Evaluation of the bronchodilator properties of Ro 31-6930, a novel potassium channel opener, in the guinea-pig

1. Ro 31-6930 (0.001-0.3 microM), cromakalim (0.03-3.0 microM), salbutamol (0.001-0.3 microM) and theophylline (0.3-100 microM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC50 values of 0.044, 0.20, 0.021 and 21.0 microM respectively. All four agents also relaxed tone supported by betahistine, carbachol, 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4), U46619 and prostaglandin D2 (PGD2). The order of potency of tracheal relaxants was always salbutamol greater than Ro 31-6930 greater than cromakalim greater than theophylline. 2. All four agents evoked dose-related reductions in 5-HT- and histamine-induced bronchoconstriction in pithed vagotomised guinea-pigs. The dose of Ro 31-6930 producing 50% inhibition of a 5-HT bronchoconstriction was 11.6 micrograms kg-1 and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4 micrograms kg-1. Salbutamol was approximately 4-5 times more potent than Ro 31-6930 whilst cromakalim was approximately 10 times less potent than Ro 31-6930 as a bronchodilator. Theophylline was markedly less potent than any of the other agents. 3. Ro 31-6930, cromakalim, salbutamol and theophylline each protected conscious guinea-pigs from histamine-induced respiratory distress. Ro 31-6930 and salbutamol were each effective at oral doses of 1.0 and 3.0 mg kg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0 mg kg-1. Theophylline showed activity only at 300 mg kg-1 p.o. 4. Ro 31-6930 is a novel potassium channel opener which is a potent relaxant of guinea-pig tracheal smooth muscle in vitro and a bronchodilator in vivo.     

Human liver microsomal N-hydroxylation of dapsone by cytochrome P-4503A4.

One of the major routes of elimination of dapsone (4,4'-diaminodiphenylsulfone) is by N-oxidation, to produce a hydroxylamine metabolite. The specific form of cytochrome P-450 (P-450) involved in this oxidation reaction was examined in human liver microsomal preparations previously characterized with respect to their content of several known P-450 enzymes. Among five preparations, the rank order of activity for dapsone hydroxylamine formation was most well correlated with the immunochemically determined level of P-4503A4 (r = 0.94, p less than 0.03). Moreover, inhibition of microsomal oxidation was observed with antibodies specific to P-4503A, with a maximum reduction of greater than 90%, but was not produced by antibodies specific to P-4501A2, P-4502CMP, or P-4502E1. Prior incubation of microsomes with gestodene (100 microM) or troleandomycin (20 microM), known selective mechanism-based inhibitors of P-4503A enzymes (in the presence of NADPH), led to 75% and 40% reductions in catalytic activity, respectively. In contrast, preincubation with increasing concentrations of alpha-naphthoflavone, a known activator of P-4503A4, increased dapsone N-hydroxylation in a concentration-dependent manner, with 5-fold activation being observed at 50 microM alpha-naphthoflavone. Finally, P-4503A4 isolated from human liver microsomes and cDNA-expressed P-4503A4 (in yeast) were both able to catalyze dapsone N-hydroxylation, with the latter preparation exhibiting a 3-fold activation in the presence of 100 microM alpha-naphthoflavone. Collectively, these findings demonstrate that N-oxidation of dapsone in human liver is predominantly mediated by P-4503A4, and they suggest that quantitative measurement of this metabolic pathway in vivo might serve as an index of the activity of this enzyme.     

Total anomalous pulmonary venous drainage. Seventeen-year surgical experience

Between 1968 and 1985, 80 children underwent correction of total anomalous pulmonary venous drainage. There were 47 boys and 33 girls whose ages ranged from 3 days to 16 years (median 2 months, interquartile range 5 years). Seventy (87.5%) were less than 1 year of age at operation. Fifty-eight (72.5%) weighed less than 5 kg, the range being 1.6 to 42 kg (median 3.7 kg, interquartile range 2.4 kg). Forty-five (56%) patients had supracardiac, 14 (17.5%) cardiac, 15 (19%) infracardiac, and 6 (7.5%) had mixed total anomalous pulmonary venous drainage. Follow-up was complete in 78 (97.5%) and ranged from 6 to 189 months (median 58 months, interquartile range 59 months). There were 14 (17.5%) early and six (7.5%) late deaths. Analysis by various factors revealed year of operation as the only factor to affect survival at the 5% level of significance. Early mortality was 29% between 1968-1977 and 11% between 1978-1985 (p = 0.04). Postoperative pulmonary venous obstruction occurred in five (6%) patients between 6 weeks and 3 months after operation. All 5 died, three after reoperation. Five (6%) other children had reoperations, four for residual shunts and one for superior vena caval obstruction.     

Lipid lowering therapy leads to a reduction in sodium-lithium countertransport activity.

Erythrocyte sodium-lithium countertransport (SLC) was measured in 17 patients with either combined hyperlipidaemia or hypercholesterolaemia before and after lipid lowering therapy. Before treatment SLC related to the serum triglyceride level and was increased in combined hyperlipidaemia. After treatment the SLC had returned to normal and the change in SLC was related to the change in serum triglyceride levels. Raised SLC is associated with essential hypertension but is not related to blood pressure. Therefore, the association of raised SLC with hyperlipidaemia and essential hypertension appears to have different underlying mechanisms.     

Trans-perineal implantation of radio-opaque treatment verification markers into the prostate: an assessment of procedure related morbidity, patient acceptability and accuracy.

On-line imaging of prostate markers can be used to compensate for errors in radiation delivery. This study assessed the patient acceptability and morbidity associated with the trans-perineal route of implantation. A minority experienced acute pain or bleeding. Placement was accurate in all but one subject. An operator related learning curve exists. Although this is an invasive procedure most patients found it acceptable. Implementation for routine clinical practice is feasible.     

Cyclosporin A inhibits mitogen-activated but not phorbol ester-activated locomotion of human lymphocytes.

Human blood lymphocytes acquire locomotor capacity during 24 hr culture with mitogens such as monoclonal anti-CD3 antibodies, phytohaemagglutinin (PHA), or Staphylococcus aureus Cowan strain (SAC). Activation of locomotor capacity by these agents is blocked by the presence of cyclosporin A (greater than or equal to 10 ng per ml), as measured by inhibition of the development of morphological polarization of the cells in culture and inhibition of their capacity to invade collagen gels. The response to OKT3 is inhibited by lower doses of cyclosporin than the responses to SAC or PHA. Phorbol myristate acetate (PMA) induces locomotion of lymphocytes in culture that is not inhibited by cyclosporin. Cyclosporin has no effect on the locomotion of lymphocytes that already possess locomotor capacity. Thus it neither inhibits immediate stimulus-induced polarization of lymphocytes direct from blood, nor reverses polarization of lymphocytes that have acquired motility in culture. These results suggest that cyclosporin prevents events, occurring during the G1 phase of growth, that are necessary for non-motile lymphocytes to acquire locomotor capacity, but has no effect on the locomotor mechanism itself in already motile cells.     

Report of the british psychosocial oncology group annual conference 1991

The 8th Conference of the British Psychosocial Oncology Group was held in London on 9–10 December 1991 and attracted over 120 participants. The conference was extended from its usual one day format to one and a half days, to allow more time for both a formal and informal exchange of ideas. Eight invited speakers participated, but proferred papers and posters remained an important focus of the meeting. This is the largest annual conference in Britain for professionals working in psychosocial oncology and an important forum for the presentation of research. As in previous years, the conference attracted a number of newcomers, indicating the continued expansion of this field of research. A number of topical issues were presented in keynote papers by invited speakers. New work in cancer prevention and the associated areas of counselling families at risk and ethical issues, formed one symposium. Communication skills and relevant training needs in paediatric and adult oncology were an important theme of the conference and intervention studies formed the third main topic.     

Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetrahydrobiopterin-dependent hydroxylation

Serum phenylalanine and tyrosine levels were measured in 26 patients with severe depression before and after receiving electroconvulsive therapy. The phenylalanine:tyrosine [P:T] ratio declined significantly for those responding to treatment but not for nonresponders. These findings are discussed in relation to tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, dopamine and serotonin and the hydroxylation of phenylalanine to tyrosine.