COMT inhibition

Catechol O-methyltransferase (COMT) inhibitors are a new therapeutic option for patients with Parkinson's disease (PD), which affects one-half to one million individuals in North America. COMT inhibitors act by extending the duration of action of levodopa, which for 30 years has been the cornerstone of treatment for PD. This article summarizes the mechanism of action of COMT inhibitors and the results from clinical trials of two novel COMT inhibitors, tolcapone and entacapone, which are now under investigation.

Therapies for PD. The mechanisms that underlie the loss of dopamine-producing neurons in patients with PD are not completely understood. Replacement of the lost dopamine is the major strategy for treating this disease. Levodopa, together with a decarboxylase inhibitor, carbidopa (used predominantly in the United States) or benserazide, significantly reduces nausea and the total dose of levodopa required, normalizes the life expectancy of patients with PD, and improves patients' quality of life(QOL).¹

During the initial stages of PD, patients experience good control of disease symptoms (particularly the cardinal symptoms of tremor, bradykinesia, and rigidity) because of a long-lasting response to each dose of levodopa. At the beginning of treatment, patients require only one to three doses of levodopa-carbidopa per day because the response pattern is stable(nonfluctuating). Despite this stable response, some patients continue to have impairments of their QOL and activities of daily living (ADL). This stage of the disease can last from months to more than 5 years.² Over time, the clinical response to levodopa often declines to a short-duration response. Improvements become increasingly correlated with fluctuations in plasma concentrations of levodopa(figure 1).³ The symptomatic relief provided by levodopa lasts only until plasma levels of levodopa begin to drop. Such patients are described as experiencing motor fluctuations because their response to levodopa "wears off."

Typically, wearing-off fluctuations are the first fluctuations to develop. Although symptoms of PD improve after the dose of levodopa, this benefit wears off before the next dose is taken. As the disease progresses, patients develop more disabling motor response complications, including unpredictable fluctuations that are not related to the time of dosing. These fluctuations in response can be complicated by dyskinesias (i.e., choreoathetoid and dystonic movements), which initially occur when the concentration of levodopa is at its peak. Motor response complications and dyskinesias appear in the majority of patients with PD who undergo standard treatment with levodopa-carbidopa within 5 to 7 years of the initiation of therapy.⁴

A continuous infusion of levodopa relieves many of the symptoms associated with motor response complications. However, continuous infusion can be maintained only IV or intraduodenally and is therefore impractical. Controlled-release or slow-release formulations of levodopa also provide more consistent plasma levels. Patients require fewer doses of these formulations than they do of immediate-release formulations. However, absorption can be unpredictable, and peak plasma levels typically are achieved more slowly than with standard immediate-release formulations.

Dopamine receptor agonists (eg, bromocriptine, pergolide, pramipexole, and ropinirole) mimic the stimulation of brain receptors by dopamine and therefore are also used to treat patients with PD. They have a role as an adjunct to levodopa therapy in patients who have advanced, disease with motor fluctuations.^1,5,6 Patients who have early, nonfluctuating PD experience similar improvements in symptoms whether treated with agonist therapy alone^7,8 or with combined therapy with levodopa and a dopamine agonist.⁶

The continuing medical challenge in PD is to provide adequate treatment of symptoms while attempting to prevent or delay the onset of motor fluctuations and dyskinesias. Therefore, a drug that can further prolong the biologic half-life of levodopa should provide clinical benefit to patients with PD.

Metabolism of levodopa and dopamine. Peripheral absorption and active transport. After oral administration, levodopa competes with large neutral amino acids to cross the intestinal mucosa via carrier transport.³ Once absorbed, levodopa is transported across the blood-brain barrier, although because there is limited capacity to cross into the brain via the same active transport mechanism used in the gut,³ less than 1% of an orally administered dose of levodopa enters the brain. Levodopa is metabolized rapidly in the periphery (liver, kidneys, and blood), predominantly by a reaction catalyzed by the enzyme aromatic amino acid decarboxylase (AADC), which converts levodopa to dopamine (figure 2).^3,9,10 Dopamine is unable to cross the blood-brain barrier, and the resulting supraphysiologic levels of dopamine in the periphery may cause nausea, hypotension, and cardiac arrhythmias.

When selective inhibitors of AADC, such as carbidopa and benserazide, were first used in combination with levodopa in the late 1960s, treatment of PD improved dramatically because formulations of levodopa combined with either carbidopa or benserazide significantly increased the half-life of levodopa, permitting as much as a 70% reduction in the dosage of levodopa needed for optimal efficacy. As a consequence, the adverse peripheral effects associated with dopamine such as orthostatic hypotension and nausea, are diminished in patients given levodopa combined with either carbidopa or benserazide.

Significant peripheral metabolism of levodopa also is mediated by COMT, which catalyzes the O-methylation of levodopa to 3-O-methyldopa (3-OMD) (figure 2). Because inhibition of AADC shunts the peripheral metabolism of levodopa toward reactions catalyzed by COMT, only 5-10% of the orally administered dose of levodopa and carbidopa enters the brain. In patients with PD who are given levodopa and carbidopa, metabolism by COMT is responsible for the majority of levodopa metabolism in the periphery. 3-OMD has a significantly longer half-life than does levodopa (>14 hours compared with 90 minutes).¹⁰ Therefore, the addition of a peripheral COMT inhibitor as adjunctive therapy to levodopa plus either carbidopa or benserazide is a step toward reducing the peripheral metabolism of levodopa and increasing the amount of available to enter the brain through further prolongation of its half-life.¹¹

Central metabolism. AADC inhibitors (i.e., carbidopa, benserazide) do not cross the blood-brain barrier. Therefore, when levodopa is taken up in the brain, the activity of brain-associated AADC converts levodopa to dopamine (figure 2). COMT activity in the brain catalyzes the metabolism of levodopa to 3-OMD and of dopamine to 3-methoxytyramine (3-MT). Also within the brain, the metabolism of dopamine is mediated by the enzyme monoamine oxidase (MAO), which catalyzes the intraneuronal deamination of dopamine to 3,4-dihydroxyphenylacetic acid(DOPAC). Although COMT and MAO mediate different metabolic pathways in the brain, the combination results in the generation of the major final metabolite of levodopa, homovanillic acid (HVA). COMT O-methylates DOPAC and MAO deaminates 3-MT to generate HVA.

The gradual loss in efficacy of levodopa is a consequence of its peripheral pharmacokinetics and of the central pharmacodynamics of dopamine. Even when it is administered with carbidopa, levodopa has a relatively short half-life in plasma (1-3 hours).³ This causes fluctuations in plasma levels of levodopa and in its secondary levels in the CNS. In patients who do not experience fluctuations, it appears that presynaptic dopaminergic neurons can still store dopamine, which may in part account for the smoothing out or buffering of the fluctuations in levels of dopamine after administration of levodopa. This buffering capacity is further lost in patients with advancing PD. Moreover, secondary postsynaptic mechanisms also cause a decrease in response time. A proposed mechanism for the severe fluctuations experienced by these patients is that these peaks and troughs in striatal dopamine are directly associated with changes in plasma levels, because presynaptic autoregulation is no longer adequate(figure 1).³

COMT. COMT plays a major role in the peripheral metabolism of levodopa, dopamine, and norepinephrine. It is a ubiquitous enzyme and is found in the brain, liver, kidney, erythrocytes, and gastrointestinal tract.¹⁰ COMT therefore reduces the amount of levodopa that can be converted to dopamine in the brain and in the periphery(figure 2). In the brain, COMT also accelerates the breakdown of any dopamine produced. During chronic therapy with levodopa and carbidopa, COMT-mediated metabolism of levodopa can lead to very high peripheral concentrations of the metabolite 3-OMD. However, the clinical consequences of this phenomenon are not yet clearly understood.

Pharmacokinetics of COMT inhibitors: preclinical animal data. Clinical experience with the first generation of COMT inhibitors (the gallates and tropolone) was relatively unrewarding. However, the second generation, developed in the late 1980s, yielded very potent compounds and highly selective oral formulations. Preclinical results demonstrated these effects in animals.

In rats, the administration of tolcapone with levodopa and benserazide led to a large and long-lasting increase in plasma concentrations of levodopa compared with those observed after administration of the same dose of levodopa and benserazide alone. This effect amounted to a three- to fourfold increase in the area under the plasma concentration curve (AUC). Complete suppression of plasma 3-OMD production also was observed(figure 3).¹²

Similarly, whole-brain concentrations of levodopa increased dramatically and remained high for a long period after dosing. Brain concentrations of levodopa were substantially higher after the addition of tolcapone, and tolcapone completely suppressed the formation of 3-OMD in the brain(figure 4).¹² In animals, tolcapone increases striatal concentrations of dopamine by inhibiting COMT both peripherally and centrally. However, central inhibition of COMT with tolcapone has not been conclusively proved to occur in humans (unpublished data on file, Hoffmann-La Roche, Inc., Basel, Switzerland).

Results from experiments with an animal model of parkinsonism have indicated that tolcapone would be a valuable adjunct to therapy with levodopa.⁹ Rats treated unilaterally with the neurotoxin 6-hydroxydopamine, which depletes striatal stores of dopamine, respond to administration of levodopa by contralateral turning. This turning behavior is a marker of central dopaminergic activity: the greater the number of turns, the greater the central dopaminergic effect. Figure 5 illustrates the effects of COMT inhibition on levodopa-induced turning behavior and on striatal concentrations of dopamine.¹³ Administration of entacapone or tolcapone leads to significant increases in turning behavior and in the striatal content of dopamine.⁹

Figure 6 compares the concentrations of levodopa, dopamine, 3-OMD, DOPAC, and HVA in rat striatum after oral levodopa and carbidopa alone vs. those after levodopa and carbidopa plus entacapone. Administration of entacapone results in increased concentrations of levodopa and its product, dopamine, in the striatum. Both the peak concentrations of dopamine and its duration of action are increased with entacapone. In addition, concentrations of 3-OMD are reduced with entacapone. The concentrations of the main metabolites of dopamine, DOPAC and HVA, are increased after entacapone, reflecting the increased turnover of dopamine.¹³

Figure 7 shows the concentrations of levodopa during microdialysis in rat striatum after administration of levodopa and either entacapone or tolcapone. Similar doses of each COMT inhibitor were administered; both resulted in an increase in striatal levels of dopamine, but tolcapone produced a higher peak effect. Therefore, although the central actions of entacapone and tolcapone differ (entacapone acts exclusively in the periphery, whereas tolcapone acts in both the brain and the periphery), systemic administration of each leads to an increase in the level of dopamine in the brain. This is consistent with evidence showing that the clinical effect of a dose of levodopa is comparable to that achieved with a dose 30-50% less if entacapone or tolcapone is co-administered.¹⁴

In summary, animal models of PD demonstrate that COMT inhibition with these drugs reduces the metabolism of levodopa to 3-OMD and increases the amount of levodopa available to enter the brain by prolonging the plasma half-life of levodopa (figure 8), resulting in more stable levels of levodopa.

Clinical benefits of COMT inhibitors. COMT inhibitors were developed more than 20 years ago. These early inhibitors, which included gallates, tropolone, and 3,4-dihydroxy-2-methyl-propiophenone, had nonspecific actions and significant clinical toxicity.^9-11 The new COMT inhibitors, tolcapone and entacapone, are nitrocatechol-type compounds (figure 9). Both are potent, reversible inhibitors of peripheral COMT activity and exhibit an acceptable safety profile for human use.^9-11 The improved pharmacokinetics of levodopa in the presence of a COMT inhibitor just discussed (i.e., increased AUC but unchanged C_max) translates into less fluctuating plasma levels of levodopa when patients are given multiple doses of the COMT inhibitor. This provides more stable levels of levodopa than can be obtained by increasing the dosage of levodopa and carbidopa or by using a controlled-release formulation.

Because so many of the limitations of chronic therapy with levodopa are related to rapid changes in the levels of levodopa and dopamine, addition of a COMT inhibitor as adjunctive therapy to levodopa would be expected to provide significant clinical benefit. A summary of the rationale for the use of COMT inhibitors in the treatment of PD is provided in table 1.

Improved pharmacokinetics of levodopa in normal volunteers given COMT inhibitors. The improved pharmacokinetics of levodopa in the periphery have been demonstrated after administration of COMT inhibitors to normal human volunteers.^15-18 Single oral doses of tolcapone (10-800 mg) administered simultaneously with levodopa and benserazide (100 mg/25 mg) to healthy male subjects increased the AUC and the elimination half-life (t_1/2) of levodopa but did not significantly alter either the peak concentration of levodopa (C_max) or the time required to reach peak concentrations (t_max). This extended the period during which the level of levodopa remained within the therapeutic window(table 2).¹⁸ A 200-mg dose of tolcapone results in a 100% increase in the AUC of levodopa and an 80% increase in its elimination half-life. Peripheral COMT activity is inhibited by >80% at this dose of tolcapone.¹⁹

These changes in pharmacokinetics are attributed to the inhibition of peripheral COMT activity, which enables more levodopa to enter the brain.²⁰ Treatment with tolcapone is associated with similar improvements in the pharmacokinetics of levodopa in most standard formulations of levodopa-benserazide²¹ and levodopa-carbidopa.²² This applies to both single-dose and multiple-dose regimens of tolcapone.²³ Similarly, administration of the COMT inhibitor entacapone to normal human volunteers increased the relative bioavailability of levodopa, although the C_max was not significantly enhanced (figure 10).¹⁵ As a result, the plasma concentration of levodopa remained within the therapeutic range for an extended period in individuals given a COMT inhibitor plus levodopa and carbidopa compared with that in individuals given levodopa and carbidopa alone.^15,18

Use of COMT inhibitors in patients with motor fluctuations. As discussed above, inhibition of COMT activity by both tolcapone and entacapone provides benefits to patients who have fluctuating disease by improving the pharmacokinetics of levodopa.^24-33 As a consequence, both tolcapone and entacapone reduce the patient's dosage of levodopa and increase "on" time(the period during which antiparkinsonian medication provides a patient with relief of symptoms of tremor, bradykinesia, and rigidity), thus prolonging the duration of benefit from each dose. Roberts et al.²⁴ showed that the improved pharmacokinetics of levodopa after administration of a single dose of tolcapone was paralleled by a significant extension (almost 70%) of the duration of antiparkinsonian action of levodopa and carbidopa in patients who were experiencing "wearing-off" fluctuations(figure 11).

Kurth et al.²⁵ demonstrated that tolcapone prolonged the clinical benefits of levodopa in patients with fluctuating disease and also reduced their total levodopa requirement. In this multicenter, double-blind, placebo-controlled study, a clinical evaluation was made before treatment on day 1 with tolcapone (50 mg, 200 mg, or 400 mg per day) added to the levodopa and carbidopa. A second assessment was made 42 days after treatment was initiated. Both evaluations used the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale as well as assessments of"on-off" time and assessments of dyskinesia at 30-minute intervals over a 10-hour period. All three dosages of tolcapone significantly reduced "off" time by an average of 40%. Furthermore, "on" time was increased by about 25% compared with that in placebo-treated patients. Dosages of levodopa and carbidopa were reduced significantly at all dosage levels of tolcapone(table 3). Similarly, a significant reduction in the frequency of daily administration of levodopa and carbidopa was found for the 200-mg tid and 400-mg tid dosages. Tolcapone was well tolerated; patients experienced typical dopaminergic side effects that were either reduced or eliminated after the dosage of levodopa-carbidopa was decreased.

In another randomized, double-blind, parallel-group trial, 137 patients with predictable motor fluctuations were given adjunctive therapy with either 100 mg tid or 200 mg tid of tolcapone.²⁶ With either dosage of tolcapone, patients experienced a significant reduction in mean daily requirement for levodopa compared with that in patients given levodopa and carbidopa plus placebo. This dosage reduction was marked by a significant reduction in the number of daily doses. After 3 months, patients treated with either dosage of tolcapone experienced a reduction in the duration of "off" time compared with that in patients given placebo. However, this reduction was statistically significant only for patients treated with 200 mg of tolcapone tid, who experienced a reduction from baseline levels of overall"off" time of 3.25 hours (figure 12).²⁶ Data from a subgroup of patients who were given tolcapone for 12 months indicated that the reductions in both levodopa dosage and "off" time were long-term benefits. Baas et al.²⁷ also have shown, in a multicenter, randomized, double-blind trial, that tolcapone reduces the"wearing-off" time and reduces the requirement for levodopa in patients with fluctuating disease.

Similar observations have been made in patients with fluctuating disease who were treated with entacapone. In a double-blind, randomized, placebo-controlled, comparative crossover study, Ruottinen and Rinne³⁴ evaluated 26 patients who had idiopathic PD with levodopa-related fluctuations to determine the effects of repeated dosing with entacapone on pharmacokinetics and metabolism and on motor responses to levodopa. Patients were given 200 mg of entacapone or placebo with each dose of levodopa four to 10 times daily during the two 4-week treatment periods. A wash-out period was not applied in this study because of the short half-life of entacapone (1-4 to 3-6 hours).

Entacapone delayed the elimination of levodopa from plasma and increased its AUC_0-4. The C_max and t_max values for levodopa remained unchanged in all 23 patients who completed the study. In accordance with the pharmacokinetics findings, entacapone prolonged the duration of motor response to an individual dose of levodopa plus AADC inhibitor by 27 minutes (p = 0.001) and dyskinesia by 26 minutes (p = 0.002) compared with placebo, without affecting the magnitude, onset, or peak latency of the motor response (table 4). Treatment with entacapone also resulted in a 16% reduction in the mean total daily dose of levodopa. According to patients' diaries, the mean daily "on" time increased by 2.1 hours compared with placebo despite the lower mean intake of levodopa. Therefore, the results of this double-blind study confirm earlier findings of the efficacy of entacapone in open studies of repeated dosing of entacapone.

Two randomized, multicenter, placebo-controlled studies of the effect of entacapone in patients experiencing motor fluctuations recently have been completed in North America (205 patients) and in the Nordic countries (171 patients).³⁵ Patients were given either entacapone (200 mg) or a placebo in addition to their optimal dosage of levodopa and AADC inhibitor. Efficacy was judged by the change in "on" time as determined by patients' self-assessment diaries over the 24-week treatment period. In both studies, treatment with entacapone increased daily "on" time by approximately 1 hour. Also in both studies, the mean total UPDRS scores decreased by approximately 10% in patients treated with entacapone compared with those in patients treated with placebo. The benefits of treatment with entacapone were rapidly lost after the drug was withdrawn. This is consistent with the reversible inhibition of COMT caused by the agent.

Use of COMT inhibitors in patients with stable responses. In a recent study by Waters et al.,³⁶ tolcapone significantly improved the ADL and motor function of stable responders, i.e., those who had not yet developed fluctuations in their response to levodopa. Tolcapone(either 100 mg or 200 mg tid) was administered with levodopa and carbidopa to a total of 196 patients in a double-blind, placebo-controlled trial. After 6 months of therapy, both dosages of tolcapone significantly improved the UPDRS scores for ADL (subscale II) and motor function (subscale III) compared with those in patients who were given placebo (table 5). Improvements of 19% (-1.4 ± 0.6) and 20% (-1.6 ± 0.3) in subscale II scores occurred in patients given 100 mg tid and 200 mg tolcapone tid, respectively. Patients given placebo did not experience a significant change in ADL scores over the same 6 months (0.1 ± 0.6). These improvements were seen in patients who were able to reduce their total daily doses of levodopa by 6% with 100 mg tid and by 9% with 200 mg tid of tolcapone. In contrast, the requirements for levodopa of the patients in the placebo group increased over the same 6-month period.

COMT inhibitors versus dopamine agonists. Recently, one trial compared the effects of adjunctive therapy with tolcapone versus bromocriptine in patients with fluctuating PD.³⁷ The results indicated that tolcapone-treated patients required less levodopa and experienced fewer adverse CNS effects (e.g., psychosis and hallucinations) than did bromocriptine-treated patients.³⁷ Both drugs improved "on" time.

Similarities and differences between tolcapone and entacapone. Tolcapone and entacapone both provide benefits to patients who have fluctuating response patterns to levodopa. However, several distinctions can be made between the two inhibitors with respect to their pharmacokinetics and pharmacodynamic profiles.^11,38 At comparable dosages of both drugs, tolcapone is the more potent COMT inhibitor.³⁸ Furthermore, tolcapone appears to provide a greater increase in the AUC of levodopa than does an equivalent dose of entacapone. Both drugs are absorbed rapidly and exhibit linear pharmacokinetics for doses as high as 200 mg. Entacapone has a greater volume of distribution than tolcapone and is metabolized rapidly, whereas tolcapone becomes protein bound. Therefore, entacapone is cleared more rapidly from the body than is tolcapone. The bioavailability of tolcapone is almost 20-fold greater than that of entacapone.¹⁹ Consequently, entacapone must be given with every dose of levodopa, but tolcapone can be administered at 6-hour intervals. Both drugs inhibit the activity of COMT in the periphery, but only tolcapone penetrates the blood-brain barrier, as shown by the results of animal studies. However, central COMT inhibition by tolcapone has not been conclusively proved to occur in humans. Therefore, the clinical significance of this CNS activity is not yet known. A summary of these differences is provided in table 6.³⁸

Safety. Short-term administration of COMT inhibitors is safe and well tolerated in patients with PD.^25,28,29,33 Addition of a COMT inhibitor to therapy with levodopa and carbidopa or levodopa and benserazide significantly decreases the clearance of levodopa in patients with PD, thus extending the action of a given dose of levodopa. COMT inhibitors have the potential to increase dopaminergic adverse events associated with administration of levodopa. In clinical studies, the most frequently reported adverse events associated with COMT inhibitors (defined as those occurring in >5% of treated patients) have been dopaminergic (e.g., increased peak-dose dyskinesias or hallucinations). However, these events have tended to be mild.^26,27 Increased dopaminergic adverse events can be avoided by reducing the dosage of levodopa when either tolcapone or entacapone is administered.^11,29

Nondopaminergic adverse events associated with long-term administration(≥6 months) of tolcapone include diarrhea, headache, increased sweating, and abdominal pain. Of these, diarrhea is the most common and was the most frequent reason for patients' withdrawal from long-term trials.^26,36

Between 6 and 12 weeks after initiation of treatment with tolcapone, eight stable responders developed elevated levels (defined as more than three times the upper limit of normal) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).³⁶ In the four patients who withdrew from the trial prematurely, elevated ALT and AST levels returned to normal within 2-6 weeks after discontinuation of tolcapone treatment. In the four patients who remained in the study, ALT and AST levels returned to normal spontaneously. No other adverse hepatic events were reported by patients who either continued or discontinued treatment with tolcapone, and the elevated hepatic levels had no clinical consequences.³⁶

In an early randomized, double-blind, crossover, single-dose study with entacapone³² involving 12 patients who had PD with motor fluctuations, no significant changes in clinical hematologic or biochemical variables were seen. Other than a transient strong orange coloration observed in the urine of patients given entacapone, no adverse events were reported.

In the 1-month crossover comparative study with entacapone (200 mg) or placebo by Ruottinen and Rinne,³⁴ the adverse events reported with entacapone were mainly mild to moderate. The most frequently reported adverse events during the 4-week study period were diarrhea or loose stools (n = 4, entacapone; n = 1, placebo), abdominal pain or discomfort(n = 5, entacapone; n = 3, placebo), confusion (n = 2, entacapone; n = 0, placebo), anxiety and insomnia (n = 2, entacapone; n = 0, placebo), faintness (n = 3, entacapone; n = 1, placebo), mood elevation (n = 2, entacapone; n = 0, placebo), and dyskinesia (n = 6, entacapone; n = 1, placebo).³⁵

In two independent, placebo-controlled, double-blind, parallel-group multicenter trials of entacapone in patients who had PD with motor fluctuations (205 patients in North America and 171 patients in the Nordic countries), transient dyskinesia and mild nausea were reported in the entacapone-treated groups. Overall, however, the drug was generally well tolerated and was not associated with abnormalities in vital signs or in laboratory test results.³⁵

Summary and conclusions. All clinical studies reported to date have clearly demonstrated that COMT inhibitors extend the half-life of levodopa in plasma. Patients with PD can gain notable benefits from the addition of a COMT inhibitor to therapy with levodopa and carbidopa or levodopa and benserazide. The available data demonstrate that COMT inhibitors extend levodopa's duration of action, prolonging "on" time in patients with fluctuating PD. COMT inhibitors permit a reduction in the daily dosage of levodopa and enhance the benefits of long-term therapy with levodopa and carbidopa or levodopa and benserazide. Patients given adjunctive therapy with a COMT inhibitor experience an improvement in their QOL (e.g., improved daily activities, restoration of motor function, and reduced "off" time) compared with that in patients who are not given a COMT inhibitor.^24-29,31,32 Finally, adjunctive therapy with a COMT inhibitor has the advantage of providing rapid-onset improvement in the pharmacokinetics of levodopa, so patients quickly and safely receive a clinical benefit.^{18,19,21,24-26,28,29,31-33}

Acknowledgments

Dr. Adler and Dr. Kurth have received research grants from Hoffmann-La Roche Inc. and Novartis Pharmaceuticals Corp. The authors wish to thank Dr. Peter LeWitt and Dr. Caroline Tanner for their critical review of this manuscript.