Parkinson Disease: Stacy M

Stacy M. · No affiliation provided · Curr Med Res Opin. · Pubmed #14741080 No free full text.

This publication has no abstract.

Ferrara JM, Stacy M. · Baylor College of Medicine, Houston, TX, USA. · CNS Spectr. · Pubmed #18704024 links to  free full text

Abstract: Parkinson's disease is a neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, and resting tremor. Increasingly, Parkinson's disease has been associated with a broad spectrum of non-motor symptoms, such as olfactory loss, sleep disorders, autonomic dysfunction, cognitive impairment, psychosis, depression, anxiety, and apathy. In addition, a minority of Parkinson's disease patients develop compulsive behaviors while receiving dopamine-replacement therapy, including medication hoarding, pathological gambling, binge eating, hyperlibidinous behavior, compulsive shopping, and punding. These behaviors may result in psychosocial impairment for patients and therapeutic challenges for clinicians. This article reviews the anatomic substrates, behavioral spectrum, associated factors, and potential treatments for dopamine-replacement therapy-related compulsions in Parkinson's disease.

Stacy M, Galbreath A. · Division of Neurology, Duke University Medical Center, Durham, NC 27705, USA. · Clin Neuropharmacol. · Pubmed #18382184 No free full text.

Abstract: There is currently no satisfactory treatment for dyskinesia in patients with Parkinson disease because most antidyskinetic strategies have the effect of aggravating Parkinsonian symptoms, and most pharmacological strategies for reducing "off" periods have increased dyskinesia as a treatment complication. Therefore, physicians and patients often have to balance treatment of its effects on Parkinsonian symptoms and on dyskinesia. In patients with advanced Parkinson disease, it is often not possible to induce periods of good mobility without dyskinesia.

Stacy M, Galbreath A. · Division of Neurology, Duke University Medical Center, Durham, North Carolina 27705, USA. · Clin Neuropharmacol. · Pubmed #18303491 No free full text.

Abstract: The treatment of Parkinson disease (PD) involves pharmacological treatment, often with levodopa or dopamine agonists, to restore the dopaminergic deficit associated with parkinsonian symptoms. Either agent provides symptom relief that becomes less effective in the course of PD, and switching or combining these agents or adding other therapies becomes necessary for symptom control. In an effort to delay the development of motor complications, dopamine agonists are often used in the initial treatment of PD. However, control of PD symptoms is superior with levodopa. Moreover, dopamine agonists are less well tolerated overall and are associated with a number of rare but serious adverse effects. In the long-term management of PD, treatment-associated dyskinesia often becomes sufficiently troublesome as to compromise the effective dosing of antiparkinsonian medication. More effective strategies for managing dyskinesia are needed.

Stacy M, Silver D. · Division of Neurology, Duke University, 932 Morreene Road, MS 3333, Durham, NC27705, USA. <> · Parkinsonism Relat Disord. · Pubmed #18083605 No free full text.

Abstract: Many patients with advanced Parkinson's disease (PD) experience motor complications, which negatively impact quality of life, despite optimized oral therapy. It is important for patients to have a treatment option that may provide rapid relief from "off" episodes. In three pivotal, randomized, placebo-controlled trials, subcutaneous apomorphine was effective in acutely treating "off" episodes, significantly improving Unified Parkinson Disease Rating Scale motor scores and reducing the number of "off" hours per day, with a significantly shorter time to patient-declared onset of relief than placebo. Thus, clinical trial data support the efficacy of intermittent subcutaneous apomorphine as a rapid acute treatment for "off" episodes in advanced PD.

Menon R, Stacy M. · Duke University Medical Center, Durham, NC 27705, USA. · Expert Opin Pharmacother. · Pubmed #17696795 No free full text.

Abstract: Motor fluctuations, refractory to conventional medical management, are one of the most troubling aspects of Parkinson's disease. Apomorphine is a dopaminergic agent that has been known to the medical community for more than a century, but has only recently been developed to treat such motor fluctuations. In this article, the authors review the historical background, structure, mechanism of action, pharmacologic properties, clinical trials, indications and side effects, as well as avenues of further research, of apomorphine.

Jankovic J, Stacy M. · Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas 77030, USA. · CNS Drugs. · Pubmed #17630819 No free full text.

Abstract: Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists.Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity.Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa.Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility.All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.

Kolls BJ, Stacy M. · Division of Neurology, Duke University Medical School, Durham, NC 27705, USA. · Clin Neuropharmacol. · Pubmed #16960475 No free full text.

Abstract: Parkinson disease is one of the most common neurodegenerative diseases in the United States, and the number of late stage patients is rising. In advance-stage disease, fluctuations in motor function, variability in response to dopaminergic therapy, and dyskinesias related to increasing doses of dopamine agonists and levodopa, present a variety of challenges to a managing physician. Traditional methods of treatment have concentrated on therapies to anticipate or prevent states of poor motor function. With the approval of apomorphine as a rapid-acting, subcutaneous injectable anti-Parkinson disease therapy, these off periods may now be treated with apomorphine as a "rescue" medication when they occur. This article reviews the pharmacology of apomorphine, the clinical data that support its use and suggest dosing and methods for initiating therapy in this challenging population of patients with Parkinson disease.

Koller W, Stacy M. · Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA. · Neurology. · Pubmed #15037668 No free full text.

Abstract: This manuscript reviews apomorphine administration in formulations other than intermittent bolus injection, and comments on other potential uses for this unique compound. Continuous sc apomorphine therapy has been shown to alter peak-dose dyskinesia thresholds in advancing patients, and in some instances may replace all other anti-parkinson therapies. In general continuous infusion of sc apomorphine at a rate of 4 mg/h is well tolerated, and has been postulated to be equivalent to approximately 600 mg levodopa/day. This therapy is associated with skin complications, particularly nodule formation, and focal panniculitis is seen in more than 50% of subjects. Optimal dosages for intranasal apomorphine range from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and duration of effect of 45 to 55 minutes. Side effects included nasal irritation, vestibulitis, dyskinesias, yawning, and nausea. Comparison of 3 mg sc and 30 mg sublingual apomorphine in 9 Parkinson's disease subjects in a blinded cross-over trial found that the time to peak benefit was beyond 40 minutes with sl apomorphine, compared to 21 minutes in the sc preparation. Chronic use of the sublingual formulation was associated with severe stomatitis in half the subjects, and markedly limited the treatment. Rectal administration of apomorphine has been evaluated in limited, usually post-operative settings. Administration of a 200 mg apomorphine rectal suppository resulted in an average time to benefit of 32 minutes with an average duration of 195 minutes. Sedation, nausea and faintness were reported as side effects. Although the diagnostic confirmation potential of this agent has been questioned, the drug may have an important role in evaluating the potential for benefit in the deep brain stimulation surgical setting.

Stacy M. · Movement Disorders Program, Duke University, Durham, North Carolina 27705, USA. · Neurology. · Pubmed #15037667 No free full text.

Abstract: This manuscript reviews North American clinical trials examining subcutaneous injection of apomorphine in Parkinson's disease (PD) patients, and the available, cumulative apomorphine safety data for the US. These data provide strong documentation concerning dosing range (2-6 mg/injection), dosing frequency (1-10 injections/day), therapeutic response, and duration and onset of benefit. The US pivotal trial for subcutaneously injected apomorphine demonstrated robust and statistically significant benefit from drug administration when compared to subjects receiving placebo. Interestingly, these changes closely mirrored the response to levodopa in the same population, as measured by Unified Parkinson's Disease Rating Scale and Webster Step Seconds, and suggests that apomorphine may have greater potency than other agonists. A study of subjects ranging from early to advanced disease, conducted at the NIH, demonstrated a decline in duration of response and increased time to response in the advanced group when compared to levodopa naïve subjects, despite the observation that threshold and optimal response dosages did not differ. Pharmacodynamic responses from a single average-dosage administration of 4.2 mg apomorphine in several studies demonstrated a benefit as early as 7.5 minutes with a duration of benefit as long as 90 minutes. Serious adverse events occurred in 16% of the subjects in these studies with the most common adverse events including dyskinesias (21%), hallucinations (11%), and orthostatic hypotension (9%).

Stacy M. · Muhammad Ali Parkinson Research Center, Barrow Neurological Institute, Phoenix, Arizona 85013, USA. · Drugs Aging. · Pubmed #12390050 No free full text.

Abstract: 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.

Stacy M. · Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, Arizona 85213, USA. · Pharmacotherapy. · Pubmed #10641987 No free full text.

Abstract: Medical management of Parkinson's disease consists of two strategies. A presynaptic strategy attempts to maintain physiologic synaptic concentrations of dopamine, usually by individualizing delivery of levodopa (or exogenous dopamine) by varying the rate of gastrointestinal absorption or blood-brain barrier passage. A postsynaptic strategy bypasses degenerating nigrostriatal neurons by stimulating striatal neurons directly with dopamine agonists. With advancing disease, motor fluctuations appear, related to physiologic changes that narrow the window of levodopa concentration in which symptoms are under control. Then it becomes necessary to add dopamine agonists to therapy.

Stacy M. · Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, Arizona, USA. · Med Clin North Am. · Pubmed #10093588 No free full text.

Abstract: Treatment of parkinsonism becomes more difficult as the disease progresses, and results from increasing neuronal degeneration, side effects from antiparkinsonian medications, or most often, a combination of each. Neurodegenerative parkinson symptoms may result from substantia nigra destruction, or from other areas in the nervous system. These include the cortex (cognitive and psychiatric disorders), brainstem (bulbar abnormalities), intermediolateral cell column (autonomic disturbances), among others. Medication side effects produce motor fluctuations, dyskinesias, delirium, hallucinations, psychosis, orthostatic hypotension, sleep disorders, and a host of other well-recognized complications. This article is divided into sections concerning motor fluctuations, gait difficulty bulbar disturbances, autonomic disturbances, sleep disorders, cognitive disorders, and psychiatric disorders, and is an attempt to provide the reader with strategies for treating common complications in the advanced Parkinson's disease patient.

Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M. · Toronto Western Hospital, University of Toronto, Ontario, Canada. · Ann Neurol. · Pubmed #16429411 No free full text.

Abstract: OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A, Anonymous00163. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Arch Neurol. · Pubmed #15262734 links to  free full text

Abstract: BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER, Lozano AM, Penn RD, Simpson RK, Stacy M, Wooten GF, Anonymous00009. · Oregon Health & Science University, Portland 97201-3098, USA. · Neurology. · Pubmed #12525720 No free full text.

Abstract: OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Shoulson I, Penney J, McDermott M, Schwid S, Kayson E, Chase T, Fahn S, Greenamyre JT, Lang A, Siderowf A, Pearson N, Harrison M, Rost E, Colcher A, Lloyd M, Matthews M, Pahwa R, McGuire D, Lew MF, Schuman S, Marek K, Broshjeit S, Factor S, Brown D, Feigin A, Mazurkiewicz J, Ford B, Jennings D, Dilllon S, Comella C, Blasucci L, Janko K, Shulman L, Wiener W, Bateman-Rodriguez D, Carrion A, Suchowersky O, Lafontaine AL, Pantella C, Siemers E, Belden J, Davies R, Lannon M, Grimes D, Gray P, Martin W, Kennedy L, Adler C, Newman S, Hammerstad J, Stone C, Lewitt P, Bardram K, Mistura K, Miyasaki J, Johnston L, Cha JH, Tennis M, Panniset M, Hall J, Tetrud J, Friedlander J, Hauser R, Gauger L, Rodnitzky R, Deleo A, Dobson J, Seeberger L, Dingmann C, Tarsy D, Ryan P, Elmer L, Ruzicka D, Stacy M, Brewer M, Locke B, Baker D, Casaceli C, Day D, Florack M, Hodgeman K, Laroia N, Nobel R, Orme C, Rexo L, Rothenburgh K, Sulimowicz K, Watts A, Wratni E, Tariot P, Cox C, Leventhal C, Alderfer V, Craun AM, Frey J, McCree L, McDermott J, Cooper J, Holdich T, Read B, Anonymous00161. · No affiliation provided · Neurology. · Pubmed #11222787 No free full text.

Abstract: BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Stacy M. · Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA. · Neurol Clin. · Pubmed #19555824 No free full text.

Abstract: The cardinal characteristics of Parkinson disease (PD) include resting tremor, rigidity, and bradykinesia. Patients may also develop autonomic dysfunction, cognitive changes, psychiatric symptoms, sensory complaints, and sleep disturbances. The treatment of motor and non-motor symptoms of Parkinson disease is addressed in this article.

Wingo TS, Evatt M, Scott B, Freeman A, Stacy M. · Emory University School of Medicine, Atlanta, GA, USA. · Clin Neuropharmacol. · Pubmed #18978496 No free full text.

Abstract: OBJECTIVE: We report 3 cases of impulse control disorders (ICDs) that developed in patients with Parkinson disease treated with the novel dopamine agonist, rotigotine. METHODS: Three patients were identified retrospectively who developed symptoms of an ICD while taking rotigotine. The ICD symptoms developed at 4, 5, and 8 years after diagnosis of Parkinson disease in these patients and while they were taking rotigotine and levodopa. Other drugs included entacapone, amantadine, and selegiline. The first patient developed symptoms of hypersexuality while taking rotigotine 18 mg (40-cm2 patch) daily and levodopa 300 mg/d. The second patient developed pathological gambling while taking rotigotine 22.5 mg (50-cm2 patch) daily and levodopa 300 mg/d. The third patient developed symptoms of hypersexuality, punding, and pathological gambling, losing more than $100,000 while taking rotigotine 18 mg (40-cm2 patch) and levodopa 400 mg/d. In the first 2 patients, the development of the ICD was temporally associated with an increase in rotigotine dosage, whereas the third patient experienced a dramatic increase in his gambling with the addition of rotigotine. Both subjects who developed pathological gambling had a history of recreational gambling for many years, and 1 of the 2 subjects who developed hypersexuality had a history of cross-dressing since childhood. RESULT: The ICDs in these patients were effectively treated with rotigotine reduction or discontinuation. CONCLUSION: Rotigotine has the potential for causing ICD, similar to other dopamine agonists.

Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, Sussman NM. · Division of Neurology, Duke University Medical Center, Durham, NC 27705, USA. · Neurology. · Pubmed #18519872 No free full text.

Abstract: BACKGROUND: The safety and efficacy of istradefylline, a selective adenosine A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications. METHODS: Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs). RESULTS: Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20 mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01) for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations. CONCLUSIONS: Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, Aarsland D, Babcock D, Cummings J, Endicott J, Factor S, Galpern W, Lees A, Marsh L, Stacy M, Gwinn-Hardy K, Voon V, Goetz C. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA. · Mov Disord. · Pubmed #17266092 No free full text.

Abstract: There are no standardized diagnostic criteria for psychosis associated with Parkinson's disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV-TR. PDPsy has a well-characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinson's disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Stacy M, Hauser R, Oertel W, Schapira A, Sethi K, Stocchi F, Tolosa E. · Division of Neurology, Duke University Medical School, Durham, North Carolina 27705, USA. · Clin Neuropharmacol. · Pubmed #17095894 No free full text.

Abstract: We have previously reported that the use of a 32-symptom Wearing-off Questionnaire (WOQ-32) identified wearing off more frequently than a clinician's evaluation or the complications subscale of the Unified Parkinson Disease Rating Scale (UPDRS). However, this prototype tool was not designed for clinical practice and required simplification for daily use. Although wearing off is a commonly understood concept among neurologists caring for Parkinson disease patients, there are a number of definitions in the literature. For the purpose of this study and to include both motor and nonmotor parkinsonian symptoms, wearing off was defined as a generally predictable recurrence of motor and nonmotor symptoms that precedes scheduled doses of anti-parkinsonian medication and usually improves after those doses. Using this definition, retrospective analysis and expert opinion were used to identify the 9 most predictive and relevant of the symptoms previously identified as part of the WOQ-32. The resulting 9-symptom questionnaire (WOQ-9) identified 158 (95.8%) of the 165 subjects captured by the 32-Symptom Wearing-off Questionnaire as having wearing off, excluding 7 subjects reporting only balance difficulty (n = 3), numbness (n = 2), difficulty standing (n = 1), and abdominal discomfort (n = 1). Subjects reporting wearing off with the WOQ-9 were significantly younger, had been longer diagnosed with Parkinson disease, experienced a longer duration of levodopa therapy, exhibited a higher UPDRS total score, had higher levodopa equivalent dosages, and increased dyskinesia compared with patients not identified as wearing off with the WOQ-9. No statistical differences were noted with respect to sex, UPDRS subsection scores, Schwab & England Scale, or Hoehn & Yahr Scale.

Stacy M, Hauser R. · Duke University Medical Center, Durham, North Carolina 27705, USA. · J Neural Transm. · Pubmed #16897594 No free full text.

Abstract: We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) identified symptoms of wearing-off more frequently than standard assessments conducted by movement disorder specialists during a routine office visit. In the previous study we used a WOQ of 32 symptoms; however this tool was not designed for daily use. In this paper we describe the retrospective development of a simpler, 19-symptom WOQ more suitable for routine clinical use.

Karamohamed S, Golbe LI, Mark MH, Lazzarini AM, Suchowersky O, Labelle N, Guttman M, Currie LJ, Wooten GF, Stacy M, Saint-Hilaire M, Feldman RG, Liu J, Shoemaker CM, Wilk JB, DeStefano AL, Latourelle JC, Xu G, Watts R, Growdon J, Lew M, Waters C, Vieregge P, Pramstaller PP, Klein C, Racette BA, Perlmutter JS, Parsian A, Singer C, Montgomery E, Baker K, Gusella JF, Herbert A, Myers RH. · Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. · Mov Disord. · Pubmed #15966003 No free full text.

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Stacy M, Bowron A, Guttman M, Hauser R, Hughes K, Larsen JP, LeWitt P, Oertel W, Quinn N, Sethi K, Stocchi F. · Duke University Medical Center, 932 Morreene Road, Durham, NC 27705, USA. · Mov Disord. · Pubmed #15719426 No free full text.

Abstract: This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of <5 years duration were evaluated; the mean subject age was 72 +/- 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearing-off was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature.