Lack of effectiveness of the platelet-activating factor antagonist SR27417A in patients with active ulcerative colitis: a randomized controlled trial. The Platelet Activating Factor Antagonist Study Group in Ulcerative Colitis.

BACKGROUND & AIMS: Platelet-activating factor (PAF) is increased during relapse of ulcerative colitis. In animal models of experimental colitis, specific inhibition of PAF has reduced inflammation. The aim of this study was to evaluate the efficacy and safety of the PAF antagonist SR27417A in moderately active UC. METHODS: A double-blind multicenter trial was conducted during a 28-day period in hospital outpatients with an exacerbation of ulcerative colitis. Patients were randomized to receive 10 mg/day SR27417A or placebo, and both groups were also given 2.4 g mesalazine. Patient classification at the end of the treatment period was based on sigmoidoscopy and clinical scores. RESULTS: One hundred fifty-one subjects entered the study (75 placebo and 76 SR27417A). The remission rate between placebo- and SR27417A-treated patients at 28 days was not significantly different (29.0% and 35.6% respectively; P = 0.44). Similarly, 49.2% treated with SR27417A had a definite or possible improvement of their symptom score compared with 48.3% of those treated with placebo (P = 0.43). Four subjects in the placebo group and 5 subjects in the SR27417A group discontinued the drug treatment because of adverse events. No significant adverse events were thought to be caused by SR27417A. CONCLUSIONS: Although the specific PAF antagonist SR27417A is safe in humans, there is no evidence of efficacy in the treatment of acute ulcerative colitis.

Cardiac electrophysiological effects of rilmenidine, a novel antihypertensive agent, in the conscious dog: comparison with clonidine.

The cardiac electrophysiological effects of rilmenidine, a novel antihypertensive agent, and clonidine were studied in the conscious dog. Sinus rate, corrected sinus recovery time (CSRT) and Wenckebach point (WP) were measured in seven intact dogs. Atrial rate and atrial effective refractory period (AERP) were measured in six atrioventricular (AV)-blocked dogs with ventricular pacing. In both groups, blood pressure was also monitored. Each dog received with at least a three-day interval rilmenidine as dihydrogen phosphate and clonidine as hydrochloride in four successive intravenous injections, 30 min apart. In intact dogs, rilmenidine was administered at 50, 50, 100 and 200 micrograms/kg and clonidine at 2.5, 2.5, 5 and 10 micrograms/kg. In AV-blocked dogs, doses of rilmenidine were 25, 25, 50 and 100 micrograms/kg, those of clonidine 5, 5, 10 and 20 micrograms/kg. Rilmenidine and clonidine decreased sinus rate and atrial rate from the first dose. In this regard, rilmenidine was respectively 24 and 23 times less potent than clonidine. A lengthening of CSRT was observed at all doses with rilmenidine and at the last three doses with clonidine (ratio: 17) and a lowering of WP at all doses with rilmenidine and clonidine (ratio: 22). A shortening of AERP was also seen with rilmenidine and clonidine from the second dose (ratio: 6). All these effects may at least partly be explained by a cholinergic activation mechanism. In intact dogs both drugs produced a lowering of mean blood pressure (ratio: 17), whereas in AV-blocked dogs, in which ventricular rate was kept constant by pacing, pressure effects were more complex, being the resultant of hypotensive and hypertensive effects, the latter due to alpha vascular stimulation. Taken together, these results indicate that in the conscious dog, rilmenidine and clonidine exert qualitatively identical electrophysiological effects, but with different potency ratios.

Overview of clinical safety and efficacy of tertatolol.

Tertalolol is a noncardioselective beta-blocker, devoid of intrinsic sympathomimetic activity. Its renal vasodilating properties have been demonstrated both in animals and in man. The beta-blocking activity of tertatolol was assessed on the reduction of heart rate at submaximal exercise. The oral dose of 5 mg was optimal, leading to a significant reduction of diastolic blood pressure throughout 24 h. The efficacy was confirmed in mid- and long-term studies. In mid-term, randomized controlled studies, versus beta-blockers, the antihypertensive efficacy of tertatolol 5 mg was comparable to that of acebutolol 400 mg but of earlier onset, and comparable to that of atenolol 100 mg. Its efficacy was confirmed in 3 long-term studies. In the first study, tertatolol 5 mg alone or combined with a diuretic and, if necessary, dihydralazine, controlled 93.6% of patients (supine DBP < 90 mm Hg). 72.7% of patients were controlled with tertatolol alone, 16.4% with tertatolol plus diuretic, and 4.5% with tertatolol plus diuretic and dihydralazine. In a second study, 88.5% of patients were controlled, 56.3% with tertatolol alone and 32.2% with tertatolol plus diuretic. In the third study, 88.8% of patients were controlled after 1 year treatment, 66.1% with tertatolol alone and 22.7% with tertatolol plus diuretic. The overall clinical safety was excellent: only 6.6% of the 2,706 patients treated for 1 year withdrew from the study because of side effects. In patients followed for 1 year, side effects were rare, transient and mostly of mild severity. Biochemical surveillance did not show any adverse metabolic effects of tertatolol. Conversely, in two long-term studies, creatinine and cholesterol levels decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Best mode of expression of acute reversibility of airway obstruction in patients with asthma: application to a new beta-2 agonist, RU 42 173.

Lung function tests must distinguish a true drug-induced bronchial response from changes not related to the drug itself, mainly due to intra-individual variability. We compared the variability and ability to detect true drug-induced bronchodilation of 3 modes of expression of the increase in forced expiratory volume in 1 second (delta FEV1) following administration of a 0.25 mg single oral dose of RU 42 173, a new beta 2-agonist. The study was performed in 12 patients with reversible obstructive asthma in a double-blind, crossover, placebo-controlled, randomized manner. The variability of each index was assessed by calculating the coefficient of variation (SD/mean). True drug-induced bronchodilation was assessed by calculating the F value of each index corresponding to the ratio of between-treatment to within-group differences. Three modes of expression of delta FEV1 were compared: delta FEV1 (L) = the absolute increase in FEV1, delta FEV1 (% baseline) and delta FEV1 (% predicted) where delta FEV1 (L) is divided by baseline FEV1 or predicted FEV1, respectively. A statistically significant increase in FEV1 was found up to respectively 3, 2 and 4 hours after dosing when using delta FEV1 (L), delta FEV1 (% baseline) and delta FEV1 (% predicted). The highest F value was obtained for delta FEV1 (% predicted). The coefficient of variation was lower with delta FEV1 (% predicted) than delta FEV1 (L) and delta FEV1 (% baseline). In conclusion, RU 42 173 showed a bronchodilating effect which appears to be clinically relevant. delta FEV1 (% predicted) was to be the least variable and most powerful index and should be preferred to delta FEV1 (L) and even more to delta FEV1 (% baseline) to assess the acute airway response to a bronchodilator drug.

Electrophysiological effects of intravenous rilmenidine in man.

Ten patients (44 y), 6 with the Wolff-Parkinson-White syndrome, and none with hypertensive disease, underwent electrophysiological studies before and after intravenous infusion of a single dose of 1 mg rilmenidine administered over 15 min. The regimen produced a mean plasma rilmenidine concentration of 3.16 ng.ml-1 at the end of the infusion. There was no significant change in sinus cycle length, PR interval, QRS, QT duration or in PA, AH and HV intervals. Estimated sinoatrial conduction time and corrected sinus node recovery time did not significantly change. In one patient, however, an abnormal pause was noted after termination of rapid atrial pacing. The right atrial effective refractory period decreased from 209 to 194 ms. There was no significant change in the anterograde and retrograde block cycle length or in the refractoriness of the nodal, ventricular and accessory pathways. The cycle length of induced reciprocating tachycardia decreased slightly from 374 to 351 ms. No patient exhibited an abnormal response to the carotid sinus massage. The findings indicate that intravenous administration of 1 mg rilmenidine exerts modest effects on the electrophysiological parameters of the human heart.

Effects of rebreathing conditions and body size on normal human lung tissue volume.

To evaluate the consequences of breathing pattern variations inherent to lung disease on the rebreathing measurement of lung tissue volume (Vt), we carried out a study of ten normal human subjects in whom we assessed the effects of changes in rebreathing volume (Vreb), additional deadspace volume (AVD), respiratory rate (RR), and body height. Vt and alveolar volume (VA) were determined from the end-tidal concentrations of acetylene and helium. We performed Vt measurements using different combinations of Vreb (20, 30 and 50% of predicted vital capacity), of AVD (0, 100, and 200 ml) and of RR (10, 25, and 40 br.min-1). Only slow RR (10 br.min-1) resulted in a higher Vt (p less than 0.001). An increase in Vreb induced an increase in VA but not in Vt. VA and Vt were positively correlated with the height of the subjects. We conclude that, in normal subjects, Vt increases: 1) with the height of subjects; and 2) when the respiratory rate is low. Interpretation of Vt results must take into account these two variables.

Respiratory and haemodynamic effects of lateral thoracotomy or sternotomy in mechanically ventilated rats.

We compared left lateral thoracotomy and sternotomy in rats which were mechanically ventilated for at least 1 h in order to perfect the technique and the surveillance of thoracic opening. Lateral thoracotomy proved to be superior to sternotomy as it was associated with a lower mortality within the first 24 h (20% compared with 50%; p less than 0.05). Lateral thoracotomy causes a smaller reduction in mean blood pressure (104 +/- 11 vs. 71 +/- 7 mm Hg; mean +/- SD; p less than 0.05). Furthermore, following lateral thoracotomy, the rats had a higher postoperative PaO2 (77 +/- 16 vs. 72 +/- 7 Torr) and a lower PaCO2 (29.5 +/- 1.5 vs. 35 +/- 4.3 Torr), although these differences were not statistically significant.

[Diffuse interstitial pneumopathy during treatment with gold salts]. / Pneumopathie interstitielle diffuse au cours d'un traitement par les sels d'or.

A case of severe diffuse interstitial pneumonia is reported in a 69 year old after 5 weeks treatment with gold salts. Regression of symptoms on withdrawal of gold salts and under steroid therapy, the similarity with previously published cases, the absence of another cause lead us to incriminate the gold salts. The case is documented with optical and electronic microscopic studies of transbronchial biopsy and repeated examination of bronchoalveolar lavage fluid. A general review of the literature is included with a critical discussion of the physiopathogenic mechanisms. The results of the examination of the bronchoalveolar lavage fluid are further evidence in favour of cell-mediated hypersensitivity reaction.

Non-hypoxaemic pulmonary oedema induced by alpha-naphthyl thiourea in the rat.

The time course of the respiratory consequences of alpha-naphthyl thiourea (ANTU)-induced lung oedema was studied in adult albino rats, up to 6 h after the injection of 5 mg/kg ANTU. Control rats were injected with olive oil (ANTU solvent). After 6 h, pulmonary extravascular water increased by 50% in ANTU-treated rats and the volume of the pleural effusion reached 3.4 +/- 0.1 ml (mean +/- s.e. mean). The most striking point is the absence of hypoxaemia in the ANTU-treated rats: PaO2 = 103 +/- 1.5 Torr vs 100 +/- 1 Torr in the control rats. The non-decreased PaO2 can be related to the patency of the alveolar airspaces. The predominant location of the oedema in the lung interstitium is caused by a specific lymphatic drainage pathway towards the pleura in the rat which prevents alveolar flooding. Histological findings support this hypothesis. PaCO2 is unaltered: 32 +/- 1 Torr in ANTU rats vs 33.5 +/- 1 Torr in control rats. A slight downward shift of arterial pH is found in ANTU rats: (7.440 +/- 0.010 vs 7.475 +/- 0.010, P less than 0.01). Concomittently (HCO3-)a decreases in ANTU-treated rats (22.2 +/- 1.2 mmol l-1 vs 24.8 +/- 0.6 mmol l-1, P less than 0.01). The absence of hypoxaemia is common with normobaric oxygen (02) and ANTU-induced lung oedema in the rat. A comparison is made between 02 and ANTU toxicity, as for respiratory events and histological features.

[Albumin exchange and polymorphonuclear vascular transit in hyperoxic pulmonary oedema in awake rats]. / Echange d'albumine et transit vasculaire des polynucléaires au cours de l'oedème pulmonaire hyperoxique chez le rat éveillé.

Vascular inflammatory response to hyperoxia (FIO2 greater than 0.98) was studied in awake jugular and carotid catheterized rats. Simultaneous i.v. injection of 125I albumin (125I A), 99mTc polymorphonuclear cells (99mTc PMN) and 51Cr red blood cells (51Cr RBC) allowed to study both the macromolecule exchange through vascular endothelium and the leukocyte uptake by several organs (liver, lungs, spleen) with respect to radiolabelled red blood cells, as an intravascular reference. Rats were exposed to O2 for 24, 38 and 45 h. They were anesthetized and killed by exanguination 15 to 120 min following the tracer injection. After 45 h exposure, the plasmatic 125I A half-life decreased significantly (158 +/- 42 min for the control; 106 +/- 34 min for the exposed animals). The ratio 125I A/51Cr RBC varied significantly in the lung. The iodinated albumin exchange through lung vascular endothelium was altered at the 24th h, with a significant difference reached by the 45th h. At the same time, the pulmonary decreasing curve of 99mTc/51Cr RBC ratio versus time was not not modified. In our experimental conditions, there was no detectable variation in the lung uptake and vascular transit of PMN cells. The discussion of the results must be related with the technics used in the present work when the albumin exchange increased.