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BACKGROUND Increases in PKC-theta (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary-induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC-theta mRNA expression has not been previously reported in patients with T2DM or in relation to in-vivo measurements of insulin sensitivity. METHODS Diet-only treated patients with T2DM (n=7) and healthy nondiabetic controls (n=7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75-g oral glucose load and measurement of whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. RESULTS Type 2 DM patients were insulin resistant (M-value 3.0 +/- 0.4 vs. 8.6 +/- 0.8 mg glucose kg(-1) min(-1)) with fasting hyperinsulinaemia (306 +/- 116 vs. 34 +/- 9 pmol L(-1), P

Original article can be found at: http://www.sciencedirect.com/science/journal/10785884 Copyright Elsevier Ltd. DOI: 10.1053/ejvs.2002.1953, Objectives: to assess the effects of posture, endothelial function and venous insufficiency on cutaneous microvascular vasodilator function in the gaiter area, in particular defining factors which may affect microangiopathy and ulcer formation

Aims To compare the metabolic and vascular effects of two sulphonylureas (SU), gliclazide (specific for the pancreatic [SUR1] receptor) and glimepiride (a nonspecific agent that also binds to vascular and cardiac [SUR2] receptors), during chronic administration in metformin-treated patients with Type 2 diabetes (T2DM). Methods A randomized, double-blind, crossover study of gliclazide 80 mg BID and glimepiride 2 mg OD, each for 4 weeks as add-on therapy to metformin, with a 4-week washout period. Patients attended four study mornings after first dose and 4 weeks’ SU treatment for measurements of arterial distensibility (Ax), pressor responsiveness to i.v. angiotensin II (ANGII), and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Results Glycaemic responses were similar (e.g. serum fructosamine was 315 vs 329 µmol l−1 after 4 weeks), and there was no change in augmentation index during treatment with either SU (9.1 vs 9.8 mmHg after 4 weeks [95% confidence interval −8.1, 10.5]). Similarly, there were no differences between treatments in pressor responsiveness (e.g. PD10[dose of agonist required to increase mean BP by 10 mmHg] for ANGII was 1.37 vs 1.68 ng kg−1 min−1[−4.3, 6.9]) or cutaneous microvascular vasodilator responses (peak ACh response 68 ± 36 vs 63 ± 34 perfusion units [−82.7, 79.1]). Conclusions There is no evidence that SUR1-specific and nonspecific SUs have differential effects on arterial distensibility, endothelial function or vasodilator mechanisms in metformin-treated patients with T2DM.

To quantify changes in 30 day and one year mortality among patients with acute myocardial infarction in southern Derbyshire (population 560 000) in each of five consecutive years (1995-1999) before the publication of the National Service Framework for coronary heart disease, and to assess the proportion of one year survivors in whom serum lipids were measured and were below target values.All hospital admissions coded on the patient administration system (PAS) as "AMI" (ICD codes I-21, I-22, and I-23) and with a creatine kinase measurement in the pathology database were identified over a five year period (n = 4912). All deaths in the district are automatically notified to the PAS. Total mortality after acute myocardial infarction (30 days and one year) and lipid levels were analysed by year of admission, age group (35-74 years vor = 75 years), and sex using unconditional logistic regression analysis.An acute hospitals trust and pathology laboratory, as sole service providers for a catchment population of 560 000.The number of admissions for acute myocardial infarction was similar in each of the five years (n = 4912, 62% male, 63%75 years old). Overall, among patients aged 35-74 years there were 396 deaths (13%) at 30 days and 585 (19%) at one year; mortality was higher in women (1.28-fold at 30 days, p = 0.02) and in subjects aged 75 years or more (3.26-fold at 30 days, p0.0001). There was a progressive reduction in 30 day mortality of 9%/year over the five year period (95% confidence interval, 4% to 13%, p = 0.012). The proportion of one year survivors (35-74 years) in whom serum lipids were measured at least once increased from 74% in 1995 to 88% in 1999; of these, 27% of men and 23% of women had a total serum cholesterol of5 mmol/l in 1995, increasing to 65% and 74%, respectively, in 1998 and 1999 (p0.0001).In the five year period 1995-1999, there was a significant year on year decline in 30 day and one year mortality after admission for acute myocardial infarction, and progressively more patients achieved cholesterol levels below 5 mmol/l. Men were more likely than women to have their lipids measured after myocardial infarction. Mortality at one year was 1.32-fold higher among women than among men.

Aims: To evaluate endothelial-dependent and -independent cutaneous vasodilator responses in the feet of patients with peripheral arterial disease (PAD) with or without Type 2 diabetes.\ud Methods: Cutaneous microvascular responses in the dorsum of both lower limbs were measured in the supine position using Laser Doppler Fluximetry combined with iontophoretic administration of endothelial-dependent (acetylcholine, Ach) and -independent (sodium nitroprusside, SNP) vasodilators in diabetic (n = 19) and non diabetic (n = 17) patients with PAD (presenting as unilateral calf intermittent claudication (IC).\ud Results: In patients with diabetes and IC, endothelial-dependent vasodilation was significantly impaired in the symptomatic limb [74 (57,105) vs 68 (24,81) PU, Z = -2.79, p = 0.005] compared to the asymptomatic limb. Patients without diabetes showed no impairment of vasodilation. Resting ankle-brachial pressure index did not identify the presence of abnormalities in microvascular function. Conclusions: The combination of diabetes and PAD is associated with a reduction in endothelial-dependent cutaneous vasodilation in the feet without an associated reduction in endothelial independent vasodilation.

Hyperendothelinaemia is associated with various insulin-resistant states, e.g., diabetes, obesity and heart failure, but whether endothelin-1 (ET-1) has a direct effect on insulin-mediated glucose uptake is unclear because the interpretation of in vivo metabolic studies is complicated by ET-1 effects on muscle blood flow and insulin secretion. This study investigated the effects of ET-1 (1–10 nM) on basal and insulin-stimulated 2-deoxy-D-[3H]glucose (2-DOG) uptake in cultured L6 myoblasts and 3T3-adipocytes. RT-PCR analysis showed that both cell types express ETA but not ETB receptors. ET-1 had no effect on basal (non-insulin-mediated) glucose transport, but there was evidence of a tissue- and time-dependent inhibitory effect of ET-1 on insulin-stimulated glucose uptake. Specifically, ET-1 10 nM had a transient (0.5 h) inhibitory effect on glucose uptake in 3T3 cells (CI-150 [dose of insulin required to increase glucose uptake by 50%, relative to control 100%] increased from 89 ± 14 nM to 270 ± 12 nM at 30 mins, P

Aims Raised homocysteine (hcy) levels are associated with premature coronary arterydisease, but the underlying vascular mechanism and the extent to which hcy affectssmall vessel vasodilator responses (especially non-nitric oxide mediated pathways) areunclear.Methods This double-blind, placebo-controlled crossover study in 14 healthy malesubjects evaluated the effects of single-dose oral methionine 15 g (to induce acutehyperhomocysteinaemia) on cutaneous microvascular vasodilator responses toincremental-dose iontophoretic administration of acetylcholine (Ach) and sodiumnitroprusside (SNP) using laser Doppler fluximetry (LDF), and the effects on vonWillibrand factor (vWF) levels and systemic haemodynamics.Results Methionine administration produced a three fold rise in plasma hcy levelsat 8 h, which was accompanied by a significant increase in pulse pressure (53 vs49 mmHg, P

Objectives To evaluate in vivo microvascular responses to incremental doses of the endothelial-dependent vasodilator, acetylcholine, and the endothelial-independent vasodilator, sodium nitroprusside, in women with pre-eclampsia and gestation-matched normotensive pregnant controls. Design Prospective clinical study. Setting Southern Derbyshire Acute Hospitals Trust, and University of Nottingham Division of Vascular Medicine. Population Thirteen women with pre-eclampsia and 16 normotensive pregnant controls. Methods Cutaneous microvascular vasodilator responses to iontophoretic administration of incremental doses of acetylcholine and sodium nitroprusside (25-100μC) were evaluated under temperature-controlled conditions using laser Doppler fluximetry. Results Resting skin temperature and blood flow were similar among 13 women with pre-eclampsia [mean blood pressure 151/93 mmHg (4/3); mean gestation 35.6 weeks (1.0); and mean proteinuria 1.1 g/24h (0.2)] and 16 normotensive pregnant controls [mean blood pressure 111/63 mmHg (2/2); mean gestation 34.3 weeks (0.9)]. Peak vasodilator responses to acetylcholine were increased in women with pre-eclampsia (median flux ratio 15.1 [IQR 12.3-17.6] vs 11.7 [IQR 8.4-12.6], P

An absent or diminished blood pressure (BP) fall during sleep (so-called "nondipping") has been associated with a higher risk of cardiovascular complications, but the long-term reproducibility of dipper status and the relationship between diurnal changes in BP and perceived sleep quality have not been previously documented in untreated hypertensive patients. Ambulatory BP (ABP) and dipping status were examined in 79 subjects (69 hypertensives and 10 normotensives) at 0, 6, and 12 months. Fifty-six percent of subjects had no change in their dipping status, the majority (53%) dipping normally on all three occasions. However, 44% of patients had variable dipping status, and normal nighttime dipping in BP was observed more often when patients perceived their sleep quality to be good during the period of ABP recording. These results highlight significant intrasubject variability in the diurnal fluctuations in ABP and dipper status, which may in part reflect day-to-day variations in sleep disturbance during ABP monitoring. Classifying hypertensive patients into dippers or nondippers on the basis of a single ABP recording is unreliable and potentially misleading.

Aims Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat-dose inhalation. Methods This pharmacokinetic substudy was part of a previously published open-label, randomised, placebo-controlled, 7-period crossover study to evaluate the short-term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 µg twice daily) and FP (375, 750, 1000 µg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 µg twice daily and FP 1000 µg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non-compartmental analysis and a mixed effects model were used to characterize the disposition profiles. Results Both drugs had a rapid absorption half-life (BUD 10 min vs FP 11.3 min), but quite different elimination half-lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R-and 22S-epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP’s higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung. Conclusions This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t½,z for BUD, resulting in higher and more sustained plasma drug levels in the 4–12 h postdose period than would be predicted from single-dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher-than-expected plasma drug concentrations in the morning compared with the evening.

Angiotensin-converting enzyme (ACE) inhibitors are increasingly used as first-line therapy for hypertension in type 2 diabetes mellitus and are widely believed to improve insulin sensitivity (M). However, the evidence for the latter effect does not stand close scrutiny. We have assessed the effect of the ACE inhibitor trandolapril on M in 16 patients (mean ± sd age, 58 ± 10.6 yr) with mild-to-moderate essential hypertension (initial blood pressure, 173 ± 14.5/93 ± 8.0 mm Hg), obesity (body mass index, 30 ± 5.4 kg/m2), and impaired glucose intolerance (n = 4) or type 2 diabetes (n = 12) in a double-blind, placebo-controlled crossover design. All patients underwent three 3-h euglycemic hyperinsulinemic clamp studies (soluble insulin, 1.5 mU/kg·min) after a 2-week placebo run-in and at the end of two 4-week periods of treatment with 2 mg trandolapril or placebo (2-week washout). M (mean ± sd) did not change with trandolapril: placebo (run-in), 5.2 ± 1.98 mg/kg·min; placebo, 5.3 ± 1.70 mg/kg·min; trandolapril...

The adenosine (A1) receptor agonist, GR79236 (N-[(1S,trans)-2-hydroxycyclopentyl]adenosine), inhibits catecholamine-induced lipolysis in vitro, but the short-term metabolic and haemodynamic effects have not been previously reported in the fructose fed model of insulin resistance, dyslipidaemia and hypertension. This study reports the effects of GR79236 (1 mg/kg/day for 8 days) on nonesterified free fatty acid and triglyceride metabolism, oral and i.v. glucose tolerance, blood pressure and heart rate, and insulin sensitivity, in normal rats and rats fed a fructose-enriched diet. In normal rats, GR79236 significantly reduced fasting glucose (25%), free fatty acid (50%) and triglyceride (55%) concentrations, and improved glucose tolerance (AUC[glu] 21.2 +/- 1.3 vs. 16.5 +/- 1.1 mmol h/l, p0.05). Fructose feeding induced a state of insulin resistance and dyslipidaemia, as shown by an increase in steady-state plasma glucose levels (7.1 vs. 6.1 mmol/l), impaired i.v. glucose tolerance and a 3-fold rise in fasting triglyceride levels; fructose-fed rats also developed a significant increase in blood pressure. GR79236 ameliorated the effects of fructose feeding on fatty acid and triglyceride levels, and blood pressure, and improved i.v. glucose tolerance in fructose-fed rats. The hypotriglyceridaemic effect was due to a reduction in triglyceride secretion rate (17.3 +/- 1.7 vs. 30.2 +/- 1.1). Thus, in normal rats and in a dietary-induced rodent model of insulin resistance, dyslipidaemia and hypertension, GR79236 has lipid-lowering and glucose-lowering activity, as well as haemodynamic effects, which are potentially useful for treating both the metabolic and haemodynamic features of insulin resistance and NIDDM in humans.

The mechanism of insulin resistance in the spontaneously hypertensive rat (SHR) has not been clearly identified, but protein kinase C (PKC) has been implicated as a mechanism of insulin resistance in obesity and diabetes mellitus and in a diet-induced (fructose-fed) model of insulin resistance and hypertension. This study compared PKC enzyme activity (cytosol and particulate fractions) and expression of the muscle-specific isoform, PKC-theta (Western blotting), in red (soleus) and white (tensor fascia latae) hindlimb muscles from SHR (n = 12) and WKY (n = 12) rats. SHRs were hypertensive and insulin resistant, as shown by higher insulin (188 +/- 34 v 169 +/- 22 pmol/L), triglycerides (1.65 +/- 0.07 v 1.38 +/- 0.06 mmol/L), and nonesterified fatty acids (0.99 +/- 0.05 v 0.78 +/- 0.04 mmol/L) concentrations. PKC activity was significantly greater in the membrane fraction, compared with the cytosol, but there were no significant differences either in PKC activity or subcellular distribution, or expression of PKC-theta, between the two strains. Thus, insulin resistance in the SHR (in contrast to the fructose-fed dietary model of insulin resistance and hypertension) is not related to changes in PKC signaling or expression of PKC-theta in skeletal muscle.

The extent to which hypertension is detected and adequately treated in the general population is often described by the 'rule of halves', but corresponding figures for patients with non-insulin-dependent diabetes mellitus (NIDDM), based on current American Diabetes Association (ADA) criteria, have not been previously reported. This study looked at the detection and management of hypertension among 2331 consecutive patients with NIDDM attending for annual complications assessment. Hypertension was defined according to ADA criteria, i.e. systolic blood pressure (sBP) > 140 mmHg and/or diastolic blood pressure (dBP) > 90 mmHg. A total of 69% of patients were hypertensive, with proportionately more women in the hypertensive group (48 versus 39%, P < 0.002). Among those with hypertension, 59% were taking antihypertensive drugs but only 31% of treated hypertensives were adequately controlled. Thus, hypertension affects roughly two-thirds of patients with NIDDM and compared with treatment strategies reported in the literature for the non-diabetic population (summarised in the 'rule of halves'), proportionately more hypertensive patients with NIDDM are treated with BP-lowering drugs (59%) but proportionately less (31%) have adequate BP control.

Optimizing the therapeutic response for an individual patient is at the heart of good clinical decision-making, but for most drugs the prescriber has very little information about clinical, demographic, or metabolic factors that influence outcome. Nowhere is this better illustrated than in cardiovascular therapeutics, where pharmacodynamic and pharmacokinetic variability accounts for significant inter- and intra-subject differences in drug response (see Figure 1). For example, antihypertensive and cholesterol-lowering drugs are prescribed extensively, but only a fraction of treated patients achieve target blood pressures and serum lipids [1, 2]. Clinical decisions about drug and dosage selection, combination therapies, and drug sequencing are largely empirical. This issue of the Journal contains several research studies that use different approaches to characterize cardiovascular drug responses and investigate factors that contribute to variability in treatment outcome. Figure 1 Pharmacodynamic and pharmacokinetic variability accounts for the large inter- and intraindividual differences in cardiovascular treatment responses. Genetics, clinical factors and disease-related mechanisms may affect circulating drug concentrations and/or ... MacFadyen et al. (pp 622–631) undertook a longitudinal study in patients with stable chronic heart failure (CHF) to investigate factors that contribute to within- and between-patient differences in response to furosemide. Changes in diuretic therapy or effectiveness may account for some episodes of CHF hospitalization, and diuretic resistance seems to indicate a poor prognosis [3]. The thrust of the study was to investigate whether over 2 years diuretic resistance, changes in diuretic absorption, and/or non-adherence to treatment contributed to the outcome (e.g. hospitalization or death from CHF). There were several important conclusions: (1) although furosemide dosage requirements varied widely (20–370 mg/day), there was a linear relation between dose and urinary furosemide excretion and the within-subject variability in furosemide excretion was relatively low; (2) there was a progressive rise in the prescribed doses of furosemide over time, but diuretic responsiveness (calculated as mmoles of Na+ excreted per mg of furosemide in the urine) within an individual remained constant, despite variations in prescribed dose and outcome; and (3) patients who died during follow-up had evidence of furosemide resistance (i.e. impaired sodium excretion per unit drug reaching the renal tubules). Another interesting observation was that non-adherence to medication among CHF patients seems to be selective. Statins are another major class of drugs used in long-term therapy for patients with cardiovascular disease, but there are considerable inter-individual differences in lipid-lowering responses, dosage requirements, and disease-modifying effects. The clinical and cost-effectiveness of statin therapy has been evaluated in different patients, e.g. in primary versus secondary prevention of coronary heart disease (CHD), in older patients, in those with diabetes, and in those who have had a stroke as opposed to a CHD event. Crucial public health decisions about the balance of benefit and harm and the availability of statins are often based on estimates of the number needed to treat (NNT) for different patient subgroups and different cardiovascular outcomes, but conclusive analyses require tight confidence intervals [2]. Cheung et al. (pp 640–651) report a meta-analysis of 10 placebo-controlled trials of statin therapy in 79 494 subjects, to derive more reliable estimates of the treatment effect on different end-points, e.g. major CHD events, strokes, all-cause mortality, and non-cardiovascular mortality, in specific patient subgroups. Statin therapy reduced major CHD events by 27% (95% CI 23, 30), stroke by 18% (95%CI 10, 25), and all-cause mortality by 15% (95% CI 8, 21). In addition, there was a non-significant 4% reduction in non-cardiovascular mortality. This meta-analysis has shown that the magnitude of reduction in major CHD events with statin therapy is independent of sex and the presence of hypertension or diabetes. But the risk reduction was significantly greater among smokers. This study also provides information about the comparative effects of different statins. Pravastatin reduced stroke incidence by only 12% (95% CI 1, 21), whereas the other statins reduced it by 24% (95% CI 16, 32) (P < 0.04). Pharmacokinetic factors also influence inter- and intra-individual differences in drug response, as do adverse effects. Calcium channel blockers exemplify this. Clinical observations in the 1980s first suggested that the antihypertensive effect of calcium channel blockers may be greater in older patients [4], but this was not solely due to an effect of age on pharmaco-dynamic sensitivity to calcium channel blockers, since reduced hepatic metabolism accounts for higher plasma drug concentrations in the elderly [5]. Minami et al. (pp 632–639) have shown how pharmacokinetics, especially the rate of drug absorption, can have an important effect on the pharmacodynamics of calcium channel blockers. They compared 24-hour blood pressure and heart rate profiles in hypertensive patients taking two modified-release formulations of nifedipine, one taken once a day and one twice a day. Although 24-hour blood pressure reduction was similar in the two groups, there was much less evidence of reflex sympathetic activation (i.e. increased heart rate) after treatment with controlled-release nifedipine. Since reflex autonomic stimulation often causes the adverse effects of headache, flushing, and palpitation, these observations may have important implications for improving the tolerability profile of nifedipine. Characterizing treatment responses using an integrated approach to pharmacokinetic and pharmaco-dynamic modelling provides a more scientific basis for analysing factors that account for inter- and intra-subject differences in drug effects. Persky et al. (pp 552–562) have applied pharmacokinetic–pharmacodynamic modelling to the unwanted effects of ephedrine on blood pressure and heart rate. Ephedrine is a key ingredient in some popular aids to weight reduction, which have been associated with serious adverse cardiovascular effects (e.g. hypertension, myocardial infarction). During 8 hours after a single dose of ephedrine there was clockwise hysteresis – i.e. the change in blood pressure lagged behind the change in plasma drug concentrations. There was a linear concentration-effect relation for the increase in heart rate, and there was tolerance to the effect of ephedrine on blood pressure. Such information will undoubtedly help to define the relation between ephedrine dose and adverse cardiovascular effects, and therefore reduce the likelihood of serious adverse events. In a similar study Cantarini et al. (pp 657–660) have used pharmacokinetic–pharmaco-dynamic modelling to characterize the pressor effect of intravenous tyramine and to investigate inter-subject variability. They measured the dose of tyramine required to increase the systolic blood pressure by 20 mmHg in each healthy volunteer and found no evidence of tachyphylaxis. These results will be of practical benefit for the future design of phase 1 safety studies to characterize possible interactions between tyramine and new drugs in the pipeline. There is much interest in genetic effects on pharmacokinetic and pharmacodynamic variability of cardiovascular drugs [6]. Several DNA polymorphisms have been implicated in specific mechanisms responsible for such variability (see Table 1). For example, P glycoprotein, which is encoded by the MDR-1 gene, is involved in the acquisition of multidrug resistance phenotypes in cancer cells and various other tissues, but P glycoprotein also limits intestinal drug absorption and oral drug availability (e.g. digoxin). Single nucleotide polymorphisms of the MDR-1 gene have been associated with lower intestinal P glycoprotein activity [7]. Two polymorphisms of the MDR-1 gene had no effect on the oral availability and disposition of risperidone (pp 569–575), although this gene seems to have widespread effects on the absorption profiles of orally administered drugs. Table 1 Examples of DNA polymorphisms implicated in the variable treatment outcomes with cardiovascular drugs; adapted from [6] These six papers in this issue of the Journal illustrate a variety of scientific approaches in characterizing therapeutic responses and adverse effects of cardiovascular drugs. Their common goal is to provide more information about variability in outcome, so that decisions in routine practice can be more informed and less empirical.

The aim of the present study was to compare the effects of rilmenidine (1-2 mg/day) and atenolol (50-100 mg/day) on tests of mental arithmetic, bicycle exercise, and autonomic function. Twelve male patients with mild-to-moderate hypertension (blood pressure, 160/95 +/- 15/7 mm Hg; age range, 32 to 60 years) completed a randomized, double-blind, crossover study. Both drugs were well tolerated and, after 4 weeks of monotherapy, were associated with significant reductions in supine and erect BP. Hemodynamic responses to mental arithmetic were similar for both drugs, and neither agent affected mental performance as judged by psychomotor testing. The increase in heart rate during bicycle exercise was significantly greater with rilmenidine (50 vs. 41 beats/min, p = 0.04), and during the postexercise recovery phase, areas under the curve for diastolic blood pressure and heart rate were smaller after atenolol than after rilmenidine: 46,450 versus 51,400 mm Hg.s (p = 0.02) and 49,445 versus 63,597 beats/min.s (p = 0.001), respectively. In conclusion, rilmenidine and atenolol exert comparable antihypertensive effects both at rest and during mental and dynamic exercise. Although atenolol blunted the heart rate responses to dynamic exercise and the Valsalva maneuver, rilmenidine showed no interference with physiological hemodynamic responses of blood pressure and heart rate during tests of sympathetic and parasympathetic function.

Aims: The regulation of uncoupling protein-3 (UCP-3) expression in muscle remains unclear, specifically in relation to dietary and drug treatments. The present study evaluated the effects of oleic acid and rosiglitazone on UCP-3 mRNA expression in differentiated L6 myotubes. Methods: L6 myocytes were cultured and differentiated prior to exposure to rosiglitazone 10 µmol/l, oleic acid 100 µmol/l, or the combination, for 24 h, prior to semiquantitative evaluation of UCP-3 mRNA relative to GAPDH mRNA by RT-PCR. Results: Exposure to oleic acid produced a significant increase in UCP-3 mRNA (0.012 ± 0.007 vs. 0.0011 ± 0.0006 for untreated cells, relative to GAPDH mRNA, p

Background Findings of prior studies have been inconclusive about the ocular effects of thiazolidinediones on diabetic macular edema (DME). We evaluated, in patients with type 2 diabetes (T2D), the short-term and long-term risks of developing DME among users vs nonusers of thiazolidinediones. Methods A retrospective cohort study of 103 368 patients with T2D and no DME at baseline using The Health Improvement Network (THIN) database. Clinical, biochemical, and demographic information was obtained for the period January 1, 2000, through November 30, 2009. Results At 1 year, the incidence of DME was 1.3% (n = 41) and 0.2% (n = 227) among thiazolidinedione users (n = 3227) and nonusers (n = 100 141), respectively (odds ratio [OR], 5.7 [95% CI, 4.1-7.9]). After Cox multiple regression analysis (adjusted for age; systolic blood pressure; levels of lipids and hemoglobin A 1c ; and use of aspirin, fibrates, insulin, oral antidiabetic drugs, or renin-angiotensin system blockers), multiple imputation analysis to adjust for missing values, and propensity score analysis to exclude for any selection bias, thiazolidinedione use was associated with an increased risk of DME at 1-year follow-up (OR, 2.3 [95% CI, 1.5-3.6]) and 10-year follow-up (hazard ratio [HR], 2.3; [95% CI, 1.7-3.0]). The effect was similar for pioglitazone and rosiglitazone. Combination therapy with insulin plus a thiazolidinedione was associated with a higher risk of DME after propensity score adjustment (HR, 3.0 [95% CI, 1.5-5.9]), while aspirin use (HR, 0.6 [95% CI, 0.4-0.9]) and angiotensin-converting enzyme inhibitor use (HR, 0.4 [95% CI, 0.2-0.7]) were associated with a reduced risk of DME. Conclusion Among patients with T2D, treatment with a thiazolidinedione was associated with an increased risk of DME at 1-year and 10-year follow-up evaluations.

Although individualised antihypertensive therapy is widely recommended, prospective methods for optimising treatment are hampered by the paucity of basic information about dose-plasma concentration-response relationships for commonly used drugs. Concentration-effect analysis has been applied to a number of therapeutic areas. With antihypertensive drugs this approach has clearly identified direct relationships between pharmacokinetic and pharmacodynamic profiles within individual patients. Thus, either a linear or nonlinear model can be used to quantify the antihypertensive drug response in terms of parameters that incorporate pharmacokinetic and pharmacodynamic information. Furthermore, these models take account of placebo effects and time-dependent changes in blood pressure and drug concentrations during a dosage interval. Concentration-effect analysis has been used to characterise the responses to a range of calcium antagonist drugs. These studies have demonstrated that these analyses are useful for optimising dosage schedules, identifying determinants of blood pressure response, and predicting steady-state profiles of blood pressure (including peak/trough effects) after administration of a single ('test') dose. This mode of analysis warrants early inclusion in the clinical development of any new antihypertensive agent, so that the familiar difficulties in identifying the optimum dosage range are avoided.

Obesity and diabetes mellitus are 2 of the most important metabolic disorders. In particular, noninsulin-dependent diabetes mellitus (NIDDM) accounts for over 75% of all cases of diabetes mellitus and has a prevalence of 0.5 to 2.0% in most Western populations (Alberti & Hockaday 1987). Obesity is even more common and, since diabetic and overweight patients experience much higher rates of cardiovascular morbidity and mortality than normal (Kannel et al. 1967), the underlying metabolic derangements have obvious clinical implications. Standard drug therapies for both conditions are far from ideal. For example, sulphonylurea drugs, which have been the mainstay of oral treatment for NIDDM for over 30 years, are associated with a 40% rate of secondary failure (Shen & Bressler 1987). Since defective insulin action is thought to be more important than failure of insulin secretion in the development of NIDDM, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. In obesity, many of the pharmacological agents are only transiently effective and carry risks of habituation as well as adverse cardiovascular and psychomotor reactions. Although various pathophysiological mechanisms contribute to the aetiology and complications of NIDDM and obesity, recent therapeutic developments have focused on pharmacological modulation of insulin-dependent pathways of glucose and lipid metabolism. Thus, a number of new drugs are now entering clinical evaluation with potential applications in NIDDM, obesity and possibly some forms of dyslipidaemia (table I).

The predictability of the long term antihypertensive response to nifedipine in individual patients has been assessed by an analysis based upon the concentration-effect parameters defined following the first dose administration of 20 mg nifedipine (Retard). The predicted and measured reductions in blood pressure during steady state nifedipine treatment were compared for the trough and peak responses and there was reasonable agreement for the group of patients as a whole. However, when the measured and predicted blood pressure profiles were compared for each individual patient there was close agreement for the majority of patients but there were significant discrepancies in a few cases. Further analysis of the steady state concentrations in these cases revealed that there was no change in their responsiveness to nifedipine and that discrepancies were directly attributable to inappropriate compliance with the drug regimen. The analysis was further extended to simulate the blood pressure responses to alternative fixed dosage regimens. Assessment of these simulations suggests that blood pressure control with nifedipine Retard is significantly improved by three times daily drug administration.

Malignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51-year-old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio-frequency ablation. He remains symptom-free 18 months later and levels of insulin and pro-insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio-frequency ablation offers an alternative if vascular access to the tumour is no longer possible.

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half-life, are presumed to translate directly to a prolonged duration of action, but the concentration-effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic-pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo-corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was -3.1 +/- 0.9 mm Hg/ng/ml. By characterizing the concentration-effect relationships in individual patients, this study has confirmed that the plasma concentration-time profile is an appropriate index of the effect-time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough-to-peak variability.