Abstract: BACKGROUND: Sympathetic nervous system hyperactivity promotes vascular disorders by its catabolic effects and by increasing arterial blood pressure. Levodopa-derived dopamine modulates sympathetic overactivity and is known to reduce blood pressure, but its effects on glucose and lipid metabolism have not been studied in large series of patients. METHODS: We retrospectively examined 483 consecutive parkinsonian patients, admitted to a single institute between 1970 and 1987, before statins were available. We compared risk factors for vascular disease in the 305 who were on levodopa with the 178 who had never received the drug. RESULTS: On admission levodopa-treated patients had significantly lower plasma levels of triglycerides, total cholesterol and lipids, and lower frequency of diabetes and hypertension than untreated patients. Mean body mass index, resting blood pressure, fasting plasma glucose, and smoking did not differ between the groups. A year after enrollment 160 patients were re-hospitalized; of these 63 had started levodopa during first hospitalization. In these new levodopa users total cholesterol, triglycerides and lipids had reduced to levels comparable with those of longer-term levodopa users. CONCLUSION: Levodopa use in parkinsonian patients is associated with reduced vascular risk factors. In causal terms this finding might be attributed to the inhibitory action of levodopa-derived dopamine on the sympathetic nervous system.
Abstract: Alterations of the cardiovascular system and of the glucose and lipid metabolism can represent important factors of vascular risk. The autonomic nervous system, through its two efferent branches, the parasympatheticcholinergic and the sympathetic-adrenergic, plays an important role in the control of the cardiovascular activity and of the glucose and lipid metabolism, and its impaired working can interfere with these functions. An increased sympathetic activity and an increased frequency of diabetes, dyslipidemia, hypertension and obesity have been reported in untreated schizophrenic patients, and a further worsening of these vascular risk factors has been signalled as a side effect of treatment with neuroleptic drugs. The opposite is observed in Parkinson's disease, where the reduced autonomic activity induced by the illness is associated with a decreased frequency of vascular risk factors, and their occurrence is further reduced by the treatment with dopaminergic drugs.
Abstract: BACKGROUND AND PURPOSE: Sympathetic hyperactivity is a contributing cause of vascular disorders because it increases blood pressure, blood sugar, and blood lipids. Pervasive compromise of the central and peripheral autonomic nervous systems is common in idiopathic Parkinson disease (IPD) resulting in reduced sympathetic and parasympathetic function. We hypothesized that IPD was associated with reduced prevalence of cardiovascular disease risk factors as a result of reduced sympathetic activity. METHODS: We performed a retrospective case-control study on 178 newly diagnosed consecutive IPD patients, and 533 age- (+/-3 years) and sex-matched controls with other neurological diseases seen over the same period at the same hospital. For each case and control the following were noted on admission: smoking, diabetes, hypertension, body mass index, serum glucose, plasma cholesterol, triglycerides and total lipid levels, and blood pressure. RESULTS: Diabetes, history of smoking, high blood pressure, high blood glucose, high blood cholesterol, and triglycerides were significantly less frequent in IPD than controls. CONCLUSIONS: IDP is a natural model of impaired hypothalamic-pituitary-adrenal axis activity and generalized sympathetic denervation. We interpret the association of untreated IPD with reduced vascular diseases risk factors as attributable to reduced autonomic activity, suggesting that autonomic hyperactivity may be involved in the pathogenesis of vascular disorders.
Abstract: 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.
Abstract: We performed a longitudinal study (mean follow-up 86.7 months) to evaluate motor and mental deterioration in patients with Parkinson's disease. Of the original 91 patients, only 61 could be re-examined 7 years later and 11 of these had become demented (PD-Dems). PD-Dems were older with worse motor and, obviously, cognitive performance than non-demented parkinsonian patients (PDs). A global cognitive decay index (DI) was calculated for each patient. Based on this, non-demented PDs were further split into 38 stable parkinsonian patients (S-PDs) with DI-30% to +30%, and 10 deteriorated but non-demented parkinsonian patients (D-PDs) with a DI worse than -30% (as had PD-Dems). D-PDs were older and had greater motor impairment than S-PDs but did not differ from PD-Dems on these measures. D-PDs and PD-Dems deteriorated especially in attention, visuospatial and executive ability tests. Ageing seems to be the main predictive factor for mental deterioration.
Abstract: 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.
Abstract: The study was conducted on 120 patients (76 men and 44 women) affected by idiopathic Parkinson's disease (IPD) responsive to L-dopa and observed for many years. Sixty had clinical onset between the ages of 20-40, representing 10.2% of our PD population; in the others the symptoms began after the 40th birthday. The two groups were matched for sex and length of illness. In all patients a diagnosis of IPD depended on history and clinical and neuroradiological findings. Clinical, pharmacological, evolutive, and epidemiological data were collected on all patients. Thirty-six patients from each group performed motor dexterity tests (reaction time to expected and unexpected stimuli) and cognitive tests (Wechsler Adult Intelligence Scale. Benton, Short tale, and Zazzo's speed and accuracy test). To assess the prevalence of dementia and the severity of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients. Five percent of early-onset PD patients had a family history of the disorder. Our study showed that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture and deterioration of the therapeutic efficacy of L-dopa, with an earlier appearance of side effects. The results of our neuropsychological investigations suggest that early-onset PD may be a "pure" form of extrapyramidal compromise with exclusively motor manifestations.
Abstract: 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.
Abstract: Terguride, a partial DA-agonist with both dopaminergic and antidopaminergic properties, was tested in 11 PD patients in the "decompensated" phase of the disease, characterized by the presence of dyskinesias and motor fluctuations. Combined treatment of these patients with 1 mg/day of terguride and stabilized doses of levodopa reduced the severity and frequency of dyskinesias and motor fluctuations along with a slight but significant improvement of parkinsonian clinical picture. The "modulatory" effect of terguride on DA receptors, in this experimental conditions, is discussed.
Abstract: 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.
Abstract: Akinesia and mental decline appear to be more appropriate criteria than hyperkinesia for the evaluation of the stage and progression of Huntington's disease (HD). In order to establish the relationship between motor and cognitive impairment in the disease, 20 non-demented HD patients were compared with 44 control subjects with respect to motor and cognitive performance. HD patients were significantly impaired in almost all cognitive functions in comparison with controls. Reaction time (RT) and movement time (MT) were considerably slower in HD patients when compared with controls and with patients with parkinsonism. Hyperkinesias did not correlate with cognitive impairment, but there was a good correlation between RT, MT and cognitive functions. Therefore, it seems that akinesia evaluated by RT and MT is an important sign in HD and proceeds at the same rate as mental decay.
Abstract: Lisuride at a mean daily dose of 3.2 mg was given to 15 untreated idiopathic Parkinson's disease patients. There were 10 dropouts, due mainly to inefficacy in the first months of therapy. The parkinsonian pattern in the patients who remained in the study for the full 4 years showed distinct improvement, which was maintained for less than 2 years. The patients did not develop "on-off" phenomena or abnormal involuntary movements during follow-up.
Abstract: Lisuride at a mean daily dose of 3 mg was given to 48 patients with idiopathic Parkinson's disease. Twenty received lisuride alone (Group A) and 36 received lisuride + L-Dopa + peripheral decarboxylase inhibitors (Group B). Dropouts were due primarily to lack of efficacy in Group A patients and to mental side effects in Group B patients. The patients who remained in the study for the full 4 years showed distinct improvement, which was maintained. Group A patients did not have the on-off phenomenon or abnormal involuntary movements.
Abstract: Neuropsychologic studies on Parkinson's disease have shown an impairment of specific cognitive functions and a greater evidence of dementia. Cognitive alterations are related to the gravity of some peculiar motor symptoms of the disease and show a major role of motor disturbances in intellectual disorders. The concept of bradyphrenia and subcortical dementia still seems to be suitable to define the cognitive disorders of Parkinson's disease.
Abstract: Six patients with different forms of dystonia were treated with gamma-vinyl GABA, a specific enzyme-activated inhibitor of GABA-transaminase, in a double-blind, placebo-controlled crossover study. gamma-Vinyl GABA therapy, 2 g daily for 2 weeks, was compared with placebo by weekly assessments. There were no consistent changes in three evaluation scores. Agents that augment CNS GABA are unlikely to benefit patients with generalized dystonia.
Abstract: The pharmacological approaches to Parkinson's disease in the different phases of evolution (initial or slight, complete and complicated) are discussed. The modality of confronting the therapeutic approach according to the different evolutive phases makes it possible to personalize the therapy, in an attempt to obtain the optimal clinical effect with minimum side effects. Various drugs available and future perspectives are considered.
Abstract: The aim of this study was to evaluate the therapeutic activity of Deprenyl in patients with Parkinson disease already being treated with L-Dopa + PDI. 15 selected patients were allocated to two groups according to clinical features and course of the disease, the first consisting of 9 patients with a mean disease duration of 5 years without any side-effects attributable to L-Dopa and the second of 6 patients with long-term illness (a mean disease duration of 8 years), side-effects and "on-off" phenomenon. All the patients of the first group completed the scheduled 10-week course of Deprenyl treatment obtaining a significant improvement on the baseline WRS scores, in tremor, in rigidity, in motility and a 30.5% reduction in the L-Dopa dose. The patients of the second group showed no significant modification of the symptoms; in 2 cases the treatment was discontinued due to acute delusional-hallucinatory disorders and deterioration of the involuntary movements. A more precise evaluation of Deprenyl activity in the L-Dopa syndrome will depend on further studies.
Abstract: Eighteen patients with Huntington's chorea were examined before and after neuroleptic treatment (haloperidol, pimozide, tiapride) to study the effect of such treatment on hyperkinesia and motor performance. Pimozide and haloperidol improved hyperkinesia; none of the drugs significantly affected motor performance. No correlation was found between the severity of hyperkinesia and motor performance scores, or between hyperkinesia and intelligence score, before and after therapy.
Abstract: In a double-blind, crossover study gamma-vinyl GABA, 2 g/day, and placebo were administered orally for 2 weeks each to six patients with Huntington's disease. Five patients were treated concomitantly with a neuroleptic maintained at constant dose. No consistent beneficial effects on the hyperkinetic movements, abnormal motor function, or ability to carry out normal activities were evident with gamma-vinyl GABA treatment. Treatment was tolerated without clinically significant alterations in the physiologic or biochemical tests used for monitoring. These results suggest that increasing CNS GABAergic function is unlikely to ameliorate Huntington's disease.
Abstract: Huntington's chorea (HC) was studied in 14 untreated patients, in six patients receiving long-term neuroleptic treatment, and in four patients after drug withdrawal. Our results showed that patients with HC may be divided into three groups, otherwise clinically indistinguishable, on the basis of growth hormone responsiveness to dopaminergic stimuli. The existence of subpopulations of patients with HC must be considered in further studies on these subjects.
Abstract: 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.
Abstract: A total of 15 patients affected by idiopathic dystonia (7 with generalized and 8 with focal or segmental dystonia) were subjected to therapy with bromocriptine at low doses, pimozide and trihexyphenidyl. The symptoms were evaluated by giving a progressive score in relation to the intensity of the dystonic symptom to each of the body segments involved by the dystonia. Bromocriptine did not significantly modify the dystonia. Pimozide showed a slight nonsignificant improvement of the dystonic symptoms. Trihexyphenidyl was effective in the generalized dystonias, in agreement with previous reports in the literature. The variation in the pharmacological results could be due to the diversity of the dystonic syndromes, which comprise cases that are different in age at onset, site of dystonic symptoms, and evolution.
Abstract: 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.
