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The aim of this trial was to evaluate the effects of the COMT inhibitor entacapone on both the pharmacokinetic profile and clinical efficacy of controlled release levodopa in Parkinson's disease (PD) patients. Twelve PD patients experiencing "end-of-dose" type motor fluctuations were evaluated in this single-blind, randomized cross-over study. A single dose of either entacapone (200 mg) or placebo was co-administered with controlled release levodopa. Blood samples were taken every 30 minutes for 3 hours, and in 6 patients, sampling was continued for a further 3 hours. The clinical response to treatment was evaluated using the Unified Parkinson's Disease Rating Scale motor score. Addition of entacapone to levodopa treatment prolonged the "on" phase of the PD patients by 37% (p<0.05). This increased duration of 'on' time was concomitant with a significant increase in levodopa bioavailability (AUC). These data confirm the ability of entacapone to enhance the clinical efficacy of controlled release levodopa formulations, and provide further evidence that entacapone is of value in extending the benefits of levodopa in PD patients experiencing motor fluctuations.

The purpose of this study was to quantitatively compare the motor response to L-dopa in Parkinson's disease (PD) and striatonigral-type multisystem atrophy (MSA) patients. Ten consecutive MSA patients were compared with nine PD patients selected to have similar overall motor compromise, age, and mental state. The performance of simple repetitive axial movements plus bilateral proximal and distal limb movements; overall motor response assessed by the Unified Parkinson Disease Rating Scale (UPDRS); as well as scores from the UPDRS items evaluating speech/facial expression, postural stability, and posture/gait were assessed 90 min and 12 h (baseline) after L-dopa administration. The total UPDRS score, all subcategory scores, and all body movements improved significantly in the PD group. Proximal and distal limb akinesias and speech/facial expression improved in some MSA patients. Lack of response of axial akinesia to L-dopa in MSA correlates with a presumed greater loss of postsynaptic dopaminergic receptors in the dorsolateral putamen, while improvement in distal and proximal limb muscle akinesias in MSA patients may be related to relative preservation of the ventral putamen.

Oxidative damage by free radicals may contribute to the etiology of Parkinson's disease (PD), and increased oxidative stress in the nigral cells of PD patients may occur following L-dopa treatment, prompting suggestions that L-dopa therapy should be delayed as long as possible. Bilirubin is a potent antioxidant in vitro, even when bound to albumin, suggesting a physiological role as an antioxidant. Calculations indicate that bilirubin can pass the blood-brain barrier in sufficient quantity to exert a significant antioxidant effect in the brain. We have found a highly significant (about 20%) increase in plasma bilirubin in 162 PD patients on chronic L-dopa treatment compared to 93 untreated parkinsonians and 224 non-parkinsonian controls. We propose that L-dopa-induced increase in nigral oxidative stress in PD may be effectively counteracted by increased bilirubin levels. The mechanism by which plasma bilirubin is increased in patients receiving L-dopa is at present unknown.

A poor response to L-DOPA in addition to parkinsonian, cerebellar, and autonomic signs is commonly regarded as indicative of clinical multiple system atrophy (MSA). We compared the motor response to a single oral administration of 250 mg L-DOPA/25 mg carbidopa in eight MSA patients and eight Parkinson's disease (PD) patients with the "on-off" phenomenon, evaluating L-DOPA peripheral pharmacokinetics. Motor response was consistently good in all PD patients, but only four MSA patients had a (moderate) response. Pharmacokinetic parameters did not differ between the groups. The varying extent of putaminal damage could be responsible for the differing motor response to L-DOPA in MSA patients.

The aim of this study is to evaluate what factors influence the risk of occurrence of motor fluctuations in patients with Parkinson's disease (PD) with particular reference to the role of early or delayed introduction of levodopa therapy during the course of the disease. One hundred twenty-five consecutive newly diagnosed patients with PD started levodopa treatment at the time diagnosis and were followed for 2 to 10 years. During follow-up, 60 patients had wearing-off or early morning akinesia. We estimated the cumulative time-dependent risk of motor fluctuation occurrence through a multivariable analysis. The risk was lower for patients with tremor-predominant PD, for those with shorter disease duration prior to levodopa, and for those who were relatively older at levodopa initiation. Our results suggest that, as far as motor fluctuations are concerned, disease prognosis is not influenced by early levodopa treatment. These observation support the introduction of levodopa as soon as there is a subjective need for the patients to maintain their level of social and work performance.

A retrospective study of variations of therapeutic response (dyskinesia and on-off phenomenon) in Parkinson's disease was conducted on 278 patients treated with levodopa for at least 6 months and hospitalized at National Neurological Institute "C. Besta" of Milan between 1974 and 1984. Variations of therapeutic response (TRV) were present in 105 of 278 patients; in this group, age at illness onset was significantly lower, while duration of levodopa treatment and also duration of illness were longer than in the group of patients without TRV. Multiple logistic regression analysis showed that the most important variables were age at illness onset and duration of treatment, but they were only modestly predictive. Other factors connected with progression of disease must also contribute to the TRV.

We evaluated the possible influence of early levodopa treatment on the mortality of Parkinson's disease (PD). One hundred forty-five consecutive parkinsonian patients initiated treatment with levodopa between 1970 and 1983. Ninety-eight of those started levodopa therapy 2 or more years after symptom onset, while 47 received levodopa within the 1st 2 years of the disease. At the end of follow-up, in December 1985, 49 patients had died. Mortality was 2.5 times higher among patients who delayed initiation of levodopa therapy 2 or more years than among those who initiated the therapy earlier. Age and disease severity were the most significant predictors of survival after initiation of levodopa treatment. The risk of death was 10% higher every year of age increase and was 2 and 4 times higher, respectively, for patients at Hoehn and Yahr stages II and III than for patients at Hoehn and Yahr stage I. When we controlled for the effect of age and disease severity on mortality, the cumulative death probability was no longer significantly higher among patients who delayed levodopa treatment than among patients treated within 2 years from disease onset. As far as mortality is concerned, the results show that the time of levodopa treatment initiation during PD has no influence and the drug can be introduced as soon as indicated by the severity of the disease progression.

Madopar, a combination of levodopa with benserazide, induced an inconsistent rise in plasma growth hormone in unmedicated patients with Parkinson's disease and in controls, and a greater growth hormone rise in Parkinsonian subjects on chronic Madopar therapy. In subjects on chronic therapy with levodopa and carbidopa (Sinemet), the growth hormone releasing effect of Madopar was blunted. Madopar increased plasma prolactin (PRL) in controls, unmedicated patients and patients on Madopar therapy while in patients on Sinemet therapy the PRL-releasing effect of Madopar was strikingly reduced. Since these data were interpreted as due to a defective dopamine tone in the hypothalamus of Parkinsonian subjects on Madopar but not Sinemet therapy, a direct dopamine receptor agonist, lisuride was administered. Lisuride, however, elicited a blunted growth hormone response both in patients on Madopar and Sinemet therapy, without revealing a state of supersensitivity of dopamine receptors for growth hormone control in Parkinsonian subjects on Madopar therapy. No difference was present in the PRL-lowering effect of lisuride in the different experimental groups. These findings suggest that: (1) hypothalamic dopamine function is impaired in Parkinsonian subjects on Madopar therapy, preserved in unmedicated patients and enhanced in patients on Sinemet therapy; (2) the endocrine effects observed in Parkinsonian subjects on chronic Madopar therapy may be due to some penetration of benserazide across the blood brain barrier in the region of the hypothalamus; (3) since Madopar and Sinemet are in essence equally effective antiparkinsonian remedies, penetration of benserazide does not occur across the blood brain barrier surrounding the nigrostriatal system.

In this study the author's experience of Parkinson Disease treatment with long-term Bromocriptine (Br) administration, is summarized. Br, which acts directly on dopaminergic receptors, was introduced in combination with L-Dopa and peripheral decarboxylase inhibitors (PDI). The reasons for this association were: 1) the reduced effectiveness of the current treatment (L-Dopa + PDI) 2) onset of AIM (abnormal involuntary movements). 3) patient's desire to try new drugs. Only the patients who had been on the triple association for at least a year, were considered. Therefore of 50 patients originally considered only 19 were included in this study. The addition of Br allowed a reduction of the mean daily dose of L-Dopa(30%) and the therapeutic efficacy of the drug remained unchanged even after more than 4 years treatment. The "on-off" effect and AIM, are reduced by Br especially in the first months of treatment. The triple association is regarded at present as the best treatment for Parkinson disease.

The most important current problem in the treatment of Parkinson disease in the so-called L-dopa long-term-treatment syndrome. We present here the results of our experience with Madopar HBS in the treatment of two groups of patients suffering from L-dopa long-term treatment syndrome. In the first study we replaced the standard Madopar with Madopar HBS. In the second study, after identifying the most disabling "off" periods, we added Madopar HBS to the previous treatment in such a way as to control these "off" phases. Our study suggests that Madopar HBS is useful in reducing typical fluctuation phenomena in the majority of patients.

In eight subjects with Parkinson's disease under an optimal daily dose of L-dopa, acute administration of MIF-I (200 mg i.v.) did not ameliorate either the total disability score or the intellectual test PM 38 when evaluated in comparison with the effect induced by acute administration of a placebo. Also concomitant evaluation of the effect of MIF-I on the secretion of anterior pituitary hormones which are under dopaminergic control i.e., growth hormone and prolactin, did not reveal any potentiation of the L-dopa-induced stimulus.

The latest improvements in Parkinson's disease therapy are reviewed with particular emphasis on the management of long-term treatment syndrome, which has become the chief problem for Parkinson patients since the introduction of levodopa. Current research is directed at overcoming this effect by 1) combining levodopa with new dopamine agonists such as cabergoline or terguride, which have useful pharmacological properties; 2) administering the drugs in different ways to improve their bioavailability (intravenous or subcutaneous infusion); 3) understanding the neurobiological implications of cellular brain grafting; 4) safely transferring the surgical procedure from the experimental to the clinical field.

Twenty-six patients affected by Parkinson's disease were treated with a 2-Br-alpha-ergocriptine (CB 154): 14 cases were given CB 154 alone, and 12 were given CB 154 along with L-dopa plus benserazide (Madopar). Both CB 154 and combined therapy (CB 154+Madopar) induced a significant improvement in total disability score, tremor, rigidity, akinesia, self-sufficiency, and some motor performance tests (dynamic tests). No significant difference was found between results obtained with CB 154 therapy and with Madopar treatment, while the improvement induced by combined therapy (CB 154+Madopar) was significantly higher than that obtained by Madopar alone. The averse reactions caused by CB 154 alone or associated with Madopar are similar to those observed during other dopaminergic treatment. CB 154 alone or combined with Madopar appears to be a useful advance in the management of Parkinson's disease.

One hundred ninety L-dopa-treated parkinsonian patients have been studied according to the age at onset and to age at last examination. The frequency of major mental disturbances was significantly higher in patients older than 60 years, whereas abnormal involuntary movements and on-off phenomenon were more frequent in patients with onset before age 60. The association of normal aging and of Parkinson's disease may be responsible for the prevalence of mental disease in older patients.

The thyrotrophin (TSH) and prolactin (Prl)-releasing effects of TSH-releasing hormone (TRH) were investigated in 20 subjects with Parkinson's disease (PD), unmedicated, on chronic treatment with a combination levodopa-benserazide (Madopar) or levodopa-carbidopa (Sinemet) or withdrawn from therapy. Administration of TRH (200 micrograms iv) induced in unmedicated patients TSH and Prl responses significantly lower than those of sex-and age-matched controls. In patients on Madopar therapy the TSH and Prl responses to TRH were greater than in unmedicated patients and comparable to those of controls, while in patients on Sinemet therapy the pituitary responses were undistinguishable from those of unmedicated subjects. Withdrawal of Madopar therapy resulted in a marked diminution of the TSH response but did not affect the Prl response to TRH. Withdrawal of Sinemet therapy did not alter the TSH and Prl responses to TRH. Concomitant evaluation of growth hormone (GH) levels, in none of the subjects evidenced non-specific changes in plasma GH following TRH. Since TSH and Prl responses to TRH are inhibited by an enhancement of the dopaminergic tone, it would appear that the latter is preserved in the tuberoinfundibular system of unmedicated subjects and subjects on chronic Sinemet therapy, but is defective in subjects on chronic Madopar therapy.

Some aspects of the problems of long-term L-dopa treatment syndrome are reviewed, with special attention to the changes in response to treatment with dopaminergic agents, specifically end-of-dose deterioration, the on-off phenomenon and hyperkinesia. The various hypotheses for interpreting these are presented, with particular stress on changes in the function of DA-ergic receptors. It is concluded that the on-off phenomenon is probably related to changes in plasma L-dopa levels and to decreased stores of intraneural dopamine.