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Biomedical subjects

T R Evans

Publications and source records attributed to T R Evans.

At least 55 records · Page 3Linked to original sources
PubMed1992

Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women.

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5, 5, 12.5, 25, 50, 200, 400, and 800 mg (n = 3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35, 28, and 39% of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under the detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, all biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges.

Aged↗
PubMed1992

Lactic acidosis. A presentation of metastatic breast cancer arising in pregnancy.

Lactic acidosis B is a rare metabolic complication of malignancy. It usually is associated with advanced and extensive metastatic disease. The authors report a case in which lactic acidosis was the presenting feature of a previously undiagnosed case of metastatic breast cancer in a pregnant woman and that resolved with successful antineoplastic treatment. The authors review the likely cause and management of the condition.

Acidosis, Lactic↗
PubMed1992

A double-blind study of the efficacy of metronidazole gel in the treatment of malodorous fungating tumours.

A double-blind placebo-controlled trial was undertaken to assess the value of topical metronidazole gel preparation in the palliation of the offensive odour of fungating tumours. This 5 day trial was followed by a 6 day period during which all patients received the active gel. Subjective odour assessments were performed by both patients and medical staff. 11 patients were entered and the randomisation was then halted because of an obvious overall benefit over the whole 11 days. There was a non-significant trend in favour of the active treatment during the initial double-blind placebo-controlled phase of the trial, and no side-effects were observed.

Administration, Topical↗
PubMed1992

Exemestane (FCE 24304), a new steroidal aromatase inhibitor.

Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.

5-alpha Reductase Inhibitors↗
PubMed1992

Oestrone sulphatase activity in mammary tumours and the liver of N-nitrosomethylurea treated rats.

Oestrone sulphatase may be an important means of production of intra-tumoural oestrogens in breast cancer cells. The N-nitrosomethylurea induced rat mammary tumours, which is a good model of human breast carcinoma, was utilised to examine the significance of intra-tumoural oestrone sulphatase levels. The particular fraction (100,000 g pellet) was prepared from both the liver and the tumour of NMU treated rats and assayed for sulphatase activity. The tumour enzyme had an optimum pH of 7.2, Km value of 14.8 microM and Vmax of 0.90 nmoles min-1 mg-1, while the hepatic enzyme was optimal at pH 7.4, Km of 10.8 microM and Vmax of 3.71 nmoles min-1 mg-1. The relationship of intra-tumoural sulphatase levels with tumour regression and progression in endocrine responsive tumours was investigated. Tumour regression as a result of oophorectomy was associated with a significantly decreased intra-tumoural sulphatase level (mean level = 0.165 nmoles min-1 mg-1) in comparison to a control group (mean level = 0.319 nmoles min-1 mg-1, P less than 0.05) in which the tumours remained stable. This significant difference was not observed in the corresponding hepatic samples suggesting that it is the intra-tumoural rather than the peripheral production of oestrogens by oestrone sulphatase that is important in supporting growth of endocrine responsive tumours.

Animals↗
PubMed1992

Instructors--a weak link in resuscitation training.

One explanation for the well documented poor basic resuscitation skills of health-care professionals is that these skills are not acquired during initial training. The first aim of our study was to assess the basic life-support skills of trainers teaching basic resuscitation. The second aim was to examine the relationship between the trainers' confidence and actual skill. We found that practical basic life-support skills prior to the two-day training course were poor. They were still inadequate after training. Assessments before and after the course showed significant positive correlation between confidence at performing basic life-support and actual skill. There is an urgent need for formal instructor training in the UK. The training programme should be evaluated, as should the performance of both trainers and trainees, to ensure that all have acquired the requisite skills.

Certification↗
PubMed1991

Inhibition of estrone sulfatase enzyme in human placenta and human breast carcinoma.

Estrone sulfatase is an important mechanism of local synthesis of biologically active estrogens in human breast cancer. The human placental microsome and breast carcinoma mitochondrial/microsomal estrone sulfatase activity were characterized and inhibition studies performed. The Km of the placental tissue enzyme was 6.83 microM, Vmax 0.015 nmol/min/mg, and for the breast carcinoma tissue Km was 8.91 microM and Vmax 0.022 nmol/min/mg. Danazol produced a significant inhibition of estrone sulfatase (20% with 50 microM danazol). No significant inhibition was seen in the presence of aminoglutethimide, rogletimide, tamoxifen, 4-hydroxyandrostenedione, stilboestrol, or any metabolites of danazol or tamoxifen. Studies with synthetic and naturally occurring steroids demonstrated that the presence of a sulfate group at the 3 position to be the most important factor in determining inhibition, and the most potent inhibitor was 5 alpha-androstene-3 beta,17 beta-diol-3-sulfate (Ki of 2.0 microM). The naturally occurring 3-sulfated steroids all demonstrated competitive inhibition. These studies could form the basis for the design of a potent estrone sulfatase inhibitor which would have potential therapeutic activity in the management of breast cancer.

Androgens↗
PubMed1990

An advanced resuscitation training course for preregistration house officers.

Preregistration house officers need to be able to manage the first 5-10 minutes of a cardiac arrest. A course has been designed based on the recommendations of the Resuscitation Council UK 1984 and the format of the American Heart Association advanced cardiac life support course. Fifty-nine newly qualified doctors from the same medical school class were studied in two consecutive groups: Group 1 (n = 31) were commencing their first post and Group 2 (n = 28), whose first preregistration post had been at other hospitals without practical resuscitation training, were commencing their second post. They were pretested and taught in three 2-hour sessions. Five months later they were tested to measure retention of knowledge and skills. Before training there was no difference in knowledge between the two groups but Group 1 were more skilled. The knowledge and skills of both groups immediately after training were significantly improved and at 5 months skills were subject to modest decay only. Experience of managing cardiac arrests was not a substitute for formal practical training.

Educational Measurement↗
PubMed1988

Haemodynamic effects of DPI 201-106, following single intravenous dose administration to patients with moderate cardiac failure.

DPI 201-106 is a novel compound unrelated to other cardioactive agents and has been shown to have an inotropic effect in animal preparations. The drug was given by intravenous infusion (20 mg over 10 min) to 10 patients with moderate cardiac failure and the haemodynamic effects measured at intervals up to 1 h following infusion. Maximal effects were seen immediately following the infusion of DPI 201-106. Cardiac index showed an increase from baseline 2.72 (0.16) 1 min-1 m-2 to 3.18 (0.21) 1 min-1 m-2 at the end of infusion (P less than 0.001). Subsequent values were not significantly raised. Pulmonary capillary wedge pressure and pulmonary artery pressure fell from 27.6 (3.2) and 36.9 (4.4) to 15.3 (3.6) and 24.2 (4.9) mmHg, respectively (P less than 0.001 in both cases). A statistically significant effect on cardiac index was not seen at 1 h. However, pulmonary pressures remained reduced at this point. Radionuclide ejection fraction showed a significant increase from 15.4 (1.5) to 21.9 (2.2)% (P less than 0.005) at the end of infusion, and maintained a significant increase at 1 h. Having demonstrated beneficial, acute haemodynamic effects in this study, further work should be undertaken with DPI 201-106 to investigate the effect of chronic treatment in patients with cardiac failure.

Adult↗
PubMed1988

Haemodynamic effects of intravenous and oral alifedrine in patients with cardiac failure.

A randomized, double-blind, double-crossover, placebo-controlled haemodynamic study was undertaken in patients with Grade II/III (NYHA) cardiac failure to examine the acute effects of intravenous alifedrine, 20 mg and 40 mg (17 patients), and oral 40 mg alifedrine (8 of these patients). Patients received single doses of alifedrine and placebo on separate days, with invasive monitoring. Alifedrine resulted in a significant (p less than 0.001), dose-dependent increase in cardiac output. The peak effect (+23% with 20 mg i.v., +42% with 40 mg i.v. and +29% with 40 mg orally) was seen approximately 1 hour after intravenous administration (with about half of these increases still apparent at 3 hours) but developed progressively over 3 hours after oral administration. There were significant reductions (p less than 0.001) in peripheral resistance (peak mean changes -21% with 20 mg i.v., -31% with 40 mg i.v. and -23% with 40 mg orally), but little (less than +/- 6%) observed change in arterial pressure. With intravenous alifedrine, there were significant increases in stroke volume (+19% with 20 mg, +35% with 40 mg, p less than 0.001) with little (5%) change in heart rate (+3% and +7%, respectively, N.S.). With the 40 mg oral dose, there was a small increase in heart rate (+12%, p less than 0.005) associated with a 19% (N.S.) increase in stroke volume. Peak haemodynamic responses to 40 mg alifedrine orally were 50% to 75% of those seen after administration of the same dose intravenously. When assessed 3 hours after administration, responses to the two routes of administration were similar. There were no clinically or statistically significant changes in arterial (non-invasive), pulmonary artery, pulmonary capillary or right atrial pressures with any dose of alifedrine. No significant arrhythmias were noted clinically with the doses studied. Alifedrine, therefore, is an interesting agent, available both orally and intravenously, which is well tolerated and appears to produce marked acute increases in cardiac output with little change in heart rate or blood pressure. Further studies should determine whether these effects are maintained during longer-term therapy and clarify the relative contributions of positive inotropic and peripheral vasodilator activity to the effects observed.

Administration, Oral↗
PubMed1987

Effect of heparin and contrast medium on platelet function during routine cardiac catheterisation.

Platelet function was studied during coronary angiography of patients complaining of chest pain. The following changes occurred 5 min after injecting 100 IU.kg-1 body weight of a conventional high molecular weight heparin: (a) a significant fall in platelet count; (b) a significant enhancement of platelet aggregation in platelet rich plasma (turbidometric technique) and in whole blood (platelet aggregation technique); and (c) significantly enhanced release of platelet thromboxane A2, a vasoconstrictor. These changes tended to reverse towards baseline values 5 min after injecting a contrast medium (Conray 420), which was found to inhibit platelet aggregation. Thus heparinisation with a high molecular weight heparin seems to cause pronounced activation of platelets in patients undergoing coronary angiography, and this may contribute to the pathogenesis of cardiac ischaemia that may occur during this procedure. Since coronary artery bypass surgery in similar patients involves the use of heparin at much higher doses without the concomitant use of an antiaggregatory contrast medium, it is possible that platelet hyperaggregability may contribute to the well documented ischaemic brain injury associated with this form of surgery. Furthermore, the use of high molecular weight heparin after successful coronary angioplasty or thrombosis may influence the incidence of reocclusion. These findings therefore suggest that low molecular weight heparinoids should be evaluated in these situations since these anticoagulants are only weak activators of platelet aggregation.

Adult↗
PubMed1987

Cardiac Munchausen's syndrome.

Ten years' experience of cardiac Munchausen's syndrome in the Cardiac Care Unit of an Inner London teaching hospital is reported. Thirty-six admissions in this category were identified and analysed, and 4 typical cases are described. The common presenting complaints, recurring features and the relationship with other forms of Munchausen's syndrome are discussed, as are possible strategies available to deal with this clinical entity.

Adult↗