ON THE RELATIONSHIP BETWEEN RESPONSE TO TREATMENT AND SURVIVAL TIME

In this paper we review several approaches which have been used to investigate the relationship between survival time and response to treatment. We show that the approaches based on summary data are subjected to various types of biases (publication bias, confounding by prognostic features, ecologic bias) and are therefore of doubtful value. We also discuss several approaches based on individual patient data. Comparisons of survival by response are generally subject to length-biased sampling, and are therefore inadequate. The landmark method is adequate when responses occur soon after starting treatment, but not when responses may appear later in the course of the disease. For responses which can occur over extended periods of time, response must be considered as a time-dependent covariate. Using data from randomized trials in advanced colorectal cancer, we show that response is a potent and independent prognostic factor for survival in this disease. Analyses using the landmark method yield results essentially equivalent to those in which response is considered as a time-dependent covariate. The hazard rate of responders is about half that of non-responders, after taking the patient's performance status into account. The issue of response as a surrogate marker for survival is taken up further in a separate paper.     

A New Dual-Chamber Pacing Mode to Minimize Ventricular Pacing

Despite the low long-term incidence of high-degree atrioventricular (AV) block and the known negative effects of ventricular pacing, programming of the AAI mode in patients with sinus node dysfunction (SND) remains exceptional. A new pacing mode was, therefore, designed to combine the advantages of AAI with the safety of DDD pacing. AAIsafeR behaves like the AAI mode in absence of AV block. First- and second-degree AV blocks are tolerated up to a predetermined, programmable limit, and conversion to DDD takes place in case of high-degree AV block. From DDD, the device may switch back to AAI, provided AV conduction has returned. The safety of AAIsafeR was examined in 43 recipients (70 ± 12-year old, 24 men) of dual chamber pacemakers implanted for SND or paroxysmal AV block. All patients underwent 24-hour ambulatory electrocardiographic recordings before hospital discharge and at 1 month of follow-up with the AAIsafeR mode activated. No AAIsafeR-related adverse event was observed. At 1 month, the device was functioning in AAIsafeR in 28 patients (65%), and the mean rate of ventricular pacing was 0.2%± 0.4%. Appropriate switches to DDD occurred in 15 patients (35%) for frequent, unexpected AV block. AAIsafeR mode was safe and preserved ventricular function during paroxysmal AV block, while maintaining a very low rate of ventricular pacing. The performance of this new pacing mode in the prevention of atrial fibrillation will be examined in a large, controlled study.     

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60  min after oral administration of 4  mg molsidomine then 15  min after intravenous administration of 15  mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (−7.9%, P <0.01), cardiac output (−7.3%, P <0.01), pulmonary wedged pressure (−45.8%, P <0.05) and hepatic venous pressure gradient (−11.7%, P <0.01). Propranolol decreased heart rate (−21%, P <0.01), further decreased cardiac output (−20.6%, P <0.01) and hepatic venous pressure gradient (−10.5%, P <0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (−8%, P <0.01), heart rate (−19%, P <0.01), cardiac output (−26.5%, P <0.01) and hepatic venous pressure gradient (−21%, P <0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.     

Synthesis and Biological Evaluation of New 3-Aralkylamino-2-aryl-2H-1,2,4-pyridothiadiazine 1,1-dioxides as Potential CCK-Receptor Ligands

A series of 2-aralkyl-4H-pyridothiadiazine 1,1-dioxides and 3-aralkylamino-2-aryl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to quinazolinone CCK receptor antagonists were synthesized and evaluated as CCK-A and CCK-B receptor ligands. The compounds were effective as cholecystokinin-ligands in the micromolar range of concentration, c.f. the cholecystokinin receptor antagonists asperlicin, lorglumide or benzotript, and were thus less potent than the best quinazolinones previously reported. Although the compounds were unsuitable for drug use, the work contributed to our understanding of the chemistry of unusual 2,3-disubstituted pyridothiadiazinedioxides.     

How can the aromatic side-chains modulate the conductance of the gramicidin channel? A new approach using non-coded amino acids

In order to elucidate the role of the aromatic side-chains in the mechanism of transduction of monovalent cations through the channel of linear gramicidin, two series of analogues containing non-coded aromatic amino acids were synthesized. In the first series, the four tryptophans were replaced by either four l -3-(8-quinolyl)alanyl or four l -3-(4-quinolyl)alanyl residues and single channel conductance measurements showed that these substitutions led to a strong lowering of the channel conductance, which is attributed to a modification of the orientation of the aromatic side-chains due to an increase of their hydrophobicity. In the second series, the analogues contained both tryptophyl and naphthylalanyl residues in various amounts and positions. The single channel conductance data indicated that the conductance was mainly governed by the number of polar residues (Trp) and not by their positions. The conformational consequences of these results are discussed together with their influence on the energy profile of the gramicidin channel.