Practical application of a low-protein diet for Parkinson's disease

Thirty-eight patients with Parkinson's disease were treated with a protein-restricted diet in addition to their usual drug regime. Patients who had failed to obtain a significant response to levodopa previously did not benefit. Sixty percent of those with fluctuations in response to levodopa improved, primarily obtaining an increase in the ratio of "on" to "off" hours. Benefit was always noted within a week of diet initiation. The diet was well tolerated with a low incidence of side effects, which could usually be reversed by a reduction in levodopa dosage. A low-protein diet is a simple adjunct to levodopa therapy that can be readily instituted on an outpatient basis. It may improve even those patients with fluctuations who have failed to obtain optimal benefit from all forms of manipulation of the dosage schedule of levodopa or the addition of newer ancillary medications.     

Protein redistribution diet and antiparkinsonian response to levodopa

Sixteen parkinsonian patients with daily fluctuations in the clinical response to levodopa have been placed on a redistribution protein diet. The diet was virtually protein-free until the evening meal and then unrestricted until bedtime. While on the redistribution protein diet, a group of patients (5 out of 16) had a clear and significant benefit from dietary therapy showing a definite reduction of diurnal motor performance fluctuations. In addition, all patients tended to show an improvement and a more constant response to levodopa treatment. A trial of redistribution protein diet appears a simple, reasonable, worthwhile approach to PD patients who begin to experience oscillating clinical response to levodopa treatment.     

Open study of sustained-release formulation of levodopa and benserazide in parkinsonian patients

The efficacy of a novel oral sustained-release preparation of levodopa/benserazide (Madopar HBS) was compared to that of previous conventional levodopa/benserazide treatment in 15 patients with idiopathic Parkinson's disease and with severe fluctuations in motor response to long-term levodopa therapy. In ten patients who suffered from clear-cut "end-of-dose" deterioration, significant benefit was obtained on HBS form, while 5 patients did not respond well to the new levodopa preparation. Plasma levels of levodopa were more stable with HBS compared to conventional levodopa preparation in our patients, although doses of HBS form required for an optimal response averaged 1.48 times that of previous conventional levodopa.     

The apomorphine test in parkinsonian syndromes.

The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.     

Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy

The objective was to determine the extent to which psychiatric disturbances (especially mood disorders) generally considered poor prognostic factors, are present in patients with striatonigral (SND) type multiple system atrophy (MSA) compared with patients with idiopathic Parkinson's disease (IPD). The Hamilton depression scale (HAM-D), brief psychiatric rating scale (BPRS), and Unified Parkinson's disease rating scale (UPDRS) were administered to clinically probable non-demented patients with SND-type MSA and patients with IPD matched for age and motor disability, at baseline and after receiving levodopa. At baseline total HAM-D score was greater in patients with IPD. Overall, BPRS score did not differ between the two groups; however, patients with IPD scored higher on anxiety items of the BPRS, and patients with MSA had higher scores on the item indicating blunted affect. After levodopa, both groups improved significantly in UPDRS and HAM-D total scores (just significant for patients with MSA). Patients with IPD improved significantly in total BPRS score but patients with MSA did not. At baseline patients with IPD were more depressed and anxious than patients with MSA who, by contrast, showed blunted affect. After levodopa, depression and anxiety of patients with IPD improved significantly whereas the affective detachment of patients with MSA did not change. Major neuronal loss in the caudate and ventral striatum, which are part of the lateral orbitofrontal and limbic circuits, may be responsible for the blunted affect not responsive to levodopa therapy found in patients with MSA.     

Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications. DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient multicenter study. PATIENTS: Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality of life. RESULTS: The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population. CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.     

The long duration response to levodopa in Parkinson's disease

The duration of effect of levodopa has been reported by some authors to be shorter in fluctuating parkinsonian patients with long standing disease than in stable patients. Other authors report no difference in the two groups of patients. We assessed motor fluctuations and response duration in 15 Parkinson's disease patients. Three patterns of response were observed: deterioration within one day on placebo and marked fluctuations on levodopa; deterioration after one day on placebo and moderate fluctuations on levodopa; no deterioration during 3 days of placebo and no fluctuations on levodopa. One patient who did not deteriorate or fluctuate did both when restudied 12 years later. This study confirms that, in addition to the short duration response to a single dose of levodopa, there is a long duration response to levodopa which is lost as the disease progresses. Loss of this long duration response to levodopa may be a key factor in the emergence of fluctuations in Parkinson's disease.     

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.     

A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations

BACKGROUND: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN: A double-blind, randomized, comparative clinical trial. SETTING: Forty-four sites in the United States and Canada. PATIENTS: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE: Change from baseline in total daily TTON as measured using home diaries. RESULTS: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.     

Controlled-release levodopa/carbidopa. I. Sinemet CR3 treatment of response fluctuations in Parkinson's disease

Eight Parkinson patients with response fluctuations completed an open-label trial of a controlled-release carbidopa/levodopa preparation (Sinemet CR3). At the end of 6 weeks, percent "on" time and mean interdose interval increased, the number of daily doses and "off" periods was decreased, and the variability of plasma levodopa levels and disability scores was reduced. However, response fluctuations continued to occur, day-to-day consistency was poor, and the bioavailability of levodopa appeared less than that of standard Sinemet. Overall benefit waned over the next 3 to 6 months. Oral controlled-release carbidopa/levodopa is capable of reducing fluctuations in plasma levodopa levels and clinical performance in Parkinson's disease. The response to this particular controlled-release formulation was suboptimal and unsustained.     

Deprenyl in the management of response fluctuations in patients with Parkinson's disease on levodopa.

Fluctuations in response to levodopa are a common and serious complication of long-term levodopa therapy. It may be possible to prolong the effect of each dose of levodopa by retarding the breakdown of dopamine. The selective monoamine oxidase type B inhibitor deprenyl, which is extensively metabolised to amphetamine and methamphetamine, has this effect as well as possible actions on dopamine release and re-uptake. In a double-blind crossover trial against placebo, deprenyl prolonged the action of levodopa and produced an objective improvement in mobility in five of 10 patients with dose-related response swings, and a subjective improvement in a further four patients. In another group of seven patients with random fluctuations in symptoms, only two noted subjective improvement, and there was an apparent increase in the severity of response swings in five patients. Deprenyl exacerbated dyskinesias, but had no serious side-effects. We conclude that deprenyl is unlikely to benefit patients with random response swings, and may cause deterioration in such cases. However, it may be a useful adjuvant in the management of dose-related response fluctuations in patients already on optional levodopa therapy.     

Nighttime levodopa infusions to treat motor fluctuations in advanced Parkinson's disease: preliminary observations.

We report the clinical response of a parkinsonian patient with severe motor fluctuations who was begun on continuous, nighttime-only levodopa infusions accompanied by oral carbidopa/levodopa use during the day. Sleep disturbances improved immediately. There was a gradual reduction in "off" time and severity of dyskinesias during the waking day. Nighttime-only levodopa infusions have a carryover benefit to the waking hours and may be suitable for long-term therapy to reduce daily motor fluctuations in some patients with Parkinson's disease.     

Diurnal differences in response to oral levodopa.

Diurnal differences in duration and quality of motor response to levodopa are frequently described by patients. The quality and duration of motor responses were objectively assessed to morning and afternoon oral levodopa doses in five patients with Parkinsonian motor fluctuations who complained of diurnal variation in response to their normal levodopa medication. Results suggest that under controlled conditions which eliminated the effects of diet and overlapping levodopa effects the response to levodopa remained unchanged throughout the day, and that the duration of response could be predicted by plasma levodopa levels.     

Levodopa and 3-O-methyldopa plasma levels in parkinsonian patients with stable and fluctuating motor response

Many parkinsonian patients with motor fluctuations in response to levodopa show a good response to initial morning doses but fail to respond in the afternoon and evening. We have studied levodopa and 3-O-methyldopa (3-OM-dopa) plasma profiles in 21 patients with fluctuations and eight patients with stable motor function throughout the day. Levodopa plasma peaks and valleys were similar for both group of patients. No significant difference for levodopa absorption index [defined as levodopa plasma levels after each dose divided by the quantity (mg) of ingested levodopa] was found between the first and the second levodopa-carbidopa dose in either group of patients. Even in patients who failed to improve after the second levodopa-carbidopa tablet (p.o.) on the day of the study, no significant variation in levodopa absorption index was observed. 3-OM-dopa values depended mainly upon levodopa consumption and were not different for patients with fluctuating or stable motor response. These findings provide further evidence of the prime role of central pharmacokinetic and pharmacodynamic factors in the pathogenesis of motor fluctuations in Parkinson's disease.     

Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson''s disease: implications for the pathogenesis of the on-off phenomenon.

OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.     

Response fluctuations in Parkinson's disease

We studied the influence of several factors on the occurrence of response fluctuations in 91 Parkinson's disease patients. These included the age at onset, the presenting symptom, the duration of illness, and the stage of the disease at the time of initiation of levodopa treatment as time-independent covariates, and the mean and last dosage of levodopa as time-dependent covariates. Taken separately, none of the factors was related to the occurrence of response fluctuations. We found no evidence to delay levodopa treatment to a later stage of the disease. In the analysis of the combined influence of the age at onset and the interval before levodopa treatment, we noted a tendency for response fluctuations to occur less frequently in those patients with age at onset of 60 years and over who had started levodopa treatment more than 2 years after the 1st symptom. Our analysis of the combination of time-dependent factors suggests that response fluctuations are a likely event in those patients in whom the course of the disease recently necessitated an increase in the dosage of levodopa.     

Entacapone in the treatment of Parkinson's disease

BACKGROUND: The development of fluctuations in motor response and involuntary movements commonly complicate the treatment of Parkinson's disease (PD). Catechol-O-methyltransferase (COMT) inhibitors delay the breakdown of levodopa, which leads to an increase in levodopa bioavailability and more stable concentrations of plasma levodopa. The addition of a COMT inhibitor therefore combines the rapid onset of levodopa with prolonged efficacy, and theoretically provides a more continuous stimulation of dopamine receptors with reduced risk of motor complications. Randomised, controlled trials have shown that in patients with PD who have motor fluctuations, the addition of the COMT-inhibitor entacapone results in an improvement in motor fluctuations, particularly of the "wearing-off" type, with about 1.0-1.7 h more on-time and less off-time per day, reduced required levodopa dose, modest improvement in motor and disability scores (mean total unified PD rating scale [UPDRS] scores of about 4.5), and in some but not all studies improvement of health-related quality of life [HRQOL] scores. RECENT DEVELOPMENTS: Patients with stable PD, without motor fluctuations, also have improved HRQOL scores on treatment with entacapone in addition to levodopa with a dopa-decarboxylase inhibitor. However, in a recent large multicentre study, UPDRS motor and disability scores were not improved despite significant improvements in HRQOL scores. The disparity between results on clinical rating scales and HRQOL scores suggests that these scales give different and potentially complementary information on health status changes in PD, and that entacapone provides benefit that may not be captured with standard clinical rating scales. Whether entacapone combined with levodopa can delay dyskinesia or motor fluctuations in patients with untreated PD is unknown; however, in animal studies, a decrease in motor complications has been reported in drug-naive animals given frequent doses of levodopa combined with entacapone. WHERE NEXT?: Clinical studies are underway to address the hypothesis that motor complications in PD can be delayed if entacapone is given from the start of treatment. Until the results of these trials are available, entacapone is indicated as a useful adjunct to levodopa in the symptomatic treatment of patients with PD with and without motor fluctuations. In addition, future trials should specifically assess the effect of entacapone on HRQOL in PD.     

Short-term levodopa test assessed by movement time accurately predicts dopaminergic responsiveness in Parkinson's disease

Short-term challenges with dopaminergic agents are used in patients with idiopathic Parkinson's disease (IPD) to predict the therapeutic effect of sustained levodopa treatment, but false-negative results often occur. We prospectively evaluated 74 patients with clinically diagnosed IPD and compared the predictive value of a short-term levodopa test assessed by movement time (MT) with the predictive value obtained by the evaluation with the motor examination part of the Unified Parkinson's Disease Rating Scale (UPDRS-ME). The response to long-term levodopa was accurately predicted in 96% of patients by assessing the response to the short-term test with MT and in 80% of cases with UPDRS-ME. Similar predictive values were obtained by separately analyzing 21 de novo patients. The short-term test also accurately predicted the magnitude of improvement with long-term treatment. We conclude that the predictive value for long-term dopaminergic responsiveness may be further enhanced by evaluating the short-term pharmacologic challenges with MT analysis. This is particularly useful to select de novo patients for drug trials with dopaminergic agents.     

Regional cerebral blood flow in patients with Parkinson''s disease under chronic levodopa therapy: measurements during "on" and "off" response fluctuations.

In ten Parkinsonians who developed dose-related response fluctuations under long-term levodopa therapy, regional cerebral blood flow (rCBF) and plasma levodopa levels were measured simultaneously, once during an "off" phase and again at an "on" stage of clinical benefit induced by a single oral dose of levodopa. Although plasma levodopa increased threefold during the "on" period, rCBF and the degree of its reduction from normal age-matched control values remained unchanged and similar to those in the "off" phase. Study suggests that the rCBF decreases in Parkinson's disease are unaffected by levodopa and are not due to deficient dopaminergic neurotransmission in the brain.     

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

ABSTRACT — 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.