Comparative profile of tizanidine in the management of spasticity.

The therapeutic profile of a new antispastic drug cannot be defined solely on the basis of placebo-controlled studies. Its potential advantages must be evaluated in comparison with existing drugs. This review compares the efficacy and tolerability of tizanidine, a newer muscle relaxant, with that of baclofen and diazepam, the most widely used antispastic agents, for a variety of diagnoses and target symptoms associated with spasticity. More than 20 double-blind, comparative studies were conducted between 1977 and 1987. These included a total of 777 patients suffering from spasticity of various causes. The collected clinical data have been integrated into a combined analysis. Tizanidine emerges from this comparison as a valuable drug in the treatment of spasticity related to cerebral and spinal disorders.

A randomized double-blind placebo-controlled study of tropisetron in the treatment of outpatients with generalized anxiety disorder.

The selective 5HT3 antagonist tropisetron was studied in 91 outpatients meeting DSM-III criteria for Generalized Anxiety Disorder. Following a placebo washout period of up to 1 week, one of three active treatments (tropisetron 0.5 mg, 5 mg, or 25 mg daily) or placebo was given for a further 3 weeks. After 7 days treatment termination rates due to inefficacy showed a statistically significant dose-related therapeutic effect of tropisetron. Similar effects were seen on the Hopkins Symptom Check List total score and the Global Impression Scale. The Hamilton Anxiety Scale showed a similar trend which, however, failed to reach statistical significance. At day 21 tropisetron showed significant dose-dependent effects on all anxiety-related outcome measures. The incidence of adverse events was low and the severity generally mild. Most frequent complaints were headache, nausea, constipation and nervousness. Laboratory tests and physical examination performed at baseline and study end showed no significant treatment effects.

Neuroendocrine profile of SDZ HDC-912 and OPC-4392, two new atypical antipsychotic drugs, in schizophrenic patients.

The aim of this study was to evaluate the effect on the activity of the hypothalamic-pituitary dopaminergic system of two new atypical antipsychotic drugs: the ergoline derivative SDZ HDC-912, which is a dopamine (DA) D2 receptor partial agonist; and the quinolinone derivative OPC-4392, which acts as an agonist at presynaptic DA autoreceptors and as an antagonist at post-synaptic D2 receptors. The effects of both compounds were compared to the effects of the benzamide derivative amisulpride. Prolactin (PRL) and growth hormone (GH) levels before and after challenge with apomorphine (Apo), a dopaminergic agonist, were determined after at least 2 weeks washout and again after 1 month of treatment in DSM-III-R schizophrenic inpatients. SDZ HDC-912 significantly decreased Apo-induced PRL inhibition, and tended to decrease PRL secretion and Apo-induced GH stimulation. OPC-4392 induced a significant decrease in baseline PRL and in Apo-induced PRL suppression, and a non-significant decrease in Apo-induced GH stimulation. The neuroendocrine profiles of these two compounds agree with their dopaminergic properties; however, the decrease in PRL basal level differentiates the two drugs from neuroleptic agents.

The blood-brain barrier in hypoxia.

The concept of blood-brain barrier has moved over the past years from a passive and relatively immutable structure to a more dynamic interface between blood and brain tissue. The transport mechanisms regulating this adaptative interface might be considered as the most sensitive elements to change such as hypoxia. Among various carrier mediated transports existing at the blood-brain barrier, glucose transport seems to play a predominant role. In severe hypoxia, progressive changes in glucose transport are occurring. These modifications associated with hypoxia can lead to deleterious events when reaching critical threshold. In addition the appearance of vasogenic edema due to changes in cerebral-blood flow, can possibly be prevented by some pharmacological interaction such as the use of selective brain calcium channel blockers.

Effects of a selective partial D1 agonist, CY 208-243, in de novo patients with Parkinson disease.

A selective dopamine D1-receptor agonist, CY 208-243, was administered to 23 de novo patients who had had Parkinson disease (PD) for less than or equal to 3 months. The drug was first used as monotherapy and then in some patients in combination with a dopamine D2-receptor agonist, bromocriptine. Results showed that CY 208-243 exerted a mild antiparkinsonian action, and tremor was the main symptom that consistently improved. The addition of bromocriptine less than or equal to 15 mg to CY 208-243 did not result in additional improvement, but this might be due to the short duration of treatment and the low doses of bromocriptine. The study was prematurely discontinued for safety reasons. We conclude that D1-receptor stimulation may result in improvement of motor disability in PD.

CQA 206-291 in Parkinson's disease: an acute single escalating dosage study.

CQA 206-291, a new ergot derivative with a "biphasic" dopaminergic profile, was studied in 6 patients with longstanding Parkinson's disease suffering from pronounced fluctuations in hourly mobility. On alternate days, up to seven single doses, escalating from 0.2 to 20 mg, were given as replacement for the usual first morning dose of levodopa. At the most effective dosage, four of the six patients obtained as good a peak response to CQA (8-20 mg) as to L-dopa. Side effects were common and similar to other ergot derivatives, suggesting that the initial weak dopamine antagonist properties of the parent compound, documented in animals, may be of little clinical significance. However, comparative studies will be needed to confirm this suspicion. The addition of domperidone successfully reduced the incidence and severity of side effects. CQA 206-291 has potent anti-parkinsonian properties; further longer-term treatment trials are indicated.

CQA 206-291: a novel dopamine agonist in the treatment of Parkinson's disease.

The antiparkinsonian efficacy and tolerability of CQA 206-291, a novel ergoline derivative with potent dopamine agonist properties, were studied during 2 months of treatment in 72 parkinsonian patients. In 36 de novo patients (patients who have not previously been treated with levodopa or dopamine agonists), CQA 206-291 was studied in an open design, while in 36 levodopa-treated patients, CQA 206-291 was studied in a randomized, double-blind, parallel-group, placebo-controlled design. CQA 206-291 induced in both groups a significant antiparkinsonian effect with an effective dose range of 5-30 mg/day. The spectrum of adverse events was similar to what is commonly observed with dopamine agonists. Further studies are required to assess the putative therapeutic advantages of CQA 206-291 when compared to other antiparkinsonian drugs.

Blood pressure and plasma catecholamines in never-treated parkinsonian patients: effect of a selective D1 agonist (CY 208-243).

We found blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), and epinephrine (E) levels in the lying and the standing positions to be similar in never-treated parkinsonian patients (stages 1 and 2) and age-matched controls. CY 208-243, a new centrally active D1 agonist, significantly decreased BP, HR, and NE (but not E) values in the lying position; it elicited orthostatic hypotension and blunted the rise in NE elicited by standing up. These results indicate that the early stages of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and suggest the involvement of central D1-receptors in the control of sympathetic tone.

Isradipine in patients with acute ischaemic cerebral infarction. An overview of the ASCLEPIOS Programme.

Calcium-related mechanisms are an integral part of metabolic reactions during acute cerebral infarction. In an animal model of stroke, the calcium antagonist isradipine was shown to protect neurons against ischaemia. In order to improve the neurological and functional outcome of human stroke patients, a randomised, double-blind, placebo-controlled multicentre study was started in up to 600 patients with acute ischaemic brain infarction. Since early treatment is considered to be of great importance, patients must be recruited no more than 12 hours after stroke onset. Medical, ECG, laboratory, neurological and functional evaluations are conducted for up to 90 days after stroke.

The antiparkinsonian activity of CQA 206-291, a new D2 dopamine receptor agonist.

CQA 206-291, a new D2 dopamine receptor agonist with a biphasic dopaminergic profile, was given to six patients with idiopathic Parkinson's disease after overnight drug withdrawal. With incremental single oral doses of CQA, a dose-related, clinically significant, and prolonged antiparkinsonian effect was observed. Most subjects experienced drowsiness after the drug while a minority of subjects experienced nausea and/or vomiting or postural hypotension. Further study of this drug in humans is indicated.

Antiparkinsonian activity of CY 208-243, a partial D-1 dopamine receptor agonist, in MPTP-treated marmosets and patients with Parkinson's disease.

The effect of stimulation of cerebral dopamine D-1 receptors by CY 208-243 on motor disability was tested in MPTP-treated parkinsonian marmosets and patients with Parkinson's disease. CY 208-243 (0.5-1.25 mg/kg s.c.) produced a dose-related reversal of akinesia and rigidity in the marmosets, lasting some 2 h. Single morning doses of CY 208-243 (5-40 mg) were compared with the usual morning dose of levodopa in eight patients with Parkinson's disease on long-term levodopa therapy who had developed motor fluctuations from immobility with akinesia and rigidity (off) to mobility often with dyskinesias (on). CY 208-243 alone was capable of switching such patients from off to on; five of the eight patients responded to the highest dose (40 mg), sometimes with dyskinesias. The response to CY 208-243 was comparable to that produced by levodopa in these cases. Drugs designed to stimulate both dopamine D1 and D2 receptors in the brain may improve the therapy of Parkinson's disease.

Tizanidine in the management of trigeminal neuralgia.

In a double-blind study the efficacy and tolerability of tizanidine was compared with those of carbamazepine in the management of trigeminal neuralgia. Six patients were allocated to treatment with tizanidine and six to carbamazepine. After individual titration the maximum daily doses were 18 mg and 900 mg, respectively. Among the efficacy factors used, the visual analog scale (VAS) and the overall efficacy as assessed by patients and investigator turned out to be the most appropriate. The results indicate that tizanidine was well tolerated, but the effects, if any, were inferior to those of carbamazepine.

The history and pharmacology of dopamine agonists.

The recognition of the dopaminergic properties of some ergot derivatives has initiated new therapeutical approaches in endocrinology as well as in neurology. The pharmacological characterization of the different ergot derivatives during the last decade has largely improved our understanding of central dopaminergic systems. Their development has yielded valuable information on the pharmacology of dopamine receptors involved in the regulatory mechanisms of prolactin secretion and in striatal functions. The clinical application of such new neurobiological concepts has underlined the therapeutical interest of such compounds either in the control of prolactin-dependent endocrine disorders or in the treatment of parkinsonism. Owing to their pharmacological profiles, dopaminergic agonists represent a valuable clinical option especially in the management of Parkinson's disease in view of the problems arising from chronic L-Dopa treatment.

Clinical evaluation of fluproquazone in post-operative pain. A report of double-blind comparative trials in patients after surgical interventions.

A collaborative double-blind randomized trial was carried out involving 123 hospitalized patients with moderate or severe pain following surgical interventions such as episiotomy, vaginal uterus extirpation or meniscectomy. The analgesic effect of multiple oral doses of 4-(p-fluorophenyl)-1-isopropyl-7-2(1H)-quinazolinone (fluproquazone) (100 mg) was compared with that of paracetamol (500 mg). Self-assessments were made of pain relief by the patients over a 3-day period. The results showed that fluproquazone produced at least comparable relief to paracetamol after the first dose and at the end of the overall treatment period. Furthermore, the analgesic effect of fluproquazone was significantly superior to paracetamol after a 6-h period. Over-all tolerance to multiple doses was assessed as excellent or good by all the patients receiving fluproquazone. The commonest side-effects in both treatment groups were gastrointestinal symptoms. However, the overall incidence of side-effects was lower in the fluproquazone group and those that were reported were mostly mild as compared with the paracetamol group.

Comparative study of fluproquazone in the management of post-operative pain.

41 patients suffering from moderate to severe pain were included in a multicentric double-blind study comparing 100 mg 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) to 250 mg mefenamic acid during a three-day period. Both medications produced a clinically highly relevant analgesic effect in the patient population considered. Fluproquazone appears to be significantly more effective than mefenamic acid after the first dose as well as after 6-h period. Fluproquazone was better tolerated than mefenamic acid: one and four patients, respectively, experienced side-effects in the two treatment groups. These results indicate a significantly better therapeutic profile for fluproquazone as compared to mefenamic acid in the management of post-operative pain.

Fluproquazone in the management of strains and sprains.

A double-blind randomized trial was carried out in 59 patient suffering from moderately severe to severe strains and sprains to compare the efficacy of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) in the relief of pain. Patients received either 50 mg or 100 mg fluproquazone up to 6 times daily for 3 days. The results of subjective assessments showed that after 2 days pain had either completely resolved or markedly improved in all patients. Both treatments were equally effective in relieving both spontaneous pain and pain on movement after 1 and 2 days. No differences were found between the two groups in the patients' overall evaluation of treatment or physicians' assessment of therapeutic response. Both dosage were well tolerated during the short-term trial.

[Study on a mock cerebro-spinal fluid (author's transl)]. / Etude d'un liquide céphalo-rachidien artificiel.

The work presented was initiated in order to evaluate the biological and clinical tolerance of the isotonic saline solution (9 p. mille) usually used in neuro-surgery directly in contact with the nervous tissue in comparison with a new solution proposed as a a mock cerebrospinal fluid. Clinically, two patient' populations including 75 patients each, were compared during dynamic investigation of intracranial pressure with intra-ventricular injections of different solutions. The effects of prolonged intra-ventricular perfusion with each solution were studied in animal models by: --electrophysiological analysis of EEG activity during perfusion --morphological observation: electronic microscopy of different cerebral structures after the perfusion. The biological tolerance was analyzed by the use of routine tissue culture of CNS tissue exposed to the two solutions. The results obtained show the toxicity of isotonic saline solution (9 p. mille) and the perfect tolerance of S.21.001 solution as a mock cerebro-spinal fluid.