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Biomedical subjects

Henry Krum

Publications and source records attributed to Henry Krum.

At least 91 records · Page 5Linked to original sources
PubMed2003

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy?

Since neither angiotensin-converting enzyme inhibitors (ACE-I) nor angiotensin II receptor blockers (ARB) can completely suppress aldosterone levels, there is a need for alternative/supplementary antihypertensive medications, such as the selective aldosterone blocker eplerenone (Inspra). This multicenter study measured the safety and efficacy of add-on eplerenone therapy to reduce blood pressure not controlled by ACE-I or ARB monotherapy. An ad hoc analysis evaluated whether active plasma renin or serum aldosterone levels could predict blood pressure response to eplerenone therapy. Patients (N = 341) with a diastolic blood pressure > 95 mmHg on a fixed dose of ACE-I or ARB were randomized to 8 weeks of double-blind treatment with eplerenone 50 mg qd or placebo. If blood pressure remained uncontrolled following 2, 4, or 6 weeks of treatment, the eplerenone dose was increased to 100 mg qd. In a combined cohort analysis of these patients, the placebo-adjusted change in systolic and diastolic blood pressure was -5.9/-2.4 mmHg (p< 0.001 and p = 0.006, respectively). While adding eplerenone to an ACE-I or ARB is safe and effective for blood pressure reduction, there was no baseline value or range of values of active plasma renin, serum aldosterone, or their ratio that predicted a favorable response to either of these drug combinations.

Adolescent↗
PubMed2003

Physiologic determinants of endothelin concentrations in human saliva.

BACKGROUND: Salivary endothelin (ET) concentrations have been shown to correlate with disease severity in patients with chronic heart failure (CHF). We undertook the present study to evaluate the stability of salivary ET under different handling conditions to assess its suitability as a biochemical marker in screening, diagnosis, and management of CHF. METHODS: Saliva samples were collected from healthy individuals and/or CHF patients, subjected to different handling conditions, and then stored at -80 degrees C until assayed by an ELISA for ET. RESULTS: Salivary ET concentrations showed a time-dependent increase during storage at room temperature. After 72 h of incubation at room temperature, ET increased approximately 2.8-fold (P = 0.03). Simultaneously, salivary big ET showed a time-dependent 11.2-fold decrease (P <0.0001). This activity was blocked by an ET-converting enzyme (ECE) inhibitor, suggesting that these changes were attributable to ECE-dependent cleavage of endogenous big ET in saliva. Ex vivo conversion was also observed when samples were stored at 4 degrees C, but the magnitude of these changes was markedly smaller (P <0.0001). Posture also affected salivary ET concentrations in CHF patients. With a change from supine to seated rest, salivary ET concentrations increased 1.5- and 1.8-fold after 20 and 40 min, respectively (P = 0.01). With a return to supine rest, salivary ET concentrations returned to baseline concentrations (P = 0.008). CONCLUSIONS: These data suggest that saliva sampling and handling conditions could markedly affect measurement of salivary ET. In particular, care should be taken to minimize ECE-dependent enzymatic conversion of endogenous big ET in saliva.

Adult↗
PubMed2003

New developments in the pharmacological treatment of chronic heart failure.

In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical.

Arginine Vasopressin↗
PubMed2003

Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant?

The present review outlines the clinical relevance of pharmacokinetic drug interactions within the HMG-CoA reductase inhibitor class. These interactions can result in markedly increased or decreased plasma concentrations of some drugs within this class. However, the relationship between altered plasma concentrations and adverse effects or toxicity may not be linear. It is likely that other variables affect this concentration-effect relationship including: rapid changes in the concentration, concomitant lipid-lowering therapy or host genetic factors that code for different forms or amounts of metabolising enzymes and drug receptors. It is not currently possible to predict which patients will manifest clinically important drug-drug interactions, nor what concentration of an HMG-CoA reductase inhibitor will cause rhabdomyolysis. Thus, until prescribers have better scientific information from which to develop a 'therapeutic range' for each agent, caution should be exercised. In particular, patients taking a CYP3A4-metabolised agent, e.g. atorvastatin, simvastatin and lovastatin, should not be started on a CYP3A4 inhibitor or inducer without close monitoring.

Beverages↗
PubMed2003

Rationale for a trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular dementia in the elderly: Aspirin in Reducing Events in the Elderly (ASPREE).

Low-dose aspirin (acetylsalicylic acid) therapy has been shown to reduce the risk of vascular events and there is increasing evidence of its potential to reduce the rate of cognitive decline in the elderly. Adverse effects including gastrointestinal and intracranial haemorrhage may offset these benefits. The balance of risks versus benefits of aspirin for the primary prevention of cardiovascular disease and vascular dementia has not been established in the elderly. There is clearly a need to conduct a study in family practice to investigate whether routine use of low-dose aspirin for the primary prevention of cardiovascular disease and vascular dementia in the elderly is beneficial or harmful. Aspirin in reducing events in the elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular dementia. It will follow 15,000 subjects aged 70 years or more for an average of 5 years. This sample size has a power of 87% to detect a 15% reduction in primary events in the aspirin group, with an anticipated combined primary event rate of 20 per 1000 patient years.

Aged↗
PubMed2003

Aldosterone receptor antagonists for hypertension: what do they offer?

Aldosterone is an important and independent target for therapeutic intervention in hypertension and hypertension-related diseases. Its actions, once thought to be limited to the distal convoluted tubule of the kidney, are now recognised to be wide-ranging, including interactions with mineralocorticoid receptors in diverse cardiovascular sites to mediate vascular and myocardial remodelling and dysfunction. The latter are referred as non-epithelial actions. Spironolactone, an aldosterone receptor antagonist, is indicated for the treatment of mineralocorticoid hypertension, but its use is limited by an adverse effect profile that includes not only by hyperkalaemia, but also antiandrogenic and progestational effects resulting from its poor specificity for the aldosterone receptor. Eplerenone is the first selective aldosterone receptor antagonist to be developed and recently gained approval from the US FDA for treatment of systemic hypertension. This was based on studies which demonstrated that eplerenone had a blood pressure-lowering profile that was equivalent to existing antihypertensive agents, was useful for treatment of low-renin and systolic hypertension, maintained utility even as add-on therapy to other antihypertensive agents, and exerted beneficial effects on hypertension-related left ventricular hypertrophy and renal impairment. Perhaps most notably, eplerenone was generally well tolerated, and did not cause the antiandrogenic and progestational adverse effects commonly observed with spironolactone.

Aldosterone↗
PubMed2003

Factors influencing family physician adherence to hypertension treatment guideline recommendations on the initiation of pharmacotherapy: questionnaire survey.

BACKGROUND: Family physicians do not prescribe antihypertensive medication according to current guidelines. This study investigates possible reasons for this. The objectives were to measure the knowledge, attitude and stated practice of family physicians to the initiation of pharmacotherapy for uncomplicated hypertension and to explore the reasons why clinical practice differs from guideline recommendations. STUDY DESIGN: A cross-sectional postal survey conducted between June and October 1999. Simple frequency analysis and a chi(2) test comparing family physician characteristics and responses. METHODS: A three-phase postal survey was undertaken of a random sample of family physicians. Telephone and facsimile contact was made to non-responders. The survey instrument included respondent characteristics, preference for initiation of antihypertensive drug therapy and their opinion of efficacy, adverse effects and long-term safety, as well as knowledge of guidelines. PARTICIPANTS: Family physicians in the state of Victoria, Australia. MAIN OUTCOME MEASURES AND RESULTS: Ranked preference of drugs for uncomplicated hypertension. Opinion of drug efficacy, adverse effects, safety and cost. Knowledge of guidelines for first-line antihypertensive drugs. Newer agents are preferred to older agents in the initiation of antihypertensive drug therapy contrary to current guideline recommendations. Newer agents were thought to be more efficacious, have better short- and long-term adverse effect profiles and be more expensive than older agents. Younger doctors most often held these attitudes. Guidelines influenced decision making but were not the most important factor. CONCLUSIONS: There is a demonstrable need for governments to invest in the promotion of accurate information on drugs through continuing education of prescribers and facilitating the production of standardized paper and web-based clinical guidelines. A program of targeted investment in clinical trials that examine the justification for more expensive classes of agents should also be considered in appropriate circumstances.

Antihypertensive Agents↗
PubMed2003

Should patients with chronic heart failure be treated with "statins"?

There are a number of theoretical reasons as to why 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) should be prescribed to patients with chronic heart failure (CHF). These agents are proven to prevent coronary heart disease, the major etiological factor in the development of CHF. Potential additional effects of these agents include inhibition of proinflammatory cytokine activity and other potential beneficial effects on cardiac remodeling. However, there are also possible adverse effects of this strategy, supported by the overriding observation that low plasma lipid levels portend a poorer prognosis in patients with established CHF. Potential mechanisms by which statins may directly confer adverse effects include a reduction in levels of the antioxidant ubiquinone and an increase in blood endotoxin levels, both of which may contribute to CHF disease progression. Given these uncertainties, an answer to the question of whether or not therapy for CHF should include statins requires a definitive clinical trial. The importance of such a trial is further highlighted by the already commonplace usage of statins amongst patients with CHF.

Antioxidants↗
PubMed2003

Current status of endothelin blockade for the treatment of cardiovascular and pulmonary vascular disease.

With recognition of the significant role of the endothelin system in cardiovascular and pulmonary vascular diseases, attention has turned to the therapeutic application of agents that antagonize this system. Three strategies can be employed: dual endothelin receptor (ETA and ETB) antagonism, selective ETA antagonism and inhibition of endothelin-converting enzymes. The first two strategies have been evaluated in late-phase clinical trials, with mixed results. The use of the dual endothelin receptor antagonist bosentan in pulmonary arterial hypertension has been successful. Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure. Both types of receptor antagonists, however, have been evaluated in systemic hypertension and chronic systolic heart failure and are unlikely to be further developed in these areas. For the treatment of hypertension, their (moderate) efficacy and safety/tolerability profiles appear no more favorable than existing antihypertensive agents. In terms of treatment for chronic heart failure, these agents appear to offer no further benefit over standard therapy for the treatment of chronic heart failure, and in fact, may be associated with poorer outcomes. The complexity of the endothelin system and its diverse roles in multiple disease states will ensure its position as a target for drug development.

Clinical Trials as Topic↗
PubMed2003

Eplerenone. Pharmacia.

Pharmacia Corp (formerly GD Searle & Co) is developing eplerenone, an aldosterone receptor antagonist, as a potential treatment for congestive heart failure and systemic hypertension. The compound has been registered for hypertension and Pharmacia plans to submit a supplemental NDA for congestive heart failure in the first half of 2003 based on positive results from a phase III clinical trial.

Animals↗
PubMed2003

Tolerability of beta-blockers in heart failure: reassurance needed, reassurance provided.

In contrast to widely held perceptions regarding tolerability of beta-blockers in heart failure, it is clear that initiation and uptitration is not as complex as perceived. In particular, there is no increased risk of intolerance and/or worsening of heart failure symptoms with initiation of beta-blocker therapy (at least as demonstrated by carvedilol in COPERNICUS). Furthermore, the perceived delay in beneficial effects on outcomes is perhaps challenged by the COPERNICUS study. Interestingly, all of the above observations appear to hold true in patients with advanced disease. Because of the unique history of beta-blockers in systolic heart failure, physicians have needed particular reassurance regarding the tolerability of these agents. Reassurance regarding tolerability has now been definitively provided.

Adrenergic beta-Antagonists↗
PubMed2002

Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.

BACKGROUND: Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. METHODS AND RESULTS: We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. CONCLUSION: In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

Adrenergic beta-Antagonists↗
PubMed2002

Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort.

OBJECTIVES: To identify simple long term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in elderly patients in general practice. DESIGN: Prospective cohort study. SETTING: 169 general practices in Victoria, Australia. PARTICIPANTS: 503 patients aged 65-84 with treated hypertension who were withdrawn from all antihypertensive drugs and remained drug free and normotensive for an initial two week period; all were followed for a further 12 months. MAIN OUTCOME MEASURES: Relative likelihood of maintaining normotension 12 months after drug withdrawal; relative likelihood of early return to hypertension after drug withdrawal. RESULTS: The likelihood of remaining normotensive at 12 months was greater among younger patients (65-74 years), patients with lower "on-treatment" systolic blood pressure, patients on single agent treatment, and patients with a greater waist:hip ratio. The likelihood of return to hypertension was greatest for patients with higher "on-treatment" systolic blood pressure. CONCLUSIONS: Age, blood pressure control, and the number of antihypertensive drugs are important factors in the clinical decision to withdraw drug treatment. Because of consistent rates of return to antihypertensive treatment, all patients from whom such treatment is withdrawn should be monitored indefinitely to detect a recurrence of hypertension.

Aged↗
PubMed2002

Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).

BACKGROUND: Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. METHODS AND RESULTS: We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment--was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P=0.187)--a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P=0.024) and a 6% lower risk of death (P=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P=0.012). CONCLUSION: Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Statins and chronic heart failure: do we need a large-scale outcome trial?

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are of proven clinical benefit in coronary heart disease, at least in those patients who do not have overt chronic heart failure (CHF). However, as there have been no prospective clinical trials of statins in CHF patients, the question arises as to whether the benefits observed in the absence of CHF can be necessarily inferred in those patients in whom CHF is established. In this review, the evidence base stating support of the use of statins in CHF is presented, as well as theoretical considerations as to why these agents may not necessarily be of benefit in this setting. The beneficial potential of statins clearly relates to their plaque stabilization properties and associated improvements in endothelial function, which together should reduce the risk of further infarction and, perhaps, the ischemic burden on the failing ventricle. Furthermore, these agents may have beneficial effects independent of lipid lowering. These include actions on neoangiogenesis, downregulation of AT(1) receptors, inhibition of proinflammatory cytokine activity and favorable modulation of the autonomic nervous system. The potential adverse effects of statins in CHF include reduction in levels of coenzyme Q10 (which may further exacerbate oxidative stress in CHF) and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins entering the circulation via the gut. In support of these possibilities are epidemiologic data linking a lower serum cholesterol with a poorer prognosis in CHF. These uncertainties indicate the need for a definitive outcome trial to assess the efficacy and safety of statins in CHF, despite their current widespread, non-evidence based use in this population.

Anticholesteremic Agents↗
PubMed2002

Effect of endothelin blockade on basal and stimulated forearm blood flow in patients with essential hypertension.

Endothelin receptor antagonism lowers blood pressure in patients with essential hypertension, but the contribution of the endothelin system to increased vascular tone in these patients remains controversial. We used strain-gauge venous plethysmography to measure changes in basal and metabolically stimulated (peak reactive hyperemia [PRH]) forearm blood flow (FBF) induced by continuous intrabrachial infusion of SB 209670, a dual endothelin type A/endothelin type B receptor antagonist (ETRA) in 11 patients with hypertension and 12 healthy age-matched control subjects. In both groups, ETRA caused significant vasodilation (increase in FBF compared with baseline over the last 30 minutes of ETRA infusion: 75+/-12% in control subjects, 40+/-13% in hypertension patients; P<0.01 for both groups). By repeated-measures ANOVA, there was no greater increase in FBF after ETRA in hypertension patients compared with control subjects. In addition, FBF responses to PRH, expressed as percent change from baseline (prePRH), were similar in both groups (control subjects: preETRA, 1381+/-222%; during ETRA, 921+/-178%; and hypertension patients: preETRA, 1232+/-221%: during ETRA, 865+/-285%). We conclude that basal and stimulated vasodilation induced by short-term ETRA infusion in the forearm vasculature of hypertension patients is not increased compared with that of control subjects. An enhanced contribution of the endothelin system to vascular tone in hypertension patients could not be demonstrated using this experimental approach.

Blood Flow Velocity↗
PubMed2002

Role of valsartan and other angiotensin receptor blocking agents in the management of cardiovascular disease.

Blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients post-myocardial infarction as well as in chronic heart failure and hypertension. ACE inhibitors also have a well-established place in the treatment of diabetic nephropathy. Angiotensin receptor blockers (ARBs) have been developed to produce a more complete blockade of the actions of angiotensin II as compared to other drug classes, as well as an improved side effect profile. This article provides an overview of the place of ARBs in general and of the ARB valsartan in particular, and draws comparisons to ACE inhibitors in the treatment of cardiovascular diseases.

Angiotensin Receptor Antagonists↗