Jack J. Chen

Monoamine Oxidase-B Inhibition in the Treatment of Parkinson's Disease

Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B prolong the activity of both endogenously and exogenously derived dopamine, making them an option either as monotherapy in early Parkinsons disease or as adjunctive therapy in patients treated with levodopa who are experiencing motor complications. In addition to symptomatic benefits, experimental data suggest that MAO‐B inhibitors may be neuroprotective through MAO‐B inhibition and other mechanisms that have yet to be clearly defined. The two available MAO‐B inhibitors approved for use in the United States, rasagiline and selegiline, each provide symptomatic relief as monotherapy and as adjunctive therapy, and have shown potential disease‐modifying effects in experimental models and clinical studies. Selegiline in a conventional tablet formulation is less bioavailable than rasagiline, resulting in limited potency. It also has amphetamine metabolites that may produce adverse effects and interfere with any putative disease‐modifying effects. The oral disintegrating tablet formulation of selegiline allows pregastric absorption, minimizing first‐pass metabolism, thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline, more potent than selegiline, exhibits disease‐modifying effects in experimental models and lacks amphetamine metabolites. Both the symptomatic and potential disease‐modifying effects of rasagiline are under investigation. A third agent with MAO‐B inhibition properties, safinamide, is in phase III development. Although not yet approved, safinamide may offer the added advantage of combined MAO‐B and dopamine reuptake inhibition.

Clinical Pharmacology of Rasagiline: A Novel, Second-Generation Propargylamine for the Treatment of Parkinson Disease

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.

Pharmacotherapy for Parkinson's Disease

The available pharmacotherapies for Parkinsons 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 Parkinsons 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 Parkinsons disease therapies. Increasingly, initial monotherapy begins with a nondopaminergic agent or, if the patient is considered functionally young, a dopamine agonist. Since Parkinsons 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.

Essential Tremor: Diagnosis and Treatment

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 pharmaco‐therapy 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.

Anxiety in Parkinson’s disease: identification and management

Anxiety disturbances are recognized as common psychiatric comorbidities in Parkinson’s disease (PD) and contribute to significant impairments in areas of cognitive, functional, motor and social performance. Anxiety in PD results in reduced quality of life, higher levels of care dependency and increased caregiver burden. Surprisingly, there is a paucity of treatment data. In one randomized, controlled study, bromazepam was found to be effective for anxiety in PD. However, usage of benzodiazepines in the PD population is limited by potential risk of confusion and falls. There are no controlled studies of selective serotonin reuptake inhibitors (SSRIs) for anxiety in PD. However, results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD, although in these studies anxiety outcomes were secondary. This review underscores that, given the high prevalence of anxiety disturbances in PD, there is a significant paucity of treatment data for this population. Additional studies are warranted. In the meantime, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions. Cognitive and behavioral therapies (with or without pharmacotherapy) have demonstrated efficacy and warrant consideration. When feasible, a targeted and individualized multimodal approach utilizing psychotherapeutic interventions along with pharmacologic therapies should be considered.

Transdermal Rotigotine: A Clinically Innovative Dopamine-Receptor Agonist for the Management of Parkinson's Disease

Rotigotine is a highly lipophilic dopamine‐receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinsons disease and to reduce “off” hours in levodopa‐treated patients with advanced Parkinsons disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D2 and D3 receptors. With once‐daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine‐receptor stimulation. In early Parkinsons disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinsons disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinsons disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2–3 weeks, and the once‐daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24‐hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinsons disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine‐receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early‐to‐advanced Parkinsons disease, as well as a brief summary for its role in restless legs syndrome.

Abo-, inco-, ona-, and rima-botulinum toxins in clinical therapy: a primer.

Botulinum neurotoxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular‐blocking agent used for the treatment of a variety of medical and cosmetic indications. Currently, in the United States, there are four BoNT formulations licensed for use: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB. These revised name designations were established to reinforce the understanding that each BoNT product has an individual potency and is not interchangeable with any other BoNT product. The therapeutic use of BoNTs is expanding and new formulations are on the horizon. This article is a primer that describes distinctions among currently available, licensed BoNT formulations. Toxin pharmacology, product characteristics, storage, handling, preparation, and dosages will be reviewed. In addition, issues related to dose equivalency ratios, immunogenicity, potency, and toxin spread will be discussed. Therapeutic indications and safety are discussed briefly. Knowledge of the available and licensed BoNT formulations and the ability to make distinctions in toxin pharmacology, product characteristics, and indications are vital for product selection, preparation, drug information, avoidance of drug errors, quality assurance, and patient safety.

Effect of Exercise on Motor and Nonmotor Symptoms of Parkinson’s Disease

Background. Novel rehabilitation strategies have demonstrated potential benefits for motor and non-motor symptoms of Parkinsons disease (PD). Objective. To compare the effects of Lee Silverman Voice Therapy BIG (LSVT BIG therapy) versus a general exercise program (combined treadmill plus seated trunk and limb exercises) on motor and non-motor symptoms of PD. Methods. Eleven patients with early-mid stage PD participated in the prospective, double-blinded, randomized clinical trial. Both groups received 16 one-hour supervised training sessions over 4 weeks. Outcome measures included the Unified Parkinsons Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Modified Fatigue Impact Scale (MFIS). Five patients performed general exercise and six patients performed LSVT BIG therapy. Post-intervention evaluations were conducted at weeks 4, 12 and 24. Results. The combined cohort made improvements at all follow-up evaluations with statistical significance for UPDRS total and motor, BDI, and MFIS (P < 0.05). Conclusion. This study demonstrated positive effects of general exercise and LSVT BIG therapy on motor and non-motor symptoms of patients with PD. Our results suggest that general exercise may be as effective as LSVT BIG therapy on symptoms of PD for patients not able to readily access outpatient LSVT BIG therapy.

Depression in Parkinson's disease: identification and management.

Depression is a common psychiatric comorbidity in Parkinsons disease (PD) and contributes to significant impairments in cognitive, functional, motor, and social performance. This results in reduced quality of life, higher levels of care dependency, and increased caregiver burden. When treating depression, it is important to ensure that the patients response to treatment will be adequately monitored. This can be accomplished in neurology or primary care settings, or in clinical settings with interdisciplinary treatment teams. Mental health services should be engaged early as a component of ongoing comprehensive care. This article reviews a general approach to treating the pharmacotherapy of depression in PD. Ultimately, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions and should include a targeted and individualized multimodal approach that utilizes psychotherapeutic interventions along with pharmacologic therapies.

The Monoamine Oxidase Type B Inhibitor Rasagiline in the Treatment of Parkinson Disease: Is Tyramine a Challenge?

Rasagiline is an irreversible monoamine oxidase type B (MAO‐B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO‐A), but not MAO‐B, poses a risk of the “cheese effect,” a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize rasagiline selectivity for the MAO‐B enzyme and tyramine sensitivity, demonstrate that rasagiline, when used at the recommended dose, is selective for MAO‐B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical trials of rasagiline in Parkinson disease involving 2066 rasagiline‐treated patients who did not require dietary tyramine restriction per protocol. In late 2009, US labeling for rasagiline was modified to state that dietary tyramine restrictions are not ordinarily required when rasagiline is administered at recommended doses. In addition, because rasagiline has been demonstrated to be selective for MAO‐B at the approved dose of up to 1 mg/d, contraindications regarding concomitant use with sympathomimetic amines, use of sympathomimetic vasopressors in conjunction with general or local anesthesia, and use in patients with pheochromocytoma also were removed.