Effects of the 5-HT3 antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy man: a double-blind crossover trial.

AIMS: 5-hydroxytryptamine3 receptor antagonists act antiemetically and slow colonic transit. This study evaluated effects of the high-affinity 5-HT3 antagonist, cilansetron, on fasting, meal-and anticholinesterase-stimulated phasic contractile activity of the human sigmoid colon as well as on bowel habits and stool consistency. METHODS: Five female and seven male healthy volunteers received, during three 7 day periods separated by 7 day wash-out periods, 4 mg cilansetron, 8 mg cilansetron or placebo three times daily orally under random, double-blind, crossover conditions. On day 8 of each treatment period, motility 20-40 cm from the anal verge was recorded using five pressure sensors spaced at 5 cm intervals. After a basal 30 min, subjects swallowed a further dose of the scheduled treatment; 60 min later, blood was taken for the determination of plasma cilansetron levels. Thereafter, subjects ingested a 4200 kJ meal and 250 ml sweetened mallow tea (166 kJ); 90 min after meal onset, 1 mg neostigmine was administered intramuscularly and motility recording was continued for 60 min RESULTS: Phasic contractile activity and intraluminal base-line pressure increased postprandially and more so after neostigmine. With cilansetron, the area under the pressure curve as the primary outcome variable and the number of contractions were significantly greater than with placebo (P = 0.005), amplitude and duration of contractions and base-line pressure were not affected. The effects of the two cilansetron dosages did not differ. With cilansetron, stool tended to become firmer. No adverse effects were observed. Plasma levels were highest with 8 mg cilansetron. CONCLUSIONS: Cilansetron slightly augments meal-stimulated and markedly neostigmine-stimulated phasic motility of the sigmoid colon. When administered over 7 days, it tends to increase stool consistency and is well tolerated.

Effects of PAF on cardiac function and eicosanoid release in the isolated perfused rat heart: comparison between normotensive and spontaneously hypertensive rats.

The aim of this study was (a) in isolated perfused rat heart to characterize the effects of platelet-activating factor (PAF) on coronary flow, ventricular contractility, and eicosanoid release and (b) to determine whether PAF effects are altered in hearts from spontaneously hypertensive rats (SHR). PAF (10(-10)-10(-7) mol) dose-dependently decreased coronary flow and ventricular contractility; concomitantly, coronary effluent concentrations of thromboxane (TX)B2 and prostaglandin F2 alpha (PGF2 alpha) were elevated but not those of prostacyclin. The PAF receptor antagonist WEB 2086 (10(-7)-10(-5) mol/l) concentration-dependently antagonized these PAF effects. In addition; the cyclo-oxygenase inhibitor indomethacin (5 x 10(-5) mol/l) prevented PAF (10(-9)-10(-7) mol) induced eicosanoid release; in the presence of indomethacin PAF caused coronary constriction and ventricular depression only at the highest dose (10(-7) mol) but had no effect at 10(-9) or 10(-8) mol. Moreover, the TXA2 antagonist SQ29,548 (10(-6) mol/l) completely inhibited 10(-8) mol PAF induced ventricular depression but did not effect coronary constriction. In SHR PAF (10(-9)-10(-7) mol) evoked decreases in coronary flow and ventricular contractility did not differ from those in normotensive Wistar-Kyoto rats while PAF induced TXA2 and PGF2 alpha release was markedly enhanced. In addition, decreases in coronary flow and ventricular contractility induced by the TXA2 agonist U 46619 (10(-7) mol/l) were markedly depressed in SHR. We conclude that in isolated perfused rat heart PAF causes coronary constriction and depression of ventricular function mainly indirectly through released TXA2 and/or PGF2 alpha. Moreover, the fact that in SHR the PAF effects on coronary flow and ventricular function are not altered despite markedly enhanced TXA2 and PGF2 alpha release supports the view that in the SHR the receptors mediating TXA2 and/or PGF2 alpha effects are desensitized.

Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia.

A 2-day-old girl developed a severe lactic acidosis with a normal lactate/pyruvate ratio and hyperammonaemia. Plasma arginine and citrulline levels were below the limit of detection. In muscle total pyruvate dehydrogenase complex (PDHC) and pyruvate decarboxylase (E1) activities were reduced to a fraction of lower control values. The acute neonatal period was bridged with peritoneal dialysis, dichloroacetate therapy, supplements of arginine and branched chain amino acids, a complete vitamin B complex and lipoic acid. Lactate homeostasis responded to pharmacological supplements of lipoic acid. At age 1 year the child was hypotonic, showed severe developmental retardation, optic atrophy and cranial dysmorphism. She died aged 1 year 8 months with signs of respiratory paralysis but with normal lactate levels under assisted breathing. Pathological findings at autopsy were suggestive of Leigh syndrome, interstitial pneumonia and extensive fatty infiltration of hepatocytes. Regression analysis of data from 187 plasma amino acid determinations from the patient over a period of 1 year 8 months revealed a persistent-imbalance involving alanine, glutamic acid, glutamine, proline, citrulline and branched chain amino acids. Aspects of acute and long-term therapy in this patient and some implications of the imbalances in plasma amino acids are discussed.

[The effect of trapidil and the trapidil derivative AR 12463 on blood pressure and thromboxane formation in spontaneously hypertensive rats]. / Zur Wirkung von Trapidil und Trapidilderivat AR 12463 auf Blutdruck und Thromboxanbildung spontanhypertoner Ratten.

The trapidil derivative AR 12463 has a much more stronger inhibiting effect than trapidil on different atherosclerotic parameters of the cell cultures obtained from normal intima and fatty streaks of human aorta, on thromboxane (TX) formation and on the aggregation of human platelets in vitro, and on the activity of phosphodiesterase. In addition to these present results, AR 12463 reduced significantly the mean arterial blood pressure of spontaneously hypertensive rats (at a dosage of 20 mg/kg/d administered orally for 2 weeks) in contrast to the same dosage of trapidil. Simultaneously, TX formation is significantly reduced in serum by 48% in aorta thoracica by 29%, and in aorta abdominalis by 19%. Due to these properties, AR 12463 seems to be suitable for a therapeutic and prophylactic strategy in chronic ischemic diseases.