Exacerbated physical fatigue and mental fatigue in Parkinson's disease.

OBJECTIVE: To characterize fatigue in Parkinson's disease (PD). BACKGROUND: Fatigue is a recognized problem in PD. Fatigue can be in the physical realm or in the mental realm. Fatigue has not been characterized in PD. METHODS: We characterized fatigue in 39 PD patients and 32 age-matched normal controls using five questionnaires: A. The Multidimensional Fatigue Inventory (MFI), which measures five dimensions of fatigue independently including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. B. The Fatigue Severity Inventory (FSI), which quantifies fatigue in general. C. The Profile of Mood States (POMS), which assesses six subjective subscales: tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. D. Center for Epidemiological Studies-Depression Scale (CES-D). E. Visual Analog linear scale of energy (VA-E). RESULTS: PD patients scored higher in all of the five dimensions of fatigue in the MFI including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue (P < 0.001 except for mental fatigue P = 0.005). The severity of physical fatigue did not correlate with that of mental fatigue. PD patients scored higher on the FSI, POMS, CES-D, and scored lower on the VA-E. The scores in the FSI correlated with general fatigue, physical fatigue, reduced activity, and reduced motivation but not with mental fatigue in the MFI. Depression correlated with all dimensions of fatigue except physical fatigue in the MFI. Disease severity, as measured by Modified Hoehn and Yahr staging, did not correlate with any of the measures. CONCLUSIONS: PD patients have increased physical fatigue and mental fatigue compared to normals. Physical fatigue and mental fatigue are independent symptoms in PD that need to be assessed and treated separately.     

Treatment Detection and Movement Disorder Society-Unified Parkinson's Disease Rating Scale,Part III Estimation Using Finger Tapping Tasks

The validation of objective and easy-to-implement biomarkers that can monitor the effects of fast-acting drugs among Parkinson's disease (PD) patients would benefit antiparkinsonian drug development. We developed composite biomarkers to detect levodopa/carbidopa effects and to estimate PD symptom severity. For this development, we trained machine learning algorithms to select the optimal combination of finger tapping task features to predict treatment effects and disease severity. Data were collected during a placebo-controlled, crossover study with 20 PD patients. The alternate index and middle finger tapping (IMFT), alternative index finger tapping (IFT), and thumb–index finger tapping (TIFT) tasks and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III were performed during treatment. We trained classification algorithms to select features consisting of the MDS-UPDRS III item scores; the individual IMFT, IFT, and TIFT; and all three tapping tasks collectively to classify treatment effects. Furthermore, we trained regression algorithms to estimate the MDS-UPDRS III total score using the tapping task features individually and collectively. The IFT composite biomarker had the best classification performance (83.50% accuracy, 93.95% precision) and outperformed the MDS-UPDRS III composite biomarker (75.75% accuracy, 73.93% precision). It also achieved the best performance when the MDS-UPDRS III total score was estimated (mean absolute error: 7.87, Pearson's correlation: 0.69). We demonstrated that the IFT composite biomarker outperformed the combined tapping tasks and the MDS-UPDRS III composite biomarkers in detecting treatment effects. This provides evidence for adopting the IFT composite biomarker for detecting antiparkinsonian treatment effect in clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Fatigue in multiple sclerosis: association with disease-related, behavioural and psychosocial factors

We determined biopsychosocial correlates of general, physical, and mental fatigue in MS patients, by evaluating the additional contribution of potentially modifiable factors after accounting for non-modifiable disease-related factors. Fifty-three ambulatory MS patients, along with 28 normal controls were recruited for a cross-sectional study. Subjects completed the Multidimensional Fatigue Inventory (MFI) and Fatigue Severity Scale. Potential correlates evaluated were: disease-related factors (disease duration and type, immunomodulating treatment, muscle strength, pain, forced vital capacity (FVC), respiratory muscle strength, body mass index, disability, fibromyalgia), behavioural factors (physical activity, sleep quality) and psychosocial factors (depression, stress, self-efficacy). Multivariate models were calculated for MFI General, Physical, and Mental Fatigue. Age-adjusted multivariate models with non-modifiable factors included the following predictors (P < or = 0.10) of 1) MFI General and Mental Fatigue: none; and 2) MFI Physical Fatigue: FVC and disability. The following potentially modifiable predictors (P < or = 0.10) made an additional contribution to the models 1) MFI General Fatigue: sleep quality, self-efficacy, pain; 2) MFI Physical Fatigue: self-efficacy, physical activity; and 3) MFI Mental Fatigue: stress, self-efficacy. Fatigue in MS is multidimensional. Correlates of general and physical fatigue are disease-related, behavioural and psychosocial factors. Correlates of mental fatigue are psychosocial factors. Potentially modifiable factors account for a considerable portion of fatigue.     

Pharmacokinetics of etilevodopa compared to levodopa in patients with Parkinson's disease: an open-label, randomized, crossover study

"Dose failures" and "delayed on" phenomena following an intake of levodopa dose in patients with Parkinson's disease (PD) with motor fluctuations may be caused by stagnation of poorly soluble levodopa in the atonic stomach. Etilevodopa is a unique, highly soluble prodrug of levodopa. When ingested, etilevodopa is more readily dissolved in the stomach than levodopa. It passes unchanged through the stomach to the duodenum, where it is rapidly hydrolyzed by local esterases and rapidly absorbed as levodopa. To compare the pharmacokinetics of three different modes of etilevodopa/carbidopa administration with standard levodopa/carbidopa tablets in fluctuating PD patients, 29 patients with PD and response fluctuations were enrolled in an open-label, randomized, four-way crossover study of single doses of 4 treatments: swallowed etilevodopa/carbidopa tablets, etilevodopa/carbidopa tablets dissolved in water, etilevodopa oral solution with carbidopa tablets, and standard levodopa/carbidopa tablets. To measure the maximal concentration (Cmax), time to Cmax (tmax), and area under the curve (AUC) of plasma levodopa, etilevodopa, and carbidopa, blood samples were drawn before drug administration and at intervals up to 240 minutes thereafter. Plasma levodopa tmax was significantly shorter with all three modes of administration of etilevodopa (mean of about 30 minutes) than with levodopa treatment (mean of 54 minutes). During the first 45 minutes after drug ingestion, plasma levodopa AUC was significantly greater after etilevodopa administration than after levodopa administration. Levodopa AUC for 0 to 1 hour and 0 to 2 hours were also significantly greater following administration of etilevodopa/carbidopa swallowed tablets than following administration of levodopa/carbidopa tablets. Mean levodopa Cmax was in the range 2.3 to 2.7 microg/mL for all treatments. Levodopa Cmax was significantly greater following treatment with etilevodopa swallowed tablets than with levodopa tablets. Etilevodopa/carbidopa was well tolerated, with a safety profile comparable to that of levodopa/carbidopa. The shorter levodopa tmax observed with etilevodopa potentially translates to a shorter time to "on". Clinical trials with etilevodopa/carbidopa tablets should be carried out in PD patients with response fluctuations such as "delayed on" and "dose failures".     

Mood fluctuations in Parkinson's disease: a pilot study comparing the effects of intravenous and oral levodopa administration

OBJECTIVES: Parkinson's disease (PD) is associated with motor fluctuations that have been shown to improve when stable plasma levodopa levels are achieved with continuous levodopa infusions. Many patients also develop mood fluctuations. In this pilot study, we gathered preliminary information about the relationship between changing mood states and plasma levodopa levels. METHODS: Six patients with idiopathic PD and histories of motor and mood fluctuations participated in a double-blind levodopa infusion study. Subjects received active oral carbidopa/levodopa and a placebo levodopa infusion on one day and placebo oral carbidopa/levodopa and an active levodopa infusion on the other day, in a randomly determined order. Evaluations included serial plasma levodopa levels and assessments of mood and motor states. RESULTS: Only 4 of the 6 subjects demonstrated mood fluctuations on at least one of the treatment days. All subjects achieved more stable plasma levodopa levels on the active infusion day. Two subjects experienced fewer mood fluctuations on the active infusion day and two experienced fewer on the oral day. Conclusions The results of this pilot study suggest that the relationship between mood state and plasma levodopa level may vary among PD patients.     

Immediate placebo effect in Parkinson's disease--is the subjective relief accompanied by objective improvement?

BACKGROUND: A recent well-conducted meta-analysis showed that placebo effect is associated with a possible small benefit for subjective outcomes, but has no significant effects on objective outcomes. Objective: Herein, we aimed to investigate the immediate effects of two different types of placebo [placebo pill and sham transcranial magnetic stimulation (TMS)] in Parkinson's disease (PD) patients and compared them to the standard treatment (levodopa) in a proper randomized, double-blind, crossover clinical trial. METHODS: PD patients received three different interventions on different days: levodopa, placebo pill, and sham TMS. The motor function was assessed using simple and choice reaction time, Unified Parkinson's Disease Rating Scale (UPDRS), finger tapping, Purdue Pegboard test, time to button up, walking time and supination-pronation. The subjective motor function was measured by a visual analogue scale (VAS). RESULTS: The results showed that there was a significant motor function in the motor function only after the treatment with levodopa, but not after treatment with placebo pills or sham TMS. However, patients reported a similar subjective improvement in motor function indexed by VAS following these three treatments. CONCLUSION: These results suggest that placebo interventions in PD may have an immediate subjective sensation of improvement but result in no significant objective motor changes compared with levodopa treatment. Although physiological changes are possible after a placebo intervention, our findings suggest that the acute placebo effect in PD may be the result of the subjective change in the motor rating only.     

The influence of external timing cues upon the rhythm of voluntary movements in Parkinson''s disease.

The ability of patients with Parkinson's disease (PD) and healthy subjects to synchronise finger tapping, produced by rhythmic wrist movements, with auditory signals of target frequencies (range 1-5 Hz) and to sustain such rhythms following sudden withdrawal of auditory cues was studied. Healthy subjects were able, in the presence of auditory cues, to duplicate target frequencies accurately over the range investigated both in terms of mean tapping rate and in regularity of tapping. PD patients were less accurate under these conditions and on average tended to tap too rapidly at the lower (1-3 Hz) target frequencies and too slowly at the highest (5 Hz) target frequency. In addition, the variability of their tapping rhythms was generally greater. Healthy subjects were able to sustain tapping rhythms well following suppression of auditory signals. By contrast, withdrawal of external timing cues resulted in marked impairment of the patients' rhythm generation. At lower frequency targets (1-3 Hz) patients' tapping rates increased over rates which were already elevated in the presence of external cues. Conversely, at higher target frequencies (4-5 Hz), the average tapping rate tended to decline further from previously depressed levels. The accuracy of almost all patients fell outside the normal range. Two patterns of tapping errors were found. The first was hastening of tapping which was most evident at intermediate target frequencies. The second was faltering which occurred mainly at the higher target frequencies. These forms of behaviour may result from inherent abnormalities of internal rhythm generation since they occurred both in the presence and absence of external timing signals. Overall, our findings are consistent with the view that the basal ganglia have a role in the internal cueing of repetitive voluntary movements.     

Clinical and psychosocial factors associated with fatigue in patients with Parkinson's disease

Fatigue is an important contributor to poor quality of life. The aim of our research was to identify factors associated with fatigue among patients with Parkinson's disease (PD). The sample consisted of 150 patients. The Multidimensional Fatigue Inventory (MFI), Unified Parkinson's Disease Rating Scale (UPDRS), Hospital Anxiety and Depression Scale (HADS) and Charlson co-morbidity index were used for analysis. Demographic data were obtained in a structured interview. T-test, χ²-test and general linear regression were used. Fatigue was reported in 81% of the patients, with the worst scores in physical fatigue. Mood disorders and worse UPDRS scores were associated with fatigue.     

Is impact of fatigue an independent factor associated with physical activity in patients with idiopathic Parkinson's disease?

To investigate the longitudinal association between fatigue and physical activity in Parkinson's disease (PD) and determine whether this association is distorted by potential confounders. Data from baseline, 3, 6, and 12 week assessments in a single blind randomized clinical trial with cross‐over design were used (N = 153). The Multidimensional Fatigue Inventory (MFI) was used to assess fatigue and an activity monitor to measure amount of physical activity (defined as % dynamic activity during each monitoring session). Time‐independent and time‐dependent factors were investigated for their possible univariate association with dynamic activity. Random coefficient analysis was applied. Candidate confounders were successively added to the longitudinal association model to determine if the association between dynamic activity and fatigue was distorted. A proportional change beyond 15% was considered to be significant. Fatigue was significantly associated with physical activity (β = ?0.099, SE = 0.032, P = 0.002). This association was not significantly distorted by type of intervention, age, gender, social support, disease duration, disease severity, motor impairment, cognition, anxiety, or medication intake. Depression caused proportional change of 22.2% in the regression coefficient of MFI. After controlling for depression, a significant association between MFI and dynamic activity remained (β = ?0.121, SE = 0.036, P = 0.000). The association found between fatigue and dynamic activity suggests that patients who experience higher levels of fatigue are less physically active. However, the total explained variance of dynamic activity by fatigue alone was small, suggesting that fatigue is only a minor factor in the complex of behavioral aspects that affect the amount of physical activity in patients with PD. © 2009 Movement Disorder Society     

Reliability and structural validity of the Multidimensional Fatigue Inventory (MFI) in patients with idiopathic Parkinson's disease

IntroductionThe Multidimensional Fatigue Inventory (MFI) is commonly used in patients with Parkinson's disease (PD). However, most measurement properties have not been investigated in this population. The aim of this study was to investigate internal consistency, test-retest reliability, measurement error, structural validity, and floor and ceiling effects of the MFI in PD.MethodsPatients with PD (N = 153) completed the MFI at baseline and week 3 in a randomized clinical trial. Cronbach's α, intraclass correlation coefficient (ICC), and the smallest detectable change (SDC) were calculated. Bland and Altman analysis was performed. Principal Component Analysis (PCA) was used to explore structural validity. Floor and ceiling effects were investigated.ResultsCronbach's α for the MFI-total and subscales ranged from 0.74 (reduced motivation (RM)) to 0.92 (MFI-total). ICC's ranged from 0.65 (mental fatigue (MF) to 0.81 (physical fatigue (PF)), SDC ranged from 4 points (PF and RM) to 15 points (MFI-total). Bland and Altman analysis showed no systematic differences between assessments. A floor effect was found for MF and ceiling effects for PF and reduced activity (RA). A four-factor model was extracted, combining general fatigue (GF) and PF as one factor.ConclusionsThe MFI is reliable and valid to assess fatigue in patients with PD. Clinicians and researchers interested in assessing specific aspects of fatigue should consider interpreting GF and PF as one subscale measuring physical aspects of fatigue. To establish whether the MFI can detect meaningful changes, studies on anchor-based responsiveness and the minimal important change are needed in PD.     

Methylphenidate improves fatigue scores in Parkinson disease: a randomized controlled trial.

Fatigue is a common nonmotor symptom in idiopathic Parkinson disease (IPD) that can prominently affect everyday function. This study was a randomized, double-blind, placebo-controlled trial evaluating methylphenidate for the treatment of fatigue in patients with IPD maintained on their regular medications. Thirty-six patients were randomized to receive either methylphenidate (10 mg three times per day; n = 17) or placebo (n = 19) for 6 weeks. Primary outcomes were the change from baseline on two separate self-report fatigue questionnaires: the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI). Secondary outcomes included the Unified Parkinson Disease Rating Scale (UPDRS) motor score and the five individual domains of the MFI. Fourteen patients in the methylphenidate group and 16 patients in the control group remained on the intervention for the entire study period. In the treatment arm, mean FSS score was reduced by 6.5 points (from a baseline of 43.8) and mean MFI score was reduced by 8.4 points (from a baseline of 51.0). Both these reductions were significant (P < 0.04). Smaller reductions in the placebo group were nonsignificant. Mean UPDRS motor score did not change significantly in either group. Analysis of MFI subscores showed a significant reduction in General Fatigue in the methylphenidate group (P < 0.001). Overall, adverse effects of medication were more frequent in the placebo group. In conclusion, methylphenidate was effective in lowering fatigue scores in patients with IPD following a 6-week treatment period.     

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized,placebo-controlled phase 2 study

IntroductionND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.MethodsThis was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h.ResultsND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC_0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H₀ of μ₀ ≤-1.6).ConclusionLevodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.     

Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.     

A Double‐Blind,Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (?106 min; 95%CI: ?192; ?21) and entacapone 200 mg (?81 min; 95%CI: ?142; ?19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.     

Effect of dopamine agonists on fatigue and somnolence in Parkinson's disease.

Dopamine agonists are becoming increasingly important in the treatment of early and advanced symptoms of Parkinson disease (PD). Although dopamine agonists are known to increase somnolence, their effect on fatigue and the relationship between fatigue and somnolence have not been investigated thoroughly. The objective of this study is to quantitatively measure fatigue in patients with PD treated with dopamine agonists and to correlate fatigue with somnolence. Fifteen patients with PD (mean age, 60.6 +/- 9.7 years; mean disease duration, 4.1 +/- 1.9 years) underwent a continuous (30-second) motor task using four muscle groups before and after 3 months of treatment with dopamine agonists. A fatigue index, defined as the decay of maximal force during continuous exercise, was calculated. Findings were compared with 15 healthy, age-matched control subjects. Patients also completed the Multidimensional Fatigue Inventory (MFI), the Epworth Sleepiness Scale (ESS), and the Hamilton Depression Scale at the same time points. Mean fatigue index (FI) before treatment was significantly higher in PD patients than controls (31.37% +/- 3.81% vs. 23.39% +/- 3.03%, P < 0.001). There was no significant between-group difference after 3 months of treatment. There was no difference in FI of the more affected side before and after treatment (33.33% +/- 6.18% vs. 34.08% +/- 5.43%, P > 0.1). No significant change in MFI scores were noted after treatment, although scores on the ESS increased significantly (6.6 +/- 2.63 vs. 11.7 +/- 5.16; P < 0.05). Fatigue is prevalent in patients with PD but is not influenced by dopamine agonists. Somnolence cannot be attributed to the increase in fatigability and apparently involves a different mechanism.     

Dopamine agonist therapy for Parkinson disease and pathological gambling

We report 6 patients with pathological gambling during pharmacologic treatment for Parkinson disease (PD). Four patients were treated with levodopa/carbidopa and dopamine agonist (DA), and 2 patients received DA monotherapy. We reviewed several published reports regarding pathological gambling and antiparkinsonian therapy and suggest that more advanced PD and antiparkinsonian combination therapy (e.g., levodopa/carbidopa and DA) increases the risk for development of pathological gambling behavior compared with monotherapy with either DA or levodopa/carbidopa.     

Quality of life in early Parkinson's disease treated with levodopa/carbidopa/entacapone

We aimed to investigate whether treatment with levodopa/carbidopa/entacapone when compared with levodopa/carbidopa improves quality of life in Parkinson's disease (PD) patients with no or minimal, nondisabling motor fluctuations. This is a multicenter, randomized, double‐blind study. One hundred eighty‐four patients on 3 to 4 equal doses of 100/25 to 200/50 mg levodopa/carbidopa or levodopa/benserazide, 0 to 3 hours of nondisabling OFF time over a 48 hour period and no dyskinesia were randomized to levodopa/carbidopa/entacapone or levodopa/carbidopa treatment for 12 weeks. The primary outcome measure was quality of life as assessed by the PDQ‐8. Secondary outcome measures were the UPDRS parts I–IV, and the Wearing Off Card. Treatment with levodopa/carbidopa/entacapone resulted in significantly greater improvements in PDQ‐8 scores compared to treatment with levodopa/carbidopa (mean difference 1.4 points, P = 0.021). Statistically significant improvements were seen predominantly in nonmotor domains (depression, personal relationships, communication, stigma, all P < 0.05; dressing P = 0.056). Patients who were randomly assigned to levodopa/carbidopa/entacapone also showed significantly greater improvement in UPDRS part II scores (P = 0.032) with UPDRS part III scores showing borderline significance. Differences in UPDRS parts I and IV and Wearing Off Card scores were not significant. Treatment with levodopa/carbidopa/entacapone results in improved quality of life compared with levodopa/carbidopa in PD patients with mild or minimal, nondisabling motor fluctuations. © 2007 Movement Disorder Society     

Efficacy and tolerability of a novel sublingual apomorphine preparation in patients with fluctuating Parkinson's disease

We tested a novel preparation of sublingual apomorphine hydrochloride (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. After dose titration, patients underwent a blinded comparison of APO versus placebo, and an unblinded comparison of APO versus optimally dosed carbidopa/levodopa using timed tapping and walking paradigms. APO was significantly better than placebo in both measures: Tapping speed was 30.8% faster than with placebo (p < .0005), and ambulation speed was 45.2% faster than with placebo (p < .05). Ambulation speed with APO was also 15.9% faster than that with optimal doses of carbidopa/levodopa (p < .05). The latency to onset of clinical improvement with each APO dose was 10 to 40 minutes, and the duration of effect was 60 to 130 minutes. Adverse events included nausea, orthostatic hypotension, and disagreeable taste in the patient's mouth. Aside from the bitter taste, all other side effects resolved with continued use and did not limit dosing in any case. We feel that the good short-term efficacy and tolerability demonstrated in this study warrant further study of this new preparation, as there are several potential advantages of sublingual administration compared with traditional APO preparations.     

A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome

OBJECTIVE: There is no management regime for chronic fatigue syndrome (CFS) that has been found to be universally beneficial and no treatment can be considered a "cure". Patients with CFS may use complementary and alternative medicine (CAM). Our aim was to evaluate homeopathic treatment in reducing subjective symptoms of CFS. METHOD: Using a triple-blind design (patient and homeopath blind to group assignment and data analyst blind to group until after initial analyses to reduce the possibility of bias due to data analyst), we randomly assigned patients to homeopathic medicine or identical placebo. One hundred and three patients meeting the Oxford criteria for CFS were recruited from two specialist hospital out patient departments. Patients had monthly consultations with a professional homeopath for 6 months. Main outcome measures were scores on the subscales of the Multidimensional Fatigue Inventory (MFI) and proportions of each group attaining clinically significant improvements on each subscale. Secondary outcome measures were the Fatigue Impact Scale (FIS) and the Functional Limitations Profile (FLP). Ninety-two patients completed treatment in the trial (47 homeopathic treatment, 45 placebo). Eighty-six patients returned fully or partially completed posttreatment outcome measures (41 homeopathic treatment group who completed treatment, 2 homeopathic treatment group who did not complete treatment, 38 placebo group who completed treatment, and 5 placebo group who did not complete treatment). RESULTS: Seventeen of 103 patients withdrew from treatment or were lost to follow-up. Patients in the homeopathic medicine group showed significantly more improvement on the MFI general fatigue subscale (one of the primary outcome measures) and the FLP physical subscale but not on other subscales. Although group differences were not statistically significant on four out of the five MFI subscales (the primary outcome measures), more people in the homeopathic medicine group showed clinically significant improvement. More people in the homeopathic medicine group showed clinical improvement on all primary outcomes (relative risk=2.75, P=.09). CONCLUSIONS: There is weak but equivocal evidence that the effects of homeopathic medicine are superior to placebo. Results also suggest that there may be nonspecific benefits from the homeopathic consultation. Further studies are needed to determine whether these differences hold in larger samples.     

Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single‐dose,double‐blind,double‐dummy,placebo‐controlled,crossover trial

Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) “off” motor score of ≥25 in a 2‐day, single‐dose, double‐blind, double‐dummy, crossover study. Patients arrived in the morning in the practically defined “off” state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5‐minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to “on” and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to “on,” latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit. © 2010 Movement Disorder Society