The effects of head cooling on endurance and neuroendocrine responses to exercise in warm conditions.

The present study investigated the effects of head cooling during endurance cycling on performance and the serotonergic neuroendocrine response to exercise in the heat. Subjects exercised at 75 % VO(2max) to volitional fatigue on a cycle ergometer at an ambient temperature of 29+/-1.0 degrees C, with a relative humidity of approximately 50 %. Head cooling resulted in a 51 % (p<0.01) improvement in exercise time to fatigue and Borg Scale ratings of perceived exertion were significantly lower throughout the exercise period with cooling (p<0.01). There were no indications of peripheral mechanisms of fatigue either with, or without, head cooling, indicating the importance of central mechanisms. Exercise in the heat caused the release of prolactin in response to the rise in rectal temperature. Head cooling largely abolished the prolactin response while having no effect on rectal temperature. Tympanic temperature and sinus skin temperature were reduced by head cooling and remained low throughout the exercise. It is suggested that there is a co-ordinated response to exercise involving thermoregulation, neuroendocrine secretion and behavioural adaptations that may originate in the hypothalamus or associated areas of the brain. Our results are consistent with the effects of head cooling being mediated by both direct cooling of the brain and modified cerebral artery blood flow, but an action of peripheral thermoreceptors cannot be excluded.

Beta-adrenoceptor blocking drugs: adverse reactions and drug interactions.

Beta adrenoceptor blocking drugs are relatively well tolerated and adverse reactions to them are not common. The ones that do occur are reviewed in this paper under the following headings: Short term adverse reactions, drug interactions, long term adverse reactions, risks in pregnancy and hazards of abrupt withdrawal. Predictable short term effects may be caused either by the actions of these drugs on the beta 1- or beta 2-receptors. The beta 1 adverse effects are hypotension, bradycardia and cardiac failure; these are best avoided by not giving beta-adrenoceptor blocking drugs to susceptible patients with cardiac disease. The beta 2 adverse effects on the bronchi, the peripheral arteries and various metabolic functions may be reduced to some extent by using a relatively cardioselective drug. Unpredictable short term effects such as fatigue, sexual dysfunction and gastrointestinal symptoms may occur but are not common problems with this group of drugs. Similarly, serious drug interactions are infrequent. Under the heading of long term adverse effects the practolol problem and the risk of causing malignant disorders have been considered. There is no evidence that any of the currently available drugs will cause either a practolol syndrome or malignant disease in man. However, the need for careful appraisal by drug regulatory bodies and continued vigilance by all prescribers of beta-adrenoceptor blocking drugs remains. The possible adverse effects of treatment during pregnancy are also considered. It now appears that beta-adrenoceptor drugs can be used safely in pregnancy but since neonatal bradycardia and hypoglycemia may occur, care should be taken to look for these complications. A serious deterioration may occur when beta-adrenoceptor drugs, given to patients with significant ischemic heart disease, are suddenly stopped. This is a rare occurrence but prescribers should be aware of it.

Investigation of low density lipoprotein subfractions as a coronary risk factor in normotriglyceridaemic men.

There is an increasing interest in low density lipoprotein (LDL) subfractions since some of them are associated with a higher risk for coronary artery disease (CAD). Small LDL particles are particularly atherogenic and more of those are produced in hypertriglyceridaemia. However, high triglyceride concentrations are not the only explanation for the predominance of small LDL particles and other influences, including genetic factors, are also responsible for LDL particle size. We investigated LDL subfraction profiles in two groups: 46 men with and 21 men without CAD proven angiographically. For the separation of LDL subfractions, we used continuous disc polyacrylamide gel electrophoresis (PAGE) that is rapid and easier to perform than the other methods usually used which, although more precise in terms of measuring particle diameter, are much more demanding of time and equipment. The described method is suitable for routine use in assessing large numbers of patients. All studied men had triglyceride concentrations below 2.3 mmol/l. LDL scores were calculated on the basis of all LDL subfractions present in a particular profile; the higher the score, the greater the proportion of small LDL particles. LDL cholesterol (P < 0.05) and LDL score (P < 0.001) were the only significant discriminators between two groups. LDL score was significantly correlated with CAD, even after adjusting for triglyceride and HDL cholesterol concentrations and it was the best discriminant factor for the presence of CAD.

Effect of changes in dietary sodium and potassium on blood pressure and cellular electrolyte handling in young normotensive subjects.

In a study on 22 normotensive male subjects, a change in dietary sodium intake from 29.6 +/- 6.0 to 332.5 +/- 13.9 mmol/day (mean +/- s.e.m.), over 7 days, was associated with a significant rise in supine and standing systolic blood pressure and a fall in sodium pump activity. Intracellular sodium remained constant, while intracellular potassium fell. These changes appeared to be reversed by the addition of potassium (96 mmol/day) to the high sodium diet. The 12 subjects with a family history of essential hypertension, as determined by measurement of parental blood pressure, did not differ in their response from those whose parents were normotensive.

Ranitidine versus cimetidine. A comparison of their potential to cause clinically important drug interactions.

The literature on H2-antagonist drug interactions is now extensive. The whole subject is so complicated as to make things difficult for the potential prescriber. However, it is possible to reduce most of the information contained in the literature to a few simple messages. Firstly, H2-antagonists bind to cytochrome P450 and may inhibit the metabolism of drugs eliminated by the mixed function oxygenase system. In this respect, cimetidine has a marked effect which, in most studies, has reached statistical significance. Ranitidine, on the other hand, has a much weaker effect which, even if demonstrable, is statistically non-significant. The potential benefit of ranitidine, however, has to be weighed against the relative costs of the 2 drugs. Secondly, H2-antagonists inhibit gastric acid production and may alter the rate of gastric emptying, and hence the rate of drug absorption. They may also have some effect on portal vein and hepatic artery flow. However, these effects are small and probably not clinically relevant. Thirdly, pharmacodynamic effects of H2-antagonist-drug interactions are difficult to demonstrate in planned studies, and although they are reported from time to time, adverse reactions of consequence are relatively uncommon. Fourthly, the prescriber needs to be aware that cimetidine may produce higher plasma concentrations of some drugs which have a fairly narrow therapeutic range, and this may be clinically important. Examples of drugs for which it may be undesirable to inadvertently increase plasma concentrations include warfarin, theophylline and phenytoin. Finally, for most drugs metabolised by the liver, the risk of an important interaction is small. However, if such an interaction is noted it may be helpful to refer to the other reported cases, and a number of references are included here.

Controlled release metoprolol. Clinical pharmacokinetic and therapeutic implications.

Metoprolol is a relatively beta 1-selective beta-blocker used extensively to treat hypertension and angina and as a prophylaxis after myocardial infarction. Conventional formulations are usually administered twice daily and the drug has a tendency to lose its selectivity of action at higher plasma concentrations. Two controlled release formulations, metoprolol CR and metoprolol 'Oros', have made it possible to achieve sustained beta 1-blockade over an entire 24h period and to minimise the loss of selectivity associated with higher plasma concentrations. The CR formulation has been extensively investigated and is the major subject of this review. The 'Oros' formulation is pharmaceutically different from the CR, yet both produce similar plasma concentration profiles and comparable beta 1-blocking effects. The availability of these preparations occurs at a time when increasingly persuasive data are becoming available on the cardioprotective or coronary preventive action of metoprolol.

Impact of beta 1 selectivity and intrinsic sympathomimetic activity on potential unwanted noncardiovascular effects of beta blockers.

Beta-adrenoceptor-blocking drugs are widely used as effective antihypertensive and antianginal agents, but treatment with these agents may be contraindicated in hypertensive patients in whom receptor blockade would interfere with noncardiovascular activities dependent on sympathetic drive. beta blockade impairs pulmonary function in asthmatic patients through antagonism of beta 2 bronchodilation. However, patients with chest problems may be treated effectively with beta 1-selective drugs, including acebutolol, atenolol and metoprolol. The metabolic response to hypoglycemia, which is mediated by beta-receptor stimulation, involves insulin release, gluconeogenesis, tachycardia and increased systolic pressure. Beta 1-selective drugs are preferred in patients who need to increase blood glucose levels because they do not interfere with glycogenolysis. Hypertension induced by pregnancy may be treated with a beta blocker with no apparent adverse effects on the fetus or neonate. Those possessing intrinsic sympathomimetic activity may be preferable.

Pharmacokinetics of oxprenolol in the elderly.

This paper is a brief review of the problems associated with drug therapy in the elderly. Although the elderly are more prone to suffer adverse reactions to drugs and to respond abnormally, impaired drug handling should not be blamed for these problems until other factors have been evaluated. Renal function deteriorates as people grow older, but the absorption, metabolism and distribution of most drugs may not be adversely affected by advancing age. Evidence to the contrary is sometimes based on studies of convalescent patients in whom an effect of disease or drug therapy cannot be excluded. For an assessment of the effects of aging on the pharmacokinetics of oxprenolol, 2 groups of 8 healthy females, mean age 21 and 68 years, respectively, were studied. Oxprenolol, 80 mg, was given orally in a single dose on day 1 and day 8 of a course of treatment; on the intervening days, oxprenolol, 80 mg, was given twice daily. The mean plasma concentration:time curves for both day 1 and day 8 for the 2 age groups were comparable. Thus, age alone does not affect the pharmacokinetics of oxprenolol.

Clinical relevance of pharmacokinetic differences between beta blockers.

Fundamental differences in the pharmacodynamic and pharmacokinetic profiles of beta-adrenergic blocking agents must be considered in optimizing their efficacy and determining the appropriate selection of these drugs in different patients. Beta blockers are contraindicated in patients with asthma and should be used cautiously in heart failure. Clinically important distinctions are related to whether a beta blocker is beta1-selective or nonselective. Most adverse effects of beta-blocker use are related to interference with beta2-mediated functions including bronchodilation, vasodilation, and mobilization of free fatty acids. To achieve the potential benefits of beta1 blockade (decreased heart rate, blood pressure, cardiac workload, and excitability), a low plasma concentration of a beta1-selective drug is required. Adverse effects of beta blockers can be further decreased by selecting a sustained-release beta1-selective drug. Beta blockers are further differentiated on the basis of lipophilicity or hydrophilicity. Lipophilic beta blockers cross the blood-brain barrier, whereas hydrophilic agents do not enter the central nervous system. Some lipophilic agents (metroprolol, timolol, and propanolol) have been shown to decrease mortality in coronary heart disease, particularly sudden cardiac death.

Oxprenolol: clinical pharmacology, pharmacokinetics, and pharmacodynamics.

Oxprenolol is clinically a well-established beta blocker that shares with other members of this group the ability to control a variety of disorders, in particular, hypertension and angina. Pharmacologically it is a nonselective beta blocker that possesses partial agonist activity (intrinsic sympathomimetic activity). Pharmacokinetically, oxprenolol behaves as a moderately lipophilic agent. This means that it is well absorbed, but then undergoes considerable first-pass loss. It penetrates well into most tissues, including the central nervous system. About 80% of oxprenolol is bound to protein in the blood, and when acute-phase proteins increase, as, for example, in patients with inflammatory disease, total plasma concentrations of oxprenolol also increase. Apart from this, the plasma concentration:time profile produced after the oral administration of oxprenolol is remarkably consistent and reproducible. Intrasubject and intersubject variability is small, and the administration of the drug after food or with many other drugs has very little effect. The beta-blocking effects of oxprenolol correlate well with the plasma concentrations, but as with other beta blockers, it has not been possible to correlate plasma concentrations directly with its therapeutic actions such as lowering blood pressure or controlling arrhythmias.

Approaches to meeting the criteria for fixed dose antihypertensive combinations. Focus on metoprolol.

Fixed dose antihypertensive combinations are being used increasingly in the management of hypertension. There are advantages and disadvantages of this form of therapy. The key aims are to: (i) achieve increased efficacy by using drugs that complement each other's actions; (ii) use low doses to minimise adverse effects; and (iii) provide a simple once daily regimen. Fixed dose combinations containing metoprolol have the advantage that beta-blockers are drugs for which there is most evidence that they are cardioprotective; metoprolol is the best documented beta-blocker in this context. The early combination of conventional release metoprolol and hydrochlorothiazide was inadequately investigated by modern standards, but proved well tolerated and effective in clinical practice. The introduction of the long acting metoprolol CR/ZOK (controlled release/zero order kinetics) produced a very satisfactory once daily preparation with no major pharmacokinetic interactions. The fixed dose combination of felodipine and metoprolol CR/ZOK has been well investigated. The two agents complement each other's actions and together provide very effective blood pressure control, cardioprotection and very good tolerability. A case can be made that this preparation more closely meets the requirements of an ideal antihypertensive than a single agent given alone.

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.

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.

Review article: esomeprazole--the first proton pump inhibitor to be developed as an isomer.

Omeprazole is a racemate, from which the R- and S-isomers can be isolated. At the cellular level, both of these isomers convert to the same inhibitor of the H+,K+-ATPase and produce the same reduction in gastric acid secretion. However, the S-isomer, esomeprazole, is metabolized more slowly and reproducibly than the R-isomer and omeprazole, and therefore produces higher plasma concentrations for longer and, as a result, inhibits gastric acid production more effectively and for longer. Thus, esomeprazole has the pharmacological properties of a more effective form of treatment for disorders related to gastric acid secretion. Clinical studies have confirmed the anticipated increased efficacy, but have shown no evidence of impaired tolerability or increased toxicity when compared with omeprazole.

Co-administration of misoprostol or ranitidine with indomethacin: effects on pharmacokinetics, abdominal symptoms and bowel habit.

This three-way randomized crossover study in 18 healthy male volunteers compared the pharmacokinetics of 50 mg indomethacin b.d. during concomitant twice daily dosing with 400 micrograms misoprostol, 150 mg ranitidine or placebo. Plasma indomethacin concentrations were determined by HPLC assay of samples collected over 12 h after the first dose, and over 14 h after the last dose on Day 8 of each dosing period. A daily diary of bowel habits, and the occurrence and severity of abdominal symptoms, was kept by each subject throughout the study. Statistical comparisons were made by analysis of variance. In the presence of misoprostol there was a 13% decrease in the area under the plasma concentration-time curve of indomethacin over one dosing interval on Day 1 (P less than 0.01), and at steady state there was a 24% decrease in the maximum plasma concentration (P less than 0.02). The pharmacokinetics of indomethacin were not affected by co-administration of ranitidine. Accumulation of indomethacin after repeated oral dosing was not significantly altered by the co-administration of either misoprostol or ranitidine. The frequency and severity of abdominal symptoms was significantly increased (P less than 0.01) during misoprostol dosing, compared with either ranitidine or placebo plus indomethacin. When the dosing phase (Days 1-8) was compared with the washout phase (Days 9-15) in each period, misoprostol, but not ranitidine or placebo, plus indomethacin resulted in an increase (P less than 0.001) in abdominal symptom severity, frequency of bowel motions and a decrease in faecal consistency.

The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol.

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P less than 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.

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.

Measurement of vascularity as a diagnostic and prognostic tool for well differentiated thyroid tumours: comparison of different methods of assessing vascularity.

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.

Age-independent oxidative stress in elderly patients with non-insulin-dependent diabetes mellitus.

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.