Effect of a slow release preparation of levodopa on Parkinson's disease in combination with a peripheral decarboxylase inhibitor
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Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.Keywords:
Carbidopa
Decarboxylase inhibitor
Abstract 5‐Hydroxytryptophan has been found to be beneficial when administered alone or in combination with extracerebral aromatic amino acid decarboxylase inhibitors for therapeutic purposes in various disorders in which myoclonus is prominent. In five subjects the effect of decarboxylase inhibitors on the accumulation and elimination of 5‐hydroxytryptophan in plasma was studied. The plasma concentrations of 5‐hydroxytryptophan were increased about ten fold by pretreatment with the decarboxylase inhibitors, carbidopa and benserazide. Half‐lives of 2.2‐3.0 hrs. were obtained following oral administration of a single dose of 5‐hydroxytryptophan with or without pretreatment. In one subject the half‐life of 5 hydroxytryptophan in plasma increased to 5.5 hrs. during long‐term treatment with carbidopa.
Benserazide
Carbidopa
5-Hydroxytryptophan
Decarboxylase inhibitor
Plasma levels
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Benserazide
Carbidopa
Decarboxylase inhibitor
Entacapone
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Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.
Carbidopa
Decarboxylase inhibitor
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Levodopa is the most efficacious drug in the symptomatic treatment of Parkinson's disease. However, exogenously administered levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) so that only 1% of an administered dose gains access to the brain. Even when levodopa is co-administered with an inhibitor of AAAD such as benserazide or carbidopa, the bulk (90%) of levodopa is converted by COMT to the therapeutically inactive 3-O-methyldopa. Two COMT inhibitors, tolcapone and entacapone, have recently been introduced as adjuncts to levodopa to further inhibit peripheral levodopa metabolism and thereby enhance brain levodopa availability. This paper reviews the pharmacokinetics, dosing schedule, peripheral and central effects, and safety profile of these agents.
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Carbidopa
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The first truly effective medical therapy for Parkinson disease (PD), levodopa, was introduced in the 1960s. Patients had to take huge doses of levodopa, with treatment limited by peripheral decarboxylation of levodopa to dopamine by dopa decarboxylase (DDC), resulting in substantial peripheral side effects.1 Benserazide and carbidopa were developed as dopa decarboxylase inhibitors (DDCIs); because they do not cross the blood-brain barrier, they effectively block the peripheral decarboxylation of levodopa to dopamine. The combination of carbidopa and levodopa (Sinemet; Merck, Whitehouse Station, NJ) was marketed in 1975. This allowed for levodopa dose reduction due to increased (brain) bioavailability and a marked reduction of peripheral side effects.2 The total daily dose of carbidopa needed to effectively block peripheral decarboxylation of levodopa has been 75 to 100 mg, although some patients require supplemental higher doses of carbidopa (Lodosyn; Aton Pharma, Lawrenceville, NJ). Doses of carbidopa up to 400 mg per day are tolerable and safe.3
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This chapter discusses two particular pharmacologic problems in Parkinson disease, which are investigated with stable isotope labeled levodopa. It presents the rational for applying stable isotope technology over other existing pharmacologic methods. Levodopa infusion studies examining response to increasing infusion rates indicate that once clinical improvement is noted in advanced Parkinson disease, the magnitude of that response cannot be improved by simply increasing the levodopa infusion rate. The peripheral decarboxylation of levodopa to dopamine after sole levodopa administration is responsible for significant side effects, which include nausea, vomiting, and potentially fatal cardiac arrhythmias. Carbidopa blocks this peripheral conversion by acting as a competitive inhibitor of dopa decarboxylase. As it does not cross the blood-brain barrier, there is no interference with central decarboxylation of levodopa to dopamine. Thus, the effect of carbidopa when coadministered with levodopa is to substantially reduce systemic side effects of levodopa and make more systemic levodopa available for central conversion to dopamine.
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Decarboxylase inhibitor
Decarboxylation
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Carbidopa
Decarboxylase inhibitor
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Introduction: Parkinson's disease (PD) is a common neurodegenerative disease.In the 1960s, it was shown that the degeneration of dopamine producing neurons in the substantia nigra (SN) caused the motor features of PD.Dopamine replacement with levodopa, a dopamine precursor, resulted in remarkable benefit.Yet, the intermittent administration of levodopa is a major cause of motor complications, such as "wearing-off " of levodopa's benefit and involuntary movements, known as dyskinesia.Therefore, agents that prolong levodopa's half-life were employed, such as carbidopa, an aromatic amino acid decarboxylase (AADC) inhibitor, and entacapone, a catechol-O-methyltransferase (COMT) inhibitor.The combination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients.Aims: To assess the evidence for the place of CLE in the treatment of PD.Evidence review: CLE has a good efficacy, safety and tolerability profile, similar to that of entacapone taken separately with carbidopa/levodopa (CL).Compared to CL alone, it prolongs levodopa's benefit, and improves the quality of life but not the motor performance in PD patients with nondebilitating "wearing-off " or dyskinesia.However, it increases the dyskinesia rate in early PD patients, and has adverse events in advanced patients with significant motor complications.There is insufficient evidence regarding cost-effectiveness.Place in therapy: CLE is an attractive alternative for patients with nondisabling "wearing-off " or dyskinesia taking CL with or without entacapone.It cannot be recommended for early PD patients, as it can induce more dyskinesia than CL alone, or in any patients who seem to have more adverse events.
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Objective: To study the dose effects of a novel catechol-O-methyl transferase (COMT) inhibitor ODM-104 and the aromatic L-amino acid decarboxylase (AADC) inhibitor carbidopa on levodopa pharmacokinetics (PK) at 3 modified release (MR) levodopa strengths and to compare with a standard carbidopa/levodopa immediate release (IR) formulation. Background: In Parkinson’s disease, stable levodopa concentration in plasma predicts improved treatment response with reduced motor fluctuations. MR formulations of levodopa help to achieve stable concentrations but levodopa biovailability may be reduced. When AADC is inhibited, levodopa is metabolized increasingly by COMT. Simultaneous COMT-inhibition improves levodopa bioavailability. Design/Methods: An open, randomized, repeated dose PK study with 56 healthy males. The study consisted of 4 parallel groups with 4-treatmet crossover design. The effect of two carbidopa and ODM-104 doses on MR levodopa PK was investigated. AADC and COMT inhibitors were administered q.i.d for 7 days and on the 7 th day MR levodopa 50, 100 or 150 mg was added into the treatment. Results: At each levodopa dose level, 65 mg of carbidopa significantly increased the exposure (AUC 0–24h ) of levodopa when compared to standard (1:4 carbidopa to levodopa ratio) dose. Addition of ODM-104 (50 or 100 mg) dose dependently significantly further increased the AUC 0–24h and also the minimum concentrations (C min,tau ) of levodopa without significantly increasing its maximum concentrations (C max,tau ). When compared to standard carbidopa/levodopa, ODM-104 100 mg + carbidopa 65 mg + MR levodopa treatment decreased levodopa fluctuation (PTF tau ) 62% (p min,tau 212% and AUC 0–24h 105% (p max,tau was increased 24% (p=0.5). Conclusions: Increased carbidopa dose and ODM-104 have a role in increasing the exposure and decreasing the fluctuation of MR levodopa. When compared to standard carbidopa/levodopa, ODM-104 100 mg + carbidopa 65 mg + MR levodopa treatment doubles the AUC 0–24h and triples the C min,tau of levodopa without significantly increasing its C max,tau . Disclosure: Dr. Tuunainen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Ellmen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Vahteristo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Vahteristo holds stock and/or stock options in Orion Oyj. Dr. Holopainen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Orion Oyj. Dr. Strugala has nothing to disclose.
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