Synthesis, SAR and pharmacology of CP-293,019: a potent, selective dopamine D4 receptor antagonist.

A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.

Discovery of CP-96,345 and its characterization in disease models involving substance P.

Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.

The proper use and benefits of veterinary antimicrobial agents in practice in cattle.

A rational basis for the therapeutic and prophylactic use of antimicrobials is discussed. Different approaches are needed to deal with the individual animal, group or herd disease problem. Improved antibiotic preparations are needed to enhance the efficacy of treatment and minimise suffering and lost production.

The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.

Intracavitary right heart cooling during coronary bypass surgery. A prospective randomized trial.

Augmented right heart cooling (RHC) with bicaval cannulation, pulmonary artery venting, and intracavitary cooling has been advocated for prevention of right ventricular failure and supraventricular tachyarrhythmias after open heart surgery. To evaluate RHC, 78 patients undergoing coronary bypass surgery were prospectively randomized to receive added RHC (n = 38) or standard protection with single atrial cannulation (SC) (n = 40). RHC and SC patients were similar regarding right coronary artery occlusion (n = 10 and 12, respectively), number of grafts performed (3.7 +/- 1.0 and 3.4 +/- 0.9), and cross-clamp time per graft (10.2 +/- 1.8 and 9.8 +/- 2.3 minutes). RHC led to significantly lower right atrial (11.6 degrees +/- 1.0 degree vs. 19.5 degrees +/- 3.3 degrees C) and right ventricular (7.2 degrees +/- 1.9 degrees vs. 12.2 degrees +/- 1.9 degrees C) temperatures. There was no detectable deterioration in right heart function or left heart function in either group after cardiopulmonary bypass. Bypass time was longer in RHC patients (86.7 +/- 17.9 vs. 76.0 +/- 18.2 minutes, p less than 0.05). Technical problems related to multiple cannulation occurred in four RHC patients. After cross-clamp removal, creatine kinase-MB levels were significantly higher with RHC at 2 hours (14.2 +/- 7.6 vs. 6.4 +/- 4.6 IU/l, p less than 0.001), 12 hours (19.1 +/- 19.5 vs. 8.6 +/- 10.3 IU/l, p less than 0.005), and 24 hours (14.1 +/- 19.6 vs. 7.1 +/- 9.2 IU/l, p less than 0.05). Mortality and morbidity were similar in the two groups. In particular, supraventricular tachyarrythmias occurred in 11 (28.9%) RHC and 10 (25%) SC patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Trends in invasive treatment of single-vessel and double-vessel coronary disease.

We examined our practice of invasive therapy for one- and two-vessel coronary disease to assess the impact of the randomized trials of coronary surgery and the current use of angioplasty. We first reviewed our results with coronary artery bypass graft in equivalent patients in the Coronary Artery Surgery Study with one- and two-vessel disease between 1976 and 1981. Among 1376 patients, hospital mortality was 0.07%, and 5-year survival was 95.2% +/- 0.8%. To define trends in invasive therapy, which have since occurred, we compared 100 patients with one- and two-vessel disease in each of three groups: 1979 coronary artery bypass graft, 1984 coronary artery bypass graft, and 1984 percutaneous transluminal coronary angioplasty. Preoperative characteristics in the average 1979 and 1984 patients were similar; however, in 1984, patients who had a coronary artery bypass graft were older than patients who had percutaneous transluminal coronary angioplasty (61.5 versus 56.7 years, p less than 0.01), they required more heart medications (2.1 versus 1.5, p less than 0.01), had more previous infarctions (0.8 versus 0.5, p less than 0.01), and more patients had an ejection fraction of less than 50% (34% versus 7%, p less than 0.01). Patients who had angioplasty had a shorter postoperative stay (median number of days 7, 7, 2, p less than 0.01). Freedom from major complications was similar among the groups (91%, 87%, 85%). Unstable symptoms were the most frequent indication for invasive therapy (approximately 80%), whereas long-term symptoms, those considered in the randomized trials, occurred in relatively few patients. The number of patients without at least one definite indication for invasive therapy was 13%, 3%, and 11%, p less than 0.05, suggesting that the indications for the 1984 coronary artery bypass graft group have become more restrictive since the 1979 coronary artery bypass graft group. Indications for the 1984 percutaneous transluminal coronary angioplasty group remained less restrictive, being similar to those for the 1979 coronary artery bypass graft group. A continuing trend toward the use of percutaneous transluminal coronary angioplasty was evident, as 56% of the 1979 coronary artery bypass graft group of patients and 32% of the 1984 coronary bypass group of patients would be offered percutaneous transluminal coronary angioplasty rather than coronary artery bypass graft on the basis of 1986 percutaneous transluminal coronary angioplasty criteria. The p values were obtained with analysis of variance or chi 2 test.

Gene networks in development.

A model is presented for the formation of temporal and spatial patterns of cell types during the development of organisms. It is demonstrated that very simple random networks of interactions among genes that affect expression may lead to the autonomous development of patterns of cell types. It is required that the networks contain active feedback loops and that there is limited communication among cells. The only elements of the model, gene interactions, are specified by the DNA nucleotide sequences of the genes. Therefore, the model readily explains how the control of development is specified by the organism's DNA. In the context of this model, the formation of positional information and its interpretation becomes a single process.