Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial.

BACKGROUND: Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks. OBJECTIVE: The aim is to study short-term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ-9-tetrahydrocannabinol (THC) to provide preliminary data for a longer trial. METHODS: Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5 mg/kg/day. Primary outcome was change in motor MDS-UPDRS from baseline to final dose. RESULTS: Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS-UPDRS was reduced by 4.57 (95% CI, -8.11 to -1.03; P = 0.013) in CBD/THC group, and 2.77 (-4.92 to -0.61; P = 0.014) in placebo; the difference between groups was non-significant: -1.80 (-5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL. CONCLUSIONS: The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Using a mixed-reality headset to elicit and track clinically relevant movement in the clinic.

Background: 21st century neurology will require scalable and quantitative tools that can improve neurologic evaluations over telehealth and expand access to care. Commercially available mixed-reality headsets allow for simultaneous presentation of stimuli via holograms projected into the real world and objective and quantitative measurement of hand movement, eye movement, and phonation. Methods: We created 6 tasks designed to mimic standard neurologic assessments and administered them to a single participant via the Microsoft HoloLens 2 mixed-reality headset. The tasks assessed postural hand tremor, finger tapping, pronation and supination of hands, hand and eye tracking of a center-out task, hand and eye tracking of a random motion task, and vocal assessment. Findings: We show the utility of the HoloLens for commonly used neurological exams. First, we demonstrate that headset-derived holograms can project hand movements and objects in 3D space, providing a method to accurately and reproducibly present test stimuli to reduce test-test variability. Second, we found that participant hand movements closely matched holographic stimuli using a variety of metrics calculated on recorded movement data. Third, we showed that the HoloLens can record and playback exam tasks for visual inspection, sharing with other medical providers, and future analysis. Fourth, we showed that vocal recordings and analysis could be used to profile vocal characteristics over time. Together, this demonstrates the versatility of mixed reality headsets and possible applications for neurological assessment. Interpretation: Administering components of the neurologic exam via a self-contained and commercially available mixed-reality headset has numerous benefits including detailed kinematic quantification, reproducible stimuli presentation from test to test, and can be self-administered expanding access to neurological care and saving hospital time and money.

Patient and Family Outcomes of Community Neurologist Palliative Education and Telehealth Support in Parkinson Disease.

Importance: Parkinson disease and related disorders (PDRD) are the fastest growing neurodegenerative illness in terms of prevalence and mortality. As evidence builds to support palliative care (PC) for PDRD, studies are needed to guide implementation. Objective: To determine whether PC training for neurologists and remote access to a PC team improves outcomes in patients with PDRD in community settings. Design, Setting, and Participants: This pragmatic, stepped-wedge comparative effectiveness trial enrolled and observed participants from 19 community neurology practices supported by PC teams at 2 academic centers from March 8, 2017, to December 31, 2020. Participants were eligible if they had PDRD and moderate to high PC needs. A total of 612 persons with PDRD were referred; 253 were excluded. Patients were excluded if they had another diagnosis meriting PC, were receiving PC, or were unable or unwilling to follow study procedures. Patients received usual care or the intervention based on when their community neurologist was randomized to start the intervention. Data were analyzed from January 2021 to September 2023. Intervention: The intervention included (1) PC education for community neurologists and (2) team-based PC support via telehealth. Main Outcomes and Measures: The primary outcomes were differences at 6 months in patient quality of life (QOL; measured by the Quality of Life in Alzheimer Disease Scale [QOL-AD]) and caregiver burden (Zarit Burden Interview) between the intervention and usual care. Results: A total of 359 patients with PDRD (233 men [64.9%]; mean [SD] age, 74.0 [8.8] years) and 300 caregivers were enrolled. At 6 months, compared with usual care, participants receiving the intervention had better QOL (QOL-AD score, 0.09 [95% CI, -0.63 to 0.82] vs -0.88 [95% CI, -1.62 to -0.13]; treatment effect estimate, 0.97; 95% CI, 0.07-1.86; P = .03). No significant difference was observed in caregiver burden (Zarit Burden Interview score, 1.19 [95% CI, 0.16 to 2.23] vs 0.55 [95%, -0.44 to 1.54]; treatment effect estimate, 0.64; 95% CI, -0.62 to 1.90; P = .32). Advance directive completion was higher under the intervention (19 of 38 [50%] vs 6 of 31 [19%] among those without directives at the beginning of the study; P = .008). There were no differences in other outcomes. Conclusions and Relevance: PC education for community neurologists and provision of team-based PC via telehealth is feasible and may improve QOL and advance care planning. Overall treatment effects were small and suggest opportunities to improve both the intervention and implementation. Trial Registration: ClinicalTrials.gov Identifier: NCT03076671.

Assessing the state of care for Huntington disease in the United States: Results from a survey of practices treating Huntington disease patients.

Background: No study to date has thoroughly examined US Huntington disease (HD) care delivery in a variety of clinic settings by HD specialists and non-specialists. Objective: To obtain a clearer understanding of current care structure and delivery of care through a survey of representative US physicians treating HD patients. Methods: We designed and fielded a survey of 40 closed-ended evaluative items and one open-ended item to a sample of 339 US practices. Unique to this survey was the inclusion of non-specialists. Results: Responses were received from 156 practices (overall response rate 46.02 %), with 52.6 % from academic sites, 35.3 % from private practices, and 12.2 % from the VA. More than half (63.5 %) of the practice leads were movement disorder trained or Directors of HDSA Centers of Excellence and 58.3 % had an HD or multidisciplinary care clinic. However, 48.7 % of the practices saw 1-25 HD patients, 28.2 % saw 26-100 HD patients, and 23.1 % served over 100 HD patients annually. Most practices (>69 %) reported having difficulty providing social work, genetic counseling, care coordination and psychologists/psychiatrists. Increased HD practice size was associated with higher rates of pre-visit screenings, care navigator/care coordinators, routine monitoring of weight, and provision of genetic counseling by genetic counselors. Conclusions: Not surprisingly, we found that HD care was inconsistently applied across the US. Practices led by neurologists trained in movement disorders, and higher HD volume practices, tended to be better equipped to provide multi-disciplinary staffing and procedures as compared to those with fewer numbers of HD patients.

Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design.

BACKGROUND: - The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies. METHODS: - Based on a large natural history study, the Friedreich's Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich's Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status. FINDINGS: - Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification. INTERPRETATION: - Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

Scoliosis in Friedreich's ataxia: longitudinal characterization in a large heterogeneous cohort.

OBJECTIVE: The objective of this study was to characterize the incidence and progression of scoliosis in the natural history of Friedreich's ataxia (FRDA) and document the factors leading to the requirement for corrective surgery. METHODS: Data on the prevalence of scoliosis and scoliosis surgery from up to 17 years of follow-up collected during a large natural history study in FRDA (1116 patients at 4928 visits) were summarized descriptively and subjected to time to event analyses. RESULTS: Well over 90% of early or typical FRDA patients (as determined by age of onset) developed intermediate to severe scoliosis, while patients with a later onset (>14 years) had no or much lower prevalence of scoliosis. Diagnosis of scoliosis occurs during the onset of ataxia and in rare cases even prior to that. Major progression follows throughout the growth phase and puberty, leading to the need for surgical intervention in more than 50% of individuals in the most severe subgroup. The youngest patients appear to delay surgery until the end of the growth period, leading to further progression before surgical intervention. Age of onset of FRDA before or after reaching 15 years sharply separated severe and relatively mild incidence and progression of scoliosis. INTERPRETATION: Scoliosis is an important comorbidity of FRDA. Our comprehensive documentation of scoliosis progression in this natural history study provides a baseline for comparison as novel treatments become available.

Complementary Therapies in Parkinson Disease: a Review of Acupuncture, Tai Chi, Qi Gong, Yoga, and Cannabis.

Parkinson disease (PD) is a progressive neurodegenerative condition characterized by bradykinesia, rigidity, resting tremor, and postural instability. Non-motor symptoms, including pain, fatigue, insomnia, anxiety, and depression to name a few, are increasingly recognized and often just as disabling at motor symptoms. The mainstay of treatment is dopamine replacement; however, the beneficial effects tend to wane over time with disease progression, and patients often experience motor fluctuations and medication side effects. The lack of a disease-modifying intervention and the shortcomings of traditional symptomatic medications have led many patients to pursue complementary therapies to alleviate motor and non-motor symptoms associated with PD. The term complementary implies that the therapy is used along with conventional medicine and may include supplements, manipulative treatments (chiropractic, massage), exercise-based programs, and mind-body practices. As these practices become more widespread in Western medicine, there is a growing interest in evaluating their effects on a number of medical conditions, PD included. In this review, we provide an update on clinical trials that have evaluated the effectiveness of complementary treatments for patients with PD, specifically focusing on acupuncture, Tai Chi, Qi Gong, yoga, and cannabis.

Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study.

Background: Cannabis is increasingly used in Parkinson disease (PD), despite little information regarding benefits and risks. Objectives: To investigate the safety and tolerability of a range of doses of cannabidiol (CBD), a nonintoxicating component of cannabis, and it's effect on common parkinsonian symptoms. Methods: In this open-label study Coloradans with PD, substantial rest tremor, not using cannabis received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL). CBD was titrated from 5 to 20-25 mg/kg/day and maintained for 10-15 days. Results: Fifteen participants enrolled, two were screen failures. All 13 participants (10 male), mean (SD) age 68.15 (6.05), with 6.1 (4.0) years of PD, reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20-25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. Ten (eight male) that completed the study had improvement in total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores of 7.70 (9.39, mean decrease 17.8%, p=0.012) and 6.10 (6.64, mean decrease 24.7%, p=0.004), respectively. Nighttime sleep and emotional/behavioral dyscontrol scores also improved significantly. Conclusions: CBD, in the form of Epidiolex, may be efficacious in PD, but the relatively high dose used in this study was associated with liver enzyme elevations. Randomized controlled trials are needed to investigate various forms of cannabis in PD.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Movement disorders associated with aripiprazole use: a case series.

Aripiprazole is an atypical antipsychotic that is a partial agonist at the D2 and 5HT1a receptors and an antagonist at 5HT2a receptors. Despite previous hypotheses that it would be less likely to cause movement disorders, recent reports suggest it actually may be more likely to cause movement disorders than other atypical antipsychotics. This case series illustrates the variety of movement disorders associated with aripiprazole use at three movement disorder clinics. It also suggests that aripiprazole be used with caution in patients with a prior history of dystonia, parkinsonism, or previous tardive dyskinesia.

Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases.

Objective: To describe novel clinical features of GlyRα1-IgG-positive patients. Methods: Patients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado. Results: Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms. Conclusions: Clinicians should consider testing for GlyR antibodies in GAD65 antibody-negative or low-positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy.

Optimizing bioavailability in the treatment of Parkinson's disease.

The bioavailability of drugs used to treat chronic diseases such as Parkinson's disease may have important implications for their clinical utility. Drugs with low bioavailability may cause a wide variation in clinical response between patients and even in the same patient. In addition, numerous factors - including gender, age, and gastric motility - may affect a drug's bioavailability. This is especially important in patients with Parkinson's disease, who develop response fluctuations as the disease progresses. Strategies that may improve the bioavailability of levodopa, the most efficacious medication for Parkinson's disease, include coadministering levodopa with carbidopa, a decarboxylase inhibitor, or with a catechol-O-methyltransferase inhibitor or using an alternative route of administration. Other adjunctive therapies used to treat Parkinson's disease have a wide range of bioavailabilities, which may also affect clinical outcomes. The bioavailability of adjunctive medications may be improved by the use of alternative formulations as well, such as orally disintegrating tablets or transdermal delivery. Considering bioavailability of a medication when prescribing drugs to treat Parkinson's disease may improve patient response and minimize adverse effects.

Valbenazine for the treatment of tardive dyskinesia.

INTRODUCTION: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Carbidopa levodopa enteral suspension.

INTRODUCTION: The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains. AREAS COVERED: An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall "on" time compared with oral immediate release formulation of carbidopa/levodopa. EXPERT OPINION: The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.

Reliability of measurements of patient health status: a comparison of physician, patient, and caregiver ratings.

The purpose of this preliminary study was to investigate the inter-rater reliability among physician, patient, and caregiver ratings on the Hoehn & Yahr (H & Y) and Schwab & England (S & E) rating instruments. We also examined differences in ratings between patients who attended clinic with and without caregivers (spouses and adult children). Patients and caregivers coming for an appointment at Colorado Neurological Institute were asked to independently complete the H & Y and S & E scales. Physicians rated the patients during the exam. In the group of patients who came to clinic with caregivers, there was significant agreement on both the H & Y and S & E (P<0.001). For patients not accompanied by caregivers, patients rated themselves as more debilitated on the S & E than physicians (P<0.001). Patients without caregivers rated themselves as more functional than patients with caregivers on both scales (P<0.001). Physicians also rated patients without caregivers as more functional on both scales (P<0.001). Results indicated there was consistency among ratings of physicians and patients accompanied by caregivers on both scales. Patients attending clinic alone rated themselves as worse on the S & E than physicians. Patients alone were rated as more functional than patients accompanied by caregivers on both scales regardless of rater.

Examination of the UPDRS bradykinesia subscale: equivalence, reliability and validity.

Administering items or subscales separately from the measure for which they were designed to be a part may have unintended consequences for research and practice in Parkinson's disease (PD). The current study tested the equivalence of the bradykinesia subscale when administered alone versus as a component of the full 14-item Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, as well as examined the reliability and validity of the bradykinesia subscale. The study sample consisted of 112 patients with PD. Patients were randomly assigned to either the bradykinesia subscale alone group (n = 56), who were administered the bradykinesia subscale separately from the rest of the UPDRS motor examination, or the full scale group (n = 56), who were administered the UPDRS motor examination in its standard format. The two one-sided t-test (TOST) procedure was used to test for mean equivalency between the two administration groups. Additionally, reliability and validity analyses were performed. The bradykinesia subscale mean scores from the full scale group and the subscale alone group were not statistically equivalent. However, in both groups, the bradykinesia subscale had exceptional reliability and was strongly and similarly related to age, activities of daily living, disability, and other assessments of motor symptom severity. The bradykinesia subscale is a valid and reliable assessment when administered separately from the rest of the UPDRS motor examination; however, caution should be taken when comparing mean scores across studies or occasions when different administrations are used.

Rasagiline: time to onset of antiparkinson effect is similar when used as a monotherapy or adjunct treatment.

OBJECTIVE: Rasagiline, a monoamine oxidase type B inhibitor, is indicated for both the initial treatment of Parkinson disease (PD) and as adjunctive (add-on) treatment for patients already taking dopaminergic therapy. This open-label prospective community-based clinical trial was designed to determine the time-to-onset and the magnitude of the beneficial effects of rasagiline in PD patients. METHODS: Patients received rasagiline of 1.0 mg once daily as monotherapy or 0.5 mg once daily as adjunct therapy (adjunct therapy dose could be increased to 1 mg/d if clinically indicated) for 12 weeks. Dietary restrictions and recommendations regarding concurrent antidepressant treatment consistent with the Food and Drug Administration (FDA) regulations were in keeping with typical usage. Effectiveness was measured as change from baseline in bradykinesia scores and physicians' and patients' global impression. Patients were prospectively monitored for treatment emergent dopaminergic side effects, tyramine reactions, and possible interactions with commonly used antidepressants. RESULTS: Objective and subjective measures of symptom severity improved at 1 week in 272 PD patients treated with once-daily rasagiline (n=123 monotherapy, n=149 adjunct therapy). The magnitude of beneficial effect was similar in monotherapy and adjunct therapy patients. No significant dopaminergic side effects, tyramine reactions, or interactions with antidepressants were observed in the 12-week trial. CONCLUSIONS: Rasagiline has a measurable beneficial effect on PD symptoms within 1 week of treatment. Rasagiline has a similar magnitude of benefit in monotherapy and adjunct therapy patients. Adverse interactions between antidepressants and rasagiline were not observed in patients in this trial. The usual use of rasagiline in community neurology practice, consistent with the FDA labeling, seems safe and effective.

Levodopa/carbidopa/entacapone in Parkinson's disease.

Levodopa is the most efficacious agent for the treatment of motor features of Parkinson's disease but its chronic use is associated with the development of motor complications. Mounting evidence indicates the short half-life of levodopa and resultant pulsatile stimulation of striatal dopamine receptors leads to wearing off, motor fluctuations and dyskinesias. Longer acting dopaminergic agents, such as dopamine agonists, are less likely to cause motor fluctuations and dyskinesias but are not as efficacious for control of motor symptoms. Therefore, there is interest in exploring ways to deliver levodopa in a more continuous fashion, in an effort to maintain benefit through the day and reduce the development of motor fluctuations and dyskinesias. A dopa decarboxylase inhibitor (DDCI), such as carbidopa or benserazide, is administered with levodopa to attenuate its peripheral conversion to dopamine, reduce nausea and increase central bioavailability. When levodopa is administered with a DDCI, its main route of peripheral metabolism is via catechol-O-methyl transferase (COMT). A COMT inhibitor can be added to the combination of levodopa and a DDCI to further extend the levodopa peripheral half-life and increase central bioavailability. Stalevo is a combination tablet comprised of levodopa, carbidopa, and the COMT inhibitor entacapone. It is available in fixed-dose combinations of levodopa/carbidopa/entacapone, 50/12.5/200, 75/18.75/200, 100/25/200, 125/31.25/200, 150/37.5/200 and 200/50/200 mg. Stalevo is currently approved for use in Parkinson's disease patients with end-of-dose wearing off.