entacapone and Movement-Disorders

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Topics: Apomorphine; Benzophenones; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Ergolines; Humans; Levodopa; Movement Disorders; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

In advanced Parkinson's disease, the combination of disease progression and levodopa therapy leads to the development of motor problems complicating the therapeutic response, known as motor response complications. The nonphysiological, pulsatile stimulation produced by most currently available dopaminergic therapies triggers a complicated series of responses resulting in the dysregulation of glutamate receptors and many other neurotransmitter systems on striatal neurons. Although a number of novel compounds that provide a more continuous dopaminergic stimulation are becoming available, no practical way to accomplish this in a truly physiological manner currently exists. Novel strategies for pharmacological intervention with the use of nondopaminergic treatments, with drugs targeting selected transmitter receptors expressed on striatal neurons appear more promising. These include NMDA or AMPA antagonists, or drugs acting on 5-hydroxytryptamine subtype 2A, alpha2-adrenergic, adenosine A2A and cannabinoid CB1 receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern, like synaptic vesicle proteins, or nonsynaptic gap junction communication mechanisms, or drugs with actions at the signal transduction systems that modulate the phosphorylation state of NMDA receptors. These new therapeutic strategies, alone or in combination, hold the promise of providing effective control or reversal of motor response complications.

Topics: Administration, Cutaneous; Animals; Antiparkinson Agents; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dopamine Agonists; Drug Delivery Systems; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Indans; Levodopa; Liposomes; Monoamine Oxidase Inhibitors; Motor Neurons; Movement Disorders; Nitriles; Parkinson Disease; Receptors, Glutamate; Signal Transduction

Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.

Topics: Administration, Oral; Antiparkinson Agents; Carbidopa; Catechols; Clinical Trials as Topic; Drug Combinations; Humans; Levodopa; Movement Disorders; Nitriles; Parkinson Disease; Tablets

Movement disorders is a term applied for a heterogeneous group of diseases and syndromes sharing deficits of voluntary motor function or movement patterns. In clinical practice, the term movement disorders is usually employed to designate those syndromes and diseases that are linked to a pathology or dysfunction of cortico-basal ganglia circuits. The last years have witnessed a rapid expansion in our understanding of the etiological and pathophysiological factors underlying movement disorders such as Parkinson's disease or dystonia. The discovery of new gene mutations is bound to give rise to new insights into the molecular pathogenesis of movement disorders related to neurodegenerative processes. It is already becoming apparent that pathological protein aggregation may be a common link in the neuronal degeneration underlying such diverse entities as spinocerebellar ataxia, idiopathic torsion dystonia and Parkinson's disease. So far, these new findings have not been translated into new forms of symptomatic or preventive therapies. Nevertheless, symptomatic treatment of movement disorders, as evident in the field of Parkinson's disease, is one of the most rewarding and innovative areas of neurological therapy.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Therapy, Combination; Electric Stimulation Therapy; Enzyme Inhibitors; Globus Pallidus; Humans; Movement Disorders; Mutation; Nitriles; Nitrophenols; Parkinson Disease; Subthalamic Nucleus; Tolcapone

Catechol-O-methyl transferase (COMT) inhibition by entacapone enhances levodopa absorption and reduces 'off' time in Parkinson's disease (PD). We hypothesized that the administration of entacapone in a bimodal fashion (two doses 1 h apart) would enhance levodopa absorption and improve the motor symptoms of PD. Patients with PD (n = 17) were given immediate (IR)- or controlled (CR)-release levodopa each with either one or two doses of entacapone. Bimodal entacapone produced a significant increase in IR and CR levodopa half-life, 'area under the curve' (AUC), and C(max) with levodopa CR. For both IR and CR levodopa, bimodal entacapone resulted in a significant improvement in the Unified Parkinson's Disease Rating Scale part III (motor). Bimodal entacapone increased COMT inhibition, improved the pharmacokinetics of levodopa and improved motor scores for 6 to 8 h. Bimodal use of entacapone may be useful in selected patients to improve motor control and implies that controlled release COMT inhibition would be beneficial in PD patients.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Antiparkinson Agents; Area Under Curve; Catechol O-Methyltransferase; Catechols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Nitriles; Parkinson Disease; Severity of Illness Index

Oral administration of levodopa (L-dopa) (2.5-25.0 mg/kg) plus carbidopa (12.5 mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in locomotor activity and a corresponding decrease in motor disability. Pretreatment with the peripheral COMT inhibitor entacapone (12.5 mg/kg p.o.) enhanced the intensity and duration of the increase in locomotor activity and the reversal of motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus carbidopa. By contrast, entacapone pretreatment did not potentiate the increased locomotor activity or reversal of motor disability produced by a near-maximal dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of entacapone (5.0-25.0 mg/kg p.o.) were dose related, with doses of > 12.5 mg/kg tending to produce less potentiation of L-dopa's effects compared to lower doses. Pretreatment with entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5 mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both carbidopa and entacapone produced the greatest overall motor response. In conclusion, entacapone enhances the motor response produced by a low-threshold dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa and entacapone appears necessary to obtain the maximal therapeutic response.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callithrix; Carbidopa; Catechols; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Levodopa; Male; Movement Disorders; Nitriles; Severity of Illness Index