Pharmacokinetics of ketanserin in patients with cirrhosis.

The pharmacokinetics of ketanserin, a new serotonin S2 (5HT2) antagonist, were studied in 26 patients with cirrhosis. Patients were randomised to receive either a single oral dose of ketanserin 20mg (n = 14) or 40mg (n = 8) or an intravenous dose of ketanserin 5mg (n = 4). The plasma kinetics of ketanserin and its metabolite ketanserinol were determined over 48 hours, by high pressure liquid chromatography with a fluorometric detector. Pharmacokinetic parameters were calculated using noncompartmental analysis based on a statistical moment theory. The first-pass effect of ketanserin was markedly decreased after oral administration compared with results previously obtained in healthy subjects. The peak concentration was not higher in cirrhotic patients than in controls. This result could be due to an increase in the initial volume of distribution. The production of ketanserinol was reduced in cirrhotics. A decreased mean ketanserin elimination half-life (t1/2 = 12 +/- 4 and 10 +/- 3h vs 16 +/- 3 and 18 +/- 4h in healthy controls after oral ketanserin 40mg and intravenous ketanserin 5mg, respectively) contrasted with a substantial increase in t1/2 for ketanserinol (33 +/- 13 vs 19 +/- 4h). The volumes of distribution were also markedly reduced in patients with cirrhosis. These results suggest either a reduction in the oral dosage of ketanserin or an increase in the interval between doses in patients with cirrhosis.

Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans.

BACKGROUND AND AIM: Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity. METHODS: Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied. RESULTS: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4 +/- 0.92 vs. 12.0 +/- 1.13 mmHg; P = 0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension. CONCLUSION: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.

Effects of ketanserin on cardiovascular, sympatho-adrenal and endocrine systems during physical exercise in man.

Blood pressure, heart rate, oxygen consumption, plasma concentrations of catecholamines, renin, aldosterone and lactate were measured in 6 normotensive volunteers during a randomized cross-over study of oral ketanserin (20 mg X 7) and placebo; measurements were made at rest and during maximal dynamic exercise on a bicycle ergometer. At rest ketanserin reduced blood pressure without modifying heart rate or plasma noradrenaline and adrenaline. Duration of exercise and blood lactate levels did not differ between the ketanserin and the control group. During exercise only systolic blood pressure was significantly decreased on ketanserin at maximal work rate whereas heart rate did not change. Plasma noradrenaline was significantly increased and plasma aldosterone significantly decreased during exercise in ketanserin-treated subjects whereas plasma renin activity and plasma adrenaline remained unchanged. Finally, under ketanserin oxygen consumption during exercise was reduced. The results suggest that ketanserin might interfere with the sympathetic nervous system and aldosterone secretion in man.

Double-blind dose-response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia.

The efficacy and safety of the peripheral kappa-receptor agonist fedotozine was investigated in a double-blind, placebo-controlled, dose-ranging study involving 146 patients with nonulcer dyspepsia (NUD). After a two-week washout, patients were assigned to one of four groups to receive either placebo or fedotozine three times a day at doses of 10, 30, or 70 mg for six weeks. Analysis of mean symptom intensity scores showed that the 30-and 70-mg doses of fedotozine were superior to placebo in relieving postprandial fullness, bloating, abdominal pain, and nausea. Eructation and early satiety were marginally affected. The 30-mg dose was significantly more effective than placebo in reducing the total symptom score. Eight-two mostly minor adverse effects were recorded, but no significant differences in distribution emerged between placebo and treatment groups. The number of withdrawals declined significantly as a function of increasing dose. These results indicate that 30 mg three times a day is the minimal effective dose of fedotozine in the treatment of NUD symptoms and that this treatment is safe.

Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study.

The efficacy and safety of the peripheral kappa agonist fedotozine was evaluated in a double-blind, multicenter study involving 238 patients with the irritable bowel syndrome. After a two-week washout, patients were assigned to one of four groups to receive either placebo or fedotozine three times a day at doses of 3.5, 15, or 30 mg for six weeks. Patient assessment of mean symptom intensity indicated that the 30-mg dose of fedotozine was superior to placebo in relieving maximal daily abdominal pain (P = 0.01), mean daily pain (P = 0.007), and abdominal bloating (P = 0.02). Changes in bowel function and defecation disorders could not be evaluated reliably. According to the investigators, the highest dose of fedotozine markedly reduced overall disease severity (P = 0.003) and the pain component of the symptomatic profile (P = 0.009). Clinical and laboratory safety was very good. Fedotozine 30 mg three times a day therefore appears to be effective and safe in the treatment of the abdominal pain and bloating associated with IBS.

[Colonic tumors after ureterosigmoidostomy. Value of coloscopy in their detection and treatment]. / Tumeurs coliques après urétéro-sigmoïdostomie. Intérêt de la coloscopie dans leur dépistage et leur traitement.

Congenital malformations and tumours of the bladder are the commonest indications of uretero-sigmoidostomy, an operation associated with the name of Coffey who perfected the technique. A part from the renal and metabolic complications of this operation, the risk of benign or malignant tumours at the anastamosis should not be overlooked. Four cases are reported which underline the incidence of juvenile polyps and mixed juvenile and adenomatous polyps which tend to degenerate. The medical literature is reviewed. Uretero-sigmoidostomy is a definite cause of tumour formation. The different pathogenic hypotheses are discussed. Colonoscopy is a method of detecting the tumour, of obtaining a histological diagnosis and treating benign polyps by diathermy under endoscopic control. This technique allows preservation of the anastomosis. The prevention of these lesions should be assured by annual endoscopy for 5 years after operation.

[Schwartz-Bartter syndrome during carcinoma of the pancreas (author's transl)]. / Syndrome de Schwartz-Bartter au cours d'un cancer du pancréas.

The authors report a case of carcinoma of the pancreas with inappropriate secretion of antidiuretic hormone in a 74 years old woman; the main static and dynamic characteristics of the Schwartz-Bartter syndrome are recalled together with the various therapeutic indications. Carcinoma of the pancreas remains exceptional among the numerous causes of Schwartz-Bartter syndrome. The relationships between carcinoma of the pancreas and pancreatitis are recalled in relation to this special case.

Ketanserin in the treatment of systemic sclerosis: a double-blind controlled trial.

In a randomized, double-blind study, the selective and specific S2-serotonergic receptor antagonist, ketanserin was compared with placebo in 24 patients with systemic sclerosis. Following a 6-week placebo washout period, patients were randomly allocated to receive ketanserin or placebo for 6 months. Ketanserin failed to produce a greater improvement than placebo in functional and objective clinical signs and symptoms as well as in most subjective assessments. However, in a global rating by the physician ketanserin was superior to placebo. No difference in the frequency or severity of side-effects was found. The results cast doubt on the hypothesis that serotonin may be a major contributing factor in the pathophysiology of systemic sclerosis.

[Treatment using Motilium of gastro-esophageal reflux associated with respiratory manifestations in children]. / Traitement par Motilium du reflux gastro-oesophagien associé à des manifestations respiratoires chez l'enfant.

Eighteen children aged 1 month to 12 years 8 months (mean age, 4.9 years) with pH-metry proven gastroesophageal reflux (GOR)-associated chronic respiratory disorders were treated with Motilium, 2 mg/kg/d in four divided doses, for three months. The incidence of each of the respiratory manifestations decreased, and their cumulative score improved significantly at the end of the treatment period. Patient daily self-assessment scores also fell, but not significantly. Twenty-one hour pH recordings showed a significant reduction in the duration of nocturnal episodes below 4 (2.8 +/- 0.9% versus 8.2 +/- 2.6%, p less than 0.05). No side effects were recorded. Domperidone provides satisfactory control of nocturnal GOR and therefore emerges as a valuable agent for the treatment of chronic GOR-associated respiratory disorders in childhood.

[Presinusoidal portal hypertension in post-hepatitis cirrhosis]. / Hypertension portale de type présinusoïdal au cours des cirrhoses post-hépatitiques.

Two cases of very probable post-hepatitis cirrhosis are presented. Both were complicated by presinusoidal portal hypertension (P. H. T.), the peroperative portal pressures measured directly being much higher than the wedged hepatic venous pressures. Although post-sinusoidal P. H. T. is the usual complication of most types of cirrhosis, these two cases support recent studies reporting the possibility of pre-sinusoidal P. H. T. in post-hepatitis cirrhosis. The wedged hepatic venous pressure is not a reliable indicator of portal pressure in these cases. The presence of presinusoidal P. H. T. does not exclude the diagnosis of cirrhosis but makes that of alcoholic cirrhosis very unlikely.

Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia.

BACKGROUND: Peripheral kappa receptor agonists may provide a new therapeutic approach for the treatment of functional dyspepsia. AIMS: To evaluate, in a large multicentre trial, the use of the kappa receptor agonist fedotozine to improve symptoms associated with functional dyspepsia. METHODS: Two or more of the following persistent symptoms were required for inclusion: epigastric pain, early satiety, epigastric fullness or distension, nausea, vomiting, and a feeling of slow digestion. On completing a two week placebo washout, 271 patients were randomised into two groups to receive 30 mg fedotozine three times daily or placebo for six weeks under double blind conditions. RESULTS: The improvement in the overall intensity of dyspeptic symptoms (main efficacy criterion) was significantly more pronounced in the fedotozine group (p = 0.002) compared with placebo, as was epigastric pain (p = 0.004) and nausea (p = 0.01); the improvement in postprandial fullness was nearly significant (p = 0.052). Inability to finish a meal and slow digestion were unaffected. The patient global score, the average of the five individual symptoms, was notably ameliorated with fedotozine (p = 0.021). The safety of fedotozine was excellent. CONCLUSIONS: Fedotozine at 30 mg three times daily is safe and more effective than placebo for the relief of key symptoms associated with functional dyspepsia.

[Treatment of systemic scleroderma with ketanserin. Randomized, double-blind 6-months study of 27 cases]. / Traitement de la sclérodermie systémique par la Kétansérine. Etude randomisée, en double aveugle, sur 6 mois, de 27 cas.

Twenty-seven patients with systemic scleroderma and Raynaud's phenomenon underwent a randomised double blind therapeutic trial: monotherapy with Ketanserine (80 mg/day for 6 months) against Placebo. The secondary effects were comparable in both groups as were the withdrawals from the trial for aggravation of Raynaud's phenomenon (one in each group). No significant difference was observed between the two groups as regards the evolution of the Raynaud's phenomenon or skin changes. Dysphagia was improved in the Ketanserine group (p less than 0.05) but not in the Placebo group. Some patients in the Ketanserine group experienced an improvement in the Raynaud's phenomenon at the end of the trial period; there were no improvements in the Placebo group. Three haemorrheological parameters (total blood viscosity, plasma viscosity and thixotropism) were abnormal at the beginning of the trial and did not improve by the end in the Ketanserine group. The K infinity coefficient of Quemada's law was normal at the start of the trial and increased after treatment (p less than 0.05).

Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis.

In a double-blind, randomized, comparative trial of the prokinetic drug cisapride and the H2-blocker cimetidine, mucosal healing and changes in symptoms of gastroesophageal reflux were evaluated in patients with erosive reflux esophagitis. The patients were treated with either cisapride, 10 mg four times a day (N = 36) or cimetidine, 400 mg four times a day (N = 37) for six weeks, or for 12 weeks if mucosal healing was not obtained by week 6. Upon entry, two thirds of the patients in each group had grade I (Savary-Miller) esophagitis, and the remainder grade II or III. At the end of treatment, endoscopy showed mucosal healing in 56% (38-72%; 95% confidence interval) of cisapride and 57% (39-73%; 95% confidence interval) of cimetidine patients. After six weeks, both drugs significantly (P less than 0.01) decreased the intensity and frequency of heartburn, regurgitation, and the postural syndrome. No significant intergroup differences were found regarding endoscopic parameters or the improvement of heartburn and regurgitation. Concomitant antacid use was also comparable. Adverse effects were reported by four cisapride and nine cimetidine patients. These results indicate that the effects of cisapride compare well with those of cimetidine in terms of both esophageal mucosal healing and symptom relief.

[Moschowitz's disease: efficacy of anti-platelet aggregation agents]. / Maladie de Moschowitz: efficacité des antiagrégants plaquettaires.

In November 1976, a 52 year old woman presented with a Moschowitz syndrome with clinical manifestations of continuous fever at 39 degrees and a transient Wernicke type aphasia. Laboratory findings included schizocytosis, a peripheral thrombocytopaenia and functional renal insufficiency. The ethanol tests was positive but there was no frank defibrination syndrome. After corticosteroid therapy failed, the patient was treated with Dipyridamole 400 mg/24 hours IV and acetylsalicylic acid 4 g/24 hours IV. Fever disappeared on the same day and the thrombocytopaenia was corrected in 48 hours. The patient was considered to be cured 15 days later. No precise aetiology to explain the Moschowitz syndrome was discovered apart from the recent ingestion of oestrogens. The authors emphasise the considerable progress which this use of a combination of Dipyridamole and aspirin represents, resulting in the cure of Moschowitz syndrome, a condition considered to be fatal up until a few years ago.