Parkinson Disease: Swope DM

Chen JJ, Swope DM. · Movement Disorders Center, Schools of Medicine and Pharmacy, Loma Linda University, Loma Linda, CA 92350, USA. · Pharmacotherapy. · Pubmed #18041936 No free full text.

Abstract: The available pharmacotherapies for Parkinson's disease address symptomatology because no agent has been demonstrated to provide definite neuroprotection against the disease. Choice of pharmacotherapy must include consideration of short-term benefits as well as long-term consequences. Patients with mild Parkinson's disease often function adequately without symptomatic treatment. However, recent data suggest that initiation of treatment with a well-tolerated agent (e.g., the monoamine oxidase [MAO]-B inhibitor rasagiline) in the absence of functional impairment is associated with improved long-term outcomes. Consideration should also be given to many patient-specific factors, including patient expectations, level of disability, employment status, functional as well as chronologic age, expected efficacy and tolerability of drugs, and response to previous Parkinson's disease therapies. Increasingly, initial monotherapy begins with a nondopaminergic agent or, if the patient is considered functionally young, a dopamine agonist. Since Parkinson's disease is a progressive disorder, adjustments to pharmacotherapy must be expected over time. When greater symptomatic relief is desired, or in the more frail elderly patient, levodopa therapy should be considered. If motor fluctuations develop, addition of a catechol-O-methyltransferase inhibitor or MAO-B inhibitor should be considered. For management of levodopa-induced dyskinesias, addition of amantadine is an option. Surgery may be considered when patients need additional symptomatic control or are experiencing severe motor complications despite pharmacologically optimized therapy.

Chen JJ, Swope DM, Dashtipour K. · Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Loma Linda University, Loma Linda, California 92350, USA. · Clin Ther. · Pubmed #18035186 No free full text.

Abstract: BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.

Obering CD, Chen JJ, Swope DM. · School of Pharmacy, University of Missouri-Kansas City, and the Department of Pharmacy, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri 64108, USA. · Pharmacotherapy. · Pubmed #16716137 No free full text.

Abstract: As Parkinson's disease progresses, fluctuations between akinesia, or hypomobility ("off" times), and mobility ("on" times) increase in frequency despite optimized pharmacotherapy. Motor fluctuations include predictable shortening of therapeutic effects, nocturnal or early morning akinesia, random hypomobility, and delayed mobility (variable responses to individual doses of drugs). Current oral antiparkinson drugs are inadequate for rapid and consistent relief of symptoms during hypomobility. Apomorphine, an injectable dopamine agonist recently introduced in the United States, is indicated for the management of hypomobility associated with advanced Parkinson's disease. Subcutaneous apomorphine is effective for rapid and consistent rescue from hypomobility, with a magnitude of motor improvement similar to that of levodopa. The effect begins within 20 minutes after dosing and lasts approximately 100 minutes. Therapeutic rescue doses are 2-6 mg, and patients typically require approximately three rescue doses/day. Apomorphine is associated with a clinically significant potential to cause nausea and orthostatic hypotension. These potential effects can be managed with antiemetic prophylaxis and appropriate determination of the therapeutic rescue dose.

Chen JJ, Swope DM. · Movement Disorders Center, Loma Linda University, Loma Linda, CA, USA. · J Clin Pharmacol. · Pubmed #16027398 No free full text.

Abstract: Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.

Swope DM. · Department of Neurology, Loma Linda University, Loma Linda, California 92354, USA. · Neurology. · Pubmed #15037669 No free full text.

Abstract: Patients with advanced Parkinson's disease (PD) may develop a variety of motor complications associated with levodopa therapy. Motor fluctuations, such as early morning akinesia and "wearing-off," may respond to individualized medical management with titrated combinations of levodopa, dopamine agonists, COMT inhibitors and amantadine. Often with disease progression, dyskinesias and unpredictable, rapid "off" periods will also emerge. These motor complications are less amenable to traditional anti-parkinson therapy manipulation. This manuscript reviews approaches for "rescue" therapy in PD patients with "wearing off," sudden "offs," early morning akinesia, and variable response to individual doses of oral medications. Strategies for preparing and administering liquid levodopa are discussed within the context of gastric emptying, intestinal absorption, and active transport across the blood brain barrier. In addition other levodopa preparations in early development, including the orally administered levodopa methyl ester and the potential for a subcutaneously administered levodopa ethyl ester are reviewed. Furthermore, practical guidelines regarding the dosing, administration, use of the antiemetic trimethobenzamide (Tigan), time to "on," duration of benefit, and potential side effects associated with subcutaneously injected apomorphine are provided.

Chen JJ, Swope DM. · Department of Pharmacy Practice, College of Pharmacy, Western University of Health Sciences, Pomona, California 91766-1854, USA. · Pharmacotherapy. · Pubmed #14524643 No free full text.

Abstract: Essential tremor is a common movement disorder in adults that interferes with the performance of functional and social activities. Differentiation of essential tremor from other tremor syndromes is important in order to provide appropriate patient education and therapy. The mainstays of pharmacotherapy are propranolol and primidone; however, in selected patients, agents such as alcohol, benzodiazepines, botulinum toxin, and gabapentin may provide symptomatic benefits. Advances in surgical interventions, such as stereotactic thalamotomy and thalamic deep brain stimulation, offer patients an alternative treatment modality when pharmacotherapy is inadequate. A treatment algorithm is provided to guide clinicians in the management of patients with essential tremor.