Causality assessment of adverse drug effects: when is rechallenge ethically acceptable?
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Biomedical subjects
Publications and source records attributed to M J Kendall.
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Asthma is the most common respiratory disease encountered in clinical practice, affecting both children and adults. It is an important cause of respiratory morbidity and mortality. Recent therapeutic developments have shown that leukotrienes are the most potent and important inflammatory mediators in the pathology of both acute and chronic asthma. They cause increased bronchoconstriction, mucous secretion, and vascular permeability. Studies using compounds that block leukotrienes (receptor antagonists - montelukast and zafirlukast and 5-lipoxygenase inhibitors - zileuton) have demonstrated improved asthma control in patients aged 12 years and older. In this article we assess the therapeutic importance of these new compounds.
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Impaired antioxidant defence is implicated in the development of cardiovascular complications in non-insulin-dependent diabetes (NIDDM). However, as many of these patients are elderly, observed changes in antioxidant status may be due to the patient's age rather than their disease. We sampled blood from 47 elderly NIDDM patients (21 male and 26 female; mean age +/- SD, 75.62 +/- 7.97 years), 66 young (30 male and 36 female; 24.52 +/- 4.72 years) and 58 healthy elderly volunteers (17 male and 41 female; 70.74 +/- 4.85 years), and measured the antioxidant glutathione, the marker for free-radical-damage lipid hydroperoxide products (LHP), vitamin E and total antioxidant capacity (TAC). There was a significant increase in LHP in the healthy elderly group compared with the young volunteers (3.14 +/- 1.5 vs. 2.14 +/- 1.38 mumol/l, p < 0.01). The values were much higher in NIDDM patients (7.02 +/- 2.29 mumol/l, p < 0.0001 vs. healthy elderly). There was a reduction in TAC in healthy elderly compared with the young (359.99 +/- 54.82 vs. 471.47 +/- 94.29 mumol/l trolox equivalents, p < 0.0001), but there was no further reduction in NIDDM patients. Similarly, glutathione was reduced to the same degree in healthy elderly and NIDDM patients (0.29 +/- 0.09, 0.30 +/- 0.11 vs. 0.54 +/- 0.19 mumol/l in young volunteers, p < 0.0001). Vitamin E concentrations were comparable in all groups (26.34 +/- 5.39 young volunteers, 31.50 +/- 8.23 healthy elderly and 30.98 +/- 9.03 mumol/l NIDDM patients), but after correction for serum cholesterol there was a significant reduction in the diabetic group compared with the young, but not with the elderly (5.54 +/- 1.55 vs. 6.67 +/- 1.86 vs. 6.31 +/- 1.85 (mumol/l)/(mmol/l), p < 0.01). We have demonstrated an age-dependent reduction in total antioxidant capacity and glutathione defence and an age-independent increase in LHP in elderly patients with NIDDM. Reduced concentrations of vitamin E were demonstrated in NIDDM patients compared with young, but not elderly, volunteers. Increased oxidative damage occurs independently of age in NIDDM patients despite comparable antioxidant defences in this age group.
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AIMS: To determine whether the measurement of vascularity can be used to differentiate follicular adenomas from follicular carcinomas or to reflect the prognosis of follicular carcinomas and papillary carcinomas of the thyroid gland, and to compare four methods of assessing vascularity. METHODS: Tissue sections from 26 papillary carcinomas, 15 follicular adenomas, and 15 follicular carcinomas were stained with an antibody to CD34. A computerised image analysis system was used to calculate, for each tumour, mean endothelial areas and the mean endothelium to tumour epithelial nucleus area ratio from 10 systematically selected fields across one dimension of the tumour ("systematic field" analysis) or from the three most vascularised fields of the tumour ("hot spot" analysis). A European Organisation for Research on Treatment of Cancer (EORTC) prognostic index was calculated for each papillary carcinoma and follicular carcinoma. RESULTS: Significant differences in vascularity between the three tumour groups could only be shown by comparing mean endothelial area values measured from hot spots. While the hot spot median mean endothelial area of follicular carcinomas was significantly greater than that of follicular adenomas, there was a large overlap between the two groups. For follicular carcinomas, higher hot spot mean endothelial area values were related to worse prognosis as indicated by the EORTC prognostic indices. No association between vascularity and prognosis was found for the papillary carcinomas, regardless of the method of assessing vascularity. CONCLUSIONS: Measuring endothelial area from hot spots using a computerised image analysis system is a sensitive method of assessing the vascularity of thyroid tumours. While vascularity measurement cannot be recommended as a practical tool for differentiating between malignant and benign follicular tumours, the suggestion that vascularity may reflect prognosis for follicular carcinomas deserves further study.
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Most antihypertensives have advantages and disadvantages. The ideal antihypertensive drug should be effective in lowering blood pressure, well tolerated, safe in the long term, and easy to use. Ideally, it should be relatively inexpensive. Most importantly it should reduce the risk of the adverse effects of high blood pressure, such as myocardial infarction, sudden death, stroke, heart failure, renal damage, and retinal changes. Most antihypertensive drugs effectively reduce blood pressure, are available as once daily preparations, and are safe long-term. Unfortunately, most antihypertensive drugs cause adverse effects in some patients and for few drugs is there good evidence that they protect the heart, the brain, the kidney, and the eye? Reducing the effects of Angiotensin II (using an ACE inhibitor) has been shown to reduce the incidence of coronary events, sudden death, heart failure, renal damage, and fundal changes. AT1 blocking drugs offer the same pharmacological advantages but also very good tolerability, in particular no cough. Therefore, they have the potential to meet all the criteria for an ideal antihypertensive drug.
Claims could not easily be made that beta-blockers as a group are the most potent or best-tolerated antihypertensive drugs. However, they have a very important role in the management of hypertensive patients who are being treated to prevent cardiovascular complications. Whilst stroke incidence can be reduced by effective blood pressure control, preventing the progress of coronary artery disease to reduce the patients risk of having a myocardial infarct, dying suddenly or developing heart failure is more difficult. Beta-blockers, particularly lipophylic beta-blockers, are the antihypertensive drugs for which there is most evidence that they reduce coronary mortality. Furthermore, the adverse effects of beta-blockers have been exaggerated and there is good evidence that the elderly, diabetics, and those with impaired left ventricular function do derive considerable benefit from beta-blockade. Low plasma concentrations of beta1 selective drugs are clinically effective and are well tolerated.
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