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Biomedical subjects

H Krum

Publications and source records attributed to H Krum.

At least 19 recordsLinked to original sources
PubMed2001

A systematic review of predictors of maintenance of normotension after withdrawal of antihypertensive drugs.

BACKGROUND: The identification and treatment of hypertension in the general community has contributed to the reduction in strokes and coronary heart disease observed during the past 30 years. However, concerns have arisen that some patients may be receiving unnecessary antihypertensive drug therapy leading to wasted resources and the potential for adverse drug effects. Once therapy has been started, treating physicians have difficulty in selecting patients for withdrawal and have concerns regarding patient safety and their own legal liability. PROCEDURES: This study reviews and consolidates information from published studies to identify known predictors of the successful maintenance of normotension after antihypertensive drug withdrawal. The predictors were identified by determining the proportion of subjects with various baseline characteristics who remained normotensive while off medication for at least 12 months. From these data we have developed a clinical algorithm to help identify patients in whom antihypertensive drug withdrawal might be considered. This may assist primary care physicians in achieving successful withdrawal of antihypertensive therapy among selected hypertensive patients. RESULTS: The most consistent predictors identified were blood pressure (BP) (lower pretreatment, on treatment, and after withdrawal), nature of pharmacotherapy (fewer agents and lower dose), and preparedness to accept dietary intervention (weight and sodium reduction). CONCLUSIONS: On the basis of this information, a trial of withdrawal of antihypertensive medication might be recommended for patients who have mildly elevated, uncomplicated BP that is well controlled on a single agent, and who are motivated and likely to accept lifestyle changes.

Antihypertensive Agents↗
PubMed2001

Comparative effects of mibefradil and nifedipine gastrointestinal transport system on autonomic function in patients with mild to moderate essential hypertension.

BACKGROUND: L-type dihydropyridine calcium channel blockers (CCBs) have been implicated in increased cardiovascular events in patients with hypertension, perhaps due to adverse effects on autonomic nervous system (ANS) function. Blockade of T-type calcium channels may limit ANS dysfunction by inhibition of T channel-mediated neuroendocrine effects. OBJECTIVE AND DESIGN: This double-blind, parallel group study compared the effect of nifedipine gastrointestinal transport system (GITS) (L-type CCB) versus mibefradil (T-type CCB) on ANS function in patients with mild-moderate essential hypertension. METHODS: Sixteen patients (10 male, 6 female; age 57.2 +/- 2.3 years), diastolic blood pressure (DBP) < 95 mmHg were randomized to nifedipine 30 mg daily or mibefradil 50 mg daily (2 weeks), then nifedipine 60 mg daily or mibefradil 100 mg daily (4 weeks). Sympathetic nervous system activity (SNSA) was assessed using norepinephrine kinetics. Parasympathetic nervous system activity (PSNA) was assessed from 24 h Holter recordings of heart rate variability (HRV). Non-invasive baroreflex sensitivity (BRS) provided integrated assessment of ANS. RESULTS: Patient groups were well matched at baseline. Achieved DBP was lower in patients treated with mibefradil compared with nifedipine, (83.4 +/- 1.7 versus 95.25 +/- 3.3 mmHg). There were no significant differences in SNSA and BRS between groups, however the root mean square of successive differences and high frequency power (HFP) were increased in mibefradil compared with nifedipine-treated patients [(+ 1.07 +/- 1.6 versus -3.36 +/- 1.2 ms, P < 0.05) and (+ 0.28 +/- 0.1 versus -0.23 +/- 0.1 ms2, P < 0.01), respectively]. Furthermore, Ln HFP/Ln total power was increased from week 0 to week 6 in the mibefradil-treated group, (0.71 +/- 0.02 versus 0.74 +/- 0.03, P = 0.046). CONCLUSION: No differences existed between effect of L- and T-type CCBs on SNSA and BRS. However, T-type CCBs increased PSNA, independent of achieved changes in heart rate.

Autonomic Nervous System↗
PubMed2000

Salivary endothelin concentrations in the assessment of chronic heart failure.

We have shown that salivary endothelin concentrations are raised in patients with chronic heart failure and indicate progression of disease severity through each New York Heart Association Functional Class. Furthermore, endothelin concentrations in saliva seem to discriminate between controls and patients with mild symptoms of chronic heart failure.

Case-Control Studies↗
PubMed2000

New and emerging pharmacologic strategies in the management of chronic heart failure.

Chronic heart failure (CHF) is a complex syndrome involving activation of multiple cellular, metabolic, and neurohumoral pathways following the initial myocardial insult. Recently, there have been considerable advances in the pharmacologic management of CHF. The current approach to treatment recognizes the need to target neurohormonal activation, and the use of angiotensin-converting enzyme (ACE) inhibitors and beta blockers should now be regarded as part of standard therapy in many patients with CHF. However, because of the complexity of the disease, blockade of additional pathways is likely to be required to maximize the therapeutic benefit of intervention. To this end, there are several agents under active late-phase clinical evaluation. The most advanced of these new strategies (beyond renin-angiotensin-aldosterone blockade) is inhibition of the endothelin system. There is a substantial body of evidence that this system is intimately involved in CHF disease progression. Early-phase clinical data are very encouraging and support the potential utility of long-term endothelin inhibition. Other novel approaches involve the use of cytokine antagonists (e.g., agents that block tumor necrosis factor-alpha activity) and the augmentation of natriuretic peptides. If all these potential agents prove to be of benefit in CHF, the question of which agent or combination of agents to use in which patients will arise. There is therefore a need to develop scientific approaches in order to be able to identify more accurately patients who will obtain benefit from specific classes or combinations of drugs.

Atrial Natriuretic Factor↗
PubMed2000

Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis.

Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ganciclovir but has a relatively low bioavailability and this may be problematic in at-risk patients with malabsorption. The bioavailability and therefore therapeutic potential of oral ganciclovir in cystic fibrosis (CF) patients post-lung transplant (LT) might be expected to be inadequate given the high incidence of malabsorption in these patients. An 8 h pharmacokinetic study was performed in 12 CF patients 160 +/- 122 days post-transplant who had been taking 1 g oral ganciclovir tds for 3 days with food (plus normal enzyme supplements). Mean (range) serum creatinine was 150 Imol/L (70-280). Blood was sampled at 0.5, 1, 2, 3, 4, 6 and 8 h post-final dose. Plasma was stored at -20 degrees C and later analysed by highperformance liquid chromatography. Mean peak concentration (C(max)) was 4.8 mg/L (0. 96-12.8), mean minimum concentration (C(min)) was 3.6 mg/L (0.78-11. 7) and mean area under the curve (AUC) was 35.4 mg.8 h/L (8-99). C(max), C(min) and AUC correlated significantly with one another (P < 0.001) as well as with serum creatinine and creatinine clearance (P < 0.01). When corrected for alterations in renal function, plasma oral ganciclovir levels are as predicted for other transplant populations. Three days of oral ganciclovir results in therapeutically useful plasma drug levels in the CF LT population, despite a background of general malabsorption. C(max), C(min) and AUC are highly correlated, allowing for the possibility of steady-state drug monitoring to confirm that the recommended dosing algorithm produces appropriate plasma levels.

Adult↗
PubMed2000

Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction.

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.

Animals↗
PubMed2000

Baseline predictors of tolerability to carvedilol in patients with chronic heart failure.

OBJECTIVE: To determine baseline predictors of tolerance to the alpha/beta blocker carvedilol in everyday clinical practice. DESIGN: Retrospective analysis of tolerance to carvedilol in patients with chronic heart failure. Tolerance was defined as currently on carvedilol or on it at the time of death or heart transplantation. To meet the criteria for tolerance, carvedilol had to be prescribed at a stable dose for >/= 3 months. SETTING: Everyday clinical practice, comprising both hospital specialist practice and private practice. Tolerance was assessed in all patients prescribed carvedilol for chronic heart failure in those practices. PATIENTS: 808 consecutive patients in both hospital specialist (611 patients) and private practice (197 patients). MAIN OUTCOME MEASURES: Baseline predictors of tolerance assessed by proportional hazards analysis. Both univariate and multivariate analyses were performed. RESULTS: Within the entire cohort of 808 patients, 95 had stopped carvedilol, 606 were currently receiving the drug, 50 had died, and 44 had received a heart transplant. Overall, 88% of patients tolerated carvedilol (87% in the hospital specialist group, 92% in the private practitioner group). Factors that indicated impaired tolerance by univariate analysis were increased age in years (hazard ratio 1.01, 95% confidence interval (CI) 1.0 to 1.3), low diastolic blood pressure (hazard ratio 1.04, 95% CI 1.02 to 1.08), and raised plasma urea concentration (hazard ratio 1.04, 95% CI 1.02 to 1.05). New York Heart Association (NYHA) class was also a marker of tolerance (proportion not tolerated: 3% class I; 9% class II; 13% class III, 22% class IV). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was also assessed in relation to traditional precautions or relative contraindications to beta blockade. Tolerance in these subgroups was: chronic obstructive airways disease/asthma 85% (89 patients), diabetes 86% (127 patients), peripheral vascular disease 84% (58 patients), concomitant amiodarone treatment 83% (230 patients), and heart rate < 70 beats/min 84% (184 patients). CONCLUSIONS: beta Blocker treatment was well tolerated in everyday clinical practice, including non-hospital-based private practice. There was no single predictor of poor tolerance on multivariate analysis, although there was a clear association with NYHA class as well as age, diastolic blood pressure, and plasma urea on univariate analysis. Carvedilol was tolerated well among selected patients with traditional contraindications to beta blockade in this situation.

Adolescent↗
PubMed1999

Reduced dietary fat intake increases parasympathetic activity in healthy premenopausal women.

1. Hypercholesterolaemia has been associated with decreased heart rate variability, a measure of cardiac parasympathetic activity. However, the effect of perturbation of the lipid profile on autonomic function has not been examined systematically. 2. The effects of short-term dietary lipid modification on autonomic function are studied in 25 normotensive, non-smoking, premenopausal women with normal bodyweight. Subjects consumed either a low (L, 25%) or high fat (H, 40%) diet for 2 weeks in an open, randomized, cross-over manner with a 2 week washout. 3. Baroreflex sensitivity was determined by gating beat-to-beat heart period (RR) interval and continuous non-invasive blood pressure recordings. Heart rate variability measures of cardiac parasympathetic nervous system activity were obtained in the time (standard deviation of RR intervals, root mean square of successive differences (rMSSD)) and frequency (high frequency power) domains. All assessments were made at the same timepoint in the menstrual cycle. 4. Both low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased significantly (P < 0.05) with increased dietary fat intake (H, 2.7 +/- 0.1 vs L, 2.2 +/- 0.1; H, 1.3 +/- 0.1 vs L, 1.1 +/- 0.1 mmol/L, respectively) as did mean arterial pressure (H, 78.1 +/- 1.5 vs L, 74.3 +/- 1.5 mmHg). Weight was unchanged by dietary lipid intake (H, 62.6 +/- 8.5 vs L, 62.3 +/- 8.3 kg, P = NS). 5. There was a significant increase in rMSSD (H, 29.6 +/- 3.4 vs L, 38.8 +/- 6.4 msec, P < 0.05) and natural logarithm of high frequency power following low fat diet (H, 4.4 +/- 0.2 vs L, 4.8 +/- 0.3 msec2, P = 0.01). Baroreflex sensitivity also increased following the low fat diet (H, 13.91 +/- 2.2 vs L, 16.9 +/- 3.2 msec/mmHg, P = 0.23). 6. Short-term dietary lipid modification can significantly increase cardiac parasympathetic nervous system activity in healthy premenopausal women. These changes in autonomic status appear to be independent of changes in bodyweight and may be of clinical relevance considering the prognostic implications of heart rate variability in cardiovascular disease.

Adolescent↗
PubMed1999

Sympathetic activation and the role of beta-blockers in chronic heart failure.

Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods as chronic catecholamine excess appears to contribute to disease progression and increased mortality in this condition. Therefore, blockade of sympathetic activation represents a logical, if somewhat counter-intuitive, approach to the management of the patient with systolic CHF. Pharmacological approaches to blockade of this system include inhibition of central sympathetic outflow (using central sympatholytics, e.g. rilmenidine, moxonidine), blockade of the catecholamine biosynthetic pathway (dopamine beta hydroxylase antagonists) and blockade of the cardiac effects of sympathetic activation (beta-adrenoceptor blocking agents). Beta-blockers have now been extensively studied in patients with symptomatic CHF of the New York Heart Association (NYHA) Class II and III severity. Provided beta-blocker therapy is carefully up-titrated from sub-therapeutic doses and given for at least three to four months, these agents have been associated with favourable long term haemodynamic, functional and mortality outcomes. Furthermore, beta-blockers delay disease progression in CHF by reversing the pathological myocardial remodelling process that accompanies the disease. Non-selective beta-adrenoceptor blocking drugs appear to be of particular benefit in CHF therapy. Myocardial beta2 receptors are down-regulated to a lesser extent than beta1 receptors in CHF, therefore blockade of the beta2 receptor sub-type may assume greater importance in inhibiting the deleterious effects of sympathetic activation on the myocardium in this disease. Newer agents that possess additional vasodilator properties (carvedilol, bucindolol, nebivolol) may be useful in overcoming the initial negative inotropy of the beta-blocking component of the drug, however, it is unlikely that vasodilation contributes greatly to long term clinical benefits. Drugs such as carvedilol are also anti-oxidant, anti-proliferative and have anti-endothelin actions; the clinical significance of these properties is yet to be determined. Unanswered questions remain regarding the use of beta-blockers in heart failure. Ongoing studies are further examining mechanisms underlying the clinical benefits of these agents as well as their therapeutic potential in NYHA Class IV patients, heart failure post-myocardial infarction and patients with asymptomatic left ventricular dysfunction.

Adrenergic beta-Antagonists↗
PubMed1999

Beta-blockers in heart failure. The 'new wave' of clinical trials.

There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of beta-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.

Adrenergic beta-Antagonists↗
PubMed1998

The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.

BACKGROUND: Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. METHODS: We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. RESULTS: As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). CONCLUSIONS: An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.

Adult↗
PubMed1998

Effect of endothelin-1 on exercise-induced vasodilation in normal subjects and in patients with heart failure.

Forearm blood flow (ml/min/100 ml) was determined with strain-gauge venous occlusion plethysmography at rest and in response to handgrip exercise in 7 patients with congestive heart failure and in 9 normal subjects before and after regional administration of endothelin-1 in the brachial artery. Administration of endothelin-1 significantly decreased forearm blood flow at rest and during exercise in normal subjects but did not change it at rest or during exercise in patients with congestive heart failure.

Adult↗