Parkinson Disease: Hauser RA

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill, USA. · Eur Neurol. · Pubmed #19176961 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms, and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews efficacy and safety data for the newest PD treatment options, as well as for established therapies. Part 2 of the article, presented here, reviews key data relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill 60611, USA. · Eur Neurol. · Pubmed #19176960 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Encarnacion EV, Hauser RA. · Department of Neurology, Texas A&M Health Sciences Center, Scott and White National Parkinson Foundation Plummer Movement Disorders Center, Temple, TX, USA. · Eur Neurol. · Pubmed #18480609 links to  free full text

Abstract: Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson's disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in the basal ganglia. Dyskinesias have been associated with decreased quality of life, and a number of methodologies to evaluate severity of dyskinesias are now available. Strategies to avoid, reduce, or eliminate dyskinesias include providing more continuous dopaminergic stimulation, administering an antidyskinetic agent, and surgery. Several new compounds that may provide an antidyskinetic effect are also under investigation.

Seeberger LC, Hauser RA. · Parkinson's Disease Institute and Movement Disorders Center, Idaho Elks Rehabilitation Hospital, 600 North Robbins Road, Boise, ID 83702, USA. · Neuropharmacology. · Pubmed #17936857 No free full text.

Abstract: 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.

Simonson W, Hauser RA, Schapira AH. · Commission for Certification in Geriatric Pharmacy. · Ann Pharmacother. · Pubmed #17878397 No free full text.

Abstract: OBJECTIVE: To evaluate the role of the practicing pharmacist in the identification and current treatment of the levodopa wearing-off phenomenon experienced by patients with Parkinson's disease (PD) who are receiving chronic levodopa therapy. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1967-June 2007) using the terms levodopa, wearing-off, and Parkinson's disease. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles that were identified from the data sources and written in English were evaluated. DATA SYNTHESIS: Levodopa is the most efficacious therapeutic agent in PD; however, the response of patients to levodopa changes over time. Eventually, the duration of response becomes shorter and more unpredictable, and complications emerge. One of the first complications observed with levodopa therapy is wearing-off, which can emerge within 1-3 years of initiation of levodopa treatment. Wearing-off is characterized by the predictable emergence of motor and nonmotor PD symptoms before the next scheduled dose of medication. Despite effective treatment options to tackle wearing-off, it remains underrecognized and under treated. With early identification and optimization of treatment, wearing-off can be managed effectively, resulting in improved quality of life for patients with PD. CONCLUSIONS: Owing to their training and accessibility, pharmacists play an increasingly important role in the management of patients with PD. Pharmacists are uniquely placed to identify wearing-off, offer timely advice, and facilitate the optimization of treatment regimens to improve patients' quality of life and enhance long-term outcomes.

Zesiewicz TA, Sullivan KL, Hauser RA. · Parkinson's Disease and Movement Disorders Center, University of South Florida, Tampa, Florida 33612, USA. · Curr Neurol Neurosci Rep. · Pubmed #17618536 No free full text.

Abstract: Although levodopa is the gold standard for treating motor symptoms of Parkinson's disease (PD), long-term therapy leads to levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists of chorea that occurs when levodopa-derived dopamine is peaking in the brain ("peak-dose dyskinesia"). However, dyskinesia can also consist of dystonia or myoclonus and occur during other parts of the levodopa dosing cycle. New validated rating scales and home diaries can better help the health care provider assess the timing and severity of dyskinesia. The exact etiology of LID is unknown, but there is evidence that abnormal pulsatile stimulation of dopamine receptors may be contributory. Treatment of LID includes adjustment of PD medications to maximize "on" time without troublesome dyskinesia. Amantadine is the only medication available with demonstrated ability to reduce the expression of established LID without reducing antiparkinsonian benefit. Other medications that are currently being studied to treat established LID include antiepileptics and serotonergic medications. Deep brain stimulation of the subthalamic nucleus is now the most commonly used surgical procedure for PD patients, and it is very effective in treating LID.

Hauser RA, Zesiewicz TA. · Department of Neurology, Parkinson's Disease and Movement Disorders Center, University of South Florida and Tampa General Healthcare, Tampa, Florida 33606, USA. · Neurologist. · Pubmed #17495756 No free full text.

Abstract: BACKGROUND: Levodopa, in combination with a dopa decarboxylase inhibitor, provides the greatest symptomatic benefit with the fewest short-term side effects in the treatment of Parkinson disease (PD). However, the disease continues to progress, and the long-term use of levodopa is associated with the development of motor fluctuations and dyskinesias. REVIEW SUMMARY: Alternatives to the use of levodopa in early PD include monoamine oxidase B (MAO-B) inhibitors, dopamine agonists, and amantadine. Although no medication has been proven to slow the progression of Parkinson disease, preclinical studies have demonstrated neuroprotective effects of MAO-B inhibitors, and a recent study of rasagiline found that PD patients treated with rasagiline for 12 months experienced less progression of symptoms than patients treated with placebo for 6 months followed by rasagiline for 6 months. Several clinical trials have demonstrated that the initial use of a dopamine agonist to which levodopa can be added is associated with fewer motor complications than treatment with levodopa alone. In addition, preclinical studies suggest that adjunctive use of the catechol-O-methyltransferase (COMT) inhibitor entacapone when levodopa is first introduced may be associated with fewer motor complications than treatment with levodopa alone. CONCLUSION: Treatment of early PD with an MAO-B inhibitor, dopamine agonist, or amantadine, may provide useful alternatives to treatment with levodopa. Adding entacapone at the initiation of levodopa therapy may reduce the development of motor complications. Long-term studies are required to evaluate the potential long-term benefits of these treatment strategies.

Samanta J, Hauser RA. · University of Arizona, Banner Good Samaritan Medical Center, Department of Neurology, College of Medicine, Phoenix, AZ 85258 USA. · Expert Opin Pharmacother. · Pubmed #17376020 No free full text.

Abstract: Motor fluctuations are a common problem in the long-term management of Parkinson's disease (PD), resulting in disability and impaired quality of life. The relatively short serum half-life (approximately 90 min) of oral levodopa/carbidopa and its erratic absorption due to delayed and inconsistent gastric emptying (a non-motor feature of PD) are thought to be important factors in the development of motor fluctuations. Continuous infusion of levodopa/carbidopa directly into the small intestine of PD patients results in marked reduction of motor fluctuations by reducing plasma levodopa variability by an order of magnitude over oral therapy. Previously, the use of long-term intraduodenal infusion of levodopa/carbidopa was limited by the relatively large volumes of infusate necessitated by the low solvency of levodopa. The development of a micronized levodopa (20 mg/ml) and carbidopa (5 mg/ml) suspension utilizing a methylcellulose gel provides the high levodopa concentration and physical and chemical stability necessary for long-term enteral therapy. Clinical evidence indicates that a marked reduction of motor fluctuations and dyskinesias can be achieved and maintained by intraduodenal administration of this suspension. This article reviews the published data describing the efficacy and safety of duodenal levodopa, and discusses its current and potential role in meeting the needs of PD patients.

Zesiewicz TA, Sullivan KL, Hauser RA. · Parkinson's Disease and Movement Disorders Center and Department of Neurology, University of South Florida,12901 Bruce B. Downs Blvd, MDC Box 55, Tampa, FL 33612, USA. · Expert Rev Neurother. · Pubmed #17181428 No free full text.

Abstract: Nonmotor symptoms occur commonly in Parkinson's disease (PD) patients and are frequently under-recognized and undertreated. Symptoms include sleep abnormalities, fatigue, autonomic disturbances, mood disorders and cognitive dysfunction. Early recognition and treatment of nonmotor symptoms in PD is critical to providing optimal management. A new screening questionnaire and the revised Unified PD Rating Scale should assist healthcare providers to better identify and evaluate these symptoms. This article reviews the identification and treatment of nonmotor symptoms in PD.

Hauser RA. · Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, University of South Florida, Tampa, FL, USA. · Geriatrics. · Pubmed #16989543 No free full text.

Abstract: Long-term care of elderly patients with Parkinson's disease (PD) is challenging for long-term care staff and physicians. Because the progression of PD varies among patients, an individualized treatment plan, updated as necessary based on disease progression, comorbid conditions, and side effects, is essential. Education regarding PD management is also needed to provide optimal care, and treatment guidelines from professional associations are available. Especially important is the management of motor complications, which usually emerge after treatment with antiparkinsonian medications, particularly levodopa/carbidopa. Current treatment strategies to avoid or treat motor complications aim at providing a more continuous (ie, physiologic) dopaminergic stimulation, rather than the pulsatile (intermittent) stimulation provided by traditional PD treatments. Catechol O-methyltransferase (COMT) inhibitors prolong the levodopa serum half-life and allow more levodopa to be delivered to the brain over a longer time, thereby smoothing dopaminergic stimulation. Dopamine agonists also provide more continuous dopaminergic stimulation but are associated with a greater likelihood of hallucinations and confusion, especially in the elderly. Treatments that reduce motor complications, allowing a higher level of functioning, lessen the burden of care in long-term care settings and increase quality of life for patients and their families.

Zesiewicz TA, Wecker L, Sullivan KL, Merlin LR, Hauser RA. · Parkinson's Disease and Movement Disorders Center, University of South Florida, Tampa, 33612, USA. · Clin Neuropharmacol. · Pubmed #16772808 No free full text.

Abstract: Levodopa treatment of Parkinson disease results in hyperhomocysteinemia (HHcy) as a consequence of levodopa methylation by catechol-O-methyltransferase (COMT). Although inhibition of COMT should theoretically prevent or reduce levodopa-induced HHcy, results from several prospective studies are conflicting. Our review of these studies suggests that the ability of COMT inhibition to reduce or prevent levodopa-induced HHcy in Parkinson disease patients may be attributed to differences in the vitamin status of the study participants. In patients with low or low-normal folate levels, levodopa administration is associated with a greater increase in homocysteine and concomitant entacapone administration is associated with a greater reduction in homocysteine.

Hauser RA, Schwarzschild MA. · Department of Neurology, University of South Florida and Tampa General Healthcare, Tampa, Florida 33606, USA. · Drugs Aging. · Pubmed #15974638 No free full text.

Abstract: Long-term disability in Parkinson's disease (PD) is related to progression of the underlying disease and the emergence of complications of chronic levodopa therapy. There is a need for new medications that can slow the underlying progression of degeneration, improve PD symptoms in early disease without inducing dyskinesia, and improve motor fluctuations and 'off' time in advanced disease without worsening dyskinesia. Much interest has focused on the development of nondopaminergic therapies, with antagonists of the adenosine A2A receptor emerging as leading candidates. A2A receptors are selectively expressed in the basal ganglia and specific A2A antagonists reverse motor deficits without causing dyskinesia in animal models of PD. The antiparkinsonian potential of A2A receptor blockade has been expanded further by convergent epidemiological and laboratory findings suggesting a possible neuroprotective effect of A2A receptor antagonists in PD. Istradefylline (KW-6002) is the first of several adenosine A2A receptor antagonists in development for PD to advance to phase III clinical trials. Initial studies indicate that in patients with motor fluctuations on levodopa, addition of istradefylline reduces 'off' time. Additional studies are necessary to evaluate the benefit of istradefylline as monotherapy in early disease, its effect on the development of dyskinesia, and its effect on disease progression.

Pahwa R, Lyons KE, Hauser RA. · Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd, Kansas City, KS 66160, USA. · Expert Rev Neurother. · Pubmed #15853577 No free full text.

Abstract: Ropinirole (Requip, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.

Hauser RA, Lyons KE. · Department of Neurology, University of South Florida and Tampa General Healthcare, Tampa, FL 33606, USA. · Neurol Clin. · Pubmed #15501363 No free full text.

This publication has no abstract.

Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, Koga K, Koike N, Kurokawa M, Kuwana Y, Mori A, Nakamura J, Nonaka H, Ochi M, Saki M, Shimada J, Shindou T, Shiozaki S, Suzuki F, Takeda M, Yanagawa K, Richardson PJ, Jenner P, Bedard P, Borrelli E, Hauser RA, Chase TN, Anonymous00418. · Kyowa Hakko Kogyo Co. Ltd., Tokyo, Japan. · Neurology. · Pubmed #14663020 No free full text.

Abstract: Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Zesiewicz TA, Hauser RA. · Parkinson's Disease and Movement Disorders Center and Department of Neurology, University of South Florida, Tampa General Healthcare, Tampa, Florida 33606, USA. · CNS Drugs. · Pubmed #12775195 No free full text.

Abstract: The aetiology of sleep disturbances in patients with Parkinson's disease is multifactorial. Medications, the disease process and underlying sleep disorders may contribute to sleepiness in patients with the disease. Somnolence, excessive daytime sleepiness and sleep attacks appear to be more common in patients with Parkinson's disease who are treated with dopamine receptor agonists than in those who are treated with other antiparkinsonian agents, although virtually all dopaminergic antiparkinsonian medications may contribute to sleepiness. Somnolence caused by dopamine agonists may be dose related and occurs most frequently during the dose-escalation phase. Somnolence may also emerge or worsen after a period of time on a stable dose. Patients with Parkinson's disease and caregivers should be informed about the risk of sleepiness and sleep attacks associated with dopaminergic medications and the potential implications for driving safety.

Zesiewicz TA, Hauser RA. · Parkinson's Disease and Movement Disorders Center, University of South Florida College of Medicine, 4 Columbia Drive, Suite 410, Tampa, FL 33606, USA. · Curr Psychiatry Rep. · Pubmed #11814399 No free full text.

Abstract: Depression is common in Parkinson's disease (PD), and its identification and treatment are critically important in disease management. Despite depression's high prevalence and major impact on patient quality of life, questions remain regarding its epidemiology and preferred treatment. The authors of this paper summarize available information on the epidemiology of depression in PD, review treatment options, and discuss possible interactions between antidepressants and other agents. This information may help guide clinical treatment and define the need for further studies.

Freeman TB, Willing A, Zigova T, Sanberg PR, Hauser RA. · Department of Neurosurgery, University of South Florida, College of Medicine, Tampa, Florida 33606, USA. · Adv Neurol. · Pubmed #11554006 No free full text.

Abstract: In conclusion, proof of the principle exists that neural grafts can survive transplantation in PD and that this graft survival is related to preliminary evidence of clinical benefit and improvement on FD-PET. Two prospective, randomized, surgical placebo-controlled trials of fetal tissue transplantation for the treatment of PD will be published in the near future, as will results of a placebo-controlled xenograft trial. Lifelong survival of human fetal nigral grafts is likely. The striatum is comparatively simple to target surgically in comparison to other sites such as the subthalamic nucleus. Several new sources of dopamine cells are being developed for transplantation purposes. Long-term monitoring for toxicity, such as the development of dyskinesias, will be needed, and dose-escalation trials should be performed slowly due to the irreversible nature of transplants. There are numerous ways to improve current techniques of neural transplantation.

Zesiewicz TA, Hauser RA. · Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of South Florida, Tampa 33606, USA. · Semin Neurol. · Pubmed #11346031 No free full text.

Abstract: Medical therapy for Parkinson's disease (PD) often becomes inadequate over several years. Disability increases despite maximal medical management and many patients develop motor fluctuations and dyskinesia. In addition, medications provide good control of tremor in only 50% of cases. In appropriately selected cases, surgical therapies for PD provide benefit for medically refractory symptoms. Recent advances have provided a greater array of surgical options. Unilateral thalamotomy and thalamic stimulation are considered safe and effective procedures to treat contralateral tremor. Pallidotomy and pallidal stimulation primarily reduce contralateral dyskinesia, with lesser effects on bradykinesia and rigidity. Studies indicate that subthalamic nucleus (STN) stimulation improves "off" period function, decreases "off" time, and lessens dyskinesia. Fetal cell transplantation remains experimental, and studies are underway to evaluate the safety and efficacy of porcine fetal cell and human retinal pigment epithelial cell transplantation. This chapter reviews the history of surgical procedures for PD, describes current procedures, and offers a look into the future of neurosurgical options for PD.

Zesiewicz TA, Gold M, Chari G, Hauser RA. · Parkinson's Disease and Movement Disorders Center, University of South Florida College of Medicine, Tampa, FL 33606, USA. · Am J Geriatr Psychiatry. · Pubmed #10322237 No free full text.

Abstract: Depression affects 40%-50% of Parkinson's disease (PD) patients. The authors, by use of a Mednet and manual search of pertinent literature, summarize current issues in the treatment of depression in PD. Open-label studies suggest that antidepressants may be effective for treating depression in PD. Although case reports indicate that selective serotonin reuptake inhibitors (SSRIs) can potentially worsen the motor symptoms of PD, this effect has not been confirmed in the small number of open-label studies that have been performed to date. The occurrence of the serotonin syndrome resulting from a combination of selegiline and an SSRI appears to be rare. Double-blind prospective studies are needed to evaluate the safety and efficacy of antidepressants in PD and their effect on motor function.

Hauser RA, Zesiewicz TA. · Department of Neurology, Tampa General Hospital, Florida, USA. · Med Clin North Am. · Pubmed #10093585 No free full text.

Abstract: The two major questions in the treatment of early PD are (1) Does selegiline slow neuronal loss and delay the progression of clinical disability? and (2) Should dopamine agonists be used as initial symptomatic therapy in early disease rather than levodopa/PDI to reduce long-term disability and delay the onset of motor fluctuations and dyskinesia? Selegiline affords neuroprotection for dopamine neurons in cell culture systems and the results of several clinical trials are consistent with the hypothesis that it is neuroprotective in Parkinson's disease. Several clinical trials have found that initial symptomatic therapy with dopamine agonist to which levodopa/carbidopa is later added when needed leads to a lower incidence of long-term motor complications. These strategies are now being tested in prospective, randomized, blinded trials, many of which include PET or SPECT scans to assess the rate of dopamine neuron loss. These trials will provide more definitive answers to guide the early medial management of Parkinson's disease in the future.

Olanow CW, Hauser RA, Jankovic J, Langston W, Lang A, Poewe W, Tolosa E, Stocchi F, Melamed E, Eyal E, Rascol O. · Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Mov Disord. · Pubmed #18932271 No free full text.

Abstract: A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where the treatment is delayed. We are using the delayed start design to assess the potential disease modifying effects of rasagiline in a prospective double blind controlled trial (the ADAGIO study). We here describe the rationale for the study and baseline characteristics of the 1,176 patients who have been enrolled into the trial.

Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R, Sussman NM, Anonymous00024. · Department of Neurology, University of South Florida, Tampa, Florida 33606, USA. · Mov Disord. · Pubmed #18831530 No free full text.

Abstract: The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.

Simon DK, Swearingen CJ, Hauser RA, Trugman JM, Aminoff MJ, Singer C, Truong D, Tilley BC, Anonymous00139. · Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. · Clin Neuropharmacol. · Pubmed #18670242 No free full text.

Abstract: OBJECTIVE: Caffeine use is negatively associated with the risk of developing Parkinson disease (PD) and is protective in animal models of PD, but the relationship between caffeine intake and rate of progression of PD is unknown. We assessed this relationship using data from 2 recent clinical trials of PD. METHODS: Data were ascertained from 2 recent 1-year clinical trials that together included 413 early PD subjects who did not require symptomatic therapy at the time of study entry. Exploratory analyses compared caffeine intake with rate of progression of PD, as measured by either the likelihood of progression to the point of requiring symptomatic therapy or by change in the total Unified Parkinson Disease Rating Scale score. RESULTS: Rate of progression of PD did not differ significantly between those in the highest and lowest quartiles for caffeine use for either of the primary measures or for secondary analyses of changes in scores on the motor or activities of daily living subsections of the Unified Parkinson Disease Rating Scale. Other secondary analyses yielded variable results. CONCLUSIONS: These data do not reveal a consistent relationship between caffeine intake and rate of progression of PD by these measures, although a larger study is required for sufficient power to more fully assess this relationship.

Stern MB, Marek KL, Friedman J, Hauser RA, LeWitt PA, Tarsy D, Olanow CW. · University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Mov Disord. · Pubmed #15300656 No free full text.

Abstract: Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a potent, selective, and irreversible monoamine oxidase-B inhibitor. This study was designed to evaluate the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in early Parkinson's disease (PD) patients not receiving levodopa. The study was performed as a multicenter, parallel-group, double-blind, randomized, placebo-controlled, 10-week study. Fifty-six PD patients were randomly assigned to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3-week dose-escalation period was followed by a 7-week maintenance phase. At week 10, the mean (+/-SE) changes from baseline in total Unified Parkinson's Disease Rating Scale (UPDRS) score were -1.8 (+/-1.3), -3.6 (+/-1.7), -3.6 (+/-1.2), and -0.5 (+/-0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups, respectively. Analysis of responders showed that 28% of patients (12 of 43) receiving rasagiline had an improvement in total UPDRS score of greater than 30%, compared with none of the patients receiving placebo (P < 0.05, Fisher's exact test). The frequency and types of adverse events reported by rasagiline-treated and placebo-treated patients were similar. These results suggest that rasagiline monotherapy is well tolerated and efficacious in early PD.