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Biomedical subjects

M J Kendall

Publications and source records attributed to M J Kendall.

At least 37 records · Page 2Linked to original sources
PubMed2001

Quantifying the 5-HT1A agonist action of buspirone in man.

RATIONALE: Buspirone is used as a neuroendocrine challenge in which the increase of circulating prolactin is taken as a measure of the sensitivity of central serotonergic (5-HT(1A)) pathways. Interpretation of the test is complicated, however, by the fact that buspirone possesses D(2) antagonist and 5-HT(1A) agonist activity, both of which will result in the release of prolactin. To understand the significance of prolactin secretion in response to buspirone, it is important to measure the differential actions of the two controlling pathways. OBJECTIVE: To characterise the dual action of buspirone in stimulating the secretion of prolactin by blocking the 5-HT(1A) action with the 5-HT1A antagonist action of pindolol. METHODS: Healthy male subjects (n=35) received buspirone (0.5 mg x kg bw(-1) orally) with and without pre-treatment with the 5-HT(1A) receptor antagonist pindolol (40 mg over 2 days, 0.5 mg x kg bw(-1) on test day). Nine subjects underwent two additional trials in which they received a placebo with and without pre-treatment with pindolol. RESULTS: Pindolol alone caused a small but significant reduction (18%) in the tonic release of prolactin. Buspirone alone produced a robust prolactin response which was reduced to approximately half by pindolol pre-treatment. Pindolol pre-treatment also, on average, delayed the onset and peak of the prolactin response. There was wide variation among individuals both in the absolute response to buspirone and in the proportion that could be attributed to the non-serotonergic agonist action of buspirone (22-82% IQ range). CONCLUSIONS: Our results indicate that while serotonergic pathways play a minor role in the tonic release of prolactin, the response to a buspirone challenge alone cannot be used as a simple index of central serotonergic activity. However, if two challenges are carried out, one with buspirone and the other with buspirone plus pindolol, quantitative measures can be made of the sensitivity of both the 5-HT(1A) and the putative D(2) pathways controlling prolactin release.

Adolescent↗
PubMed2001

Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.

Patients with chronic renal impairment (CRI) are at greatly increased risk for premature vascular disease; however, little is known about its evolution. This paper describes a cohort of patients with CRI and reports study design, baseline demographic and biochemical data, and comparisons with two contemporaneous age- and sex-matched control groups, one with established coronary artery disease and the other without overt vascular disease. Among 369 individuals (median age, 63 years; range, 18 to 88 years; 67% men) with CRI, 34% had a history of vascular disease and 21% had electrocardiographic left ventricular hypertrophy (LVH). Even in those with mild renal impairment (serum creatinine < 2.1 mg/dL), approximately one third had vascular disease and 12% had LVH. A history of hypertension was present in 76% of the CRI group, but as compared with controls, systolic and diastolic blood pressures were not elevated. Low-density lipoprotein (LDL) cholesterol concentration also was not elevated, but CRI was associated with elevated serum triglyceride and plasma homocysteine levels and reduced high-density lipoprotein (HDL) cholesterol, hemoglobin, and serum albumin concentrations. Across the spectrum of CRI, more severe renal dysfunction was associated with lower levels of diastolic blood pressure, LDL and HDL cholesterol, albumin, and hemoglobin, but increased levels of plasma homocysteine. This cross-sectional analysis shows that vascular disease is common in individuals with mild CRI attending a nephrology program and also suggests trends in the levels of a number of potential vascular risk factors with respect to severity of renal dysfunction. These results will be further quantified in a prospective biennial follow-up.

Adolescent↗
PubMed2001

Causality assessment of adverse effects: when is re-challenge ethically acceptable?

One of the most difficult tasks in the evaluation of a medicine is whether it causes a particular rare and unusual (idiosyncratic) adverse effect. Such causality assessments are sometimes done by drug de-challenge and re-challenge. When the adverse effect is potentially serious, there is clearly an important decision to be made as to whether the re-challenge is justifiable and hence ethical. The recent controversy about the potential cardiotoxicity of fexofenadine, the fatalities associated with penicillin re-challenge and the fatalities associated with abacavir re-challenge highlight some of the potential serious risks of drug re-challenge. The associated important ethical issues are discussed. In particular, there is the need to ensure respect for the patient and to consider the scientific and social value of the re-challenge. A framework for evaluating and assessing the appropriateness of a particular drug re-challenge is proposed in the light of recent as well as long-standing discussions of drug re-challenge, patient informed consent and the ethics of human experimentation, in general. It is suggested that a drug re-challenge should be approached with the same rigour and standards of documentation as are currently required of clinical trials. Given the potential conflicts of interest inherent with any drug study, it is argued that the safeguards, as may be provided by scrutiny by an ethics committee, are necessary for a drug re-challenge. For the investigator contemplating the conduct of a drug re-challenge we would recommend the following: (i) a careful risk-benefit assessment as part of the decision-making process; (ii) careful scientific preparation, including appropriate expert support and emergency back-up facilities, if re-challenge is deemed necessary; (iii) the writing of a detailed protocol for independent approval and for safeguarding all concerned; and (iv) meticulous record keeping.

Causality↗
PubMed2001

Beta-blockers in the management of hypertension in patients with type 2 diabetes mellitus: is there a role?

It has been conclusively established that treatment of hypertension in patients with type 2 (non-insulin-dependent) diabetes mellitus will significantly reduce the incidence of stroke, heart failure and progression of diabetic complications. Beta-blockers are effective antihypertensive agents which, in long term studies, have proven beneficial in reducing important clinical end-points. However nonselective beta-blockers may have a negative effect on lipid profiles and contribute to hypoglycaemic unawareness, thus preventing their use in some patients with diabetes mellitus. The development of newer and more selective beta-blockers has overcome many of these problems. In addition, some of the newer agents have novel properties such as release of nitric oxide, which theoretically would make them more attractive in patients with diabetes mellitus. Overall, the adverse metabolic effects of beta-blockers do not appear to be important in clinical practice and these agents should no longer be contraindicated in patients with type 2 diabetes mellitus. Their proven cardiovascular benefits would seem to easily tip the balance in favour of their use.

Adrenergic beta-Antagonists↗
PubMed2000

Clinical trial data on the cardioprotective effects of beta-blockade.

In most patients with heart failure the underlying cause is coronary artery disease (CAD). They have a poor prognosis and die slowly from deteriorating cardiac function or suddenly from ventricular fibrillation or atheromatous plaque rupture. Two key aims of treatment, therefore, are to slow the progression of the underlying CAD and the resulting heart failure and to reduce the risk of sudden death. The impact of drugs on CAD and sudden death can be assessed most effectively in patients who have recovered from a myocardial infarction (post-MI patients). Beta-blockers have been studied in at least 25 trials in post-MI patients and their capacity to reduce mortality and re-infarction has been well documented. About 50% of those who die in post-MI trials die suddenly and beta-blockers particularly propranolol, timolol and metoprolol have been shown to reduce the risk of sudden death significantly. Further evidence that beta-blockers are cardioprotective in post-MI patients can be obtained from trials of other drugs by noting the mortality rates in those patients who were also on a beta-blocker. In three trials of antiarrhythmic drugs and two trials of ACE inhibitors, those on beta-blockers had a better prognosis. There is therefore good evidence that in a patient population known to have serious CAD, beta-blockers can effectively reduce the risk of major coronary events and are particularly effective in reducing the risk of sudden death.

Adrenergic beta-Antagonists↗
PubMed2000

Beta-blockers: recognising the assets in relation to coronary artery disease.

Beta-blockers have been shown to reduce the risk of coronary events and reduce the mortality of patients with hypertension and in those who have had a myocardial infarction. Furthermore, the evidence for long-term benefits in these two patient groups are much more convincing for beta-blockers than for other therapeutic agents used to treat these patient groups. In spite of this beta-blockers are underused because doctors believe that these drugs are contraindicated in many vulnerable patient groups. The data now available from the many trials and observational studies have shown that patients such as the elderly, those with some degree of heart failure, diabetics and those with chronic lung disease not only tolerate beta blockers but derive more benefit than more healthy patient groups.

Adrenergic beta-Antagonists↗