Initiation Of Levodopa Therapy Research Articles

Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia.

Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced dyskinesia (LID) is one of the main types of drug-induced dyskinesia, occurring in patients with Parkinson's disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into "peak-dose dyskinesia," "diphasic dyskinesia," and "wearing off" or "off-period" dyskinesia, of which peak-dose dyskinesia is the most common, followed by off-period, and then diphasic dyskinesia. Treatment strategy includes identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future.

The modern pre-levodopa era of Parkinson's disease: insights into motor complications from sub-Saharan Africa.

During the past decade, a number of large drug trials suggested that the initiation of levodopa therapy should be delayed to reduce the risk of motor complications in patients with Parkinson's disease. However, the relative contribution of the cumulative exposure to levodopa and of disease progression to the pathophysiology of motor fluctuations and dyskinesias is still poorly understood. In this 4-year multicentre study, we investigated a large cohort of patients with Parkinson's disease in a sub-Saharan African country (Ghana), where access to medication is limited and the initiation of levodopa therapy often occurs many years after onset. The primary objective was to investigate whether the occurrence of motor complications is primarily related to the duration of levodopa therapy or to disease-related factors. Study design included a cross-sectional case-control analysis of data collected between December 2008 and November 2012, and a prospective study of patients followed-up for at least 6 months after the initiation of levodopa therapy. Ninety-one patients fulfilled criteria for clinical diagnosis of idiopathic Parkinson's disease (58 males, mean age at onset 60.6 ± 11.3 years). Demographic data were compared to those of 2282 consecutive Italian patients recruited during the same period, whereas nested matched subgroups were used to compare clinical variables. Demographic features, frequency and severity of motor and non-motor symptoms were comparable between the two populations, with the only exception of more frequent tremor-dominant presentation in Ghana. At baseline, the proportion of Ghanaian patients with motor fluctuations and dyskinesias was 56% and 14%, respectively. Although levodopa therapy was introduced later in Ghana (mean disease duration 4.2 ± 2.8 versus 2.4 ± 2.1 years, P < 0.001), disease duration at the occurrence of motor fluctuations and dyskinesias was similar in the two populations. In multivariate analysis, disease duration and levodopa daily dose (mg/kg of body weight) were associated with motor complications, while the disease duration at the initiation of levodopa was not. Prospective follow-up for a mean of 2.6 ± 1.3 years of a subgroup of 21 patients who were drug-naïve at baseline [median disease duration 4.5 (interquartile range, 2.3-5) years] revealed that the median time to development of motor fluctuations and dyskinesias after initiation of levodopa therapy was 6 months. We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified.

Advances in the Pharmacologic Management of Early Parkinson Disease

Levodopa, in combination with a dopa decarboxylase inhibitor, provides the greatest symptomatic benefit with the fewest short-term side effects in the treatment of Parkinson disease (PD). However, the disease continues to progress, and the long-term use of levodopa is associated with the development of motor fluctuations and dyskinesias. Alternatives to the use of levodopa in early PD include monoamine oxidase B (MAO-B) inhibitors, dopamine agonists, and amantadine. Although no medication has been proven to slow the progression of Parkinson disease, preclinical studies have demonstrated neuroprotective effects of MAO-B inhibitors, and a recent study of rasagiline found that PD patients treated with rasagiline for 12 months experienced less progression of symptoms than patients treated with placebo for 6 months followed by rasagiline for 6 months. Several clinical trials have demonstrated that the initial use of a dopamine agonist to which levodopa can be added is associated with fewer motor complications than treatment with levodopa alone. In addition, preclinical studies suggest that adjunctive use of the catechol-O-methyltransferase (COMT) inhibitor entacapone when levodopa is first introduced may be associated with fewer motor complications than treatment with levodopa alone. Treatment of early PD with an MAO-B inhibitor, dopamine agonist, or amantadine, may provide useful alternatives to treatment with levodopa. Adding entacapone at the initiation of levodopa therapy may reduce the development of motor complications. Long-term studies are required to evaluate the potential long-term benefits of these treatment strategies.

Effect of Late Initiation of Levodopa Treatment in Patients With Long-Standing Parkinson's Disease

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.

Dystonia in multiple system atrophy

Objective: To delineate the frequency and nature of dystonia in multiple system atrophy (MSA). Methods: a cohort of 24 patients with clinically probable MSA over the past 10 years were...

Levodopa improves motor function without impairing cognition in mild non-demented Parkinson's disease patients. Parkinson Study Group.

The objective of the study was to determine the effects of short-term levodopa administration on motor, cognitive, and psychiatric aspects of Parkinson's disease (PD). The effects of levodopa on mental processes in PD are controversial. Opinions range from the claim that levodopa improves cognition to the opposite view that levodopa causes or exacerbates dementia, delusions, and hallucinations. Of the 800 idiopathic PD patients enrolled in the original DATATOP study, 387 reached the end point of functional disabilities sufficiently severe to require levodopa treatment. There were 263 men and 124 women who were comparable with regard to age, symptom duration of PD, and measures of PD severity. We compared test scores on motor performance, cognitive function, and psychiatric status before levodopa and again within 6 months after initiation of levodopa therapy. Levodopa administration improved all motor functions significantly. The improvement was significantly greater in women than in men. Levodopa administration did not worsen scores on any cognitive tests, and there were quantitatively small but significant improvements in tests of frontal lobe function. Levodopa exerted only minor effects on psychiatric measures. There were small but significant decreases in scores for depression, and increases in vivid dreams and hallucinations. Levodopa administration for up to 6 months in dosages sufficient to improve motor function has only small effects on cognitive function and psychiatric status in mild to moderate PD patients. We conclude that motor symptoms in early PD, which result from dopamine depletion, are dissociable from cognitive functions and psychiatric status, which may be more dependent on nondopaminergic mechanisms.

Short-Term Beneficial Effect of Deprenyl Monotherapy in Early Parkinsonʼs Disease

It was recently shown that early treatment with deprenyl in patients with Parkinson's disease can delay the need for initiation of levodopa therapy. It was therefore suggested that deprenyl may slow down disease progression. Alternatively, the observed stabilization of clinical disability may merely reflect drug-induced symptomatic benefit. We therefore examined a possible short-term beneficial effect of deprenyl (10 mg/day) as the first and only drug in 15 consecutive de novo patients. Bradykinesia was quantitatively assessed by computerized analysis of isometric force/time curves of biceps and triceps bilaterally and by calculation of simple reaction time (RT) and maximal muscle contraction rate (MMCR). We also measured maximal muscle force, evaluated clinical status by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and recorded patients' subjective reports. All tests were carried out before and at 1 and 2 months of treatment. Only one patient reported a beneficial effect. No significant changes in the UPDRS or score or muscle force were observed. In contrast, MMCR and RT improved at 1 month by an average of 12.1 and 7.2%, respectively (p < 0.01, paired t test). This improvement persisted after 2 months of treatment. Study shows that deprenyl monotherapy exerts a short-term beneficial effect in de novo parkinsonian patients. This effect, however, appears to be small, subclinical, and probably cannot account for the observed delay in the need to start levodopa therapy.

Selegiline as a primary treatment of Parkinson's disease

In order to investigate the efficacy of selegiline as a primary treatment in Parkinson's disease (PD), we carried out a placebo controlled, double-blind prospective trial. Fifty-four de novo patients with PD were randomized to receive either selegiline (10 mg/day) or matching placebo. We continued the monotherapy until the initiation of levodopa therapy became necessary. The disability of the patients was evaluated with three different rating scales at baseline, after 3 weeks, 2, 4, 8, and 12 months, and every 4 months thereafter. Fifty-two patients were eligible for the final analysis: 27 in the selegiline group and 25 in the placebo group. The median duration of time without levodopa was 545 +/- 90 days in the selegiline treated patients and 372 +/- 28 days in the placebo treated ones (p = 0.03). The disability of the patients was significantly milder in the selegiline than in the placebo group up to 12 months. More patients showed symptomatic improvement in the selegiline than in the placebo group. However, the symptomatic effect alone did not explain the prolongation of the time without levodopa in the selegiline treated patients. Selegiline was well tolerated and no severe side effects were encountered.

Early initiation of levodopa therapy does not promote the development of treatment-associated complications ???

Early initiation of levodopa therapy does not promote the development of treatment-associated complications ???

Hemiparkinsonism with hemiatrophy.

We studied fifteen patients with hemiparkinsonism and ipsilateral hemiatrophy (HP/HA) to better characterize the clinical features of this syndrome and its rate of progression. Patients were distinguished by highly asymmetric parkinsonism with predominant signs on the side of HA, early age of onset (43.7 years versus 60.2 years in our control population of idiopathic Parkinson's disease [IPD], abnormal birth history (7/15), and dystonia occurring prior to levodopa therapy (10/15). In six patients, the mean duration of disease until the initiation of levodopa therapy was 14.2 years, as compared with 4.1 years in our control population of IPD. The slow progression of disease underscores the relatively favorable prognostic significance of HP/HA and its distinction from IPD.

Initiation of levodopa therapy in parkinsonian patients should be delayed until the advanced stages of the disease.

To date, orally administered levodopa, usually in combination with a peripheral dopadecarboxylase inhibitor, remains the most potent agent in the treatment of Parkinson's disease. It is now well established that levodopa improves many of the disabling motor symptoms and signs and the quality of life, as well as life expectancy, in parkinsonian subjects. 1-5 Nevertheless, despite its widespread use for more than 15 years, a major unsettled and often heatedly debated question concerning dopa therapy still persists: ie, when should levodopa therapy be started in such patients? 6,7 More specifically, it is uncertain whether levodopa should be given to all parkinsonian patients immediately on diagnosis and regardless of the stage and severity of the disorder or whether its long-term administration should be withheld and delayed in milder cases (stages I and II according to Hoehn and Yahr 8 ) and restricted to those patients who are in the more advanced stages

Levodopa and melanoma

We feel it prudent to sound a note of caution about the use of levodopa in patients with known melanomas or with pigmented lesions. Levodopa was administered to three of our patients with Parkinson9s disease and known melanomas or pigmented lesions. One had had a “benign” pigmented nevus for 20 years that increased in size during levodopa therapy. Excisional biopsy of the lesion revealed it to be a malignant melanoma. Levodopa was discontinued and there has been no evidence of recurrence. The second patient had had a malignant melanoma excised one year before initiation of levodopa therapy. Two months after levodopa was begun, signs of an intracerebral tumor, presumably a melanoma, developed, and the patient died. The third patient had had a melanoma excised more than seven years (88 months) before initiation of levodopa therapy. He remains well two years later. In two additional cases in the literature, a temporal association was found between initiation of levodopa therapy and growth of melanoma.

Plasma Renin Activity During Levodopa Therapy

Plasma renin activity (PRA) was studied in six patients with Parkinson disease under identical conditions of diet and posture before and after seven days of levodopa administration. Significant differences were not found at seven days, nor when the measurement was repeated under similar conditions of sodium excretion after six months of therapy. The PRA responded appropriately to posture before and after therapy. After six months of therapy, sodium restriction resulted in an appropriate response of PRA and aldosterone secretion. A small but significant fall in blood pressure took place seven days after the initiation of levodopa therapy, at which time PRA had not changed significantly. After six months of therapy, blood pressure had returned to control levels. This study suggests that the renin-aldosterone system is not significantly altered by levodopa therapy of Parkinson disease.