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The relationships between heart rates (HR) and corresponding PR intervals (PR) were studied in 12 healthy young subjects during rest, standing and graduated treadmill exercise to heart rates of 160 to 170 beats min-1 and during the infusion of isoprenaline to heart rates of 100 to 110 beats min-1. During exercise, PR diminished with increasing HR. Over the range of HR from 60 to 160 beats min-1 all 12 individual subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = −0.351 HR (beats min-1) + 176.7 for composite data. During isoprenaline infusion the PR interval also diminished with increasing heart rate. Over the range of HR from 60 to 110 beats min-1, 11 of the 12 subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = − 0.582 HR (beats min-1) + 186.5 for composite data. The exercise model was used to study the indirect (or rate-dependent) effects and the direct actions on atrioventricular conduction of beta-adrenoceptor blocking drugs and calcium channel antagonists, alone and in combination, in three groups of healthy subjects. Control and placebo observations on HR and PR at rest, standing and during exercise in these additional subjects also exhibited individual inverse linear relationships between HR and PR. Following the administration of beta- adrenoceptor blockers, PR were prolonged more than expected at the HR observed. Rate-adjusted PR prolongation during exercise exceeded standing which exceeded resting, indicating greater beta-adrenoceptor blockade in atrioventricular nodal tissue than in sinoatrial nodal tissue at each level of activity.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The plasma concentration-response relationships of oral and intravenous pindolol and propranolol have been studied in a group of eight healthy male subjects who received each dosage form in a randomized single- blind cross-over manner. Despite similar elimination half-lives, the duration of action of pindolol was longer than that of propranolol. This longer duration of action was associated with a flatter concentration-response curve for pindolol and may be related to the partial agonist activity of pindolol. Propranolol concentration- response curves were dependent on the route of drug administration whereas pindolol curves were similar following oral and intravenous routes of administration. [ABSTRACT FROM AUTHOR]

We have observed that patients on concurrent cyclosporin and phenytoin therapy required increased doses of cyclosporin to maintain therapeutic concentrations of this novel immunosuppressive drug. We have, therefore, studied the influence of phenytoin on the pharmacokinetics of oral cyclosporin in six healthy male subjects. Cyclosporin concentrations in serum and whole blood were measured by high pressure liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA). Concentrations of cyclosporin in whole blood were consistently higher than corresponding values in serum. Concentrations of cyclosporin determined by RIA were also consistently higher than those determined by h.p.l.c. Irrespective of the biological fluid (serum or whole blood) or the type of drug analysis (h.p.l.c. or RIA), changes in cyclosporin kinetics following phenytoin administration exhibited similar patterns. Phenytoin significantly reduced the maximum concentration and the area under the concentration-time curve and significantly increased total body clearance of cyclosporin. There was a statistically significant reduction of cyclosporin half-life (t 1/2) in whole blood using h.p.l.c. analysis. However, there was no significant change in cyclosporin t 1/2 in serum following phenytoin administration, using either form of drug analysis. Cyclosporin metabolites 17 and 18 were measured by h.p.l.c. in whole blood samples only, since these metabolites were found almost entirely in red blood cells. Phenytoin significantly reduced the Cmax and AUC of both metabolites, but no significant change was observed in the t 1/2 of either. Phenytoin enhanced the metabolism of antipyrine which was co-administered with cyclosporin to assess oxidative enzyme activity. We conclude that patients undergoing organ transplantation should be carefully monitored if they require phenytoin or other drugs known to accelerate oxidative metabolism. [ABSTRACT FROM AUTHOR]

Background: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.Methods: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.Findings: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001).Interpretation: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common. [ABSTRACT FROM AUTHOR]

Herein, updated evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in Canadian adults are detailed. For 2014, 3 existing recommendations were modified and 2 new recommendations were added. The following recommendations were modified: (1) the recommended sodium intake threshold was changed from ≤ 1500 mg (3.75 g of salt) to approximately 2000 mg (5 g of salt) per day; (2) a pharmacotherapy treatment initiation systolic blood pressure threshold of ≥ 160 mm Hg was added in very elderly (age ≥ 80 years) patients who do not have diabetes or target organ damage (systolic blood pressure target in this population remains at < 150 mm Hg); and (3) the target population recommended to receive low-dose acetylsalicylic acid therapy for primary prevention was narrowed from all patients with controlled hypertension to only those ≥ 50 years of age. The 2 new recommendations are: (1) advice to be cautious when lowering systolic blood pressure to target levels in patients with established coronary artery disease if diastolic blood pressure is ≤ 60 mm Hg because of concerns that myocardial ischemia might be exacerbated; and (2) the addition of glycated hemoglobin (A1c) in the diagnostic work-up of patients with newly diagnosed hypertension. The rationale for these recommendation changes is discussed. In addition, emerging data on blood pressure targets in stroke patients are discussed; these data did not lead to recommendation changes at this time. The Canadian Hypertension Education Program recommendations will continue to be updated annually., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This year's update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer., (Copyright © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010., Options and Outcomes: For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease., Evidence: A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence., Recommendations: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient's global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy. Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or betablockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered., Validation: All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually., Sponsors: The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.

Erythropoietin (EPO) and its analogs increase blood pressure (BP) in susceptible patients. The ratio of truncated to full EPO receptors (EPORs) in endothelial progenitor cells harvested from anemic patients receiving EPO while undergoing hemodialysis is related to the increased BP observed in these patients. Truncated EPORs exert a hypertensive effect by opposing full EPOR stimulation that augments cyclic guanosine monophosphate (GMP) in vascular endothelium. The contribution of this discovery to clinical practice is debatable.

Aims: The prevalence of type 2 diabetes mellitus (DM) among Emirati subjects is one of the highest in the world. This has been attributed to rising prevalence of obesity acting on genetically susceptible individuals. We analyzed the associations between TCF7L2 polymorphism and DM, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects., Methods: We genotyped the two TCF7L2 single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146 in 368 adult subjects. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA2-%B) and insulin resistance (HOMA2-IR). The SNP genotypes were analyzed against disease stage [normal glucose=0 (n=188), pre-diabetes=1 (n=85), and DM=2 (n=95)] and against clinical and biochemical measures. Age and sex were included as covariates in all association analyses. Additional adjustments were made for body mass index (BMI) and waist circumference in several analyses., Results: Diabetes disease stage was marginally significantly associated with the frequency of the T variant at rs12255372 (p=0.057; adjusted p=0.017) but not at rs7903146 (p=0.5; adjusted p=0.2). Comparison between subjects with normal glucose and the combined DM/pre-diabetes showed a significant association with rs12255372 (OR 1.47, CI 1.04-2.08; p=0.03) but not with rs7903146 (OR 1.16, CI 0.81-1.64; p=0.4). We found no association with metabolic syndrome, or with insulin and glucose levels, HOMA2-%B or HOMA2-IR. The age-standardized prevalence rate for metabolic syndrome was 43.9% in men and 42.1% in women., Conclusion: These data suggest that TCF7L2 variants are associated with increased risk for DM in Emirati subjects. We also demonstrate a high prevalence of the metabolic syndrome in this population.

Aims: To determine the prevalence of diabetes mellitus (DM) and its complications in the adult population of the United Arab Emirates (UAE) and assess the degree of metabolic control in subjects with diagnosed DM., Methods: A random sample of houses of Emirati citizens living in Al Ain, UAE was surveyed. Fasting blood glucose was determined by glucose meter and an oral glucose tolerance test (OGTT) was conducted if blood sugar was <7 mmol/l. DM was defined according to the WHO criteria. Pre-diabetes status was based on fasting venous blood glucose concentration of 5.6-6.9 mmol/l or 2h post-OGTT venous blood glucose level of 7.8-11.0 mmol/l., Results: There were 2455 adults (>18) living in the 452 surveyed houses of which 10.2% reported having the diagnosis of DM. A total of 373 men and non-pregnant women underwent testing, and after adjustment for factors affecting participation probability the prevalence of diagnosed DM, undiagnosed DM and pre-diabetes was 10.5, 6.6 and 20.2%, respectively. Age-standardized rates for DM (diagnosed and undiagnosed) and pre-diabetes among 30-64 years old were 29.0 and 24.2%, respectively. Logistic regression analysis showed that only age and body mass index (BMI) were significantly independently related to undiagnosed DM. In patients with diagnosed DM, the prevalence rates for retinopathy, neuropathy, nephropathy, peripheral vascular disease and coronary heart disease were 54.2, 34.7, 40.8, 11.1 and 10.5%, respectively. A significant proportion of subjects with undiagnosed DM and pre-diabetes also had micro- and macro-vascular complications. The proportion of subjects with diagnosed DM who achieved internationally recognized targets for HbA1c (<7%), LDL-C (<2.6 mmol/l) and blood pressure (<130/80 mmHg) was 33.3, 30.8 and 42.1%, respectively., Conclusion: This study confirms the previously reported high prevalence of DM in the UAE. Diabetic complications were highly prevalent among subjects with diagnosed and undiagnosed DM. Metabolic control was suboptimal in most subjects with diagnosed DM. Greater efforts are urgently needed to screen early and effectively treat DM in the UAE in order to prevent long-term complications.

In summary, the present information on treating hypertension in the diabetic overwhelmingly indicates a compelling need to lower BP to target diastolic BP of 80 mmHg or less, to be less concerned about the types of drugs used than the blood pressures achieved and the concordance with therapy and to rely on two or more antihypertensive drugs in the majority of cases. Management of the hypertensive diabetic is very cost-effective. It is clear that we must engage in total cardiovascular risk management if we are to prevent the microvascular and macrovascular complications in the hypertensive diabetic (or the diabetic hypertensive).

Background: Grapefruit juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly., Methods: Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg felodipine extended release with 250 mL grapefruit juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg felodipine for 2 days, followed by 5 mg felodipine for 6 days with 250 mL grapefruit juice or water in a steady-state study. Plasma concentrations of felodipine and dehydrofelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose., Results: Mean felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with grapefruit juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. Dehydrofelodipine area under the curve and maximum concentration were increased and dehydrofelodipine/felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with grapefruit juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with grapefruit juice in both studies; however, this effect was greater and more prolonged at steady state., Conclusions: A normal dietary amount of grapefruit juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion.

Medical research has helped to clarify the benefits of some therapies for improving the treatment or outcome associated with cardiovascular disease. However, the adoption of these approaches into routine clinical practice is, in many cases, inadequate. Consequently, there are many missed opportunities to reduce the burden of morbidity and mortality from cardiovascular disease. This review summarizes the factors that may prevent modified behavior in medical practice and the effectiveness of interventions that influence change. There are many barriers that may prevent or slow the adoption of new therapeutic advances into routine clinical practice. As a result, the use of well-proven, efficacious therapy can be suboptimal. Because of this underuse, the realized benefits of treatment are below the potential benefits. Adoption of new therapies is highly dependent on the use of interventions to promote clinical change. However, the effectiveness of different types of interventions varies greatly. Nevertheless, there is a wide range of strategies available that can be used to induce real changes in practice performance and potentially improve patient outcomes. It is essential that future intervention strategies focus on improving adoption of new therapies into clinical practice. The physician must be encouraged to prescribe proven treatments to those patients who stand to benefit most. In addition, better systems of care should be developed that improve the identification of patients as suitable candidates for proven treatments and sustain their long-term commitment to therapy.

A novel formulary has been developed in Nova Scotia with the objective of providing quality treatment with needed medications at affordable cost. Creation of the formulary has involved collaboration among health care professionals, seniors, the Department of Health and pharmaceutical companies. This is the first Canadian formulary to use the Anatomic, Therapeutic, Chemical system. Drug listing is comprehensive rather than exclusive. Colour-coded recommendations on use assist physicians with drug choice. Relative costs are indicated within each therapeutic grouping. Listings indicate drugs approved for reimbursement, interchangeable medications, maximum allowable cost, drug identification number and manufacturer code. Treatment summaries provide brief overviews of therapeutic advice. Updates on new products and new or modified treatment summaries are provided every 6 months. The formulary will be the focus of coordinated educational activities on treatment for seniors and health care professionals.

Objective: To provide updated, evidence-based recommendations concerning the effects of alcohol consumption on the prevention and control of hypertension in otherwise healthy adults (except pregnant women)., Options: There are 2 main options for those at risk for hypertension: avert the condition by limiting alcohol consumption or by using other nonpharmacologic methods, or maintain or increase the risk of hypertension by making no change in alcohol consumption. The options for those who already have hypertension include decreasing alcohol consumption or using another nonpharmacologic method to reduce hypertension; commencing, continuing or intensifying antihypertensive medication; or taking no action and remaining at increased risk of cardiovascular disease., Outcomes: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered., Evidence: A MEDLINE search was conducted for the period 1966-1996 with the terms ethyl alcohol and hypertension. Other relevant evidence was obtained from the reference lists of articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design, and graded according to the level of evidence., Values: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension., Benefits, Harms and Costs: A reduction in alcohol consumption from more than 2 standard drinks per day reduces the blood pressure of both hypertensive and normotensive people. The lowest overall mortality rates in observational studies were associated with drinking habits that were within these guidelines. Side effects and costs were not measured in any of the studies., Recommendations: (1) It is recommended that health care professionals determine how much alcohol their patients consume. (2) To reduce blood pressure in the population at large, it is recommended that alcohol consumption be in accordance with Canadian low-risk drinking guidelines (i.e., healthy adults who choose to drink should limit alcohol consumption to 2 or fewer standard drinks per day, with consumption not exceeding 14 standard drinks per week for men and 9 standard drinks per week for women). (3) Hypertensive patients should also be advised to limit alcohol consumption to the levels set out in the Canadian low-risk drinking guidelines., Validation: These recommendations are similar to those of the World Hypertension League, the National High Blood Pressure Education Program Working Group on Primary Prevention of Hypertension and the previous recommendations of the Canadian Coalition for High Blood Pressure Prevention and Control and the Canadian Hypertension Society. They have not been clinically tested. The low-risk drinking guidelines are those of the Addiction Research Foundation of Ontario and the Canadian Centre on Substance Abuse., Sponsors: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada. The low-risk drinking guidelines have been endorsed by the College of Family Physicians of Canada and several provincial organizations.

Objective: To provide updated, evidence-based recommendations for health care professionals on the management of hypertension in adults., Options: For patients with hypertension, there are both lifestyle options and pharmacological therapy options that may control blood pressure. For those patients who are using pharmacological therapy, a range of antihypertensive drugs is available. The choice of a specific antihypertensive drug is dependent upon the severity of the hypertension and the presence of other cardiovascular risk factors and concurrent diseases., Outcomes: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered., Evidence: MEDLINE searches were conducted from the period of the last revision of the Canadian Recommendations for the Management of Hypertension (January 1993 to May 1998). Reference lists were scanned, experts were polled and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to levels of evidence., Values: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension., Benefits: Harms and costs: The diagnosis and treatment of hypertension with pharmacological therapy will reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and mortality., Recommendations: This document contains detailed recommendations pertaining to all aspects of the diagnosis and pharmacological therapy of hypertensive patients. With respect to diagnosis, the recommendations endorse the greater use of non-office-based measures of blood pressure control (i.e., using home blood pressure and automatic ambulatory blood pressure monitoring equipment) and greater emphasis on the identification of other cardiovascular risk factors, both in the assessment of prognosis in hypertension and in the choice of therapy. On the treatment side, lower targets for blood pressure control are advocated for some subgroups of hypertensive patients, in particular, those with diabetes and renal disease. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, based on consideration of concurrent diseases, both cardiovascular and noncardiovascular., Validation: All recommendations were graded according to the strength of the evidence and the consensus of all relevant stakeholders., Sponsors: The Canadian Hypertension Society and the Canadian Coalition for High Blood Pressure Prevention and Control.

Background: Studies of monozygotic and dizygotic twins indicate an important genetic influence on the variability of responsiveness to norepinephrine in superficial human vein., Objectives: Genetic aspects of variability of alpha1-adrenergic receptor responsiveness to norepinephrine in superficial veins were further investigated by studying the response to norepinephrine in the dorsal hand veins of parents and their children., Methods: Subjects were healthy nonsmoking adults (n = 24; age range, 40 to 52 years) and their biological children (n = 20; age range, 15 to 26 years) who were free from medications likely to modify vascular tone. Superficial vein responsiveness to norepinephrine was assessed by the linear variable differential transformer technique. The dose of norepinephrine required to constrict superficial vein diameter by 50% from baseline (ED50) was calculated for each subject. Heritability was estimated by standard techniques of regression of mid-parent/child (natural logarithm) ED50 values., Results: ED50 ranged from 5.6 to 254.6 ng/min in the parents and from 7.8 to 242.3 ng/min in the children. Heritability was calculated at 0.88., Conclusions: These data confirm wide variability in superficial vein responsiveness to norepinephrine. The results confirm a major genetic influence in biological responsiveness of superficial vein to norepinephrine in healthy humans. Heritability of vascular alpha-adrenergic receptor responsiveness may influence vascular regulation during sympathetic stimulation and blockade.

The authors report the results of a literature review to identify research issues relating to physician prescribing practices and evaluate the potential for existing Canadian databases to support initiatives to improve prescribing practices. Methodologies such as small-area variation analysis and drug utilization reviews are discussed, and Canadian data sources relating to drug prescribing are assessed. The authors conclude that small-area variation analysis can be used to identify differences in drug utilization rates. A ranking method to identify drugs with the greatest variability in utilization can then be used to establish priorities for further analysis. After statistically significant factors associated with prescribing patterns are identified, intervention and policy formation will be possible. This will involve a more sophisticated integration of existing provincial information sources and the adoption of uniform guidelines to promote rational prescribing practices.

A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.

Indicators such as lowering of blood pressure in hypertension, alleviation of chest pain in angina pectoris, improvement in rest or exertional dyspnea from congestive heart failure (CHF) and suppression of ventricular arrhythmia are widely used in the management of cardiovascular diseases. There are often strong associations between the physiological indicators and the long-term clinical outcomes of cardiovascular disease such as stroke, myocardial infarction, sudden death and all-cause mortality. Physicians have assumed reasonably that early improvements in physiological markers will lead invariably to better long-term clinical outcomes. In recent years, a number of large clinical trials have demonstrated that short-term physiological improvements are not necessarily linked to better long-term clinical outcomes, but may be associated with less benefit than expected or even with detrimental outcomes. Management of cardiovascular diseases is complicated by the possibility that beneficial effects of a particular drug may be offset by its negative actions on the cardiovascular system. Effective antihypertensives may depress cardiac contractility; inotropes enhance left ventricular contractility in CHF, but may increase the risk of serious ventricular dysrhythmia; drugs which suppress ventricular arrhythmia may precipitate CHF or even excite pro-arrhythmic effects. Physicians must be conscious of this interplay of potentially beneficial and deleterious effects when cardiovascular drugs are prescribed. It is important in the analysis of large clinical trials of cardiovascular drugs to identify those situations in which the drug exhibits more benefit than harm and to determine, if possible, those aspects of drug action, drug dosage and population characteristics which contribute to the beneficial and detrimental actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive efficacy and tolerability of felodipine extended release (ER) (o.d.), felodipine plain tablet (PT) (b.i.d.), and placebo were compared in mild to moderate hypertensives whose seated diastolic blood pressure (DBP) was > or = 95 mm Hg while on hydrochlorothiazide 25 mg od. In addition to the diuretic, patients were randomised to felodipine ER 5 mg od (n = 50), PT 2.5 mg bid (n = 50), or placebo (n = 48) for 6 weeks, with clinic visits every 2 weeks. If seated DBP was > or = 90 mm Hg at any visit, daily dosage of felodipine was doubled to a maximum of 20 mg. The mean difference between ER and placebo was 5.1 mm Hg (p = 0.003); for PT vs. placebo the difference was 5.3 mm Hg (p = 0.002). Seated systolic blood pressure (SBP) was reduced by a mean difference of 6.8 mm Hg in the felodipine PT group compared with placebo (p = 0.03). Fourteen patients were withdrawn: 4 from the placebo group, 4 from the felodipine ER group, and 6 from the felodipine PT group. The most commonly reported adverse event was peripheral edema. In patients not adequately controlled on diuretic alone, felodipine ER o.d. and felodipine PT b.i.d. were superior to placebo in reducing seated DBP.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

Although beta-blockers and diuretics are presently the only medications shown to reduce morbidity and mortality in hypertensives in large clinical trials, these drugs have not exerted optimal expected benefits in reducing cardiac events. Alpha-1 selective blockers exhibit a favorable impact on lipids, particularly on HDL-cholesterol. Unlike beta-blockers, they do not increase triglycerides and they do not produce the increase in LDL-cholesterol observed with traditional doses of diuretics. Alpha-blockers should be considered in the treatment of hypertensives with lipid disorders or diabetes and in those who have contraindications, failure to respond or toxicity associated with diuretics and/or beta-blockade.

Coronary heart disease and other manifestations of atherosclerosis are leading causes of morbidity and mortality in Canada. Despite favourable trends in recent years, we should try to reduce cardiovascular events further. Physicians must translate current knowledge into public health policies and management strategems for individual patients. Patients are best served by a comprehensive risk management approach, involving nonpharmacological (mainly lifestyle) changes and drug therapy.

1. The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 2. Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days. 3. Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation. This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data. 4. The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 5. Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax. 6. The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of "tissue responsiveness" (i.e., vascular alpha-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.