Efficacy and tolerance of trandolapril (0.5-2 mg) administered for 4 weeks in patients with mild-to-moderate hypertension. Investigator Study Group.

This double-blind, placebo-controlled, dose-ranging study recruited 170 patients with mild-to-moderate hypertension from nine centers. After a 4-week, single-blind, placebo run-in phase, patients were randomized in a double-blind fashion to four parallel groups that received either placebo or 0.5, 1, or 2 mg trandolapril for 4 weeks. Treatment was administered as a once-daily dose in the morning and blood pressure was measured 24 h after drug intake. The primary criterion of efficacy was a decrease in supine diastolic blood pressure. At the end of the study, the lowest dose of trandolapril that consistently produced a significant difference from placebo in reducing blood pressure was 1 mg (-6.6 mm Hg for supine diastolic blood pressure). It was effective from around 2 weeks onward; the 2-mg dose differed significantly from placebo from around 1 week onward. At the end of the study, the 1- and 2-mg doses were equally effective. The lowest dose tested, 0.5 mg, showed some evidence of an effect on systolic blood pressure and may well prove to be a useful dose in patients who are highly sensitive to the effect of ACE inhibition. Tolerance throughout the study was good for all doses tested.

Long-term therapy with trandolapril, a new nonsulfhydryl ACE inhibitor, in hypertension: a multicenter international trial. Investigator Study Group.

An international trial recruited 1,049 patients from 122 investigators. After a 2- to 4-week, single-blind placebo run-in, patients were treated unblinded for 1 year. Therapy was started with trandolapril 2 mg once daily. The dose was increased to 4 mg/day if, after 1 month, blood pressure was not normalized, and then was combined with diuretics and/or calcium antagonists in increasing doses if necessary. At the cutoff point for this interim analysis. 481 patients had been treated for over 12 months and 960 for 3 months. At end point, trandolapril produced a significant decrease in blood pressure (-14 mm Hg for mean supine diastolic blood pressure). Blood pressure was normalized in 60% of the population with monotherapy. Trandolapril, alone or in combination with diuretics or calcium antagonists, was well tolerated clinically and biochemically. Only 3.9% patients reported dry cough. Withdrawals of patients from the study for treatment related reasons were 3.8%. Trandolapril had also an excellent antihypertensive effect and was well tolerated in elderly patients, in patients with glucose intolerance, and in patients with renal dysfunction.

Modifications of sleep structure induced by increasing levels of acoustic perturbation in normal subjects.

In each non-REM (NREM) sleep stage, the aggregation of the arousal-related phasic events permits identification of periods of arousal fluctuation (cyclic alternating pattern or CAP) and periods of long-lasting arousal stability (non-CAP or NCAP). As the ratio CAP time to NREM sleep time (CAP/NREM) measures the instability of arousal during sleep, any perturbing event determines an increase of CAP/NREM. On the basis of these premises, 6 healthy volunteers underwent 5 sleep recordings at increasing intensities of sound pressure level (basal condition followed by continuous white noise at 45 dBA, 55 dBA, 65 dBA and 75 dBA, respectively). Besides a remarkable enhancement of CAP/NREM (P less than 0.00001), acoustic perturbation induced a significant linear increase of waking time after sleep onset, stage 2, NREM sleep, stage shifts and a significant linear decrease of stage 4, deep sleep, REM sleep and total sleep time. At each step of environmental disturbance, the values of the CAP ratio were consistent with the gradual changes of sleep organization. Although the Multiple Sleep Latency Test was unremarkable during the day following the sleep recording, CAP/NREM was significantly correlated with the personal evaluation of sleep quality (P less than 0.01). Through this model of transient situational insomnia it was possible to outline different degrees of subjective complaint depending on 3 ranges of CAP/NREM. A crucial role of CAP in the pathophysiological mechanisms of clinical insomnia is hypothesized.

A phase II study of mitoguazone and vinblastine in advanced transitional cell carcinoma of the urinary tract.

This is a comparative study to evaluate response rate to mitoguazone (MGBG) and vinblastine (VLB) in 52 evaluable patients with advanced transitional cell carcinoma of the urinary tract. Of 38 patients with measurable disease, two of 18 (11%) on MGBG had partial remission (95% confidence interval: 0.01, 0.35), whereas four of 20 (20%) responded on the VLB arm (95% confidence level: 0.06-0.44). Both responses on the MGBG arm were seen in patients given prior chemotherapy. Side effects of both drugs were significant, with 46% of patients given VLB developing severe or life-threatening hematologic toxicity. Data indicate that both drugs, as single agents, are probably inferior to cisplatin for control of advanced transitional cell carcinoma of the urinary tract.

Fengabine, a new GABAmimetic agent in the treatment of depressive disorders: an overview of six double-blind studies versus tricyclics.

Fengabine is a new GABAmimetic compound active in animal models predictive of antidepressant activity. The present overview reports the results of 6 double-blind trials versus tricyclics (TCAs) (3 in outpatients and 3 in inpatients). Overall, 398 adult patients (149 males and 249 females) were treated; 194 with fengabine and 204 with TCAs (98 clomipramine, 63 amitriptyline and 43 imipramine). 284 suffered from major depression (MD) (including major depressive disorder and bipolar disorder, depressed; DSM III) and 114 from minor depression (MiD) including dysthymic disorder, atypical depression and adjustment disorder with depressive mood (DSM III). Dosage ranged from 600 to 2,400 mg/day for fengabine and 50 to 200 mg/day for TCAs. Efficacy was evaluated with the HAM-D scale. 311 subjects (154 fengabine and 157 TCAs) ended the 4-week treatment period. Considering the whole sample and mean IAM-D scores, no significant differences emerged between the 2 treatment groups at any of the assessment periods. Because of a significant treatment x type of depression interaction, MD and MiD were analysed separately, and a different trend appeared in the 2 subgroups with TCAs behaving slightly better than fengabine in MD and fengabine performing slightly better than TCAs in MiD. Using the physician's clinical improvement, 74% of patients under fengabine and 72% of those under TCAs were rated as improved or much improved. Side effects, particularly of the anticholinergic type were significantly more frequent in the TCAs group. Gamma-GT were more frequently altered in the fengabine group (30.4 vs. 10.5%); this increase was interpreted as a consequence of enzymatic induction. Lastly, more patients taking fengabine exhibited an increase in cholesterol values.

[Cyclic alternating pattern. A new approach to the pharmacology of sleep disorders]. / Les tracés alternants cycliques. Une nouvelle approche en pharmacologie du sommeil.

The Cyclic Alternating Pattern (CAP) is an intrinsic component of normal NREM sleep. This periodic activity is organized in biphasic 40-sec cycles clustered in sequences. CAP sequences are functionally correlated to long lasting arousal instability. CAP is induced by endogenous stimuli (change in sleep stage, body movements) but it is considerably increased by exogenous impulses (noise). CAP rate (CAPR) is a novel polysomnographic variable that measures the amount of CAP during sleep, and it may be calculated for total sleep time and total NREM sleep. We demonstrated that all-night exposure to a 45 dB(A) white noise induced a significant CAPR increase, correlated with impaired sleep quality, even without changes in sleep architecture. We hypothesized that administration of an hypnotic should attenuate this CAPR rise. This hypothesis was verified in a double-blind placebo study, in which 12 healthy young adults received zolpidem, a new imidazopyridine hypnotic. During the noise perturbed nights, zolpidem clearly demonstrated a protective effect on CAPR (mainly during slow wave sleep) and on sleep quality. CAPR appears to be a sensitive indicator of sleep quality, and the cumulative distribution of CAPR throughout the night represents a new method to evaluate the effects of an hypnotic in sleep.

The relationship of psychological distress, extent of disease, and performance status in patients with lung cancer.

This study examined the association between two primary covariates, extent of disease (ED) and performance status rating (PSR), and the outcome of psychological distress in patients with small cell carcinoma of the lung. Patients were studied at the time of entry onto one of three Cancer and Leukemia Group B (CALGB) protocols: 7781 (N = 165) and 8083 (N = 139) for limited disease; and 7782 (N = 151) for extensive disease. Besides ED (limited versus extensive), a four-point rating of PSR was obtained. Psychological distress was measured by the standardized Profile of Mood States (POMS). Gender, age, marital status, education, PSR, ED and two relevant interaction terms (PSR X ED; gender X ED) were analyzed using multiple linear and hierarchical regressions. Of the six main variables, gender and PSR had significant association with POMS total mood disturbance, a summary score for POMS emotional subscales, and most of the individual subscales. The PSR X ED interaction provided a rationale for testing a new regression model in which PSR and ED were combined into a single index of impairment. The final index resulted in five levels of physical impairment which bear an approximately linear relationship to increasing levels of distress (Overall regression, P less than 0.001). These data suggest that PSR is an important factor in modelling POMS distress at both levels of ED, and that ED becomes an important factor with poorer performance status only.

Pharmacokinetic and pharmacodynamic interactions between nifedipine and propranolol or betaxolol.

Pharmacokinetic and pharmacodynamic interactions between nifedipine and two beta-blocking agents were investigated. Eighty mg propranolol twice daily, and 20 mg betaxolol once daily, were randomly administered orally to six young healthy male volunteers, either singly for four days, or combined with nifedipine for the two subsequent days. Nifedipine had similar effects on the pharmacodynamics of both drugs. Nifedipine significantly enhanced propranolol bioavailability and Cmax, but reduced its tmax, in three out of six subjects who were also good absorbers of beta-blockers when taken alone. These effects might be due to enhanced intestinal absorption and/or enhanced first-pass effect, induced by nifedipine.

Progabide treatment in severe epilepsy: a double-blind cross-over trial versus placebo.

Twenty therapy-resistant epileptic patients entered a double-blind, randomized, two-period, cross-over trial comparing progabide (19.3-36 mg/kg/day) and placebo as add-on drugs to standard therapy. Each period lasted 6 weeks with a gradual crossover during 4 days. Five patients were dropped because of reasons unrelated to treatment. Among the 15 patients who completed the study, seven had partial, six primary generalized, and two secondary generalized epilepsies. Preexisting antiepileptic drugs (AEDs) ranging from one to three per patient (mean 2.2 AEDs/patient) were maintained unchanged during the trial. Efficacy was assessed biweekly by means of total seizure counts, counts of each seizure type, and global clinical judgment. At the same time intervals, safety was assessed by means of reports of adverse events, clinical and neurological examination, laboratory tests, and measurement of plasma concentrations of progabide and associated AEDs. According to the clinical global judgment, eight patients were considered improved during progabide treatment. Seizures were reduced in 14 of 15 patients during the progabide as compared with the placebo period. During the progabide period, the reduction of the total seizure count was 45 and 58% in two patients and 88-97% in six patients. A significant reduction of the total seizure number was observed in the progabide period as compared with the placebo period, both in the whole patient group (p less than 0.01) and in the two subgroups of patients with generalized (p less than 0.01) and partial (p less than 0.05) epilepsies.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind crossover trial of progabide versus placebo in severe epilepsies.

In this double-blind, two-period, crossover trial with randomized treatment assignment, progabide (+/- 30 mg/kg/day) and placebo were compared as add-on to standard therapy in 20 "therapy-resistant" epileptic patients (11 males, nine females; age range, 7-47 years). The duration of each treatment period was 6 weeks. Crossover was performed gradually over 3-4 days. Twenty-four patients entered the study: three dropped out for reasons unrelated to progabide effects; one dropped out during the placebo period because of increased seizure frequency. Of the 20 patients who completed the study, 14 had partial, two partial plus secondary generalized, and four generalized seizures. Preexisting antiepileptic treatment consisted of one antiepileptic drug (AED) in three, two AEDs in eight, three AEDs in five, and four AEDs in four patients (mean, 2.5 AEDs/patient). The following parameters were recorded at biweekly intervals: (a) efficacy parameters--total seizure count, counts of each seizure type, and global clinical judgment; (b) safety parameters--adverse drug effects, brief clinical and neurological examinations, and laboratory tests; and (c) plasma concentrations of progabide and of the associated AEDs. Twelve patients were considered to be improved (p less than 0.01) with progabide by global clinical judgment compared with two patients improved with placebo. Nine patients of 20 had a 48-100% reduction of total seizure count in the verum period, leading to a significant reduction of total seizure number and of complex partial seizures in the verum period as compared with the placebo period (p less than 0.05). Adverse effects were reported or observed in 10 patients during the progabide period and in five patients in the placebo period. The side effects were generally mild and consisted of somnolence in four cases and of tremors, dry mouth, troubles of equilibrium, anorexia, euphoria, depression, and anxiety in individual patients; a 15-20% reduction of the progabide dose was required in two cases only. No treatment-related alterations in results of laboratory tests were observed.

[Carcinomas of the nasopharynx. Relationship between histological type and anti-Epstein-Barr virus serology (author's transl)]. / Carcinomes du naso-pharynx: relations entre types histologiques et sérologie anti-virus Epstein-Barr.

This study was aimed at the comparison of values of anti-Epstein-Barr virus serology in different groups of patients suffering from carcinoma of the nasopharynx (NPC), classified according to histological type defined by the new classification of the WHO. A group of patients with other tumours of the upper respiratory and digestive tract was used as a control. Antibody levels were high in patients with undifferentiated carcinomas whilst they were low in the controls. In patients with differentiated carcinomas antibody levels were most often equivalent to those of the controls, even though high values were sometimes seen. These findings would appear to offer evidence that the new histological classification of NPC is well founded, and to a certain extent reflect the epidemiological, clinical and therapeutic classifications already seen for these two types of carcinoma.