A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson's disease.

This randomized, double-blind trial was designed to evaluate the efficacy of a transdermal system of piribedil on the motor symptoms of Parkinson's disease during 3 weeks of treatment administered to three different groups: placebo, one piribedil patch (1 PP), and two (2 PP) piribedil patches. Twenty-seven patients with idiopathic Parkinson's disease, treated with L-dopa but not sufficiently controlled, were included in this trial. The test treatment did not demonstrate any clinical efficacy on either the main end point (Unified Parkinson's Disease Rating Scale motor score) or the secondary end points (rigidity, bradykinesia, postural, and resting tremor scores). The main adverse events were nausea (11%), vomiting (7.4%), and malaise (7.4%) mainly observed in the placebo group (four of seven patients). The local acceptability of the transdermal system was good. Plasma piribedil concentrations at the end of treatment were 6.74+/-1.10 and 9.31+/-3.33 ng/mL in the 1 PP and 2 PP groups, respectively. These plasma levels could account for the lack of clinical efficacy, because a previous pharmacokinetics-PD study conducted in parkinsonian patients and treated with the intravenous route demonstrated that the critical limits of activity on tremor were between 10 and 30 ng/mL.

Effects of fenspiride on human bronchial cyclic nucleotide phosphodiesterase isoenzymes: functional and biochemical study.

We have investigated the role of human bronchial cyclic nucleotide phosphodiesterases in the effects of fenspiride, a drug endowed with bronchodilator and anti-inflammatory properties. Functional studies on human isolated bronchi showed that fenspiride (10(-6)-3 x 10(-3) M, 30 min) induced a shift to the left of the concentration-response curves for isoprenaline and sodium nitroprusside with -logEC50 values of 4.1+/-0.1 (n = 7) and 3.5+/-0.2 (n = 8), respectively. Biochemical studies were carried out on three human bronchi in which separation of cyclic nucleotide phosphodiesterase isoenzymes was performed by ion exchange chromatography followed by determination of phosphodiesterase activity with a radioisotopic method. Phosphodiesterase 4 (cyclic AMP-specific) and phosphodiesterase 5 (cyclic GMP-specific) were the major phosphodiesterase isoforms present in the human bronchial tissue. The presence of phosphodiesterase 1 (Ca2+/calmodulin-stimulated), phosphodiesterase 2 (cyclic GMP-stimulated) and, in two cases, phosphodiesterase 3 (cyclic GMP-inhibited) was also identified. Fenspiride inhibited phosphodiesterase 4 and phosphodiesterase 3 activities with -logIC50 values of 4.16+/-0.09 and 3.44+/-0.12, respectively. Phosphodiesterase 5 activity was also inhibited with a -logIC50 value of approximately 3.8. Fenspiride (< or = 10(-3) M) produced less than 25% inhibition of phosphodiesterase 1 and phosphodiesterase 2 activities. In conclusion, fenspiride is an effective inhibitor of both cyclic AMP and cyclic GMP hydrolytic activity in human bronchial tissues and this action may contribute to its airway effects.

Pre- and postjunctional inhibitory effects of fenspiride on guinea-pig bronchi.

Fenspiride is a drug with potential benefits in the treatment of obstructive airways disease. It has antibronchoconstriction and anti-inflammatory properties. The aim of this study was to investigate the effect of this drug on the contractions induced in the guinea-pig isolated main bronchus and perfused lung by electrical field stimulation (EFS) or exogenously added agents. Bronchi were stimulated transmurally in the presence of indomethacin 10(-6) M and propranolol 10(-6) M, and isometric tension was measured. In the perfused lung model calcitonin gene-related peptide (CGRP) release was determined in the perfusate fractions as a measure of neuropeptide production. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to local release of neuropeptides from C-fibre endings. Fenspiride (10(-6) to 10(-4) M) inhibited the nonadrenergic, noncholinergic (NANC) component of the contraction of the guinea-pig isolated main bronchus induced by EFS. Fenspiride significantly affected contractions induced by exogenously added substance P or [Nle10]-NKA(4-10) only at concentrations higher than 10(-3) M. In the guinea-pig perfused lung, fenspiride inhibited low pH- but not capsaicin-evoked release of CGRP. At higher concentrations (10(-4) M to 3x10(-4) M) fenspiride exhibited a significant inhibitory effect both on the cholinergic component of contractile response induced by EFS in the guinea-pig isolated main bronchus and on exogenously added acetylcholine. In conclusion, the result of this study suggests that fenspiride, in moderate concentrations, reduces the release of neuropeptides, including tachykinins, from sensory nerve endings at a prejunctional level. At higher concentrations, postjunctional actions on bronchial smooth muscle are also present.

[Therapeutic benefit of a low dose of indapamide: results of a double-blind against placebo European controlled study]. / Bénéfice thérapeutique d'une faible dose d'indapamide: résultats d'une étude européenne contrôlée en double aveugle contre placebo.

Indapamide is a diuretic prescribed in the treatment of hypertension at the dosage of 2.5 mg per day. In accordance with international recommendations concerning the need to use low doses of antihypertensives, a new lower-dose form of indapamide has been developed to achieve the best safety/efficacy ratio by decreasing the incidence of hypokalemia. A new pharmaceutical sustained-release (SR) form was developed to give a smooth pharmacokinetic profile in comparison with the indapamide instant release (IR) form. The aim of this study was to determine the lowest new dosage of the SR form producing similar hypertensive efficacy as the LR form, and decreasing the percentage of patients with a serum potassium concentration below 3.4 mmol/l. This multicenter study was designed as a single-blind, run-in, placebo period of 1 month, followed by a double-blind, active treatment period of 2 months, using parallel groups: 285 patients with essential uncomplicated mild-to-moderate hypertension (95 mmHg < or = supine diastolic blood pressure (sDBP) < or = 114 mmHg) were included and randomly treated by either IR indapamide (2.5 mg) or SR indapamide (1.5, 2.0, 2.5 mg). After 2 months of active treatment, the one-way analysis of variance on the principal criterion (difference in sDBP between M2 and M0) revealed a significant treatment effect (p = 0.016). The mean drop in sDBP (+/- standard deviation) was 5.8 mmHg (+/- 8.6) after 2 months of placebo; 10.1 mmHg (+/- 7.0) after indapamide IR 2.5 mg; and 11.0 mmHg (+/- 9.4), 8.9 mmHg (+/- 9.4), and 10.5 mmHg (+/- 8.5) after indapamide SR 1.5 mg, 2 mg, and 2.5 mg, respectively. The difference between the placebo and indapamide treatment was significant (p < or = 0.05). No significant difference was detected between the various indapamide treatments, i.e., no difference between the IR and SR formulations, no difference between the various dosages of the SR form, and therefore no dose/effect relationship in the dose interval tested (SR 1.5, 2, and 2.5 mg). The incidence of patients with a serum potassium concentration less than 3.4 mmol/l was lower with indapamide SR 1.5 mg (11%) than with indapamide 2.5 mg, SR 2 mg, and SR 2.5 mg, respectively: 29%, 18% and 14%. These results show the interest of a low dose of indapamide in improving the safety while producing the same antihypertensive efficacy.

Almitrine-raubasine and cognitive impairment in the elderly: results of a 6-month controlled multicenter study.

Two-hundred four patients between 70 and 85 years of age were included in a double-blind randomized controlled multicenter study (almitrine-raubasine/placebo). Inclusion criteria were a complaint of cognitive disorders and an objective cognitive impairment evaluated by Folstein et al. "Mini-Mental State" (MMS) and by Sandoz Clinical Assessment for Geriatrics (SCAG). Patients were treated for 6 months and evaluations were performed at the beginning of the trial (T0), then 3 (T3) and 6 (T6) months later. Evaluations included a visual analogic self-rating scale and the following psychometric tests: Trail Making A (TMA), Shopping List Task, Word Fluency, Crossing Out Letters, Logical Memory, Digit Span, and Visual Retention. Anxiety and Depression Scales were also used to assess the effects of almitrine-raubasine on affective status. Statistical analysis involving the whole sample did not show any significant difference between the almitrine-raubasine and placebo groups concerning changes in assessment criteria from T0 to T6. However, these results may have been due to the wide heterogeneity of baseline performances in psychometric tests. To prevent this possible bias, further statistical analysis was performed for each psychometric test after patients had been divided into three classes according to baseline score levels. Considering scores on TMA and Digit Span for patients with scores in the intermediate class on TMA, almitrine-raubasine induced a significantly higher improvement in performance from T0 to T6 than that induced by placebo. On the other hand, no side effects were noted with almitrine-raubasine when compared with placebo. These data suggest that almitrine-raubasine enhances concentrated attention in patients with mild to moderate impairment of this function.

A review of the EEG effects of the combination of almitrine and raubasine in animals and humans.

During recent years many studies on the electroencephalogram (EEG) changes induced by almitrine-raubasine (Duxil) have been performed in elderly patients and in animals. This article gives an overview of three questions raised by their results. Is there a simple addition of the raubasine and almitrine effects when they are coadministered? Are the EEG effects of this treatment dependent on the patient's disease? To what extent could EEG studies provide some knowledge about the mechanism of action of almitrine-raubasine therapy? In adult (8 months) and aged (22 months) rats the EEG changes induced by the coadministration of almitrine and raubasine were significantly different from the addition of individual almitrine and raubasine EEG effects. In adult rats the coadministration induced slighter EEG changes than those predicted by the addition of almitrine and raubasine effects. In aged rats, the coadministration induced a decrease in delta-theta power not predictable from the effects of almitrine or raubasine. These results could be taken as an indication that some biological targets are common for the two drugs and that the coadministration results in pharmacological effects more complicated than a simple addition of raubasine and almitrine properties. After 3 weeks of treatment in aged healthy subjects, the coadministration induced an increase in the alpha and beta power with a slight decrease of delta and beta-1 powers. In patients with cognitive decline of probable degenerative origin, 3 months of therapy with almitrine-raubasine was mainly associated with a decreased delta and theta power and a slight increase in high frequency components of the alpha band.(ABSTRACT TRUNCATED AT 250 WORDS)

[Duxil and cognitive deficiency in the elderly. Results of a 6-month controlled multicenter study]. / Duxil et déficit cognitif chez les sujets âgés. Résultats d'une étude multicentrique contrôlée d'une durée de 6 mois.

Two hundred and four patients, 70-85 years old, were included in a double-blind (Duxil/placebo), controlled, multicentric study. The inclusion criteria were a subjective complaint of a cognitive deficiency and a cognitive deficit objectively determined using the Folstein mini-mental state test and the Sandoz geriatric clinical evaluation score. The patients, treated for 6 months, were examined at the onset of the study (T0), then 3 (T3) and 6 months (T6) later. The assessment criteria included: a visual self-evaluation test measuring cognitive function and the following psychometric tests: trail making A (TMA), memorization of a shopping list, verbal fluidity, letter identification, repetition of a story, immediate recall of numbers and immediate visual memory. Anxiety and depression evaluations were also used to assess the effects of Duxil on the affective state. Statistical analysis of the observations made on the entire population did not reveal a significant difference between the treated group and the control placebo group, in terms of assessment criteria, between T0 and T6. However, this lack of a difference could be explained, in part, by the very wide variation in the initial psychometric performance scores of the subjects. In an attempt to control this possible bias, another statistical analysis was made for each psychometric test, after the patients had been divided into 3 classes based on their initial performance scores. The results of this second analysis showed that Duxil was able to improve memory performances in TMA and number retention better than the placebo. However, this effect was limited to the group of patients whose initial scores were in the intermediate class for TMA. These findings suggest that Duxil improves the concentrating ability of patients with light to moderate deficits in this function.