Controlled-release Levodopa Research Articles

The Catechol O-MethyltransferaseInhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phaseIII clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

Controlled-Release Levodopa for the Treatment of Rapid Motor Fluctuations in Parkinson's Disease Subjects with Subthalamic Nucleus Deep Brain Stimulation.

Objectives We aimed to investigate the efficiency of controlled-release levodopa/benserazide (Madopar HBS) use during daytime in our pilot study on advanced-stage Parkinson's disease (PD) subjects with deep brain stimulation of the subthalamic nucleus (STN-DBS) therapy. Methods We have evaluated all PD subjects with STN-DBS who had admitted to our outpatient polyclinic between February 2022 and March 2022. Among these patients, those who were taking levodopa therapy at least five times throughout the day and the efficiency of levodopa lasted less than 3 hours were detected. The standard levodopa therapy was switched to Madopar HBS in all patients who accepted the therapy chance and the clinical evaluation of the patients on Madopar HBS therapy was performed in the second month of the therapy. Results Ultimately, the follow-up of all four patients in whom the levodopa therapy was changed to Madopar HBS yielded a significant reduction in the "off" periods and improvement in the PSQ-39 scores. Conclusion We suggest the use of Madopar HBS in PD patients with STN-DBS surgery suffering from motor fluctuations, particularly in the subgroup with milder dyskinesias. Future study results of a large number of PD subjects with STN-DBS therapy are warranted to confirm our observations. The results of these studies may provide critical applications in clinical practice.

A Real-Life Search for the Optimal Set of Conversion Factors to Levodopa-Equivalent-Dose in Parkinson's Disease Patients on Polytherapy.

A wide variety of conversion factors for a levodopa-equivalent-dose (LED) have been proposed for each Parkinson's disease (PD) medication. The currently-used set of conversion factors is based on studies that relied on subjective experience or theoretical assumptions. This set was never validated in patients receiving polytherapy. To use real-life data to identify an optimal set of conversion factors independent of prior assumptions regarding clinical efficacy of different medications. Retrospective analysis of data from 206 cognitively-preserved patients with advanced PD receiving polytherapy before deep brain stimulation (DBS) surgery. A nonlinear automated problem solver was used to find a set of conversion factors that, when applied, minimized the coefficient of variation of LEDs in a relatively homogenous cohort of patients. Independent and model-free evaluation of a wide range of possible sets of conversion factors to LED suggested a set of normalized conversion factors for immediate release levodopa (1.00), controlled release levodopa (0.88), and amantadine (1.23). A minimal clinical benefit of entacapone was observed for patients with motor fluctuations. Our analysis could not detect conversion factors for dopamine agonists and MAO-B inhibitors, possibly because their clinical contribution when added to levodopa is limited. Independent from previous studies and prior assumptions we show that the currently-used LED conversion factors for immediate release levodopa, controlled release levodopa and amantadine are largely correct and that dopamine agonists, MAO-B inhibitors and entacapone, given in addition to levodopa, have little additional clinical value for PD patients with motor fluctuations.

Pharmacokinetics and efficacy of a novel formulation of carbidopa-levodopa (Accordion Pill®) in Parkinson's disease

IntroductionDopamine replacement via levodopa (LD) remains the most effective treatment for Parkinson's disease (PD), yet its use is often associated with motor complications within several years of continued use. The Accordion Pill® (AP-CD/LD) is a novel drug delivery system based on gastric retention of multilayer films containing immediate-release (IR) carbidopa (CD) and immediate- and controlled-release LD. The AP-CD/LD was designed to improve the consistency of LD in the bloodstream while offering patients with PD more consistent symptom management. MethodsThis phase 2, multicenter, open-label, two-way randomized crossover study included 4 cohorts of participants with PD, each receiving AP-CD/LD (50/250 mg, 50/375 mg or 50/500 mg) twice daily in one treatment period and an active comparator in the other treatment period. Pharmacokinetics (PK) and efficacy were evaluated for AP-CD/LD vs IR-CD/LD. Treatment-emergent adverse events (TEAEs) and patient- and investigator-reported measures were also evaluated. ResultsCompared with IR-CD/LD, treatment with either AP-CD/LD dose resulted in more stable LD plasma concentrations in both fluctuating and non-fluctuating PD patients, and significantly decreased Cmax (57.1% and 66.8% decreases among fluctuating and non-fluctuating patients, respectively). Both AP doses significantly improved standard measures of motor symptoms: (daily OFF time, total ON time, and good ON time), as well as patient- and investigator-assessed measures, versus IR-CD/LD. The safety and tolerability profile of AP-CD/LD was consistent with the known properties of IR-CD/LD. ConclusionsAP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced PD patients. A phase 3 randomized controlled trial is currently underway.

Controlled-release levodopa methyl ester/benserazide-loaded nanoparticles ameliorate levodopa-induced dyskinesia in rats

BackgroundLevodopa remains the most effective drug in the treatment of Parkinson’s disease. However, long-term administration of levodopa induces motor complications, such as levodopa-induced dyskinesia. The mechanisms underlying levodopa-induced dyskinesia are not fully understood.MethodsIn this study, we prepared levodopa methyl ester (LDME)/benserazide-loaded nanoparticles, which can release LDME and benserazide in a sustained manner. Dyskinesia was induced in rats by repeated administration of levodopa then treated with LDME plus benserazide or the same dose of LDME/benserazide-loaded nanoparticles. Apomorphine- induced rotations and abnormal involuntary movements (AIMs) were measured on treatment days 1, 5, 10, 15, and 20. In addition, the levels of phosphorylated dopamine- and cyclic adenosine monophosphate- regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, and ΔfosB were determined by Western blot. Tau levels were determined by Western blot and immunohistochemistry. Dynorphin levels in the striatum and cortex of rats were measured using enzyme-linked immunosorbent assay.ResultsOver the course of levodopa treatment, the rats developed abnormal AIMs, classified as locomotive, axial, orolingual, and forelimb dyskinesia. The degree of reduction of apomorphine-induced rotations was comparable in dyskinetic rats treated with LDME plus benserazide or LDME/benserazide-loaded nanoparticles. The axial, limb, and orolingual (ALO) AIMs of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 14 ± 2.5, 9 ± 2.0, and 10 ± 2.1 on treatment days 10, 15, and 20, respectively, which were significantly reduced compared with dyskinetic rats treated with LDME plus benserazide (25 ± 3.7, 27 ± 3.8, and 25 ± 3.5, respectively). The locomotive AIMs of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 2.3 ± 0.42, 1.7 ± 0.35, and 1.6 ± 0.37 on treatment days 10, 15, and 20, respectively, which were also reduced compared with dyskinetic rats treated with LDME plus benserazide (4.4 ± 0.85, 4.7 ± 0.95 and 4.8 ± 0.37, respectively). Western blot showed that the levels of phosphorylated dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa, extracellular signal-regulated kinases 1/2, tau, and ΔfosB in dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 134.6 ± 14.1, 174.9 ± 15.1, 134.2 ± 19.3, and 320.5 ± 32.8, respectively, which were significantly reduced compared with those of dyskinetic rats treated with LDME plus benserazide (210.3 ± 19.7, 320.8 ± 21.9, 340.4 ± 27.1, and 620.7 ± 48.3, respectively). Immunohistochemistry indicated that the level of phosphorylated tau was (7.2 ± 1.1) × 104 in dyskinetic rats treated with LDME/benserazide-loaded nanoparticles. However, the tau level was only (14.6 ± 2.3) × 104 in LDME plus benserazide-treated dyskinetic rats. There was a significant difference between the two groups. Enzyme-linked immunosorbent assay showed that dynorphin levels in the striatum and cortex of dyskinetic rats treated with LDME/benserazide-loaded nanoparticles were 5.7 ± 1.2 and 4.8 ± 0.87, respectively, which were significantly reduced compared with LDME plus benserazide-treated dyskinetic rats (13.3 ± 2.1 and 8.1 ± 1.1 for the striatum and cortex, respectively).ConclusionResults suggest that LDME/benserazide-loaded nanoparticles can be used to reduce the expression of dyskinesia in dyskinetic rats.

A single-blind cross over study investigating the efficacy of standard and controlled release levodopa in combination with entacapone in the treatment of end-of-dose effect in people with Parkinson’s disease

ObjectiveTo determine the efficacy of standard levodopa combined with controlled release levodopa and entacapone in controlling end-of-dose symptoms in Parkinson’s disease. MethodsA single-blind cross over design was used to compare the duration of action for three pharmacological combinations: standard levodopa (L/DDC); standard levodopa combined with entacapone (L/DDC/E); and standard levodopa combined with controlled release levodopa (CR) and entacapone (L/DDC/CR/E). Thirty two participants with wearing-off symptoms and inadequate symptom control with L/DDC/E had their optimum dose of L/DDC determined at base line. Entacapone was added to the optimal L/DDC dose and duration of action determined. Levodopa CR dosage was adjusted to match the optimal L/DDC dose for each participant. All participants were then trialed on L/DDC/CR/E and duration of response calculated. Timed Up and Go (TUG) times and magnitude of extra movements were recorded hourly throughout the day over several days to determine the optimum interval between doses for each combination. The UPDRS (Sections 2 and 3), PDQ39 and fatigue scale, the PDF-16, were recorded at base line and when dosage intervals had stabilized on L/DDC/CR/E. ResultsDuration of response was greatest with L/DDC/CR/E compared to L/DDC/E (p < 0.001) and number of daily doses were less on L/DDC/CR/E compared to L/DDC/E (p < 0.001). UPDRS, PDQ39 and fatigue scores also improved on L/DDC/CR/E compared to L/DDC (p < 0.001). Dyskinesia increased on L/DDC/CR/E (p = 0.001) however magnitude was mild. ConclusionCombining standard levodopa and levodopa CR preparations with entacapone is an additional treatment strategy to manage motor fluctuations in advanced PD.

Soluble and controlled-release preparations of levodopa: do we really need them?

The controlled-release preparations of levodopa or newer soluble preparations of levodopa may improve levodopa bioavailability and tolerability and help managing (or even preventing) motor complications. Whether the controlled-release preparations or soluble preparations can really take the place of standard levodopa remains highly controversial, especially in patients receiving chronic levodopa therapy. Controlled-release formulations have a longer half-life and provide more stable plasma levels than standard levodopa. In de novo parkinsonian patients, controlled-release levodopa and standard levodopa are equally efficacious, and carry similar motor complication rates. In patients with advanced disease, whether motor fluctuations respond better to controlled release than to standard oral levodopa remains unclear. In selected parkinsonian patients, single bedtime doses of controlled-release levodopa may improve sleep and nocturnal disability. The poor solubility of levodopa may be overcome by soluble formulations that achieve maximal absorption. A levodopa formulation that guarantees faster and more reliable absorption would be especially useful in the clinical treatment of Parkinson's disease patients experiencing "no-on" or "delayed-on" phenomena. However, further studies with these new formulations are needed to understand if they offer better benefit to parkinsonian patients. New dual formulations incorporating both a faster absorption and an increased half-life than standard levodopa are currently under study.

Effect of controlled-release levodopa on the microstructure of sleep in Parkinson’s disease

Dopamine is an important neurotransmitter in the regulation of the sleep-wake cycle, and parkinsonian patients suffer from prominent sleep abnormalities. Hence, the question arises whether the disrupted sleep pattern in Parkinson's disease (PD) is responsive to dopaminergic treatment. Thirty-two patients (18 women, 45-82 years old; mean 61 ± 8 years) with dopamine-responsive, akinetic-rigid PD, not taking neuroleptic medication or suffering from dementia were randomized into two groups. Both groups had to withhold their usual dopaminergic medication after noon. At bedtime, one group received 200 mg controlled-release (CR) levodopa/carbidopa, whilst the other group spent the night in the 'off'-state. Polysomnographic recordings were obtained in all patients and 16 age-matched, healthy controls. Compared to healthy controls, patients with PD suffered from significantly decreased total sleep time, REM sleep and slow wave sleep (SWS), whilst the time spent awake was increased. The administration of levodopa/carbidopa CR had no impact on any of these variables. Levodopa/carbidopa CR has previously been found effective for treating night-time akinesia, but according to this study, it has no impact on the altered sleep structure in PD.

Central Levodopa Influx and the Clinical Motor Response to Levodopa in Patients With Parkinson Disease Complicated With Motor Fluctuations and Dyskinesias

To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease. The clinical response to a single oral dose of standard and controlled-release levodopa/carbidopa was assessed in 12 patients with Parkinson disease complicated with motor fluctuations and dyskinesias. Plasma concentrations of levodopa and large neutral amino acids were determined, and the theoretical central levodopa influx was calculated using a model based on competitive inhibition of substrates to cross the blood-brain barrier. The mean (SD) central levodopa influxes at the onset of the antiparkinsonian clinical effect were 19.7 (10.9 x 10(-3) and 19.1 (7.4 x 10(-3) nmol min(-1) g(-)1 (P >0.1) for standard and controlled-release levodopa, respectively. The mean (SD) central levodopa influxes at the onset of choreic dyskinesias were 20.1 (8.2 x 10 (-3) and 19.9 (10.8 x 10(-3) nmol min (-1) g(-)1 (P 9 0.1) for standard and controlled-release levodopa, respectively. During the tests, choreic dyskinesias were associated with a central levodopa influx of 10 x 10(-3) nmol min(-1) g(-1) or greater, and foot dystonia occurred with a central levodopa influx less than 9 x 10(-3) nmol min(-1) g(-1). The clinical response to levodopa in patients with advanced Parkinson disease may be related to central levodopa influx. We found no differences in the central levodopa influx threshold for clinical improvement with different levodopa formulations. The central levodopa influxes at the onset of choreic dyskinesias and antiparkinsonian effect were similar. Choreic dyskinesias and foot dystonia were associated with high and low central levodopa influx, respectively.

Pharmacokinetic—pharmacodynamic interaction between nebicapone and controlled-release levodopa/benserazide: A single-center, phase I, double-blind, randomized, placebo-controlled, four-way crossover study in healthy subjects

Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect.Objectives: The primary objective of this study was to investigate the effect of nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3-O-methylated metabolite (3-O-methyldopa [3-OMD]). Nebicapone's tolerability was also assessed.Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study.Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m2) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa Cmax increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of nebicapone 50, 100, and 200 mg, respectively. After administration of nebicapone 50, 100, and 200 mg, 3-OMD Cmax decreased 44%, 57%, and 58%, and 3-OMD AUC0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC0−t, increased with all doses of nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by nebicapone occurred at ~1.5 hours postdose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity; Tmax of nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found.Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.

Botulinum toxin type A and a rehabilitation program in the treatment of Pisa syndrome in Parkinson’s disease

Lateral flexion in idiopathic Parkinson’s disease (PD) represents one of atypical postural disturbances [1]. Several authors differentiated this particular clinical picture from Pisa syndrome (pleurothotonus) [1, 2], a rare type of trunk dystonia characterized by abnormal and severe axial lateral flexion of the trunk accompanied by contraction of the trunk musculature with marked flexion of the thoracolumbar spine and backward axial rotation. In 1972, Ekbom and colleagues described Pisa syndrome (PS) for the first time [3], which initially was considered as a subtype of dystonia in patients taking typical or atypical antipsychotic agents. Later, this syndrome was described in idiopathic cases, in patients with neurodegenerative diseases or in those receiving other drugs (cholinesterase inhibitors, selective serotonin reuptake inhibitors or antiparkinsonian agents) [4–8]. A cholinegic-dopaminergic imbalance, which is strategic in the regulation of axial muscle tone, or the interactions among noradrenaline, serotonin and dopamine could be involved in the development of PS [5, 7]. In recent years, the term PS has been used to describe this feature in PD, although no universal agreement has been reached with regard to the appropriate nomenclature [1, 2, 4]. Actually, there are not common defined criteria to classify features of PS and other lateral trunk flexions in PD [1]. In the present article, we describe the case of a 68year-old man with a diagnosis of PD (stage III Hoehn & Yahr) who came to us for observation of a severe axial lateral flexion of the trunk. He was a pensioner, with about 5 years of education, and without a family history of PD. In 2000, he was first seen by a neurologist who made a diagnosis of probable idiopathic PD according to published criteria [9] and prescribed up to 400 mg/day controlled-release levodopa plus 100 mg/day decarboxylase inhibitor. The patient showed a slowly progressing clinical picture, with a gradual increase of dopaminergic drugs (600 mg/day controlled-release levodopa plus 150 mg/day decarboxylase inhibitor). A selective serotonin reuptake inhibitors drug was added to reduce a progressive depressive disorder (sertraline 50 mg/day). The patient did not effectuate a clinical checkup for 1 year, assuming drugs without any medical control. A CT scan of the brain and the cervical-thoraco-lumbar spinal cord excluded ankylosis or vertebral column deformity. He did not remember when he had developed the postural disorder. Initial symptoms involved the neck area, with subsequent spread to the back. He reported movement difficulty and severe pain in the lower back region. Physiatric examination revealed a marked trunkal deviation to the right side with increased tone of the dorsal and lumbar muscles, particularly evident on walking and sitting, suggesting a diagnosis of PS. He had severe gait disturbance and postural instability, too, caused by continuous dystonic movement of trunk. In standing position, the patient presented an angle of about 35 with trunk A. Santamato (&) M. T. Amoruso L. Amoruso P. Fiore Department of Physical Medicine and Rehabilitation, University of Foggia, ‘‘OORR’’, Viale Pinto, 71100 Foggia, Italy e-mail: a.santamato@unifg.it

Pharmacokinetic‐pharmacodynamic crossover comparison of two levodopa extension strategies

Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.

The Pharmacokinetics and Pharmacodynamics of Levodopa in the Treatment of Parkinsons Disease

Levodopa, a prodrug of dopamine, remains to be one of the main drugs in the treatment of Parkinson's disease. All current levodopa products are formulated with aromatic amino acid decarboxylase inhibitors such as carbidopa or benserazide to prevent the metabolism of levodopa in the gastrointestinal tract and systemic circulation. Levodopa pharmacokinetic profiles remain unchanged after multiple doses, and are similar between healthy volunteers and patients and among patients at different stages of disease. Entacapone inhibits the metabolism of levodopa therefore increases the area under the plasma concentration-time profile of levodopa; however, it may decrease the initial absorption rate of levodopa in some patients probably due to competitive absorption. Food appears to affect the absorption of levodopa, but its effects vary with formulations. The results of positron emission tomography study suggest that a high protein diet may compete with the uptake of levodopa into the brain, therefore, may result in reduced levodopa effects. Since infusion studies demonstrated that it is beneficial to maintain stable plasma concentrations of levodopa, controlled-release formulations have been designed to provide prolonged absorption of levodopa. However, subsequent pharmacokinetic and pharmacodynamic studies demonstrated that a threshold concentration of levodopa appears to be necessary to switch patients "on". Once patients are turned "on", the duration of levodopa effects may be correlated with plasma concentration of levodopa. As such, more recent studies have demonstrated significant clinical benefits such as shorter time to "on" and longer duration of "on" when combining the immediate- and controlled-release levodopa products as compared to controlled-release levodopa products. Given these findings, it is important for physicians to understand the relationship between the pharmacokinetics and pharmacodynamics of levodopa in order to provide dosage regimens that meet patient needs. The pharmacokinetics and pharmacodynamics data of levodopa reported in the literature are reviewed here.

Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease

In this review the effect of adjunct 5-nitrocatechol based COMT inhibitors, especially entacapone, on the pharmacokinetics and efficacy of levodopa is detailed. The safety and adverse events are considered based mainly on phase III trial data and extension studies. Entacapone used as an adjunct to regular or controlled-release levodopa preparations increased ON-time and reduced OFF-time by 1 to 2 h daily in Parkinson's disease patients with wearing-off. The daily levodopa dose could also be reduced. Entacapone was generally well tolerated. Dopaminergic adverse events, such as dyskinesia and nausea, could usually be handled by reducing the levodopa dose. Several studies indicated that entacapone improved the quality-of-life of the patients. Entacapone treatment was also cost-effective. Open trial data supporting the use of the triple combination tablet (levodopa/carbidopa/entacapone) Stalevo TM are presented. Finally, the rationale for early use of COMT inhibitors in Parkinson's disease is considered and the design of the STRIDE trial is discussed. This is a double-blind randomised placebo controlled study where entacapone is administered at the time when levodopa is first introduced. The follow-up time is at least 2 years and the primary endpoint is the time to onset of dyskinesias.

Prevalence and Costs of Parkinsonian Syndromes Associated with Orthostatic Hypotension

ObjectiveTo measure the frequency of and direct costs related to parkinsonian syndromes associated with orthostatic hypotension (OH). Patients/MethodsPatients over 45 years using at least one antiparkinsonian drug (excluding piribedil or anticholinergics prescribed alone) were identified from the Haute-Garonne Social Security prescription database and separated in two groups according to simultaneous prescription (OH group) or not (control group) of drugs for orthostatic hypotension. Direct medical costs were analysed retrospectively, over a 6-month period, from the health care payer’s perspective. ResultsEighty-eight patients (9.1%) out of 971 parkinsonian also received antihypotensive drugs. Direct medical costs were significantly higher in OH than in control group (4.425 vs. 3.074 €/patient/6 months, p < 0.05). Beside hospitalisation and ancillary cares, drugs accounted for highest expenses (989 vs. 781 €/patient/6 months in control group) since use of controlled-release levodopa formulations or dopamine agonists was higher in OH group. ConclusionOccurrence of OH is associated with higher medical expenditure in parkinsonian syndromes.

Entacapone Increases Levodopa Exposure and Reduces Plasma Levodopa Variability When Used With Sinemet CR

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

Potential of transdermal drug delivery in Parkinson's disease.

There has been a growing recognition that pulsatile stimulation of dopamine receptors may be an important mechanism in the generation of the motor fluctuations that often develop and compromise the effectiveness of long-term levodopa administration in persons with Parkinson's disease (PD). This has prompted investigation of treatment approaches that might provide more constant, and therefore physiological, dopamine receptor stimulation. Frequent levodopa administration, controlled-release levodopa preparations, inhibitors of levodopa metabolism, and duodenal, subcutaneous and even intravenous infusions of levodopa or dopamine agonists have all been employed with this goal in mind, but all have limitations. Transdermal drug delivery is a treatment approach that is not only capable of providing a constant rate of drug delivery, but is also non-invasive and relatively simple to use. However, developing a drug to be delivered transdermally for the treatment of PD has been anything but easy. Levodopa and many dopamine agonists are not sufficiently soluble to be administered via the transdermal route, and blind alleys have been encountered thus far in the investigation of suitably soluble drugs. Nevertheless, investigation continues and yet another candidate drug, rotigotine (N-0923), is currently under active investigation. Techniques designed to enhance skin permeation and thus improve the effectiveness of transdermal drug delivery are also potential sources for future treatment advances.

Sleep disorders in Parkinson's disease: epidemiology and management.

Sleep problems are an under-emphasised cause of disability in Parkinson's disease (PD) and may be seen independently of PD, associated with primary PD pathology, or as a result of antiparkinsonian medications. Common sleep disorders include excessive daytime sleepiness, rapid eye movement (REM) sleep behaviour disorder, night-time wakefulness and restless legs syndrome. A number of strategies may be used to improve sleep cycle disturbances, and often these interventions do not require pharmacological manipulation. Restoring traditional mealtimes and scheduling activities during predicted periods of sleepiness may help alleviate daytime somnolence; the use of controlled-release levodopa preparations or administration of a catechol-O-methyl transferase (COMT) inhibitor with levodopa at bedtime may reduce periods of night-time wakefulness. Administration of clonazepam at bedtime may assist with REM sleep behaviour disorder but, because this agent can result in daytime somnolence, experimentation with dosage times is recommended. Sleep attacks are described as a sudden, unavoidable transition from wakefulness to sleep and, although rare, have been described with pramipexole, ropinirole and other dopamine agonists. Although the condition has yet to be recognised by the International Association of Sleep Disorders, patients with PD who report rapid sleep onset should be evaluated for the possibility of sleep attacks. If sleep attacks are suspected, it is reasonable to strongly caution patients regarding potentially risk-associated activities such as driving, and to consider careful withdrawal of dopaminergic therapy.

Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease.

Parkinson's disease is the most common neurodegenerative disease in which the chemical pathology is known and effective symptomatic treatment, levodopa, is available. Therapy in the initial years after initiation with dopa decarboxylase inhibitors, carbidopa or benserazide, combined with levodopa results in favorable, stable responses. However, by 5 years after the initiation of treatment, over two thirds of patients experience motor fluctuations beginning initially with a "wearing-off" effect followed by more complex fluctuations including dyskinesias and "on-off" responses. A number of strategies have been developed in an attempt to deal with these complications including changing doses and frequencies, adding agonist medications, adding or substituting controlled-release levodopa, and surgical therapies. A more recent strategy has centered on increasing the availability of intracellular levodopa and synaptic dopamine by inhibiting the peripheral and central metabolism of levodopa to 3-O-methyldopa with the use of a catechol-O-methyltransferase inhibitor. To date, two of these inhibitors, tolcapone and entacapone, are available to treat the wearing-off phase of levodopa therapy.

The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson's disease

OBJECTIVESEntacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an...