopropyl-methylpropinylaminehydrochloride) is an irreversible or suicide inhibitor ofMAO-B; it forms a covalent bond with the flavin adeninedinucleotide cofactor of MAO.3 Because selegiline is anirreversible inhibitor, its inhibitory effect on MAO-B isconsiderably longer than the drug elimination half-life,depending on the resynthesis of enzyme protein. It is pos-sible that the effect can be as long as 1 month or evenlonger. Selegiline has a structure similar to amphetamineand is extensively metabolized to met-amphetamine andamphetamine.28 Although at therapeutic doses (10 mg/day) it is a relatively selective MAOBI, its selectivity is



lost at higher doses. Other effects include inhibition ofthe uptake of catecholamines, inhibition of presynapticcatecholamine autoreceptors, release of catecholamineby amphetamine metabolites, and putative neuroprotec-tive effects based on both theoretical considerations andin vitro studies.29

The efficacy of selegiline to provide symptomatic ben-efit in PD patients in monotherapy with this drug hasnot been extensively studied. However, a subanalysis ofthe DATATOP study indirectly demonstrated somesymptomatic effects as revealed by an improvement inmotor function during the “wash-in” phase of the studyand, conversely, a worsening during the “wash-out”period (DATATOP: improvement “wash-in”, UPDRSIII vs. placebo, 1 month 15.7 vs. 16.8; 3 months 15.8vs. 17.5; worsening “wash-out”).26 In a subsequentstudy of 157 de novo PD patients, comparing selegilineversus placebo, patients on the active arm showedsymptomatic improvement at 6 weeks and 3 months(total UPDRS was 22.0 1 5.3 and 1.7 1 5.4 comparedto placebo, 0.4 1 5.0 and 1.0 1 5.3; P<0.01).30 A mul-ticenter study carried out in France, evaluating selegi-line versus placebo in early untreated parkinsonianpatients, also showed selegiline to be significantly betterthan placebo for the UPDRS motor score.31 Other less-rigorous studies provided additional evidence of thesymptomatic effects of selegiline in monotherapy, whencompared to placebo.32,33

The symptomatic effects of selegiline as adjuncttherapy, either to L-dopa or DA agonists, were alsoevaluated in several placebo-controlled studies, both inearly uncomplicated patients and in those experiencingmotor fluctuations.34-38 The benefits observed withselegiline as adjunct therapy have been quite variableand nonsignificant (mostly because of the assessmentmethodology employed); however, the most consistentfinding across all studies was the presence of an L-dopa-sparing effect (up to 21% reduction in L-dopadose in selegiline-treated patients vs. placebo), the sig-nificance of which has not been clearly explained. Inaddition, several studies have looked into the effect ofselegiline in the prevention of motor complications,both motor fluctuations and dyskinesias, assessing thepercentage of patients experiencing these complica-tions, as well as the time to their development.39-41

None of these studies were able to show a significantreduction in the number of patients exhibiting motorfluctuations or a significant delay in its occurrence; therisk of developing dyskinesias, however, was signifi-cantly increased in those patients receiving selegiline.An interesting finding of the long-term follow-up ofthe patients in the original DATATOP cohort wasrelated to the occurrence of freezing of gait, whichwas significantly more frequent in the placebo groupthan in selegiline-treated patients.40 The existence ofan L-dopa-sparing effect was also confirmed in theselong-term studies.

Rasagiline

Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selec-tively and irreversibly inhibits brain MAO-B and wasspecifically designed for the treatment of PD.25,42 Rasagi-line is a close relative of selegiline, and its major metabo-lite, 1-aminoindan, does not possess amphetamine-likeactivity or appreciable affinity for any of the catechola-minergic or serotonergic receptor groups and is morepotent than selegiline. Propargyl derivative inhibitors areirreversible site-directed inhibitors, forming covalentlinkage with the N5 nitrogen of flavin.3,42 Similar to sele-giline, rasagiline is a selective MAOBI; however, its selec-tivity its lost at higher doses. Putative neuroprotectiveand antiapoptotic effects have also been attributed torasagiline based on theoretical considerations and in avariety of both in vitro and in vivo studies.3,29,42 Rasagi-line has been found to be more potent than selegiline ona weight basis. Doses of 0.5 to 1.0 mg/day produce com-plete inhibition of platelet MAO-B in humans.29 Beingan irreversible inhibitor of MAO-B, the duration of itseffect is dependent on the rate of de novo synthesis of theenzyme, which has been estimated by PET studies inhumans to be of approximately 40 days.3

The benefits of rasagiline on motor function, whengiven in monotherapy, have been evaluated in two con-trolled studies. The TEMPO study, a multicenter,randomized, double-blind, placebo-controlled trial wascarried out by the Parkinson Study Group comparingrasagiline 1 or 2 mg daily, with placebo.43 This trialenrolled 404 patients with early PD not requiring dopa-minergic therapy, and its primary outcome measurewas the change in the total UPDRS score between base-line and 26 weeks of treatment; the motor subscorechange was one of the secondary endpoints. TotalUPDRS scores were 24.20 comparing 1 mg of rasagi-line to placebo (P < 0.001) and 23.56 for 2 mg ofrasagiline versus placebo (P< 0.001), whereas themotor subscale showed a score of 22.71 for 1 mg and21.68 for the 2-mg dose, compared to placebo (no sig-nificance level was provided for this difference).43 Inthe ADAGIO trial (Delayed-Start Trial of Rasagiline inParkinson’s Disease), although the primary endpointswere designed to assess a putative neuroprotectiveeffect of rasagiline, the secondary endpoint allowed forthe evaluation of the symptomatic effects of the drug inmonotherapy. When measuring the change in the totalUPDRS score between baseline and the last observedvalue in phase I of the trial, rasagiline, at a dose of1 mg per day (1.26 6 0.36 points), proved to be supe-rior to placebo (4.27 6 0.26 points; P<0.001).27

Two additional studies assessed the efficacy of rasagi-line as adjunct therapy to L-dopa. The PRESTO studycompared rasagiline 0.5 and 1.0 mg/day and placebo in472 L-dopa-treated PD subjects with at least 2.5 hours/day OFF time. ON-period UPDRS-III improved with

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both doses of rasagiline adjusted for placebo (rasagiline0.5 mg: 22.91 [–4.59 to 21.23]; rasagiline 1 mg:22.87 [–4.58 to 21.16]; both P< 0.001).44 In an18-week study, including 687 patients, comparing rasa-giline 1 mg/day with entacapone 200 mg per dose of L-dopa, or placebo (the LARGO study), rasagilineimproved ON-period motor UPDRS-III scores, com-pared to placebo, by 22.94 points (P<0.0001).45 Thesame two studies evaluated the efficacy of rasagiline inthe control of motor fluctuations and its effects on dys-kinesias. In the PRESTO study, rasagiline 0.5 mg/daysignificantly reduced OFF time by 20.49 hours (20.91to 20.08 hours; P<0.02), whereas with the 1-mgdose, OFF time was reduced by 20.94 hours (21.36 to20.51 hours; P<0.001), adjusted for placebo. ONtime with troublesome dyskinesia was increased withrasagiline 1 mg/day by 32%, whereas with rasagiline0.5 mg, there was no troublesome dyskinesia. The dys-kinesia subscore of the UPDRS was also found to besignificantly increased with rasagiline 1 mg/day (10.37points [0.04-0.7]; P< 0.03), but not with rasagiline0.5 mg/day.44 Similar findings were reported in theLARGO study, which showed a significant reduction inOFF time of 20.78 hours (21.18 to 20.39 hours) withrasagiline, compared to placebo (P<0.0005), withouta corresponding increase in dyskinesia scores.45

Overall, both MAOBIs are well tolerated and con-sidered safe. There is no major difference between thetwo drugs in terms of tolerability and safety. A studyby Lees et al. reported increased mortality in patientswith L-dopa plus selegiline; however, these results areconsidered to be probably the result of a statisticalartifact and have not been replicated by others.46-48

The clinical relevance of the metabolism of selegilineto amphetamine and metamphetamine is not fullyclear; it may underlie the occurrence of neuropsychiat-ric side effects and insomnia. When administered incombination with L-dopa, both drugs may increasedopaminergic side effects, such as nausea, orthostatichypotension, increased dyskinesias, confusion, andhallucinations.29

COMTIs

Overview

Even after DDC inhibition only 10% of L-dopa plusDDCI crosses the BBB. Moreover, inhibition of thedecarboxylation pathway with carbidopa or bensera-zide shifts the metabolism of L-dopa to the COMTmetabolic pathway. Therefore, COMT inhibitionbecame an important therapeutic target to improveL-dopa bioavailability. COMT was identified andcharacterized in 1958 by Axelrod and Tomchick.49

The first COMTIs, introduced between 1958 and1975, were unselective, nonpotent, and considerablytoxic.7,49 The interest in COMT was revitalized in the

late 1980s when the potent and selective second-generation COMTIs were developed.49 The idea ofinhibiting COMT to delay the breakdown of L-dopaand further improve its bioavailability became a real-ity with the development of the selective second-generation compounds based on the nitrocatecholgroup, the properties of which were essential for theinhibition of the enzyme. At the end of the 1980s, twoinhibitors had been singled out as the best candidatesfor clinical use: tolcapone and entacapone, and by the1990s, both were introduced into clinical practice.49

COMT catalyzes the transfer of the methyl group ofS-adenosyl-L-methionine to one of the phenolic groupsof the catechol substrate in the presence of Mg21. Asa result of COMT inhibition, there is an increase inthe elimination half-life of L-dopa by up to 1 hour,whereas the area under the curve (AUC) of L-dopaplasma levels is increased by approximately 40%.There is also reduction of the AUC of 3OMD (prob-ably the result of peripheral effects), an increase of theAUC of DOPAC, and reduction of the AUC of HVA(probably a result of central effects in the case of tol-capone). Although, when given in a single dose, themaximum plasma concentration level of L-dopa(Cmax) is not increased, there is evidence suggestingthat Cmax is increased after several daily doses. Thetime to reach maximum plasma concentration levelsof L-dopa (Tmax) is delayed to 1.5 to 2.0 hours withL-dopa/DDCI plus COMTI versus 0.5 hours withL-dopa/DDCI alone (first dose). These effects translateinto an increase in the duration of the effect of eachL-dopa/DDCI dose, thus increasing ON time andreducing OFF time. Improvement in global motorfunction and a L-dopa-sparing effect is also observed(for a comprehensive review on the biochemistry ofCOMTIs, see Nissinen and M€anisto49).

Tolcapone

Tolcapone (3,4-dihydrox-40-methyl-5-nitrobenzophe-none) is a potent, selective, and reversible second-generation nitrocatechol inhibitor of COMT, developedby Roche (Ro 40-7592), active both in the periphery andcentrally, with a half-life of 5 to 8 hours, allowing forthree times daily (TID) administration in doses rangingfrom 100 to 200 mg per dose.49,50 Although its rate ofabsorption is comparable to entacapone, tolcapone has agreater bioavailability resulting in substantially higherCmax and AUC values. It was the first COMTI intro-duced into clinical practice based on several clinical trialsshowing its efficacy in reducing OFF time in PD patientsexperiencing motor fluctuations.50 Despite its centralCOMT inhibitory activity, no evident clinical efficacycould be demonstrated when given in monotherapy.When used as add-on therapy in combination withL-dopa/DDCI, in stable PD patients, tolcapone proved tobe efficacious both by reducing UPDRS II and III scores



and, after several months, allowed for the reduction ofL-dopa/DDCI dosage.51 Several pivotal studies lookedinto the efficacy of tolcapone in L-dopa-treated PDpatients experiencing motor fluctuations. One of the firstreports is that of Roberts et al., who demonstrated theability of tolcapone in variable doses (50-400 mg) of pro-longing the response to L-dopa in a single, open-labelstudy on 10 patients.52 Rajput et al., in a randomized,double-blind, parallel-group trial, involving 202 parkin-sonian patients under treatment with L-dopa/carbidopa,who were assigned to receive 100 and 200 mg of tolca-pone TID showed a reduction in OFF time by 3.25 hourswith the 200-mg dose, while at the same time had a sig-nificant decrease in mean daily L-dopa dose requirement,compared to placebo-treated patients (P<0.01).53

Moreover, the number of daily L-dopa intakes wasreduced significantly in each tolcapone group, comparedto placebo (P<0.01). In addition, they found significantimprovements in motor function and overall efficacy inthe tolcapone groups (P<0.01). Baas et al. carried out asimilar study adding tolcapone to 119 fluctuatingpatients receiving L-dopa/benserazide; they were able toshow that the addition of tolcapone 100 mg TIDdecreased OFF time by 31.5% and increased ON timeby 21.3%, whereas those receiving the higher dose(200 mg TID) showed a 26.2% reduction in OFF timeand a 20.6% increase in ON time.54 As with the previ-ous study, improvement in motor function and a L-dopa-sparing effect were also observed. In a larger, random-ized, double-blind, placebo-controlled, parallel-groupstudy carried out in the United States involving 250 fluc-tuating patients on L-dopa/carbidopa, the addition of tol-capone (100 and 200 mg TID) reduced OFF time by 2.0and 2.5 hours per day, respectively, and increased ONtime by 2.1 and 2.3 hours per day, respectively(P<0.001 vs. placebo).55 A reduction in total daily L-dopa dose of 185.5 mg (23%) in the tolcapone 100-mgTID group and 251.5 mg (29%) in the 200-mg TIDgroup was also reported.

The most common AEs initially reported with the useof tolcapone have been new onset or increase of pre-existing dyskinesia and diarrhea, in up to 20% of thecases, being one of the most common reasons for with-drawal. In clinical trials of tolcapone, liver enzymeswere elevated more than 3 times above the upper limitof normal in approximately 1% of patients who tookthe 100-mg dose and in approximately 3% of patientswho took the 200-mg dose.6 These findings led to therecommendation that periodic monitoring of liver func-tion be performed. Three instances of acute liver failurewith death after 60,000 patients had received tolcaponefor a total of 40,000 patient-years were reported inpostmarketing surveillance studies.6 For this reason, thedrug was withdrawn from the market in Europe andCanada and a black box warning issued in the UnitedStates. Tolcapone has been in continued use as a com-

passionate treatment, under appropriate liver functionmonitoring, and no further instances of acute liver fail-ure or death have been reported to date.

Entacapone

Entacapone (OR-611) [(E)22-cyano-3-(3,4-dihy-droxy-5-nitrophenyl)-N,Ndiethyl-2-propenamide] isalso a second-generation nitrocatechol reversible andselective COMTI developed by Orion Pharmaceuti-cals. It possesses different pharmacokinetic propertiesthan tolcapone, with a half-life after oral administra-tion to PD patients of approximately 1 to 2 hours forthe 200-mg dose, thus requiring its administrationwith each L-dopa/DDCI dose.10,49,50 It was introducedinto the market a few years after tolcapone. Beingpoorly lipophilic, it does not penetrate the BBB and itsclinical effects are the result of only peripheral COMTinhibition.50 Similar to tolcapone, it has shown to beeffective in improving motor fluctuations by prolong-ing the effects of a given dose of L-dopa.

No effects are observed when administered in mono-therapy, and it has been considered to be noneffica-cious as an adjunct to L-dopa/DDCI, despite its L-dopa-sparing properties, and modest improvements inmotor function observed in nonfluctuators.56

The efficacy of entacapone to improve motor fluctu-ations, on the other hand, has been demonstrated inseveral important clinical trials. A double-blind phar-macokinetic and clinical dose-response study of enta-capone as an adjuvant to L-dopa therapy in advancedPD experiencing motor fluctuations was carried out inFinland.57 In a single-graded-dose, crossover design offive 1-day treatment periods, each 1 week apart, enta-capone in increasing doses (50, 100, 200, or 400 mg)or placebo was given to patients with the first morningdose of L-dopa/DDCI. Motor responses were assessedat 30-minute intervals using the UPDRS part III,showing an increase in ON time of 33 minutes. In alarge, placebo-controlled, double-blind, parallel-group,multicenter trial, 205 patients were randomly assignedto receive either entacapone 200 mg or matching pla-cebo with each dose of L-dopa and were followed for24 weeks (SEESAW study).58 Entacapone was able toincrease ON time by 5% (approximately 1 hour), asmeasured by the patients’ diaries; improvement inUPDRS total, motor, and activities of daily living(ADL) were also reported. The NOMECOMT study,a 6-month randomized, placebo-controlled, double-blind, parallel-group study, involved 117 patients withmotor fluctuations who were evaluated by means ofhome diaries and UPDRS III scoring by the exam-iners.59 Entacapone 200 mg was given with eachL-dopa/DDCI dose, resulting in increased ON time of1.4 hours and decreased OFF time of 1.1 hours. Alarge, parallel-group, randomized, double-blind study

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conducted in Germany and Austria (CELOMENstudy) evaluated 301 PD patients, the majority withmotor fluctuations, who were assigned to receive enta-capone (200 mg) or placebo with each daily dose ofstandard or controlled-release (CR) L-dopa.60 Duringthe 24-week treatment period, patients completedhome diaries and were assessed by examiners usingthe UPDRS scale. Results indicated that entacaponewas able to increase ON time by 1.7 hours, whereasADL and motor scores improved by 1.1 and 3.3points, respectively. Additional large, controlled stud-ies carried out in the UK, Ireland, and Japan con-firmed those previously reported results with anaverage reduction of OFF time of 1.1 and 1.3 hours,respectively, and increased on time by 1.3 and 1.4hours, respectively.61,62

Most of the studies previously analyzed reportedvariable reductions in L-dopa/DDCI requirements afterthe addition of entacapone (L-dopa-sparing effect), themagnitude of which is approximately 15% to 19%.

The possibility that entacapone, by reducing fluctua-tions in L-dopa plasma levels through an increase inCmin and increased AUC, could prevent the develop-ment of motor complications when given early on inthe treatment was evaluated in two clinical trials usinga novel triple combination (L-dopa/carbidopa /entaca-pone) approved for clinical use in 2003 and marketedby Novartis Pharmaceuticals under the brand nameSTALEVO.7 The triple combination was developed tofacilitate the administration of the combination ofL-dopa/carbidopa with entacapone by providing sucha combination in a single tablet. The first was a large(423 patients) 39-week, randomized, double-blind,multicenter study to compare the efficacy, safety, andtolerability of L-dopa/carbidopa/ entacapone (100 mg/25 mg/200 mg, respectively) with L-dopa/carbidopa(100 mg/25 mg, respectively) in patients with earlyPD, never before treated with L-dopa; both drugs wererandomly assigned and administered three timesdaily.63 Although the results favored the use of the tri-ple combination in terms of better improvement inADL and clinical global impression, the developmentof motor fluctuations was not significantly differentfor both groups. A more ambitious attempt at demon-strating the ability of the triple combination to preventmotor complications (fluctuations and dyskinesia)was the STRIDE-PD sudy.64 This was a prospective,134-week double-blind trial comparing the risk ofdeveloping dyskinesia in 747 PD patients randomizedto initiate L-dopa therapy with L-dopa/carbidopa (LC)or L-dopa/carbidopa/entacapone (LCE), administeredfour times daily at 3.5-hour intervals. The primaryendpoint of the study was the time to onset of dyski-nesia. The rationale behind this clinical trial was basedon the assumption that by using the triple combina-tion at shorter intervals between doses, and the

increased AUC and Cmin provided by the COMTI, itwould reduce significantly the peaks and troughs offluctuating plasma L-dopa levels, thus providing morecontinuous dopaminergic stimulation. Because theresulting pulsatile stimulation of DA receptors wasbelieved to be the underlying cause of motor compli-cations, providing more-stable L-dopa plasma levelswould result in a reduction of these complications.4

Contrary to what was expected, patients receiving theLCE combination as initial treatment had a shortertime to onset of dyskinesia (hazard ratio: 1.29;P 5 0.04) and increased frequency at week 134 (42%vs 32%; P 5 0.02).64 After the publication of thisstudy, there were additional publications speculatingon the reasons for having failed to achieve theexpected results. The fact that patients in the LCEgroup received higher L-dopa dose equivalents, a spec-ulation on the possibility that even shorter intervalsbetween doses were necessary to achieve continuousDA stimulation, and having neglected the fact thatCOMTIs are able to increase the Cmax of L-dopa inmultiple dose settings were some of the hypothesesthat were put forward.49,65

In terms of the AE profile, entacapone is similar totolcapone, except for liver toxicity. However, nondo-paminergic effects, such as diarrhea, do occur in asimilar proportion, as well as dopaminergic effects,such as dyskinesia, nausea, and vomiting.

There is very limited information on the comparativeefficacy of tolcapone versus entacapone. A study com-paring the long-term experience of these two drugs inadvanced PD patients concluded that “tolcapone wasmore effective in lowering UPDRS motor and complica-tion subscores, duration of ‘off’ time, and levodopadoses.66 UPDRS motor scores and change in levodopadose in the tolcapone group remained below baselinelevel for 36 months; however, they were above baselinein the entacapone group from 6 months on.” Theresearchers stated that tolcapone had greater and longerefficacy than entacapone, and that their findings indi-cated that tolcapone continued to have a place in thetreatment of advanced PD, despite the risks associatedwith this drug.

Conclusions

The introduction of enzyme inhibitors for their usein combination with L-dopa has been a significantdevelopment that has evidently improved the efficacyand tolerability of L-dopa, while at the same time pro-viding additional pharmacological tools to potentiateand prolong its symptomatic effect and the durationof its action.

The search for ways to improve L-dopa efficacythrough enzymatic modifications is still under way,and several new compounds have been, or are in the



process of being, evaluated. Safinamide, a novel a-aminoamide derivative with both MAOBI propertiesand nondopaminergic mechanisms of action, has beentried both in early PD and as add-on therapy in fluctu-ating PD patients, showing promising results.67,68 Sim-ilarly, newer, more potent, and longer active third-generation COMTIs are under development, such asobicapone, which has proved to possess certain advan-tages over existing compounds, at least in pharmaco-kinetic studies involving healthy subjects.69

As long as L-dopa remains as the mainstay treatmentof PD, and its long-term efficacy is complicated bylimitations derived from its pharmacokinetic proper-ties, there will be room for improvement through thedevelopment of newer, more-effective compounds thatcould help in minimizing these limitations.

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improving l -dopa therapy: the development of enzyme inhibitors

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