Fluctuations In Disability Research Articles

Trajectories of Late-Life Disability Vary by the Condition Leading to Death.

Previous research suggested that there might be distinct patterns of functional decline in the last years of life depending on the condition leading to death, but the validity of these results and hence the explanatory value of the condition leading to death for late-life disability are uncertain. A total of 636 decedents from a cohort of 754 community-living persons, 70+ years of age (Yale PEP Study) provided 33 700 monthly observations of self-/proxy-reported disability during the last 5 years of life. Nonlinear trajectories and short-term fluctuations of late-life disability by condition leading to death (cancer, organ failure, frailty, severe dementia, sudden death, other) were estimated with flexible mixed spline regression models. Disability trajectories at the end of life varied distinctively by the condition leading to death. Estimated disability trajectories among cancer deaths increased gradually up until about 6 months before death, after which a steep terminal decline set in. Among those with organ failure, frailty, and dementia, in contrast, disability was higher, increased more gradually, and there was no clear-cut terminal phase. Adding the condition leading to death to other known risk factors increased the amount of explained between-person variation in late-life disability from R2 = 0.35 to 0.49. Short-term fluctuations in disability were not specific for decedents with organ failure. The condition leading to death is an important determinant of trajectories of late-life disability. These trajectories follow distinct patterns partially resembling a previously outlined theoretical typology.

Long-term bromocriptine treatment of de novo patients with Parkinson's disease. A seven-year follow-up

Thirty-nine de novo patients with Parkinson's disease were treated with bromocriptine alone and followed on average for 5.9 years. Fifteen of the 39 patients did not complete the first year of observation, 12 of them because of drug intolerance. The symptomatology was tolerated well by other 24 for the first 2 years treatment. During the third year of follow-up levodopa treatment had to be instituted because of loss of response to bromocriptine. The number of fluctuations in disability was smaller in the patients whose symptomatology was controlled by bromocriptine monotherapy than in those requiring levodopa, either alone or combined with bromocriptine.

Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator

Objective To generate evidence on the longer term cost effectiveness of disease modifying treatments in patients with relapsing-remitting multiple sclerosis.Design Prospective cohort study with historical comparator.Setting Specialist multiple sclerosis clinics...

Use of Selegiline as Monotherapy and in Combination with Levodopa in the Management of Parkinson's Disease: Perspectives from the MONOCOMB Study

The MONOCOMB study was a double-blind, randomized, controlled trial initiated to examine the impact of selegiline monotherapy on time to the start of levodopa therapy and, subsequently, to compare the progression of PD in patients treated with individualized levodopa plus selegiline or placebo.Previously untreated patients with idiopathic PD (N = 157) were randomized to receive selegiline 10 mg/day or placebo until levodopa was required; experimental medication was then withdrawn for 8 weeks. Patients were then randomized to levodopa (50 mg/day, titrated in 50 mg/day increments to 150 mg/day) plus either selegiline or placebo. Treatment was continued until patients required additional antiparkinsonian therapy or up to 7 years after initial randomization. The primary efficacy outcome for the monotherapy phase of the study was time to introduction of levodopa. Primary efficacy endpoints for the combined therapy phase were: time to development of fluctuations in disability; and time to the addition of supplementary antiparkinsonian treatment.Selegiline significantly delayed the time when levodopa therapy became necessary during the monotherapy phase, although mean total UPDRS scores at time of initiation of levodopa were similar in both groups. Selegiline was also associated with improvements in PD' symptom status and disability as reflected in a broad range of well-established indices. After the 8 week wash out period the disability of the clinical condition of the patients in the selegiline group was still significantly better in the selegiline group than in the placebo group. During the combination phase of the study, the use of selegiline as an adjunct to levodopa enabled a given degree of therapeutic effect to be achieved with a demonstrably lower total consumption of levodopa. Patients treated with selegiline plus levodopa also exhibited a distinct (p = 0.005) slowing in the anticipated increase in the UPDRS scores over time, as for example in a mean UPDRS total score after 5 years 10 points lower than in patients on levodopa and placebo. The emergence of motor (wearing-off) fluctuations was delayed by selegiline, and the proportion of patients experiencing these events was lower than with placebo (20% versus 34%; p = 0.053). Mild gastrointestinal events were significantly more common with selegiline monotherapy than with placebo (12 versus. 3; p = 0.028). The overall rates of AEs during the combination therapy phase were 69% in the selegiline group and 54% in the placebo group (p = 0.053). Significantly more patients in the selegiline group reported nausea. Of the five deaths that occurred during the combination therapy phase of the study (selegiline N = 4, placebo N = 1) none was expressly attributed to study medication.The results of MONOCOMB, among the largest and longest-duration placebo-controlled studies to report experience with selegiline monotherapy in early-phase PD, confirm that selegiline is effective in retarding the progression of early PD, that it has levodopa-sparing qualities in more advanced disease, and that it is reasonably well-tolerated in long-term use.

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

Selegiline (deprenyl), a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B) is widely used in the treatment of Parkinson's disease. As the first MAO-B inhibitor approved for the treatment of Parkinson's disease, concerns were raised about the safety of the drug based on the adverse effect profiles of older, nonselective MAO inhibitors. Unlike the nonselective MAO inhibitors, selegiline does not significantly potentiate tyramine-induced hypertension (the 'cheese effect') at the dosages (5 to 10 mg daily) used for the treatment of Parkinson's disease. Selegiline has been well tolerated when given alone. The most frequent adverse events seen during monotherapy have been insomnia, nausea, benign cardiac arrhythmias, dizziness and headache. When combined with levodopa, selegiline can potentiate the typical adverse effects of levodopa, if the dose of levodopa is not reduced sufficiently. Thus, the most common adverse effects associated with this combination are nausea, dizziness, fatigue, constipation and insomnia. At the later stages of Parkinson's disease when fluctuations in disability occur, peak dose dyskinesias, psychiatric complications like hallucinations and insomnia, and orthostatic hypotension are further potentiated by selegiline. Mortality was recently reported to be increased when selegiline and levodopa were given together in comparison with treatment with levodopa alone, but a large meta-analysis of 5 long term studies and 4 separate studies did not support this conclusion. Selegiline seems to be generally well tolerated in combination with other drugs. However, when pethidine (meperidine) has been given to patients who are receiving selegiline therapy, severe adverse effects have been reported. Thus, the concomitant use of these drugs is not recommended. A low tyramine diet is recommended if selegiline is used together with nonselective MAO inhibitors or the selective, reversible MAO-A inhibitor, moclobemide. Several adverse effects have been reported when fluoxetine and selegiline have been used together. A recent survey revealed that the incidence of a true serotonin syndrome is, however, very low with this combination. Concomitant use of selegiline and other selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) like citalopram, which have generally less interactions than fluoxetine, seems to be well tolerated. Nevertheless, caution is advised when combining a SSRI or a tricyclic antidepressant and selegiline.

Effect of One Month's Treatment with Peripherally Acting Catechol-O-methyltransferase Inhibitor, Entacapone, on Pharmacokinetics and Motor Response to Levodopa in Advanced Parkinsonian Patients

Twelve parkinsonian patients with levodopa-related end-of-dose fluctuations in disability were studied in an open-label trial to examine the effects of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on pharmacokinetics and metabolism of levodopa and on clinical response to levodopa after a single dose and after 4 weeks' medication with entacapone. The clinical response was assessed with continuous monitoring using the motor part of Unified Parkinson's Disease Rating Scale. Entacapone increased statistically significantly the mean area under the plasma concentration-time curve (AUC) of levodopa by 29% after a single dose and by 21% after 4 weeks' administration, without affecting other pharmacokinetic parameters of levodopa. The AUC of 3-O-methyldopa decreased by 45% and AUC of homovanillic acid by 21% after 4 weeks' dosing with entacapone. The duration of motor response to levodopa increased significantly from 2.3 h to 3.2 h (i.e., by 39%) after a single dose and to 3.4 h (i.e., by 48%) after 4 weeks' medication with entacapone. The magnitude of clinical response remained unchanged, but peak latency of motor response was prolonged after 4 weeks' medication. The duration and magnitude of dyskinesias also increased. Peripheral COMT inhibition with entacapone increased significantly the bioavailability of levodopa and prolonged its antiparkinsonian effect after a single dose and after repeated dosing for 4 weeks. Thus entacapone seems to be a valuable adjuvant to levodopa treatment in parkinsonian patients with end-of-dose failure.

Selegiline ? An overview of its role in the treatment of Parkinson's disease

Selegiline (10 mg per day) selectively inhibits monoamine oxidase type B and thus thwarts the metabolism of dopamine by this enzyme. Selegiline has been used in the therapy of Parkinson's disease since 1986. It enhances the efficacy of levodopa, allows a reduction of the levodopa dose, and improves fluctuations in disability. It also interacts with mechanisms suspected of playing a role in the progression of the disease. Animal studies have shown that selegiline prevents the development of a Parkinson-like syndrome induced by the neurotoxin MPTP. It decreases oxidative stress resulting from the metabolism of dopamine via MAO-B. Clinical studies have shown that selegiline is effective in the therapy of untreated de novo patients: the progression of symptoms demanding the introduction of levodopa into the therapy was delayed, and the risk of needing levodopa treatment within one year was reduced by 57% with selegiline. The mode of action of this drug in the treatment of early Parkinson's disease is still under discussion. There is strong evidence that selegiline may slow the progression of the disease, but a direct symptomatic effect cannot be excluded.

New strategies in the treatment of early Parkinson's disease

Over recent years I have been studying whether dopamine agonist treatment alone, or in early combination with levodopa, might institute a better long-term treatment in Parkinson's disease than levodopa alone. Indeed, early combination of levodopa with bromocriptine, pergolide or lisuride has indicated that this kind of treatment results in better management of Parkinson's disease with fewer fluctuations in disability, especially end-of-dose disturbances and dyskinesias, than treatment with levodopa alone. Furthermore, similar results were obtained by using lisuride in combination with selegiline and levodopa. However, during long-term treatment the changes in parkinsonian disability were equal in all treatment groups with or without selegiline. Thus, the possible efficacy of selegiline in slowing down the progression of Parkinson's disease requires further investigations. As a new treatment strategy it appears advisable to initiate the dopaminergic treatment in early Parkinson's disease by using initially selegiline and a dopamine agonist and by adding levodopa when the therapeutic response is insufficient. Another alternative would be to start with selegiline alone, then add a dopamine agonist and, finally, levodopa.

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.

Selegiline in the treatment of Parkinson's disease

Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B). It also inhibits the reuptake of catecholamines into the presynaptic nerve and enhances the synthesis of dopamine by blocking the presynaptic dopamine autoreceptors. Thanks to these properties it potentiates and prolongs the duration of action of levodopa. Several clinical trials have shown its efficacy as an adjuvant to levodopa therapy. Improvement in parkinsonian disability and reduction of fluctuations in disability can be achieved by adding selegiline to the prevailing levodopa therapy. End-of-dose type fluctuations, in particular, react favourably to selegiline. Side-effects of the therapy can be managed by reducing the dose of levodopa. According to preliminary studies selegiline may also have some benefit as monotherapy in de novo parkinsonian patients. High doses of selegiline have been found to have some antidepressant efficacy, especially in patients with nonendogenous depression. It may also have an effect on bradyphrenia and some symptoms of cognitive dysfunction and dementia. In animal models selegiline has been shown to prevent parkinsonism caused by MPTP and also to increase the life span of rats. Whether selegiline slows down the progression of Parkinson's disease needs further examination.

Madopar HBS in the long-term treatment of parkinsonian patients with fluctuations in disability.

Clinical response to a new galenic formulation of levodopa plus benserazide, Madopar HBS (hydrodynamically balanced system), was studied in 20 parkinsonian patients presenting fluctuations in disability. The follow-up period was 9 months. In patients with end-of-dose type fluctuations in disability, a significantly better control of the fluctuations was obtained with Madopar HBS as compared to standard Madopar treatment. It was possible to reduce the frequency of daily dose intake, but the daily dose needed was higher (40-60%). Especially in severely disabled patients the therapeutic response to the first morning dose of Madopar HBS appeared too slowly, and therefore a combination with standard Madopar was necessary in 4 patients after 1 month treatment and in 14 patients after 9 months treatment. The therapeutic efficacy maintained the whole follow-up period, although there was some decline during the second half of the treatment year. Madopar HBS did not have any effect on randomly occurring fluctuations. Thus, the long-term follow-up results of the present study indicate that Madopar HBS is effective in producing a prolonged and stable clinical response in parkinsonian patients with end-of-dose type fluctuations in disability.

Study on the striatal dopamine availability in Parkinson's disease.

Striatal dopamine availability in connection with the plasma levodopa levels was studied in 12 parkinsonian patients treated with optimal doses of levodopa. Three patients showed the wearing-off phenomenon and the 9 others showed no daily fluctuations in disability. All of the 3 patients with the wearing-off phenomenon showed an up-and-down pattern of dopamine availability index. Out of the 9 patients presenting no fluctuations in disability, 6 showed an ascending pattern of the dopamine availability index and 3 an up-and-down pattern. Of the former 6 patients, 2 received short-term (less than one year) levodopa therapy and the other 4 had the first onset at 42 years or under. In the latter 3 patients, the onset was at over 50 years of age and the duration of levodopa treatment was more than 3 years. In these 3 patients, the mode of action of dopamine in the striatum was considered to be insufficient despite the absence of fluctuations in disability. Thus, the dopamine availability index was considered to be very significant from the viewpoint of prognosis of levodopa therapy.

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.

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.

Deprenyl combined with levodopa and a peripheral decarboxylase inhibitor is of therapeutic value in the treatment of Parkinson's disease. This conclusion is substantiated by the improvement of akinesia, on-off phases, fluctuations of disability and rigidity. Levodopa doses can be reduced. The onset of adverse reactions is later and side-effects are even milder when compared to those with combined levodopa treatment. The most significant effect of deprenyl, however, is its ability to prolong the life expectancy of parkinsonian patients.

SUCCESS AND PROBLEMS OF LONG-TERM LEVODOPA THERAPY IN PARKINSON'S DISEASE

The patient with Parkinson's disease on chronic levodopa therapy, like the diabetic on insulin, is dependent on the drug. Like the diabetic, the patient with Parkinson's disease may run into problems during long-term treatment. Two have emerged as frequent and serious, an insidious and progressive loss of benefit and the appearance of progressively more severe fluctuations in disability. It is concluded that progression of the underlying pathology of the disease is probably responsible. Discovery of the exact causes for loss of benefit may provide a rational basis for new therapy.