Pharmacokinetics of reboxetine in healthy, elderly volunteers.

The pharmacokinetic characteristics of reboxetine, a unique selective noradrenaline reuptake inhibitor (selective NRI) for the treatment of depression, were studied in 12 healthy, elderly volunteers (mean age 81 years +/- 9 years). All subjects received a single 4-mg dose of reboxetine, and plasma reboxetine concentrations were measured by HPLC. Reboxetine was well tolerated by all subjects. Exposure to reboxetine was higher in this group of very elderly subjects, compared with data obtained in a similar study of young, healthy volunteers. Cmax in the elderly was 271 +/- 86 ng/ml, compared with 111 +/- 28 ng/ml in the young subjects after a single 4-mg dose, although in both groups Cmax was observed after 2 h. The AUC infinity was nearly four times that in the younger subjects (8345 +/- 3107 ng.h/ml vs. 2106 +/- 881 ng.h/ml) and the t1/2 was twice as long (24 +/- 6 h vs. 12 +/- 3 h). Renal clearance was also reduced. Reboxetine 8-10 mg/day has been effective and well tolerated in clinical trials in non-elderly depressed patients. The increased exposure to reboxetine observed in our very elderly subjects supports a reduction of the starting dose to 4 mg/day (in two divided doses) in the elderly.

Blind loop syndrome: an unusual cause of panniculitis.

We describe a 52-year-old woman with panniculitis and blind loop syndrome. She had undergone a gastrectomy for peptic ulcer 4 years before. Tender erythematous nodules on her palms and soles were associated with diarrhea and weight loss. A biopsy specimen revealed septal and lobular panniculitis. A glucose hydrogen breath test was consistent with bacterial overgrowth. These results were consistent with panniculitis associated with a blind loop syndrome. Only four cases of this association have been reported previously.

[Therapeutic principles in gastroesophageal reflux]. / Principes thérapeutiques du reflux gastroesophagien.

Gastroesophageal reflux is a common disease. Its chronic course, even if mild, is sometimes complicated by erosive oesophagitis. Drug therapy acts against gastric acidity and motility disorders. Treatment of gastroesophageal reflux disease has three aims: improvement of symptoms and quality of life, healing erosive lesions and prevention of symptomatic and endoscopic relapses. Non-drug measures are always useful, even if their efficacy is not well established. Initial therapy of a symptomatic reflux or mild oesophagitis is most of the time effective (antacids, prokinetics, H2 receptor antagonists). Proton-pump inhibitors are also effective in healing and preventing severe oesophagitis. Questions about long-term treatment adverse events with powerful acid inhibitors, such as hypergastrinemia and the risk of gastric carcinoid tumours seem to be resolved. Studies are requested to define the optimal long-term maintenance treatment with cisapride, H2 receptor antagonists or proton-pump inhibitors at low doses in prevention of symptomatic and mild oesophagitis relapses.

[Critical examination of scoring systems in therapeutic trials]. / Examen critique des grilles de lecture des essais thérapeutiques.

Scoring systems give a check-list and methodological informations which have to be found in controlled therapeutic trials reports and papers. These systems try to quantify each item to give a global score. The Chalmer's list is the most wellknown. It allows a balance in scoring taking in account the quality of the endpoints. Other lists are more simple. Many check-lists allow the scoring of the methodological design or the statistical analysis. In all systems the major methodological points are: the randomization, the description of the population, the double blind, the estimation of the sample size, the handling of withdrawal and drop out, the major endpoint, the patients follow-up, the statistical analysis and the data presentation. All these scoring systems have several limits: the quantitative evaluation of each item is subjective and the point scoring has never been validated, some scoring systems are old and don't integrate new methodological methods, the scores never included the clinical interest of the trial, some items are questionable, others are forgotten (intention to treat analysis, steering comity...). Scoring systems allow a control of the methodological quality of clinical trials but don't include the clinical or scientific interest of the study. These systems are a useful methodological tool for publication process in medical journals and for new drugs authorization. The evaluation by authors themselves of the quality of their papers using a standardized scoring system could clarify the reviewers decisions.

A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain.

To determine whether informed consent in a therapeutic trial modifies the analgesic effect of naproxen and placebo, we conducted a prospective, randomised, single dose, placebo-controlled trial. Patients were randomly selected to receive or not information concerning the study. All patients included were then given a single dose of naproxen and placebo according to a crossover, double-blind design. Forty-nine patients with mild or moderate cancer pain which did not need narcotic analgesics entered the study. Twenty-five received both treatments without any information and constituted the uninformed group. Twenty-four had a complete information about the trial; six refused to participate. The 18 others constituted the informed-consent group. Visual analogue scales of pain before and 30, 60, 120 and 180 min after the intake of naproxen and placebo were recorded. As an analgesic, naproxen was more effective than placebo in both groups of patients (p = 0.001). For naproxen as well as for placebo, the analgesic effect was better in the informed-consent group compared to the uninformed group (p = 0.012). The difference in therapeutic activity between naproxen and placebo was moderately higher in the uninformed patients (p = 0.08). We concluded that, in contrast with parallel studies, giving information in a crossover, placebo-controlled trial may increase the apparent efficacy of both the tested agent and the placebo, and decrease the perceived difference the two.

What is the better formulation of microencapsulated potassium chloride?

A single blind cross-over study was performed comparing a new microencapsulated potassium chloride tablet (MET) with two reference formulations of oral potassium, namely potassium chloride solution (PS), and microencapsulated potassium chloride capsules (MEC), in 18 normal healthy volunteers. The potassium chloride induced change in gastric potential difference (PD) of the mucosa was the main criterion of comparison and was assessed by the area above curve (AAC), the total duration of the effect (TDE), the maximal variation of PD (delta MAX), and the aggression index (AI). The results showed that all three formulations induced a fall in PD; the delta MAX and AAC were significantly greater for PS indicating a higher aggressive effect of the solution; MET had significantly less aggressive effect than MEC when assessed by all parameters.

Protection against aspirin-induced gastric lesions by lansoprazole: simultaneous evaluation of functional and morphologic responses.

The protective effect of lansoprazole, a new proton pump inhibitor, against aspirin-induced gastric lesions was studied in a double-blind crossover trial with a simultaneous measure of the functional capacities of the mucosal barrier (by a recording of the gastric potential difference) and of the morphologic changes in the mucosa (by gastric endoscopy). After 1 week of treatment with lansoprazole (30 mg per day) or placebo, each healthy volunteer received 1 gm aspirin by mouth. Recording of the gastric potential difference lasted for 3 hours and was followed by gastric endoscopy. Morphologic lesions induced by aspirin were effectively prevented by lansoprazole: Lanza score was 0.67 +/- 0.98 (mean +/- SD) versus 2.25 +/- 1.1 with placebo (p < 0.005, ANOVA). Conversely, the decrease in the gastric potential difference was similar. The inhibition of acid secretion induced by lansoprazole was therefore sufficient to prevent aspirin-induced mucosal lesions without reinforcing the defense capacities of the mucosa. This simple pharmacologic model makes it possible to simultaneously evaluate the functional and morphologic effects of aspirin intake on the gastric mucosa.

Correlation between echographic gastric emptying and appetite: influence of psyllium.

The correlation between ultrasonographic gastric emptying and appetite was studied. Echographic evaluation of gastric emptying by measurement of the antral vertical diameter and assessment of sensations of hunger and satiety using analogue visual scales were performed simultaneously in 12 healthy volunteers. Measurements were carried out after the intake of 10.8 g psyllium or placebo in a randomised, crossover, double blind trial. The correlation between echographic gastric emptying and sensations of hunger and satiety was excellent (p < 0.001) after the intake of either psyllium or placebo. Psyllium significantly delayed gastric emptying from the third hour after a meal. It increased the sensation of satiety and decreased hunger at the sixth hour after the meal. The association between echographic measurement and visual scales is a simple method of evaluating the relationship between the stomach and appetite. The pharmacodynamic effect of psyllium should be confirmed by longterm therapeutic trials.

[Prevention of gastroduodenal lesions induced by non-steroidal anti-inflammatory agents. Economic analysis from a survey of 356 physicians]. / Prévention des lésions gastro-duodénales induites par les anti-inflammatoires non stéroïdiens. Analyse économique à partir d'un sondage réalisé chez 356 médecins.

In order to obtain information on prescribing habits concerning the prevention of gastroduodenal lesions induced by non-steroidal anti-inflammatory agents (NSAI), 356 physicians practicing in 2 French departments were asked to fill a posted questionnaire. Fifty-one percent of these doctors gave an assessable answer. Among these, 84 percent occasionally prescribe "gastric protectors" associated with NSAI's in 32 percent of the prescriptions. They use antacids (48 percent), anti-H2 products (27 percent), sucralfate (11 percent) or prostaglandins (13 percent). This represents a daily cost of additional treatment ranging from 0.87 to 2.49 francs. If fibroscopies and further consultations necessitated by the prescription of NSAI's are taken into account, then 86 to 140 percent must be added to the cost of NSAI's. The profitability of these preventive measures in terms of public health will be really estimated only when the number of severe gastroduodenal lesions effectively prevented by taking topical gastric protectors or anti-secretory agents will be known.