Biomedical subjects
Publications and source records attributed to L Colwell.
Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.
The leading cause of death among patients with diabetes is cardiovascular disease with approximately 80% of all deaths being attributed to coronary heart disease. Acute myocardial infarctions (AMIs) in patients with diabetes are associated with an increased rate of reinfarction than those without diabetes. Following AMI, patients with diabetes are more likely to develop severe heart failure. The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) clinical trial examined the relationship between intensive insulin and conventional therapy following AMI. Results of the DIGAMI study clearly identify the need for tight glucose control following AMI in improving clinical outcomes and mortality.
The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrr ole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon.
Zaragozic acid A analogues are produced by an unidentified sterile fungus when it is exogenously supplied with 2-thiophenecarboxylic acid, 3-thiophenecarboxylic acid, 2-furoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, or 4-fluorobenzoic acid. The analogues carry 2-thiophenyl, 3-thiophenyl, 2-furyl, o-fluorophenyl, m-fluorophenyl, or p-fluorophenyl group, respectively, at C-6' of the C-1 alkyl side chain replacing the phenyl group of natural zaragozic acid A. All the new analogues of zaragozic acid A possess picomolar inhibitory activity against squalene synthase in vitro.
Explore the source record for details and available documents.
31-O-Desmethylimmunomycin O: methyltransferase (DIMT), an enzyme involved in the biosynthesis of immunomycin (ascomycin/FR-900520), was used to synthesize three analogs of this immunosuppressant compound. These compounds were assigned the following structures: 13-O-desmethyl-, 15-O-desmethyl- and 13,15-O-bisdesmethyl-immunomycins. Two of these compounds, namely, 15-O-desmethyl- and 13,15-O-bismethyl-immunomycins have novel structures and were examined for possible immunosuppressive activity by in vitro T-cell proliferation assay. The results showed that methylation of the C-15 hydroxyl is critical for full biological activity of the immunomycin.
STUDY OBJECTIVE: The aim was to measure experimentally the effects in middle aged men of stopping smoking. DESIGN: The study was a randomised controlled trial. SETTING AND SUBJECTS: The subjects were 1445 male smokers, initially aged 40-59 years, who were selected from the Whitehall study survey of 16,016 civil servants on the basis of a high risk of cardiorespiratory disease. MAIN RESULTS: During the next 20 years there were 620 deaths (231 from coronary heart disease), 96 cases of lung cancer, and 159 other cancers. Comparing the intervention with the normal care group, total mortality was 7% lower, fatal coronary heart disease was 13% lower, and lung cancer (deaths+registrations) was 11% lower. An excess rate for other cancers, reported previously, did not persist into the second decade of the trial. CONCLUSIONS: The results are consistent with observational studies, implying that smoking cessation by middle aged men substantially improves their changes of avoiding lung cancer or a fatal heart attack. Our estimate from the trial is that out of every 100 men who stopped smoking, between six and 10 were in consequence alive 20 years later.
A 20 year follow up of 1330 patients in the Medical Research Council trial of short term anticoagulant treatment in myocardial infarction showed no long term benefits; but it provided interesting data on the outcome in such patients. Sixteen per cent of the patients were alive 20 years later. The excess mortality rate in trial participants over that expected for England and Wales as a whole declined rapidly after the early months, but some excess persisted throughout the follow up. Three quarters of all the deaths were from coronary heart disease; 70% of these coronary deaths occurred after the patients had left hospital. This finding emphasises the importance of secondary prevention.
In a prospective study of insulin-dependent diabetic women who in the 1950s were involved in a drug trial, 13 (14%) of those who were still alive 27 years later were reported to have acquired thyroid disease or pernicious anaemia during the follow-up period. This suggests that their diabetes mellitus was a manifestation of a more generalised polyendocrine disorder. The pregnancy history of these 13 women differed strikingly from that of the other 82 insulin-dependent diabetic women: in the diabetic women who subsequently acquired other endocrine disease 69% of pregnancies resulted in a fetal or infant death, compared with 44% in other insulin-dependent diabetic women (p less than 0.01). This risk increased with pregnancy order, the odds ratio of an unfavourable outcome in women who later acquired thyroid disease or pernicious anaemia, compared with the other diabetic women, being 1.2 for the first pregnancy, 3.1 for the second pregnancy, 7.3 for the third pregnancy, and 14.0 for the fourth pregnancy. The mean birthweight of offspring of the women with other endocrine disease was substantially lower than the mean birthweight of offspring of other diabetic mothers (2977 g and 3430 g, respectively). These differences in birthweight and mortality could not be explained by the severity of the mothers' diabetes at the time of their pregnancies, and were evident even before the diabetes was diagnosed.
Explore the source record for details and available documents.
Ten-year results are reported from a randomised controlled trial of anti-smoking advice in 1445 male smokers, aged 40-59, at high risk of cardiorespiratory disease. After one year reported cigarette consumption in the intervention group (714 men) was one-quarter that of the "normal care" group (731 men); over 10 years the net reported reduction averaged 53%. The intervention group experienced less nasal obstruction, cough, dyspnoea, and loss of ventilatory function. Over 10 years their mortality from coronary heart disease was 18% lower than controls (49 and 62 deaths), and that for lung cancer was 23% lower (18 and 24 deaths). Deaths from non-lung cancers were higher in the intervention group (28 v 12 deaths). This unexpected difference was due about equally to an excess in intervention and a deficiency in normal care men, it showed no site specificity, and it was unrelated to change in smoking habit. These findings suggest that it is more likely to have been due to change than to intervention. The total number of deaths were 123 in the intervention group and 128 in normal care (95% confidence limits of difference -22% to +23%). The policy of encouraging smokers to give up the habit should not be changed.
The 27-year follow-up is reported of 136 children whose mothers were involved in a randomised trial of high doses of stilboestrol and ethisterone therapy during pregnancy. The children were not contacted directly. Information about them was obtained from hospitals, general practitioners, and other official sources; and the persons who responded to our inquiries were unaware of who had been exposed to hormones in utero and whose mothers had received an inactive tablet. All children were traced. Urogenital anomalies were reported more frequently in the hormone-exposed than the unexposed children (14% and 9% respectively). The earlier in pregnancy the therapy began, the higher the prevalence rate of abnormalities (X2 for trend, p less than 0.02). No malignant tumours were reported. For males, the proportion reported to be married or living as married was lower in the exposed than in the unexposed group (32% and 62% respectively). The proportion was lower the earlier in pregnancy hormonal exposure occurred and the higher the total hormone dose to which they were exposed (X2 for trend, p less than 0.02). These findings suggest that some interference with sexual function may not be uncommon in males exposed to high doses of stilboestrol and ethisterone while in utero.
In 1950 a trial was set up to evaluate the effects of large doses of stilboestrol and ethisterone on rates of fetal loss in pregnant diabetic women. Eighty women were allocated at random to receive the hormonal treatment and 76 to receive inactive tablets of identical appearance. At follow-up 27 years later, information was obtained about 97% of the women, all but four being traced. All respondents were unaware of who had received hormones. The overall mortality was 4.5 times that of women of comparable age in England and Wales, most deaths being from complications of diabetes. More tumours, mainly benign, of the reproductive tract were reported in the hormone-exposed than the non-exposed group (14 (18%) and two (3%) respectively). Four cases of malignant breast disease were reported in the hormone-exposed women and none in the non-exposed. These findings support other evidence linking oestrogen treatment and breast cancer and suggesting that the latent period before the tumour becomes clinically apparent may be 15 years or longer.