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. Thus, it appears advisable to initiate the dopaminergic treatment in early Parkinson's disease by using a combination of selegiline, levodopa and a dopamine agonist. There are many ways of building up this kind of treatment. Instead of levodopa, it is possible to use initially a dopamine agonist and to add selegiline and levodopa when the therapeutic response becomes insufficient. Another alternative would be to start with selegiline alone, then to add a dopamine agonist and, finally, levodopa when clinically indicated.

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.

Combination of a dopamine agonist, MAO-B inhibitor and levodopa--a new strategy in the treatment of early Parkinson's disease.

During 3 years' treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.

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.

Progression and survival in Parkinson's disease.

Parkinson's disease is a progressive disorder and no permanent cure has ever been documented. The clinical onset, which usually occurs at an age of 55-65 years, is probably preceded by a preclinical period of two or more decades. The progression rate of the disease is extremely variable in different patients; in individual patients on the other hand, the progression of motor symptoms is fairly constant. The tremor-dominant type of the disease usually has a more favourable prognosis than the hypokinetic type. Onset at an older age may be associated with a faster progression rate and the development of cognitive failure. In natural conditions, the average duration of Parkinson's disease is 10 years, although with a considerable range. The disease shortens life expectancy, which can be restored at least partially by treating patients with levodopa and other modern drugs. The highest benefit in increasing life expectancy is obtained when the treatment is initiated at a relatively early stage of the disease.

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.

Epidemiological approaches to the etiology of Parkinson's disease.

In the search for the cause of Parkinson's disease epidemiology serves several purposes. Valuable clues to the etiology may be derived from the epidemiological features of the disease, and the subsequent search for risk factors in analytical studies can be narrowed correspondingly. On the other hand, knowledge of the epidemiology of Parkinson's disease is necessary in creating etiological hypotheses, since only hypotheses consistent with the epidemiological profile deserve careful testing.

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.

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.

Pharmacokinetics and metabolism of selegiline.

Selegiline is readily absorbed from the gastrointestinal tract. It is distributed rapidly into the tissues, including the brain. It is the L-form of selegiline that is an active MAO-B inhibitor, the D-(+)-form being 25 times less active. Selegiline is metabolised into L-(-)-desmethylselegiline (DES), L-(-)-amphetamine (A) and L-(-)-methamphetamine (MA), mainly in the liver. We measured the steady state concentrations of the metabolites in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's or Alzheimer's diseases who were on continuous selegiline therapy. The mean concentrations in serum and CSF were similar, and were not affected by the addition of levodopa. The mean concentrations of patients with Alzheimer's or Parkinson's disease were 6.5 +/- 2.5 ng/ml for A, 14.7 +/- 6.5 ng/ml for MA and 0.9 +/- 0.7 ng/ml for DES. The metabolites of selegiline were excreted in urine, and the recovery as metabolites was 87%. Due to the stereospecificity and the low CSF concentrations of the (-)amphetamine metabolites during the therapy with 10 mg selegiline, these metabolites do not seem to contribute significantly to the clinical efficacy of selegiline.

Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone.

OBJECTIVE: To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone. METHODS: Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. RESULTS: A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. CONCLUSIONS: A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.

Brain dopamine turnover and the relief of parkinsonism.

The relationship between dopamine receptor activation and the relief of parkinsonian clinical features was studied in 40 patients with Parkinson's disease. Treatment with dopamine receptor agonists, piribedil or bromocriptine, decreased significantly both the basal level and probenecid-induced accumulations of homovanillic acid (HVA) in the CSF. But there were no changes in the concentrations of 5-hydroxyindole acetic acid (5-HIAA). Correlation analyses showed that patients who improved with both the dopamine agonists used had significantly lower probenecid response of HVA in the CSF and a less severe disease condition than those without beneficial effect. This relationship between dopamine receptor activation and improvement of parkinsonian disability suggests that the therapeutic efficacy of dopamine receptor agonists depends on the functional capacity of brain dopaminergic mechanisms.

Influenza virus antibodies in Parkinsonism. Comparison of postencephalic and idiopathic Parkinson patients and matched controls.

Hemagglutination inhibiting antibodies to four influenza virus strains: A/Swine/1976/30 (HswN1), A/PR/8/34 (HON1), A/England/1/51 (H1N), and A/Singapore/1/57 (H2N2), were studied in blood serum specimens from 20 patients with postencephalitic and 55 patients with idiopathic Parkinson disease and their age- and sex-matched controls. No significant differences were observed in the distribution or the mean titers of antibodies to any of the four strains tested, when the postencephalitic patients and their controls were compared. The postencephalitic group was also similar to the idiopathic group with regard to the influenza antibodies.

Impairment of semantic knowledge in Parkinson disease.

BACKGROUND: Parkinson disease (PD) is commonly characterized by cognitive deterioration, but it is still unclear whether PD is associated with semantic impairments. OBJECTIVE: To evaluate semantic knowledge of concepts in patients with idiopathic PD, addressing concrete and abstract concepts, conceptual attributes, and conceptual relations. METHODS: Twelve patients with preserved cognitive status, 12 patients with mildly deteriorated cognitive status, and 12 control subjects were studied. The cognitive status of patients and controls was determined using detailed cognitive testing. Patients were participants in a university-based movement disorder program, and their PD diagnoses were clinically confirmed during long-term follow-up. The 2 patient groups were similar in age, level of education, disease duration, and parkinsonian disability. Patients were required to produce verbal descriptions of concrete and abstract concepts, to give ratings of the importance of concept attributes, and to assess and construct conceptual hierarchies. The description tasks included guiding questions, which were used if the spontaneous productions of the patients lacked any essentials expected in the answers. RESULTS: Patients with mild cognitive deterioration performed less well than the other groups in defining concrete and abstract concepts (P<.001 for both). External guidance did not help them markedly improve their performance. They also had difficulties in tasks calling for knowledge of the importance of given attributes to the concepts and in tasks demanding evaluation of hierarchical semantic relations between concepts (P<.001 for both). CONCLUSION: Semantic disruption is implied in idiopathic PD in association with incipient cognitive impairment.

Interaction between dopamine and phospholipids. Studies of the substantia nigra in Parkinson disease patients.

Interaction between dopamine and phospholipids was studied in the substantia nigra of ten patients with Parkinson disease and nine control subjects. There were no differences in the total content of phospholipids. However, in parkinsonian patients without previous levodopa treatment, the amount of sphingomyelin was increased and the amount of phosphatidylethanolamine and phosphatidylcholine decreased. Levodopa treatment corrected these values to the level of controls, whereas the amount of phosphatidylserine was decreased. It is concluded that changes in phospholipids are reflections of the deficiency of dopamine and loss of dopaminergic neurons in the substantia nigra of patients with Parkinson disease.

Herpes simplex virus subunit antibodies in patients with Parkinson's disease.

Serum IgG antibodies against herpes simplex virus (HSV) type 1 capsid, envelope, and excreted antigens in 52 patients with idiopathic Parkinson's disease, and in their age- and sex-matched controls, were assayed with a solid-phase radioimmunoassay. When compared with the controls, patients with Parkinson's disease were found to have a substantially increased antibody response against each of the HSV subunit antigens tested. The increased antibody response in patients with Parkinson's disease was not associated with the occurrence of recurrent HSV infections, since the difference in antibody levels was most evident when comparing patients without recurrent HSV infections with their respective control group. Consequently, the increased HSV antibody response in patient with Parkinson's disease might depend on some antigenic stimulation other than ordinary recurrent HSV infections, or alternatively, on the generally enhanced immunological reaction of the patients against HSV.

Herpesviruses and parkinsonism. Herpes simplex virus types 1 and 2, and cytomegalovirus antibodies in serum and CSF.

Antibodies against herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus (CMV) were assayed with a microindirect hemagglutination (IHA) test in the serum of 67 pairs of patients with Parkinson's disease and controls. Cerebrospinal fluid from 30 pairs was assayed. All patient and control serum was tested with a radioimmunoassay (RIA) for antibodies against HSV type 1 subunit antigens. Serum IHA antibody level against HSV type 1 was increased in patients with Parkinson's disease and RIA antibody levels against the same viral antigen were significantly higher in the patients than controls. Herpes simplex virus type 2 and CMV serum antibodies were equal in the patient and control groups. Most of the CSF samples tested negatively for IHA; small and comparable numbers of the patients and controls had low antibody levels against HSV and CMV antigens.

Early combination of bromocriptine and levodopa in the treatment of Parkinson's disease: a 5-year follow-up.

Compared with levodopa, long-term bromocriptine treatment of parkinsonian patients for 5 years resulted in fewer fluctuations of disability and peak-dose dyskinesias, but also less improvement in parkinsonian disability. Combination of low-dose bromocriptine and levodopa resulted in a therapeutic response equal to that of levodopa alone but with fewer end-of-dose disturbances and peak-dose dyskinesias. I believe that treatment should begin promptly with a low dose of levodopa, combined with a dopamine agonist such as bromocriptine.

Lisuride, a dopamine agonist in the treatment of early Parkinson's disease.

A randomized, prospective trial in 90 de novo parkinsonian patients showed that 4 years' treatment with lisuride resulted in significantly fewer end-of-dose disturbances and peak-dose dyskinesias, but also less improvement in parkinsonian disability, than with levodopa. Early combination of lisuride and a low dose of levodopa, during a 4-year follow-up, resulted in a therapeutic response equal to that achieved with high-dose levodopa alone, but significantly fewer end-of-dose failures and dyskinesias. Thus it seems advisable that treatment should begin in the early phase of the disease with a dopamine agonist such as lisuride combined with a low dose of levodopa.