Long-term Levodopa Treatment Research Articles

Selegiline in the treatment of daily fluctuations in disability of parkinsonian patients with long-term levodopa treatment

In order to evaluate in a double-blind manner the therapeutic efficacy of selegiline in the treatment of late-phase Parkinson's disease, 19 patients with end-of-dose type fluctuations were randomized for a double-blind cross-over trial receiving either selegiline 10 mg or placebo. Each period lasted 12 weeks. During a two week prestudy period the dose of levodopa was titrated to optimal levels. The disability was evaluated using the Columbia University Disability Scale (CUDS). The patients kept a daily diary to monitor closely the frequency and severity of their fluctuations and the side-effects of treatment. Their parkinsonian disability and all main symptoms improved significantly during selegiline treatment. The mean duration of action of a levodopa dose was significantly longer and there was significantly less daily end-of-dose and early morning akinesia during selegiline treatment. The side-effects were similar in both treatments. This double-blind study confirms the findings of earlier open studies that selegiline potentiates and prolongs the therapeutic effects of levodopa and thus its use is particularly beneficial in patients with end-of-dose type fluctuations in disability.

Combination of selegiline and controlled release levodopa in the treatment of fluctuations of clinical disability in parkinsonian patients

Thirteen parkinsonians with a long duration of the disease and long-term dopa therapy, seven of them showing severe on-off oscillations and 6 an "end-of-dose impairment", were treated with a controlled release (HBS) preparation of L-DOPA/benserazide for more than 3 years. Thereafter, selegiline was added in a progressively increasing dosage up to a maximum of 10 mg/day during 4 months, with the aim of a) further improving the long-term results and b) reducing the doses of the new formula of L-DOPA. A significant decrease of early morning parkinsonism and reduction of motor disability throughout the day were observed; "wearing-off" cases showed better results compared with those presenting "on-off" oscillations. A mean reduction of 20% in the doses of levodopa was achieved. Likewise, a mild reduction of dyskinesias and a mild-moderate enhancement of dystonias were recorded. Only one patient did not tolerate selegiline and two others received lower doses due to side-effects. Selegiline was capable of enhancing the antiparkinsonian effect of the new formula of L-DOPA, while allowing a reduction of the doses administered. It must also be emphasized that such improvement was achieved in complicated patients, most of whom showed some deterioration of response in the late stages of long-term sustained-release levodopa treatment.

Modification of Parkinson's Disease by Long-term Levodopa Treatment

Levodopa treatment is unquestionably the reason parkinsonian patients now live a normal 1 or nearnormal 2 life span. When in the course of the disease levodopa therapy should begin remains controversial for several reasons: the initial favorable response to the drug is followed by a gradual decline; the impression that levodopa has a finite period of optimal usefulness 3 ; and the assumption that severe dyskinesia and a true on-off effect are related to duration of treatment. These suggestions have led some to believe that levodopa should be held in reserve until the patient is at least moderately afflicted, so that it is not wasted on early stages of the disease. Our data lead us to conclude that this reasoning is fallacious. When the condition of a patient with a progressive disease who is receiving long-term drug treatment is seen to worsen over time, two possibilities arise. The first is that

On-off fluctuations in Parkinson's disease. A clinical and neuropharmacological study.

On-off fluctuations have been studied in twenty patients with Parkinson's disease on long-term levodopa treatment. The pattern of fluctuations was related to the timing of oral levodopa ingestion in all patients. 'Predictable' fluctuators were characterized by fewer daily doses taken at longer intervals than 'unpredictable' fluctuators in whom individual dose responses tended to overlap. Most patients at least once a day experienced an unexplained failure of an oral dose to take effect. Administration of levodopa by intravenous infusion at a constant rate brought about a dramatic extension in the duration of mobility and reduced the frequency of fluctuations compared with oral therapy; apomorphine consistently reversed off phases when administered shortly after their onset, whereas lisuride was less often effective. We conclude that the development of a sustained-release formulation of levodopa would lead to improved control of the response fluctuations seen with conventional levodopa preparations.

Problems associated with long-term levodopa treatment of Parkinson's disease.

Levodopa treatment improves significantly not only the parkinsonian disability but also the mortality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia. In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctuations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of Parkinson's disease nor the disability of the patients. A readjustment of the levodopa dosage, and as an adjuvant drug treatment, deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuations in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.

Deprenyl (selegiline) in the treatment of Parkinson's disease.

The effects of deprenyl were investigated in 45 parkinsonian patients suffering from fluctuations in disability under long-term levodopa treatment. During a 1 to 3 month period of treatment, 5-10 mg of deprenyl caused a significant reduction in response fluctuations in 26 out of 45 patients (58%). This improvement was only moderate (58%) or minimal (42%). Of 11 parkinsonian patients taking deprenyl with levodopa and benserazide for up to 4 years, 6 patients (55%) showed moderate and 5 patients (45%) minimal improvement initially. The improvement in response fluctuations was maintained during the follow-up period, although there was a clear decline in the degree of improvement. The addition of deprenyl to levodopa treatment also caused a further improvement in parkinsonian disability, which, however, decreased during the treatment period. Deprenyl appears to be a useful adjuvant to levodopa in patients with daily fluctuations in disability.

The effect of deprenyl (selegiline) on cognition and emotion in parkinsonian patients undergoing long-term levodopa treatment

The effects of deprenyl on memory, other cognitive functions, vigilance and emotional processes were investigated in seven parkinsonian patients undergoing long-term levodopa treatment. The patients were selected on the basis of their cognitive impairment, observed during a follow-up study of 8-10 years. Four of the patients had progressive dementia and three did not. After deprenyl treatment lasting 4 weeks, there were two patterns of responses. Patients with slow progressive dementia failed to respond to treatment, whereas patients without progressive impairment tended to show improvement in memory and motor speed; the former group also showed more emotional changes than the latter. Typical responses in all patients treated with deprenyl were: increased arousal, paradoxical spells of tiredness, deterioration in vigilance and in set shifting, but improvement of parkinsonian disability. These preliminary findings indicate that there is a dissociation between pure motor responses and cognitive as well as other behavioural responses to deprenyl. It is probable that although enhanced availability of dopamine by MAO-B inhibition partly explains the present neuropsychological findings, also other brain mechanisms are involved.

Effect of long-term L-dopa administration on the dopaminergic and cholinergic (muscarinic) receptors of striatum in 6-hydroxydopamine lesioned rats

L-Dihydroxyphenylalanine (L-Dopa) (200 mg/kg/day) was administered for 30 days to the rats whose nigrostriatal dopamine pathway was lesioned unilaterally with 6-hydroxydopamine and the receptor binding of 3H-spiperone and 3H-quinuclidinyl benzilate ( 3HQNB) was measured in the dopaminergic and muscarinic cholinergic receptors of the striatum. 3H-spiperone binding increased by 73% and 3HQNB binding decreased by 14% in the lesioned side when compared to the control side of L-Dopa-non-treated rats. 3H-spiperone binding was measured in the lesioned sides of L-Dopa-treated and L-Dopa-non-treated rats and was found to have decreased by 21% in the former. In the control side of the L-Dopa-treated lesioned rats, however, 3H-spiperone binding increased by 27% when compared to the opposite striatum of the same rats. 3HQNB binding in the lesioned side of L-Dopa-treated rats was not significantly different from that of the control side statistically. These results suggest that changes in functional equilibrium between the dopaminergic and cholinergic mechanisms influence the muscarinic cholinergic receptors and that supersensitivity of dopamine receptors after lesion of the nigrostriatal pathway also remains after long-term L-Dopa treatment.

Plasma DOPA levels and growth hormone response to levodopa in parkinsomism.

It has been suggested that the therapeutic response to levodopa in patients with Parkinson's disease may be related to changes in plasma growth hormone concentration. In order to examine this problem, we have determined plasma DOPA and growth hormone levels after a standard oral levodopa load in 32 patients with Parkinson's disease. Levodopa caused an increase in plasma growth hormone concentration in 30 subjects. The magnitude and timing of this growth hormone response was not related to the clinical response, the presence or absence of response swings, or the occurrence of dyskinesias. The growth hormone response to levodopa is normal in patients with Parkinson's disease and not altered by long-term levodopa treatment.

Sebaceous Gland Secretion in Parkinson's Disease During L-Dopa Treatment

Sebum production was measured on the foreheads of 21 patients with Parkinson's disease before and during long-term L-dopa treatment. A statistically significant decrease in the amount of sebum was demonstrable during treatment although considerable variation in responsiveness was observed. No correlation between the dose of L-dopa and the degree of sebaceous gland inhibition could be established. The quantitative reduction of sebum could not be related to the degree of neurologic improvement.