Amisulpride versus amineptine and placebo for the treatment of dysthymia.

Amisulpride, a selective antagonist for D2 and D3 dopamine receptors, acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses. In a multicentre, 3-month, placebo-controlled study, amisulpride (50 mg/day) was compared to amineptine (200 mg/day) in the treatment of primary dysthymia. A total of 323 patients were enrolled. Amisulpride and amineptine were found to be statistically superior to placebo (p < 0.0001) on the Clinical Global Impression (item 2): 63, 64 and 33% responders, respectively; improvement of Montgomery-Asberg Depression Rating Scale and Scale for the Assessment of Negative Symptoms scores following amisulpride or amineptine treatment was twice as high as with placebo (p < 0.0001). The adverse event profile of amisulpride was similar to that of placebo except for endocrine symptoms in female patients; amineptine showed mainly events linked to psychic activation (insomnia, nervousness). Results show that amisulpride can improve symptoms of chronic depression in dysthymia.

Mizolastine therapy also has an effect on nasal blockade in perennial allergic rhinoconjunctivitis. RIPERAN Study Group.

BACKGROUND: Mizolastine is a new, nonsedating antihistamine with additional anti-inflammatory properties, providing relief in allergic rhinitis and urticaria. The aim of this study was to determine the efficacy and safety of 10 mg o.d. mizolastine given to patients with perennial allergic rhinoconjunctivitis. METHODS: This double-blind, placebo-controlled study involved 257 patients suffering from the disease for more than 10 years. They were allocated, after a 1-week placebo run-in, to receive mizolastine (n = 133) or placebo (n = 124) for 4 weeks. RESULTS: Mizolastine-treated patients showed significantly greater alleviation of nasal symptoms, with a mean decrease of 36% compared with pretreatment score, compared to a mean decrease of 10% in placebo patients (P < 0.001). Nasal blockade responded favorably to mizolastine compared to placebo and was associated with a significant reduction in rhinoscopy findings (P = 0.030). Likewise, the mean ocular symptom score decreased 40% in mizolastine-treated patients compared to 7% in the placebo group (P < 0.003). The safety profile of mizolastine was satisfactory and similar to that of placebo. CONCLUSIONS: In patients suffering from perennial allergic rhinoconjunctivitis, mizolastine is a safe and potent treatment. Mizolastine's pronounced effect on nasal blockade could possibly be linked to its anti-inflammatory properties.

Lack of subsensitivity to mizolastine over 8-week treatment.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptom relief in allergic rhinitis and urticaria. The purpose of this study was to use the wheal and flare skin reactions model to assess the maintenance of the pharmacodynamic effect of mizolastine, administered for 2 months. This double-blind, parallel-group study involved 60 atopic patients randomly allocated, after a 1-week placebo run-in, to once-daily 10 mg mizolastine (n = 29) or placebo (n = 31) groups. Treatment continued for 8 weeks. Prick tests were performed in duplicate with histamine chlorhydrate (10 mg/ml), codeine phosphate (9%), and five increasing concentrations (1-500 reactivity index/ml) of standardized allergen extracts (grass pollen or mites) at days 0, 7, 28, 42, and 56. After 7 days of treatment, inhibition of histamine-induced wheal was -76% and +20%, respectively, with mizolastine and placebo (P = 0.0001), in comparison with baseline; inhibition of flare was -86% and +5%, respectively, with mizolastine and placebo (P = 0.0001). Suppression was maintained to a similar extent throughout the study. Results were consistent between histamine-, codeine-, and allergen-induced tests. Safety was satisfactory in both groups. The study confirms mizolastine as a potent antihistamine which does not induce subsensitivity when taken for 8 weeks, and which can be safely recommended in allergic conditions.

Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptomatic relief in allergic rhinitis and urticaria. The purpose of this study was to use inhibition of wheal and flare formation after 2-mu g intradermal histamine injections as a measure of the antihistamine effect of repeated doses of mizolastine. Eight volunteers were enrolled in this four-arm, double-blind, cross-over, randomized study. Three dose levels of once-daily mizolastine (5 mg, 10 mg, and 15 mg) were compared with placebo during 5-day dose periods. Histamine tests were performed before drug intake on days 1 and 5, and then 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after drug intake on day 5. All 3 doses of mizolastine were more effective than placebo in suppressing wheal and flare reactions, and the antihistamine activity was highest at both the 10- and 15-mg dose levels. The effect on the flare reaction appeared within 1 hour, reached a maximum effect 4 hours after administration, and persisted for as long as 24 hours. The relative changes in wheal and flare areas were correlated with mizolastine trough plasma levels on day 5. Safety was satisfactory in all groups. This study confirms that mizolastine is a rapid and potent antihistamine; and its long-lasting effectiveness indicates that a once-daily regimen is acceptable for clinical use.

Effect of intravenous alfuzosin on urethral pressure in patients with neurogenic bladder dysfunction. DORALI Study Group.

In order to assess the ability of a single intravenous (i.v.) injection of alfuzosin, a selective alpha-1 blocker, in reducing high urethral tone in patients with symptomatic neurogenic bladder dysfunction (NBD), 163 patients (mean maximal urethral pressure [MUP] 108 +/- 46 cm H2O) were enrolled in a double-blind, placebo-controlled, parallel-group trial and were randomly allocated to receive 0.5 mg (n = 45), 1 mg (n = 41), 2 mg (n = 39) alfuzosin or placebo (n = 38). The decrease in MUP was dose-dependent and statistically significant (P < or = 0.05) for 1 and 2 mg alfuzosin (respectively, 43 +/- 28 cm H2O and 46 +/- 27 cm H2O decreases vs. baseline) in comparison with placebo (23 +/- 30 cm H2O). The 2 mg dose level was the most effective leading to a > or = 30 or 50% decrease in MUP in, respectively, 69 and 44% of patients. The safety of all three alfuzosin dose levels was satisfactory and comparable to placebo. I.v. alfuzosin induces, in a dose-related manner, a clinically significant decrease in urethral pressure in patients with NBD and high urethral tone, and may be safely used as a pharmacological test as part of an urodynamic investigation.

Twenty-four hour efficacy of two dose levels of a once daily sustained-release diltiazem formulation in stable angina: a placebo-controlled trial. The Dildurang Study Group.

1. This placebo-controlled study assessed once daily sustained-release (SR) diltiazem, 200 and 300 mg, in 182 stable angina patients with positive exercise test. 2. Exercise testing was performed at baseline after a 7 day placebo run-in period, and repeated after 7 days of treatment, 25.0 +/- 0.1 h postdose. 3. Diltiazem (200 and 300 mg) produced respectively a 68% and a 64% decrease in weekly angina episodes, and placebo a 15% decrease (P < 0.05). Similarly, both dose levels produced a 70% decrease in nitroglycerin consumption, whereas no difference was obtained with placebo (P < 0.01). The increase in time to ischaemic threshold was significantly superior for 200 mg and 300 mg diltiazem when compared with placebo (75.2 and 91.5 s respectively vs 47.0 s) (P < 0.05); increase in time to anginal threshold was also significantly greater for diltiazem when compared with placebo (84.6 and 85.9 s respectively vs 43.9 s) (P < 0.05). 4. Only one patient experienced worsening of angina and had to be withdrawn from the study. 5. This study demonstrates 200 and 300 mg SR diltiazem is effective when given once-a-day in the prophylaxis of stable exertional angina. This once daily formulation should improve patients' compliance and comfort.

Antihypertensive efficacy of optimally titrated doses of once-daily sustained-release diltiazem: a placebo-controlled trial. DILPLACOMP Study Group.

This study assessed once-daily sustained-release (o.d. SR) diltiazem in essential hypertension; 158 patients with supine diastolic blood pressures (BP) of 95-115 mm Hg were randomized to 200 mg diltiazem or placebo, then optimally titrated, at 2-week intervals, to 200, 300 or 400 mg to achieve supine diastolic BP < 90 mm Hg or a > or = 10 mm Hg fall from baseline. BP was measured at trough level, 24 h after dosing. After 2 weeks at the dose of 200 mg, supine diastolic BP was significantly reduced (from 101 to 92 mm Hg) compared with placebo (from 101 to 98 mm Hg; p < 0.001), and yielded 57% of responders with diltiazem against 22% with placebo (p < 0.001). Titration allowed supine diastolic BP normalization with diltiazem (88 mm Hg) compared with placebo (93 mm Hg; p < 0.001) and yielded 78% of responders with diltiazem against 37% with placebo (p < 0.01). The safety profile was similar to placebo. 200 and 300 mg o.d. SR diltiazem formulations enable safe and close regimen adjustments in mild-to-moderate essential hypertension.

Long-term treatment of benign prostatic hyperplasia with alfuzosin: a 24-30 month survey. BPHALF Group.

OBJECTIVE: To address the long-term results of alfuzosin, an alpha 1-antagonist, in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: A 6-month, placebo-controlled study involving 518 patients was followed by two successive one-year, open extensions. Only centres who wished to continue the trial participated in the extensions; 131 patients entered the first extension, with 50 continuing into the second year extension. The results of the second year follow-up are presented here. RESULTS: Depending on their initial randomization to either the placebo or alfuzosin arm, patients were treated with alfuzosin for 24 (n = 50) or 30 months (n = 22). The data collected on those 50 patients in comparison to baseline confirmed that the clinical efficacy observed in short/medium-term studies was maintained. A clinically significant improvement in urinary symptoms was observed; the Boyarsky score decreased from 8.7 (+/- 0.3) at baseline to 5.2 (+/- 0.3) at 24 months, with no deterioration in the objective parameters. In patients treated for 30 months (n = 22), symptomatic assessment and urodynamic parameters remained stable, indicating the sustained effectiveness of therapy. No serious or unexpected side-effect related to long-term exposure to alfuzosin was observed. No complications associated with BPH occurred. Two patients (4%) reported dizziness, neither of whom withdrew from the study. In this population, where 40% of patients were receiving concomitant cardiovascular therapy, no clinically significant change in standing systolic blood pressure, diastolic blood pressure or heart rate was apparent between baseline data and those at 24 months. CONCLUSION: These data demonstrate the usefulness of long-term treatment with alfuzosin in patients with uncomplicated, moderate BPH.

[Translation and application of the Simpson and Angus Scale of Extrapyramidal Symptoms]. / Traduction et utilisation de l'échelle de Simpson et Angus de symptômes extra-pyramidaux.

Extrapyramidal side effects of neuroleptics are important in clinical practice. Study of extra-pyramidal side effects is also of importance for researchers who test new antipsychotic agents or study tardive dyskinesia. A french translation of the Simpson-Angus Rating Scale of extra-pyramidal side effects thus appeared useful. This scale contains 10 items: Gait, Arm dropping, Shoulder shaking. Elbow rigidity, Wrist rigidity, Leg pendulousness, Head dropping, Glabella Tap, Tremor, Salivation. Each item is rated between 0 and 4. A total score is obtained by adding the items and dividing by 10. Scores of up to 0.3 are considered within the normal range. The scale original has been validated in a population of fourteen psychotic inpatients taking, in a double-blind procedure, placebo, haloperidol 6 mg/day or haloperidol 30 mg/day. Patients receiving haloperidol 30 mg/day presented more extrapyramidal symptoms than patients under placebo. The Simpson Angus rating scale has also been shown to have clinical validity and high inter-rater reliability. It can be routinely used in clinical drug evaluation. The french version was used in a population of 30 psychotic inpatients fulfilling the DSM III-R criteria of schizophrenic disorder. Patients were treated for at least two weeks, orally, either with a phenothiazine (chlorpromazine 350 mg) or a butyrophenone (haloperidol 15 mg). 10 of the 30 patients received, in addition, anticholinergic agents (trihexiphenidyl, 5 mg). The french version of The Simpson Angus Rating Scale appeared to be easy to use and not time-consuming. Interraters correlation was high. Patients receiving butyrophenones or phenothiazines had no significantly different ages and sociodemographic characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

European reference method for the in vivo determination of metabolisable energy with adult cockerels: reproducibility, effect of food intake and comparison with individual laboratory methods.

1. A common reference procedure adopted by several European laboratories to determine apparent metabolisable energy corrected to zero-nitrogen balance (AMEn) is described. 2. Reproducibility has been estimated by comparing results from 4 diets measured in 7 laboratories. The standard deviations between laboratories of dry matter, gross energy, Kjeldahl nitrogen and AMEn were respectively, on average, 11.29 g/kg, 0.242 MJ/kg, 1.56 g/kg and 0.380 MJ/kg dry matter; the corresponding coefficients of variation between laboratories were 1.27, 1.29, 4.39 and 2.92%. 3. Effect of food intake was tested by comparing AMEn from birds fed either 0.90 or 0.45 of ad libitum: the amount of food intake had a negligible effect on AMEn values. Endogenous energy losses corrected (EELn) or not (EEL) to zero nitrogen balance were estimated either by regression between excreted energy and ingested energy or in fasted and glucose-fed cockerels. EELn estimated by regression was, on average, 8.7 kJ/bird/d.; it was independent of diet composition. EEL and EELn determined in fasted or glucose-fed birds were higher than those determined by regression. 4. AMEn values measured by individual laboratory procedures were very close to those obtained by the reference method, except from laboratories using a tube feeding procedure, where deviations were probably a consequence of overestimated EEL.

European reference method of in vivo determination of metabolisable energy in poultry: reproducibility, effect of age, comparison with predicted values.

1. Apparent metabolisable energy corrected to zero-nitrogen retention (AMEn) was measured using the European reference procedure in 9 European laboratories. Seven pelleted diets were evaluated. AMEn was measured with adult cockerels and young birds. 2. Between-laboratory standard deviations were for dry matter (DM) 12.5 g/kg, gross energy 0.085 MJ/kg DM, Kjeldahl nitrogen 0.768 g/kg DM, AMEn (adults) 0.256 MJ/kg DM, and AMEn (young) 0.337 MJ/kg DM. Corresponding coefficients of variation between laboratories were 1.42, 0.45, 2.15, 1.88 and 2.60% respectively. 3. AMEn values of experimental diets were always significantly lower when measured with young birds. This effect was more pronounced when diets contained added fat. 4. Tallow or soyabean oil were incorporated into two basal diets at 40 g/kg inclusion rate. No significant differences were observed between AMEn values of either diet with adults or young birds, suggesting that AMEn energy values of these fats are indistinguishable at this inclusion rate. 5. Similar AMEn values were obtained in young birds by estimating nitrogen accretion, either by the difference between intake and excreta nitrogen or by measuring body weight gain. Determined AMEn values were very similar to those predicted using three different regression equations.

An improved use of buserelin in ovarian stimulation for in-vitro fertilization.

In earlier IVF programmes, subcutaneous buserelin (Suprefact, Hoechst) was initially administered three times per day (200 micrograms x 3); then twice daily (300 micrograms x 2). We now suggest that a single administration of 600 micrograms daily may be equally effective. In a preliminary study, 20 patients were selected on the basis of tubal or idiopathic infertility and received 0.6 ml buserelin subcutaneously once a day, beginning on day 1 or 2 of the cycle. A sufficient pituitary desensitization was obtained on day 10 in 75% of patients and on day 16 for 100% and the ongoing pregnancy rate was 35% per treatment cycle. A randomized study comparing the effect of 600 micrograms of buserelin administered in one (n = 50) or two injections (n = 46), has been carried out and indicates that the results in terms of the ovarian suppression and pregnancy rates, were similar. Therefore, this protocol represents a simplification of the treatment with buserelin.

[Lack of efficacy of yohimbine in the treatment of obesity]. / Absence d'efficacité de la yohimbine dans le traitement de l'obésité.

There is some evidence that blockade of alpha 2-adrenoceptors on adipocytes may lead to an increase in lipolysis, We have therefore carried out a double blind comparative study of the effects of the selective alpha 2-antagonist yohimbine in human obesity. Nineteen obese volunteers participated in the study. Subjects were randomly allocated to the yohimbine group (n = 10, 18 mg yohimbine/day), or to the placebo group (n = 9). All subject were maintained on a hypocaloric diet (1000 kcal/day) during the 8 weeks of the study. There was no difference between the two groups with respect to either body weight, blood pressure supine and erect or heart rate during the different phases of the study. We found no difference in the lipid parameters (triglycerides, cholesterol, glycerol, beta-OH-butyrate, acetoacetate and free fatty acids) between the two groups. These results suggest that at the dose used the yohimbine does not influence the function of the alpha 2-adrenoceptors on the adipocytes; does not increase the lipolysis and does not represent an effective treatment of obesity.