Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia.

Onset of involuntary movement patterns of the face, body and limbs are known as dyskinesia. They mostly appear in association with long-term levodopa (L-dopa) therapy in patients with Parkinson's disease. Consequences include patient distress, caregiver embarrassment and reduced quality of life. A severe intensity of this motor complication may result in troublesome disability; however, patients typically prefer motor behaviour with slight, non-troublesome dyskinesia to 'OFF' states. Pharmacotherapy of dyskinesia is complex. Continuous nigrostriatal postsynaptic dopaminergic receptor stimulation may delay onset of L-dopa-associated dyskinesia, while non-physiological, 'pulsatile' receptor stimulation facilitates appearance of dyskinesia. In the past, there have been many clinical trial failures with compounds that were effective in animal models of dyskinesia. Only the N-methyl-D-aspartate antagonist amantadine has shown moderate antidyskinetic effects in small well-designed clinical studies. Amantadine is an old antiviral compound, which moderately improves impaired motor behaviour. Recently, there has been a resurgence of its use due to the US Food and Drug Administration approval of an extended-release (ER) amantadine formulation for treatment of L-dopa-induced dyskinesia. This pharmacokinetic innovation improved dyskinesia and 'OFF' states in pivotal trials, with a once-daily oral application in the evening. Amantadine ER provides higher and more continuous amantadine plasma bioavailability than conventional immediate-release formulations, which require administration up to three times daily.

Evaluating ADS5102 (amantadine) for the treatment of Parkinson's disease patients with dyskinesia.

Introduction: Amantadine is an old, antiviral compound that moderately ameliorates impaired motor behaviour in Parkinson's disease. Its current resurgence results from the novel retarded release amantadine hydrochloride formulation, ADS5102, which has also received approval for the treatment of levodopa-related involuntary movements known as dyskinesia. Areas covered: This non-systematic, narrative drug evaluation discusses the value of ADS5102 for patients with Parkinson's disease. ADS5102 is orally applied once daily in the evening. This capsule provides higher and more continuous amantadine plasma concentrations than conventional amantadine immediate release formulations with their two to three times daily intake plan. Expert opinion: ADS5102 was superior to placebo in clinical trials. They aimed for the amelioration of motor complications, particularly at 'OFF' periods and with dyskinesia in fluctuating levodopa treated patients with Parkinson's disease. Side effects and tolerability were similar to the well-known effects of conventional amantadine formulations. ADS5102 simplifies treatment and improves compliance problems in the long run. The marketing of ADS5102 outside the US will be complex for return of research costs and investments required for its manufacturing. Indeed, worldwide institutional price regulation scenarios often only consider new therapeutic mode of actions as being innovative as opposed to old drugs with improved pharmacokinetic behaviour.

Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson's disease: current status.

INTRODUCTION: Brain function depends considerably on the neurotransmission of biogenic monoamines. Their metabolism employs monoamine oxidase-B in neuronal and glial cells. Inhibition of monoamine oxidase-B elevates biogenic amine levels. Accordingly, monoamine oxidase-B inhibitors provide a symptomatic effect via dopamine on motor symptoms in patients with Parkinson's disease. Areas covered: This narrative review aims to describe the pharmacokinetic characteristics of the available reversible and irreversible monoamine oxidase B inhibitors for the treatment of Parkinson's disease in daily practice. All these compounds are administered on a daily basis. Expert opinion: Reversibility or irreversibility of available monoamine oxidase-B inhibition is not relevant, due to their daily intake and half-life in clinical practice. Irreversible monoamine oxidase-B inhibitors slowed the progression of neuronal dying in experimental models of Parkinson's disease. In patients, concomitant inhibition of monoamine oxidase-B caused less increase of levodopa dosages over five years. The curve of levodopa increment diverged from the placebo curve. This reduced need for L-dopa monotherapy may be discussed as an indirect biomarker for disease severity and reflects a disease-modifying effect. In case of a symptomatic effect only, parallel curves would have occurred. Long-term L-dopa treatment should be combined with monoamine oxidase-B inhibitors when tolerated by patients.

Efficacy of carbidopa-levodopa extended-release capsules (IPX066) in the treatment of Parkinson Disease.

Introduction: Levodopa is the most efficacious and best-tolerated drug for treating Parkinson's disease (PD). To improve the treatment of PD, recent research initiatives have aimed to optimize the pharmacokinetic plasma behavior of L-dopa. Areas covered: This non-systematic, narrative drug evaluation brings the therapeutic value of IPX066 up for discussion. IPX066 is an orally applied levodopa/carbidopa containing formulation with modified drug release. It is rapidly absorbed, similar to conventional immediate-release levodopa preparations. The IPX066 capsule continuously releases levodopa during its passage through the gastrointestinal tract. Expert opinion: IPX066 provides more constant therapeutic levodopa plasma concentrations over longer periods. Furthermore, the IPX066 study program showed superior efficacy of IPX066 than conventional oral levodopa/carbidopa preparations for the treatment of motor complications, particularly with OFF intervals. IPX066 also reduced the frequency of oral levodopa intake. IPX066 may also improve the patient´s compliance due to its simplified drug regimen. The marketing of IPX066 outside the US is complex since in countries like Germany, health-care payers only consider innovation in terms of mode of action whereas innovation of pharmacokinetic and pharmacodynamic properties is disregarded.

Long-term management of Parkinson's disease using levodopa combinations.

INTRODUCTION: Parkinson's disease is a chronic, neurodegenerative disease. Its symptoms and course are heterogeneous. After several years of investigative drug studies, levodopa remains the most efficacious drug despite its long-term limitations. Consequently, research into new drug delivery modes is ongoing. AREAS COVERED: This review summarizes past and current advances of levodopa therapy with a focus on long-term patient management. Current research aims to increase drug bioavailability and to deliver it to the brain continuously. Reduced fluctuations improve drug efficacy and levodopa-associated motor complications. Less considered metabolic long-term consequences of levodopa are impaired methylation capacity and antioxidant defense. Both may contribute to disease progression and weaken physiological available human neuronal repair mechanisms. EXPERT OPINION: New developed formulations will improve pharmacokinetic and pharmacodynamic behavior. The authors suggest the regular supplementation with methyl group-donating and free radical scavenging substrates to weaken the metabolic consequences of chronic and high levodopa dosing. Many patients perform this nutrient supplementation in their diet already.