Reduction In Levodopa Research Articles

High doses of pergolide improve clinical global impression in advanced Parkinson's disease—A preliminary open label study

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate to severe Parkinson's disease (PD) in an open-label multicenter clinical trial. The primary objective was to assess the amount of reduction in levodopa, the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of 12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a maximum of 12 mg/day in combination with a simultaneous decrease of levodopa doses in 100 mg steps. Levodopa was reduced from 500 mg/day (median) to 250 mg/day. Mean UPDRS part III improved significantly ( p = 0.01). Clinical global impression improved significantly after 24 weeks ( p < 0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal pain, and peripheral edema. Twenty-two patients finished the complete study according to protocol. A possible relationship to the study medication was assumed for two serious adverse events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced stages of PD if given in appropriate regimens.

Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease.

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) micromol/L increased to 10.1 (3.1) micromol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L-dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 micromol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined.

Pain in Parkinson's Disease.

Pain is reported by nearly 50% of patients with Parkinson's disease. In some patients, it can be more debilitating than the motor deficits. In order to identify the appropriate treatment strategy for each patient, it is useful to categorize pain syndromes as follows: 1) low DOPA (end of dose wearing off, diphasic, or early morning) painful states are associated with inadequate levels of dopamine receptor stimulation; 2) high DOPA (peak dose) painful states occur at times of maximum levodopa efficacy; and 3) many patients report pain that has no obvious relation to dopaminergic medications or may even be caused by other conditions. Low DOPA painful states are best treated by trying to provide more continuous dopaminergic stimulation and thereby reduce or prevent the number and duration of "off" periods. Adding or increasing the dose of direct-acting dopamine receptor agonists or of catechol-o-methyl transferase inhibitors is the best first-line strategy. Other approaches include increasing the frequency of immediate-release levodopa preparations or using controlled-release preparations. More invasive approaches should be considered only when simpler methods fail. These include deep brain stimulation to the pallidum or the subthalamic nucleus, or direct duodenal continuous infusion of levodopa in patients who are unable to undergo surgery. Pain associated with excessive dopaminergic stimulation usually is a result of dystonia or severe chorea. Reduction of levodopa is the first step in attempting to diminish high DOPA states, followed by reduction or cessation of other dopaminergic agents such as selegiline, catechol-o-methyl transferase inhibitors, or direct-acting dopamine receptor agonists. Adding amantadine can reduce chorea significantly and it should be tried if the potential and actual side effects are tolerable to the patient. Deep brain stimulation is a good final option if medication adjustments are ineffective. Nonspecific pains of Parkinson's disease can be difficult to treat. The effective use of central pain suppressant or analgesics is anecdotal and difficult to verify. In untreated early disease, generalized pain or pain related to joint or muscle immobility may be reduced by effective treatment of the underlying Parkinson's disease.

Mania following deep brain stimulation for Parkinson's disease.

Three patients with PD developed manic behavior after bilateral implantation of electrodes for deep-brain stimulation (DBS). Common to all three patients were manic symptoms unremitting after levodopa reduction or stimulation "off," lower electrodes positioning caudal to the subthalamic nucleus area, postoperative DBS with the lower contacts (0) of the quadripolar electrodes, and resolution of the manic episodes coinciding with stimulation through higher contacts.

The long-term response to levodopa in dopa-responsive dystonia

We report the long-term response to levodopa in 20 patients with dopa-responsive dystonia (DRD). We found an inverse correlation between the daily dose of levodopa and duration of treatment ( r=−0.59, P<0.01). Mild dyskinesias were present in 20% of our patients. Dyskinetic patients were on a higher dose of levodopa than non-dyskinetics. Dyskinesias responded to a reduction in levodopa, with no deterioration in motor function. We propose that the dopamine turnover might decrease with time, which would lead to a decrease in the requirement for levodopa and the occurrence of dyskinesias late in the course of DRD.

Levodopa-induced dyskinesias treated by pallidotomy

Pallidotomy has been reported to improve parkinsonian symptoms, but its effects on levodopa-induced dyskinesia (LID) have not been thoroughly examined. We describe here the results of stereotactic, unilateral, posteroventral pallidotomy on LID in 42 patients (22 women), who were followed for up to 9 months. Their mean age was 60. 6+/-9.3 (range: 40-74), age at onset was 46.1+/-9.1 (range: 24-46), and duration of symptoms was 14.5+/-5.3 (range: 4-25) years. Three months following pallidotomy, the percent time with dyskinesia decreased from 37.0 to 17.3 (P<0.0001) and the percent time the patients were 'on' with dyskinesias decreased even more, from 71.0 to 22.9 (P<0.0001). Furthermore, the number of patients with troublesome (moderate to violent) dyskinesia had decreased from 36 (86%) prior to surgery to only 5 (12%) after surgery. The mean unified Parkinson disease rating scale (UPDRS) scores for LID-related disability and pain decreased from 1.95 to 0.74 (P<0. 0001) and from 1.02 to 0.17 (P<0.0001), respectively. Since the pre- and post-pallidotomy daily levodopa dosage remained essentially the same, the improvement in LID could not be attributed to a reduction in levodopa. Surgery-related complications occurred in eight (19%) patients, but none of them had persistent disability as a result of these complications. We conclude that pallidotomy is an effective and safe procedure in the treatment of medically intractable LID.

Pergolide for levodopa-induced complications in Parkinson's disease.

To compare the efficacy and safety of adjunct pergolide therapy versus placebo in patients with Parkinson's disease suffering from the complications of levodopa therapy. Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Eli Lilly and Company Limited. Randomised controlled trials of pergolide versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. Data was abstracted independently by each author and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of drop outs and adverse events. A large number of small RCTs were identified, but these were part of a large multicentre trial which was eventually published in full. The final publication was used as the only subject for this review. The time patients spent 'off' was reduced by 1.8 hours with pergolide compared with 0.2 hours with placebo (p < 0.001). Dyskinesia developed or deteriorated in 62% of pergolide-treated compared with 25% placebo-treated patients (p < 0. 05). The excess in dyskinesia prevalence and severity resolved by the end of the study with levodopa reduction. Levodopa dose was reduced more in those receiving pergolide (235 mg v 51 mg; p < 0. 001). Pergolide produced significant improvement in Hoehn and Yahr stage (p < 0.05) and both the motor and activities of daily living parts of a modified Columbia rating scale (both p < 0.001). Significantly more patients suffered nausea (24% v 13%; p < 0.001) and hallucinations (14% v 3%; p < 0.01) on pergolide. No difference was found in the numbers remaining on treatment at the end of the study (pergolide 84% v placebo 82%) but withdrawals due to adverse events were greater in those taking pergolide (10% v 4%). Based on this single large multicentre study, pergolide reduces 'off' time and improves impairment and disability due to Parkinson's disease whilst allowing a reduction in levodopa dose. This is at the expense of dopaminergic adverse events. Further trials are required to compare pergolide with the newer dopamine agonists.

Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson's disease

Ventroposterior pallidotomy, and pallidal and subthalamic nucleus (STN) stimulation, are proposed to treat severe Parkinson’s disease (PD) with levodopa-induced motor complications. Pallidal surgery decreases levodopa-induced dyskinesias (LID). Parkinsonism evaluated by the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS) improves by about 30% after unilateral pallidotomy. STN stimulation can greatly improve parkinsonian disability, but its effects on LID are unknown because the first patients treated with STN stimulation were selected with mild or absent LID since spontaneous STN lesions can induce hemiballism. However, our initial experience with STN stimulation showed that stimulation-induced abnormal movements could be controlled by setting the stimulation voltage below the dyskinesia threshold. Moreover, the substantial decrease in levodopa dosage, which was made possible by the antiparkinsonian benefit, allowed a decrease in LID in the long-term. Thus, STN stimulation was also proposed for patients with severe LID. We selected all consecutive patients with young-onset PD, since this population is generally levodopa-sensitive and prone to develop severe LID. Eight patients with a mean age of 51 (SD 10) years and a mean disease duration of 16 (5) years were operated on bilaterally in the STN because of severe motor fluctuations (motor score on the UPDRS 57·5 [14·5] off-drug and 18·2 [10·6] on-drug). The study was approved by the Grenoble University ethical committee and all patients gave their written, informed consent. The surgical procedure has been described previously. 6 months after surgery, the motor score of the UPDRS improved from 58 (16) to 17 (8) (–71%) in the off-drug condition when stimulation was switched on. This improvement was seen in all the major parkinsonian symptoms. The dyskinesia score (six body parts, each scored 0–4, maximum score 24), assessed during the maximum motor response of a levodopa test with the same dose as preoperatively (early morning +50–100 mg), decreased from 11·4 (6·6) preoperatively to 6·8 (4·3) postoperatively onstimulation. Dyskinesia duration and disability (UPDRS items 32+33), which assess LID during activities of daily living under chronic stimulation, decreased from 4·0 (1·9) to 1·4 (0·9) (–65%). The antiparkinsonian drug dosage calculated as levodopa equivalent decreased from 1560 (930) to 680 (420) mg daily (–56%). With chronic STN stimulation, LID were greatly improved, in a similar percentage as with bilateral globus-pallidusinternus stimulation. With unilateral pallidotomy, contralateral LID are substantially improved although a big reduction of levodopa is not possible. Targeting the STN instead of the globus pallidus internus has the advantage of inducing a more pronounced antiakinetic effect. The decrease in LID induced by STN stimulation can be explained mainly by the decrease in levodopa dosage. This is why the improvement in dyskinesias is more obvious in activities of daily living than during the levodopa test with a dose identical to that given before surgery. Moreover, as highfrequency stimulation is supposed to act through neuroinhibition, the chronic inhibition of STN neurons can change the dyskinesia threshold with time, in the same way as the progressive abatement of hemiballism after a vascular lesion of the STN. Replacing the pulsatile levodopa-induced decrease of STN activity by a chronic stable decrease seems to improve dyskinesias. After 4 years of experience of STN stimulation, this surgical treatment improves LID with time, contrary to our initial fears. As the improvement in all the main parkinsonian motor symptoms is substantial in patients with a good levodopa response, the STN is suggested as the target of choice for the neurosurgical treatment of PD, even in patients with severe LID. However, randomised studies comparing different surgical procedures are required to better understand their respective value.

Visual hallucinations associated with Parkinson disease.

To determine factors that are predictive for the development of hallucinations associated with Parkinson disease (PD). Hallucinations are a common difficulty for patients with established PD, and hallucinations and psychosis may be the most common causes for nursing home placement. The characteristics of the hallucinations associated with PD differ from the hallucinations associated with schizophrenia or cocaine abuse. Multiple factors have been suggested as causal. A total of 214 consecutive patients were interviewed during routine visits to the Parkinson's Disease Clinics in Columbus, Ohio, and Miami, Fla, using a hallucination questionnaire, Folstein Mini-Mental State Examination, and an attempt to correlate age, duration of disease, medication, and psychological or sleep disorders with the hallucinations. Hallucinations were almost exclusively visual and were present in 55 of the 214 patients. Dementia, age, duration of disease, history of depression, or history of sleep disorder were strongly associated with the hallucinations. While reduction in levodopa and anticholinergic medication doses is appropriate in the management of hallucinations, the factors that predispose patients to hallucinations include dementia and advancing age. The phenomena of visual hallucinations associated with PD, while not fully explained, are unique enough to be of interest to all neurologists and neuroscientists.

MK 458, a selective and potent D2 receptor agonist in advanced Parkinson's disease.

MK 458 is a potent and selective D2 receptor agonist. MK 458 consists of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) in a hydroxypropyl-methylcellulose-lactose matrix. MK 458, mean dose 8.1 mg (range 2.5 to 13.5 mg), was administered to 14 patients with advanced Parkinson's disease (PD) who were no longer satisfactorily responding to levodopa. The duration of the study was 4 weeks with a titration to maximum dose in 2 weeks. The addition of MK 458 resulted in a mean reduction in levodopa of 41% (range 0 to 81%). This degree of levodopa reduction was not seen in previous studies with other DA agonists. While the reduction in signs of PD was comparable to those on levodopa, MK 458 did not induce dyskinesias or dystonias. It is postulated that MK 458 may be able to replace levodopa as the primary treatment for PD.

Bromocriptine in the management of end of dose deterioration in Parkinson's disease.

Thirty-three patients with advanced Parkinson's disease complicated by end of dose deterioration were treated with bromocriptine. The drug was slowly increased so that by treatment week 24 the mean daily dose of bromocriptine was 22mg and levodopa had been decreased by an average of 15 percent. The majority of improvement in daily fluctuations and Parkinsonian disability score was documented by 8 weeks, at which time the mean daily bromocriptine dose was only 12mg. End of dose deterioration was reduced in 78 percent of the patients (mean 43% improvement). Total Parkinsonian disability score was decreased by 33 percent. Adverse effects were minimal; the most common was mild transient early treatment nausea which occurred in 15 percent of the patients. The slow introduction of small doses of bromocriptine, combined with minimal levodopa reduction, can give Parkinsonian patients significant improvement in end of dose deterioration.

Bromocriptine in the long-term management of advanced Parkinson's disease.

Thirty-seven patients with advanced Parkinson's disease who initially tolerated, and responded to bromocriptine therapy were followed for 12 to 50 (mean 28) months. Using a method of gradual increase of bromocriptine, with concomitant levodopa reduction, the peak effect of the drug was apparent by three months, at which time the mean daily dose of bromocriptine was 23.9 mg and Sinemet (levodopa + carbidopa) had been reduced by 34 percent. Eight patients had sustained improvement without further drug changes for an average of 29 (range 14-50) months. After periods of improvement varying between 3 and 30 months, 29 patients had a fall-off from peak effect. Peak effect was regained in 21 of these 29 patients for an average of 16 additional months by initially increasing bromocriptine or Sinemet, or by eventually increasing both drugs. The main adverse effect was a confusional state which necessitated late withdrawal of bromocriptine in four patients. The best results were in younger patients with end-of-dose deterioration and levodopa induced dyskinesias. With cautious introduction, and intermittent dosage adjustment, bromocriptine can be of long-term benefit to patients with advance Parkinson's disease. The majority of patients have a gradual late fall-off in effect which can frequently be reversed with dosage adjustment.

Adjuvant treatment of parkinson's disease with dopamine agonists: Open trial with bromocriptine and CU 32-085

Bromocriptine (CB-154) and the 8-alpha-ergoline CU 32-085, two dopamine receptor agonists, were administered at different times to two series of 22 patients with Parkinson's disease, most of whom took levodopa (plus benserazide) at optimum dosage. The addition of bromocriptine (mean daily dose 32 mg; after 6 months 40 mg) led to a 38.5% reduction of levodopa, while CU 32-085 (mean daily dose 15.2 mg; after 6 months 17.5 mg) permitted a 33.7% reduction in levodopa. The mean dose in two patients on CU 32-085 monotherapy was 55 mg/day. A total of 15 patients tolerated adequate doses of bromocriptine (5-75 mg/day, mean duration of treatment 7.5 months) and 15 patients long-term treatment up to 14 months with CU 32-085 (dose range 1-60 mg/day; mean duration 8.8 months). Both groups showed a significant improvement of "total disability score' at 6 months by 56% and 67%, respectively, and after 6 months by 69% and 69.4%, respectively, with a significant decrease of all types of disability. All patients with fluctuations and "on-off' effects rapidly improved on both compounds. Bromocriptine and CU 32-085 were discontinued in seven patients each (32%) because of adverse effect including mental changes (for with bromocriptine, two with CU 32-085), nausea and vomiting (one and two, respectively), hypotension (one each) and increased tremor plus vomiting (one with CU 32-085). Although adverse effects were similar to those observed with levodopa, CU 32-085 in general showed less severe dyskinesia and mental changes but more frequent nausea than bromocriptine and levodopa. While the results of treatment with bromocriptine and CU 32-085 were comparable, the antitremor effect of the latter drug developed more rapidly, even at low dosage. Both compounds were useful in the management of patients with advanced Parkinson's disease, CU 32-085 having a stronger effect on tremor, bradykinesia, fluctuations and "on-off' effects than bromocriptine.

Treatment of Parkinson's disease with dopamine agonists: a review.

Bromocriptine and lergotrile were administered to 81 patients with Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa (secondary levodopa failures). Sixty-six patients were treated with bromocriptine and 53 patients were treated with lergotrile. Both groups had significantly decreased rigidity, tremor, bradykinesia and gait disturbance upon addition of bromocriptine or lergotrile to levodopa. Twenty-five patients improved at least one-stage on bromocriptine, and 21 improved at least one-stage on lergotrile. The mean dose of bromocriptine was 47 mg, and the mean dose of lergotrile was 49 mg, permitting a 10% reduction in levodopa. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). Lergotrile was discontinued in 33 of 53 patients because of adverse effects including hepatotoxicity (11 patients) and mental changes (12 patients). The results of treatment with bromocriptine or lergotrile were comparable, with patients either responding or not. Bromocriptine will shortly be available for use in PD. Lergotrile, because of the hepatotoxicity, will not.

Treatment of Parkinson's Disease With Lergotrile Mesylate

Lergotrile mesylate, an ergot alkaloid derivative and putative dopamine agonist, was effective in the majority of patients with Parkinson's disease who were showing signs of disease progression despite treatment with levodopa combined with a peripheral decarboxylase inhibitor (carbidopa). Among 20 patients completing a six-month trial, there was a significant (P less than .01) reduction in rigidity, tremor, bradykinesia, gait disturbance, and total score when lergotrile was added to levodopa plus carbidopa. Mean daily dose of lergotrile mesylate was 52 mg, and the mean daily dose of levodopa was reduced by 15%. Abnormal involuntary movements were decreased on addition of lergotrile and reduction in levodopa while mental changes and orthostatic hypotension were increased. Elevations in serum transaminase levels were noted in three patients. The ergot alkaloids promise to be an important new class of antiparkinsonian drugs.