Bromocriptine and lisuride in Parkinson's disease.
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Biomedical subjects
Publications and source records attributed to T Caraceni.
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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.
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.
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unmedicated, on chronic treatment with a combination levodopa-benserazide (Madopar) or levodopa-carbidopa (Sinemet) or withdrawn from therapy.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.
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.
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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 endocrinological actions of quipazine, a direct serotonin receptor agonist, were investigated in both normal subjects (NS) and individuals with neurological disorders, i.e., Huntington's disease (HD), myoclonic epilepsy (ME) and cluster headache (CH). In both normal subjects and neurologic patients inconsistent and variable changes in the secretion of anterior pituitary hormones were observed. In fact, oral administration of 50 mg of quipazine elicited a rise in plasma GH in only 9/23 subjects investigated (3 NS, 2 HD, 1 ME, 3 CH), decreased GH in 4 subjects (1 NS, 2 HD, 1 CH) and left unmodified plasma GH in the remaining 10 subjects. Only 7/23 subjects showed a positive PRL response to quipazine (2 NS, 1 HD, 1 ME, 3 CH), in one subject (CH) PRL was inhibited while the drug was ineffective in the remaining 15 subjects. For gonadotropins, 5/21 subjects (2 NS, 1 HD, 2 CH) had a positive LH response and 3/20 subjects (1 NS, 1 ME, 1 CH) had a positive FSH response. In one subject (HD) there was inhibition of baseline LH levels and no effects were present in the remaining individuals. No changes in basal TSH levels were present in the 6 subjects investigated (4 NS, 2 ME). Quipazine was instead competent to increase plasma cortisol levels in 6/8 normal subjects. Pharmacodynamic, mainly gastrointestinal, effects of the drug were present in about 50% of the subjects but were not or only poorly correlated with the endocrine responses. Collectively, based on the neuropharmacologic profile of the drug, and in contrast to many animal data, these findings do not support a major role for the serotoninergic system on basal anterior pituitary hormone secretion in man, possibly with the exception of the ACTH-cortisol secretion.
Ten patients affected by various myoclonic syndromes were tested with drugs acting on cerebral serotonin metabolism and with clonazepam (CZP). After L5HTP or serotonergic drugs administration a clear cut improvement was observed in the 2 patients affected by Ramsay-Hunt syndrome, while the patients with myoclonic epilepsy have shown no effect (3 cases) or negative response (1 case). Methysergide was active only in 1 patient affected by progressive erratic myoclonus who had a striking worsening of clinical picture. The main side effects observed were: gastrointestinal distress (L5HTP--4 patients, fenfluoramine--2, quipazine--1, methysergide--2) and cutaneous rash (quipazine--1 case). These results support the possible implication of the serotonergic system in the pathogenesis of myoclonus other than post-anoxic.
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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.
Electro-oculographic recordings were obtained from 11 patients with Huntington's disease. Significant reduction of saccadic velocity was constantly found. In all the patients vertical saccades were much more impaired than horizontal. When present, vertical saccades showed long latency, low amplitude, low velocity, and disturbances related to blinking. Following movements were jerky, and ability to perform repeated rhythmic movements was impaired. These results are in agreement with previous observations and underline the selective defect of rapid movements as a characteristic feature of Huntington's disease. Further, they suggest a possible correlation between the difficulty in performing repeated ocular movements and the impaired execution of gestural sequences involving a succession of different fundamental movements.
The effect of 3 dopamine (DA) mimetic drugs, i.e. bromocriptine (Bro), apomorphine (Apo) and L-3,4-Dihydroxpenylalanine (L-dopa), was evaluated on plasma growth hormone (GH) levels in 18 patients with Huntington's chorea (HC). 27 Nonobese hospitalized patients were used as controls. Mean baseline GH levels were not altered in patients with HC. Oral administration of Bro (2.5 mg po) or L-dopa (500 mg), or subcutaneous administration of Apo (1.0 mg) resulted in a significantly greater and more prompt (Bro, L-dopa) increase in plasma GH in patients than in controls. These results suggest that presence of an altered dopaminergic regulation of GH secretion in HC.
Eaily performed tests for showing alterations in organization of programmed activities were given to 20 patients with frontal lesions, 23 with retro-rolandic lesions and 17 with Huntington's Chorea. Normal scores were determined in a group of 24 patients without any symptoms of cerebral pathology. The results showed that frontally lesioned patients and those with Huntington's Chorea have similar patterns of disorganization in reproduction of gestures, drawing and rhythmic sound sequences. The data seem to indicate that a major difficulty of these patients lies in faulty "recall" of the original model. Retrorolandic patients do not show this difference in response to the differents tests, but have problems in simultaneous organization of visual and auditory information. These results support the hypothesis of LURIA that the frontal lobes regulate programmed motor activity.
The clinical and neurological features of four siblings (2 male, 2 female) affected by syringomyelia are described. A fifth sister was affected by an acoustic neurinoma. Since neither parent showed signs of syringomyelia, this is considered to be a datum substantiating the dysembryogenetic theory of the syringomyelia syndrome.
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Lumbar cerebrospinal fluid (CSF) choline (CH) levels were measured in patients with Huntington's chorea (n = 14). This group was found not to differ significantly from normal controls (n = 13). The values for lumbar CSF Ch levels in the normal subjects were comparable with previously reported values. Of the choreic patients, seven were put on haloperidol treatment (4--6 mg daily). The CSF choline level remained unchanged with this treatment after 20 days. CSF cholinesterase activity was measured in the control and choreic group. The results were not significantly different.