Epidemiology and course of acute upper gastro-intestinal haemorrhage in four French geographical areas.

OBJECTIVE: To compare incidence rates and epidemiological characteristics of acute upper gastrointestinal haemorrhage (AUGIH) in France with those of other European studies. DESIGN: Population-based multi-centre prospective survey. SETTING: 29 public hospitals and 96 private specialists in gastroenterology in four administrative areas in France during 1996. SUBJECTS: A total of 2133 AUGIH patients 18 years and over were included in the six-month study. OUTCOME MEASURES: Incidence and mortality. RESULTS: The overall incidence in France was 143 cases per 100000 persons per year, classified as out-patients (16%), emergency admissions (59%) and in-patients (25%). The incidence rates increased with age except for in-patients, and were higher in males. Peptic ulcer (36.6%), varices (13.7%) and erosive disease (12.3%) were the most frequent diagnoses. In 677 patients (31.7%), aspirin, antiinflammatory drugs or corticosteroids were taken on the 7 days before bleeding. The overall mortality (out-patients excluded) was 14.3% (10.7% for emergency patients and 23% for in-patients). Mortality was associated with comorbidities (especially malignancies, cirrhosis, asthma or respiratory deficiency), was lower in emergency patients using non-steroid anti-inflammatory drugs, and higher in in-patients using corticosteroids. CONCLUSIONS: In France, patients with AUGIH are frequently managed as out-patients. Gastrotoxic drug use is frequently associated with AUGIH and constitutes a strategic opportunity for preventive treatment. Discrepancies between countries are not clearly explained either by demographic factors or by drug use, but this may be related to the emphasis on AUGIH in in-patients.

Efficacy of misoprostol in the prophylaxis of gastroduodenal lesions induced by short-term nonsteroidal antiinflammatory drug therapy in elderly patients. A multicenter double-blind, placebo-controlled trial.

Advanced age is an established risk factor for gastrointestinal toxicity of nonsteroidal antiinflammatory drugs, and the duration of use of these agents in elderly patients should be kept as short as possible. A multicenter, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of misoprostol in preventing gastrointestinal toxicity in elderly patients (> or = 65 years) given nonsteroidal antiinflammatory agents for no more than ten days. Patients who were to receive a nonsteroidal antiinflammatory agent for ten days to treat an acute rheumatic condition were randomly allocated to treatment with either a placebo or misoprostol in a dose of 200 micrograms bid. The primary efficacy criterion was the result of a gastroduodenal endoscopic evaluation done on day 10. The outcome of the rheumatic condition, changes in serum creatinine levels, and clinical safety were also evaluated. The study population included 208 subjects with a mean age of 81.4 +/- 6.4 years, of whom 81.3% were women. The misoprostol group (n = 104) and the placebo group (n = 104) were comparable at baseline. The incidence of endoscopically visible gastric lesions after ten days of nonsteroidal antiinflammatory drug therapy was significantly lower in the misoprostol group (25%) than in the placebo group (43%) (P = 0.001). In contrast, no statistically significant difference was found for the incidence of duodenal lesions between the two groups. The incidence of gastroduodenal ulcers was significantly lower (P < 0.021) in the misoprostol group (4.1%) than in the placebo group (13.5%). Changes in serum creatinine levels on day 10 versus baseline were similar in the two groups. The nonsteroidal antiinflammatory drug was well tolerated clinically when given alone or in combination with misoprostol.

[Treatment of uncomplicated recurrent cystitis in women: lomefloxacin versus norfloxacin]. / Traitement de la cystite non compliquée récidivante de la femme: loméfloxacine versus norfloxacine.

OBJECTIVE: compare the acceptability of 3-day regimen with that of 10-day regimen of fluoroquinolones for the treatment of recurrent uncomplicated lower urinary tract infection in women. METHODS: a multicentric, randomized open trial was conduced in 421 patients by gynecologic and general practitioners to determine acceptability, efficacy and safety of lomefloxacin 400 mg in a once a day dose given for three days compared with norfloxacin 800 mg in twice a day dose given for ten days for the treatment of recurrent uncomplicated lower urinary tract infection in women. RESULTS: acceptability, assessed at day 14, was significantly better for lomefloxacin group than norfloxacin group, respectively 57,1 p.100 and 38,0 p.100. Clinical success rate at day 14 was 97,2 p.100 for lomefloxacin and 97,5 p.100 for norfloxacin; at day 30 clinical success rate was respectively 97,6 p.100 and 98,1 p.100 relapse at one year was comparable between two groups. Adverse events were reported respectively in 15,6 p.100 and 16,6 p.100 of the patients, vaginal infections, dermatologic disorders and digestive disorders (abdominal pain, nausea) predominated. There were no serious adverse event. CONCLUSION: the acceptability is better for a 3-day regimen of lomefloxacin than a 10-day regimen of norfloxacin for treatment of recurrent uncomplicated lower urinary tract infection in women for comparable efficacy and safety.

[Treatment of non-complicated acute cystitis in women: lomefloxacin versus pefloxacin]. / Traitement de la cystite aiguë non compliquée de la femme: loméfloxacine versus péfloxacine.

OBJECTIVES: Compare the acceptability of a 3-day regimen with that of a single-dose regimen of fluoroquinolones for the treatment of lower urinary tract infection in women. METHODS: A multicentric, randomized open trial was conduced in 595 patients by general practitioners to determine acceptability, efficacy and tolerance of lomefloxacine 400 mg in a once a day dose given for three days compared with a once-a-day 800 mg dose of pefloxacin for the treatment of lower urinary tract infection in women. RESULTS: The delay to symptom relief was greater than 24 hours in both treatment groups. Symptom relief was observed after treatment onset in only 23% of the patients. Clinical success rate at day 14 was 94.2% for lomefloxacin and 95.7% for pefloxacin. The rates of bacteriological eradication were 90.6% and 92.8% respectively with no significant difference. Adverse events were reported in 27.1% and 33.3% of the patients respectively, digestive disorders (abdominal pain, nausea) and neurosensorial disorders (headache, dizziness) predominated. There was no serious adverse event. The incidence of adverse events related to the treatment according to the investigator was smaller with lomefloxacin (16.1%) than with pefloxacin (23.5%) (p = 0.026). CONCLUSION: Acceptability, assessed at day 14, was not significantly different between the two treatment groups. Lomefloxacin was the only antibiotic currently authorized for use in a three-day regimen for the treatment of lower urinary tract infections.

[Misoprostol in the prevention of gastric erosions caused by nonsteroidal anti-inflammatory agents]. / Le misoprostol dans la prévention des érosions gastriques dues aux anti-inflammatoires non stéroïdiens.

A multicenter, double-blind, placebo-controlled study was carried out to determine whether the synthetic prostaglandin E1 analog misoprostol is effective in preventing gastric and duodenal lesions induced by nonsteroidal anti-inflammatory drugs. Two hundred fifty-six patients under nonsteroidal anti-inflammatory drug treatment (diclofenac, naproxen, piroxicam, ibuprofen, indomethacin, ketoprofen, or tiaprofenic acid) for osteoarthritis, rheumatoid arthritis, or other rheumatic diseases were included in the study. None of the patients had patent gastroduodenal damage at entry (0 to 3 mucosal erosions or subepithelial hemorrhages on endoscopy). Patients were randomly assigned to treatment with misoprostol 400 micrograms/d (M 400), misoprostol 800 micrograms/d (M 800) or a placebo. Results of the follow-up endoscopy on day 28 in the 186 evaluable patients showed that gastric erosions were significantly less common (p < or = 0.02) in the two misoprostol groups (5% and 2% in the M 400 and M 800 groups respectively) than in the placebo group (19%). Similar small numbers of patients in the three groups had gastric subepithelial hemorrhages or duodenal lesions. Three patients developed gastric ulcers in the placebo group, versus none in the misoprostol groups. Misoprostol therapy did not modify the efficacy of the nonsteroidal antiinflammatory agent on pain or other rheumatologic manifestations. Diarrhea occurred in 1%, 10%, and 5% of patients in the M 400, M 800, and placebo groups, respectively. In conclusion, misoprostol given in combination with a nonsteroidal anti-inflammatory agent for 28 days significantly reduced the incidence of gastric erosions in a random sample of patients with a variety of rheumatic diseases. The daily dosage associated with the best risk/benefit ratio may be 400 micrograms/day.

Uncomplicated urinary tract infections: lomefloxacin versus trimethoprim/sulphamethoxazole.

Data were collected from 14 French centres which participated in a randomized study to compare the safety and efficacy of 400 mg lomefloxacin taken orally once daily by 62 patients with 160/800 mg trimethoprim/sulphamethoxazole (TMP/SMX) taken orally twice daily by 64 patients with uncomplicated urinary tract infections. Most patients were infected with Escherichia coli at baseline (72.4% in the lomefloxacin group and 69.0% in the TMP/SMX group) and all patients were treated for 5 days. At 5-9 days post-treatment, lomefloxacin had eradicated the causative organism of infection in 100% of evaluable patients treated with lomefloxacin compared with 86.7% of those treated with TMP/SMX. At 4-6 weeks post-treatment, there were no marked differences in eradication rates between the two treatment groups: 83.3% and 80.0% for the lomefloxacin and TMP/SMX groups, respectively. Clinical cure rates showed no marked differences between treatment groups at 5-9 days or at 4-6 weeks post-treatment. At 5-9 days post-treatment, lomefloxacin achieved a clinical cure rate of 78.6% compared with 86.7% for TMP/SMX evaluable patients. At 4-6 weeks post-treatment, the clinical cure rates were 66.7% and 86.7% for the evaluable lomefloxacin- and TMP/SMX-treated patients, respectively. Both treatment regimens were well tolerated with a low incidence of adverse events. In conclusion, once-daily oral dosing with lomefloxacin is a safe and efficacious alternative to twice-daily dosing with TMP/SMX in the treatment of uncomplicated urinary tract infections.

A multicenter study of lomefloxacin and trimethoprim/sulfamethoxazole in the treatment of uncomplicated acute pyelonephritis.

A total of 63 adult patients with uncomplicated acute pyelonephritis were enrolled in a multicenter, randomized comparison of lomefloxacin (400 mg orally once daily for 14 days) and trimethoprim/sulfamethoxazole (TMP/SMX, 160/800 mg orally twice daily for 14 days). Study participants were predominantly female (70% in the lomefloxacin group and 80% in the TMP/SMX group). Escherichia coli was isolated from pretreatment urine cultures in 87.5% of the lomefloxacin group and 80.0% of the TMP/SMX group. Baseline pathogens were eradicated in 100% of evaluable patients in the lomefloxacin group 5-9 days after the end of therapy and in 88.9% of patients in the TMP/SMX group (p = 0.05). The clinical cure rate 5-9 days after therapy with lomefloxacin was 65.0% and for TMP/SMX was 68.4%. At the 4-6 week follow-up in the lomefloxacin group, nine pathogens remained eradicated, one E. coli was isolated, and the results for 14 pathogens were unknown or unevaluable. In the TMP/SMX group, 12 pathogens remained eradicated, three E. coli and one Group D Streptococcus were isolated, and the results for nine pathogens were unknown or unevaluable. Both treatment regimens were well tolerated; adverse events occurred in 12% of patients in the lomefloxacin group and in 17% in the TMP/SMX group. Events considered by the investigators to be probably related to treatment occurred in three patients in each group. In conclusion, once-daily lomefloxacin (400 mg) was a well tolerated and effective alternative to twice-daily TMP/SMX (160/800 mg) for the treatment of adults with uncomplicated acute pyelonephritis.

A French controlled multicenter study of intraarticular orgotein versus intraarticular corticosteroids in the treatment of knee osteoarthritis: a one-year followup.

The efficacy of injection of orgotein was compared with that of betamethasone over a one-year period in 419 patients with osteoarthritis of the knee. The criteria for efficacy were the number of recurrences, the rate of persistence in the trial and, secondarily, Lequesne index and the visual analogue scale. Though betamethasone was quicker-acting, the efficacy of orgotein at low doses (4 or 8 mg) was comparable with that of the corticosteroid from Week 4 and up to a year after the beginning of the study, at the cost of a greater number of injections and more numerous local side effects.

[Pharmacokinetics in healthy subjects of althiazide and spironolactone in a fixed combination for 2 doses]. / Pharmacocinétique chez le sujet sain de l'altizide et de la spironolactone en association fixe pour deux posologies.

Pharmacokinetic plasma curves of altizide (ALT), spironolactone (SPI) and two of the main metabolites of spironolactone, 7 alpha-thiomethyl-spirolactone (7TM) and canrenone (CAN) have been established in 12 healthy human volunteers (6 men and 6 women) after unique oral administration of 1 or 2 tablets of a combination of the two diuretic compounds: altizide (15 mg per tablet) and spironolactone (25 mg per tablets). Main pharmacokinetic parameters have been calculated using a biexponential (ALT and SPI) or a triexponential model (7TM and CAN). Spironolactone is rapidly absorbed. Plasma curves show Tmax respectively equal to 1.19 +/- 0.47 hours (1 tablet) or 1.21 +/- 0.46 (2 tablets). Spironolactone is rapidly metabolized as it is shown by the mean Tmax of metabolites: 7TM and CAN Tmax are respectively 1.56 +/- 0.45 hours and 2.54 +/- 1.06 hours after administration of 1 tablet, or 1.58 +/- 0.42 hours and 2.67 +/- 1.13 hours after administration of 2 tablets. The mean residence time (MRT) of ALT [4.94 +/- 1.14 hours (1 tablet) or 5.31 +/- 1.06 hours (2 tablets)] and SPI [1.81 +/- 0.45 hours (1 tablet) or 1.88 +/- 0.50 hours (2 tablets)] shows a rapid elimination of both drugs. SPI metabolites present higher MRT than the unchanged drug. 7TM MRT after administration of 1 or 2 tablets, are 24.51 +/- 15.35 hours and 18.11 +/- 11.87 hours, respectively. CAN MRT are 39.65 +/- 23.58 hours (1 tablet) and 38.93 +/- 24.58 (2 tablets). Statistical analysis shows no significant administration order effect on the different parametres. Student' t test shows a significant sex effect on CAN AUC, for both formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Spironolactone and altizide versus converting enzyme inhibitor (enalapril).

The safety and antihypertensive effectiveness of a fixed-dose combination form of spironolactone + altizide (S/A) were compared with those of enalapril, an angiotensin-converting enzyme inhibitor in a randomized, double-blind, parallel-group study of 186 patients with moderate essential hypertension. The 2 treatment groups were comparable in terms of age, gender, duration and severity of hypertension, diastolic blood pressure (BP), serum potassium and creatinine, and 24-hour urinary sodium excretion after a 4-week washout phase. After 8 weeks of treatment, both S/A and enalapril decreased BP significantly and to about the same extent. Enalapril, however, was more effective in decreasing supine diastolic BP in patients younger than age 50, whereas S/A yielded better results in those older than 50. Laboratory values were similar after both drugs were administered, and there were no clinically significant changes. The study demonstrated that S/A safely reduces elevated BP, particularly in older patients.

Spironolactone and altizide used in combination with enalapril: twenty-four-hour ambulatory recording of blood pressure.

The addition of enalapril or acebutolol to a regimen of altizide + spironolactone in patients with moderate hypotension was investigated in a multicenter study of 53 patients. The patients underwent semiambulatory 24-hour blood pressure monitoring, especially to observe hypotensive episodes. In the 25 patients uncontrolled with altizide + spironolactone alone, enalapril and acebutolol were about equally effective in reducing blood pressure. The incidence of hypotension was low and comparable for both treatment groups, provided that the initial dose of angiotensin-converting enzyme inhibitor was low (5 mg).

Spironolactone versus nifedipine in essential hypertension.

In a double-blind, randomized, multicenter study of 194 patients with moderate hypertension, spironolactone and nifedipine were found to reduce blood pressure (BP) to about the same extent and in the same percentage of patients after 45 days of treatment (47 and 50%, respectively). At that point, the patients controlled by either drug continued on their regimen for another 45 days, while patients whose BP was still elevated (diastolic BP greater than 90 mm Hg), received the other drug in addition. After 45 days of combination therapy, 63% of the patients had normal BP, whereas those receiving monotherapy largely remained normotensive (96% in the spironolactone group and 88% in the nifedipine group). The adverse effects were not severe with either group, but the incidence was markedly higher in the nifedipine group.

Aldactazine/captopril combination, safe and effective in mild to moderate systemic hypertension: report on a multicenter study of 967 patients.

The safety and efficacy of a thiazide/potassium-sparing diuretic and an angiotensin-converting enzyme inhibitor used concomitantly was evaluated in a large, multicenter study. Aldactazine was administered alone for 2 months, after which time captopril was added in those whose blood pressure had not normalized (332 patients). At the end of the 6-month study, control of blood pressure was achieved in 88% of the patients with one or the other regimen. No clinically significant changes were recorded for a number of biologic parameters. Specifically, there was 1 case of hyperkalemia (6 mmol/liter), a very low incidence of hypotension (1.6%), and a low rate of adverse effects. Therefore, such a combination could provide important therapeutic benefits in hypertensive patients.

Relative inhibitory potency of five mineralocorticoid antagonists on aldosterone biosynthesis in vitro.

Spirolactones are mineralocorticoid antagonists which bind to aldosterone receptors in the distal nephron. During the last decade, several antimineralocorticoids, which are more potent than spironolactone in competing for mineralocorticoid receptors have been developed. In the present study, we have compared the direct activity of spironolactone and four related compounds: prorénone (SC 23133), SC 19886, SC 26304 and its carboxylic analog SC 27169, on aldosterone biosynthesis. Two of them (SC 26304 and its carboxylic analog SC 27169) had no effect on adrenal steroidogenesis, even at concentrations up to 10(-3)M. Spironolactone and prorenone (SC 23133) induced a marked but reversible inhibition of aldosterone biosynthesis. SC 19886 totally inhibited aldosterone production and the activity of this compound lasted for more than 7 hours. In addition, SC 19886 and prorenone (SC 23133) totally suppressed ACTH and angiotensin II-induced stimulation of aldosterone biosynthesis whereas SC 27169 was unable to block adrenal response to these corticotropic hormones. Our results suggest that compounds such as prorenone (SC 23133), SC 19886 and spironolactone, which are potent inhibitors of aldosterone biosynthesis could be more active in the treatment of primary aldosteronism than those antimineralocorticoids which are devoid of action on aldosterone biosynthesis.

[Direct action of mineralocorticoid antagonists on biosynthesis of aldosterone: comparative activities of several new compounds]. / Action directe des antagonistes des minéralocorticoïdes sur la biosynthèse de l'aldostérone: activités comparées de plusieurs nouveaux composés.

Spironolactone is a diuretic steroid which is capable of blocking the binding of aldosterone to its cytosol receptor at the distal convoluted tubule. In addition, it has been shown that spironolactone is a strong inhibitor of steroidogenesis. More recently, new aldosterone antagonists have been discovered. Some of these compounds are more active than spironolactone in competing with aldosterone and have higher specificity for mineralocorticoid receptors. In this study we compare the direct activity of new antimineralocorticoids (SC 23133, SC 19886, SC 26304, and SC 27169) on aldosterone biosynthesis. Marked differences were found in the activity of these compounds upon steroidogenesis. SC 23133 gave rise to a strong inhibiting activity (90%). This activity was reversible (recovery of spontaneous production occurs 150 min after the end of the administration of SC 23133). SC 19886 totally inhibited aldosterone biosynthesis (95%) in a lasting mean. Conversely, SC 27169 and SC 26304 presented no or weak inhibiting effect. Further experiments showed that SC 27169 was unable to block the stimulation of aldosterone biosynthesis induced by corticotropic peptides, whereas the administration of SC 23133 and SC 19886 totally suppressed the stimulatory effect of ACTH and angiotensin II. Owing to the important stimulation of the renin-angiotensin system induced by antimineralocorticoid treatment, these results suggest that SC 23133 and SC 19886 will exert a higher antinatriuretic activity than SC 27169.

Effect of aldosterone antagonists on mineralocorticoid synthesis in vitro. Inhibition of aldosterone production by prorenoate-K.

A perifusion technique using frog adrenal glands has been applied to investigate the effects of long-term administration of a new aldosterone antagonist (potassium prorenoate; SC 23992) on mineralocorticoid production. Whatever the duration of administration of potassium prorenoate, at a constant concentration of 5 X 10(-4) M, a significant inhibition of aldosterone output occurred during the passage of the compound. The inhibition was immediate (lag period less than 10 min); the amplitude of the inhibition was constant during the whole experiment and ranged from 77 to 89%; the aldosterone output returned to a regular basal value 80-100 min after the end of infusion of potassium prorenoate. We have also investigated the effect of a concentration gradient of potassium prorenoate (similar to the concentration gradient of aldosterone antagonist observed in plasma after a single oral administration of the molecule) upon aldosterone production over 12 h. From this study, we have established the existence of a highly significant correlation between the extent of the inhibition of aldosterone production and the concentration of the aldosterone antagonist. Finally we have observed that potassium prorenoate blocked the stimulation of aldosterone secretion induced by synthetic ACTH and significantly reduced the angiotensin-induced aldosterone stimulation. The present results indicate that, besides the well-known competitive inhibition of aldosterone binding exerted by potassium prorenoate at the renal receptor site, a direct inhibition of aldosterone biosynthesis also accounts for the pharmacological activity of this aldosterone antagonist.