Biomedical subjects

J Herbert Patterson

Publications and source records attributed to J Herbert Patterson.

11 recordsLinked to original sources

PubMed2005

Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis.

OBJECTIVES: The purpose of this study was to investigate the relationship of serum digoxin concentration (SDC) and outcomes in women with heart failure (HF). BACKGROUND: Controversy continues concerning the clinical utility of digoxin in women with HF. METHODS: Our analysis was retrospective with data from the Digitalis Investigation Group (DIG) trial. The principal study analysis reviewed 4,944 patients with HF due to systolic dysfunction who survived for at least 4 weeks (all 3,366 patients randomized to placebo and the 1,578 of 3,372 patients randomized to digoxin who had serum concentration measured 6 to 30 h [inclusive] after the last dose of study drug at 4 weeks). RESULTS: Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women (p = 0.008) and men (p = 0.002, p = 0.766 for gender interaction). Averaging hazard ratios (HRs) across serum concentrations from 0.5 to 0.9 ng/ml in women produced a HR for death of 0.8 (95% confidence interval [CI] 0.62 to 1.13, p = 0.245) and for death or hospital stay for worsening HF of 0.73 (95% CI 0.58 to 0.93, p = 0.011). In contrast, SDCs from 1.2 to 2.0 ng/ml were associated with a HR for death for women of 1.33 (95% CI 1.001 to 1.76, p = 0.049). CONCLUSIONS: Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations > or =1.2 ng/ml seem harmful.

Age Factors↗

PubMed2005

beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure.

OBJECTIVE: beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability. METHODS: Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. RESULTS: The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure. CONCLUSIONS: Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.

Cytochrome P-450 CYP2D6↗

PubMed2005

Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.

OBJECTIVE: Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients. METHODS: We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months. RESULTS: Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter. CONCLUSIONS: Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.

Adrenergic beta-Antagonists↗

PubMed2004

High-impact articles related to the pharmacotherapeutic management of systolic heart failure.

This compilation is part of a series of five articles identifying important literature in cardiovascular pharmacotherapy. This list focuses on pharmacotherapeutic management of acute decompensated and chronic heart failure. Most of the cited works present the results of landmark clinical studies that have shaped the management of patients with left ventricular systolic dysfunction. Limited primary literature is available for some topics; thus, pertinent review articles also are listed. In addition, consensus documents formed by expert panels in the United States and Europe are reviewed. This compilation may serve as a teaching tool, reference resource, or update of the literature for pharmacy clinicians, physicians, and students.

Heart Failure↗

PubMed2003

Vasopressin: a new target for the treatment of heart failure.

BACKGROUND: Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. METHODS: Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. RESULTS: Through activation of V(1a) and V(2) receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V(2) and dual V(1a)/V(2) receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V(1a) receptor antagonism requires further investigation. CONCLUSIONS: Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.

Animals↗

PubMed2003

Extended-release metoprolol succinate in chronic heart failure.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and tolerability of extended-release (ER) metoprolol succinate and its role in the management of chronic heart failure. DATA SOURCES: A MEDLINE search of English-language literature (1990-October 2002) was conducted using congestive heart failure and metoprolol CR/XL or metoprolol CR/ZOK as search terms to identify pertinent studies. STUDY SELECTION/DATA EXTRACTION: All of the articles identified from the data sources were evaluated, with priority given to randomized, double-blind, placebo-controlled studies. DATA SYNTHESIS: ER metoprolol succinate is a controlled-release tablet designed to produce even and consistent beta(1)-blockade throughout the 24-hour dosing interval, with less fluctuation in metoprolol plasma concentrations compared with immediate-release metoprolol. Three randomized, double-blind, placebo-controlled trials have evaluated the efficacy of ER metoprolol succinate in the treatment of patients with chronic heart failure. The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) study, the largest of these trials and the largest randomized mortality trial with beta-blockers in heart failure to date, demonstrated that ER metoprolol succinate reduced the relative risk of all-cause mortality by 34% versus placebo. Furthermore, the relative risk of the combined endpoint of mortality plus all-cause hospitalizations was reduced by 19% and sudden death was reduced by 41%. The benefits of therapy were evident in various patient subgroups, including elderly patients and those with diabetes mellitus. ER metoprolol succinate was generally well tolerated, with a similar proportion of patients discontinuing therapy due to adverse events relative to placebo (9.8% and 11.7%, respectively). CONCLUSIONS: ER metoprolol succinate therapy provides substantial mortality and morbidity benefits in patients with New York Heart Association class II and III heart failure who are stabilized on angiotensin-converting enzyme inhibitors and diuretics. ER metoprolol succinate is administered once daily, is well tolerated, and provides consistent beta(1)-blockade over the 24-hour dosing interval.

Delayed-Action Preparations↗

PubMed2003

Angiotensin II receptor blockers in heart failure.

Heart failure remains a significant cause of morbidity and mortality, despite major advances in therapy. Angiotensin II, the principal mediator of the renin-angiotensin system, exerts both short-term (e.g., hemodynamic, renal) and long-term (e.g., inflammation, cardiac remodeling) effects in the pathophysiology of cardiovascular disease. The effects of angiotensin II appear to be more completely inhibited by angiotensin II receptor blockers (ARBs), which act at the subtype 1 receptor level, than by angiotensin-converting enzyme (ACE) inhibitors because pathways other than that of ACE contribute to the generation of angiotensin II. Evidence demonstrates that ARBs, when added to conventional treatment for patients with heart failure, are associated with a reduction in morbidity and mortality as well as an improvement in quality of life. Clinical trials of ARB therapy indicate that these agents are generally well tolerated, both alone and in combination with other neurohormonal inhibitors. The current role of ARBs in heart failure is as an alternative for patients who cannot tolerate therapy with an ACE inhibitor. A number of ongoing clinical studies are likely to further define or expand the role of ARBs in the treatment of cardiovascular disease.

Angiotensin II↗

PubMed2003

Expanding role of beta-blockade in the management of chronic heart failure.

Although recent advances have been made in the treatment of heart failure, this disease continues to result in significant morbidity and mortality. Among the negative effects associated with progression of heart failure are decline in myocardial reserve, decreased exercise tolerance, decreased contractile function, and altered cardiac gene expression. Guidelines recommend neurohormonal antagonists for treatment and stress the importance of angiotensin-converting enzyme inhibition and beta-blockade in reversing the cardiac remodeling process. beta-Blockade slows or reverses the adverse effects resulting from chronic adrenergic stimulation. Traditionally, beta-blockers were reserved for mild-to-moderate heart failure, based on evidence from large, randomized clinical trials showing their positive effects on myocardial function and clinical outcomes. More recently, clinical data reveal that the agents can be expanded to patients with severe heart failure and those with left ventricular systolic dysfunction after myocardial infarction. Individual beta-blocking agents vary in their pharmacology and dosing requirements. These variations may influence treatment decisions and affect clinical measurements of left ventricular function and ventricular remodeling.

Adrenergic beta-Antagonists↗

PubMed2002

Clinical benefits of low serum digoxin concentrations in heart failure.

OBJECTIVES: We sought to determine whether there was a relationship between serum digoxin concentration (SDC), including SDCs typically regarded as low, and clinical efficacy related to digoxin in patients with symptomatic left ventricular dysfunction. BACKGROUND: Digitalis glycosides have been used for 200 years in the treatment of heart failure (HF), but the SDC required for optimal clinical efficacy and acceptable toxicity remains controversial. METHODS: This relationship was investigated by utilizing data from two randomized, double-blinded, placebo-controlled, digoxin-withdrawal trials: the Prospective Randomized study Of Ventricular failure and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Major end points were worsening HF, change in left ventricular ejection fraction and treadmill time after randomization. The primary analysis investigated the relationship between SDC at randomization and these end points. A secondary categorical analysis compared these end points in patients who discontinued digoxin versus patients who continued digoxin and had low (0.5 to 0.9 ng/ml), moderate (0.9 to 1.2 ng/ml) or high (>1.2 ng/ml) SDCs at randomization. RESULTS: Multiple regression analysis failed to find a relationship between randomization SDC, considered as a continuous variable, and any study end point (all p > 0.236). Multivariable Cox analysis found that the risk of worsening HF was significantly less (all p < 0.02) for patients in any category of SDC who continued digoxin, as compared with patients withdrawn from digoxin. Specifically, patients in the low SDC category were significantly less likely than placebo patients to experience worsening HF during follow-up (p = 0.018). CONCLUSIONS: The beneficial effects of digoxin on common clinical end points in patients with HF were similar, regardless of SDC.

Aged↗

PubMed2002

Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers.

BACKGROUND: Phenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration-related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9. OBJECTIVE: Our objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers. METHODS: A prospective, randomized, 3-period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3-week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic-acid metabolite E3174 were measured to determine steady-state pharmacokinetic parameters. RESULTS: Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration-time curve from time zero to 24 hours [AUC(0-24)] of losartan by 17% (355 +/- 220 ng x h/mL versus 427 +/- 177 ng x h/mL; P =.1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0-24) of losartan was increased by 29% (284 +/- 84 ng x h/mL versus 402 +/- 128 ng x h/mL; P =.008). Coadministration of phenytoin significantly reduced the AUC(0-24) of E3174 by 63% (1254 +/- 256 ng x h/mL versus 466 +/- 174 ng x h/mL; P =.0001) and the formation clearance of losartan to E3174 (1.91 +/- 0.8 mL/h per kilogram versus 0.62 +/- 0.4 mL/h per kilogram; P =.0001). CONCLUSIONS: Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9-mediated conversion of losartan to E3174.

Adult↗

PubMed2002

Surrogate end points in heart failure.

OBJECTIVE: To describe the potential utility of a true surrogate marker of heart failure outcomes, historically investigate the validity of surrogates most commonly evaluated in heart failure, and identify specific end points offering the most potential for future use. DATA SOURCES: A MEDLINE search (1966-June 2001) was completed to identify relevant literature. Additional references were also retrieved from selected articles. Search terms included b-type natriuretic peptide, cardiac remodeling, end-diastolic volume, heart failure, and surrogate end points. DATA SYNTHESIS: By definition, true surrogate end points must predict outcomes associated with disease progression and response to therapy. A validated surrogate measure of mortality would render significant utility in both heart failure drug development and clinical practice. Improvements in traditional functional markers of heart failure, including ejection fraction and exercise capacity, have produced inconsistent results in regard to mortality in a number of clinical trials. Numerous measures of cardiac remodeling and neurohormonal activation, however, have proven to be reliable predictors of disease progression and therapeutic response. These findings have contributed significantly to the current understanding of heart failure pathophysiology and approach to treatment. Specifically, measures such as left-ventricular end-diastolic volume (LVEDV) and, potentially, b-type natriuretic peptide (BNP) concentrations may correlate with disease progression and parallel the mortality reductions observed with angiotensin-converting enzyme inhibitor and beta-blocker therapy. CONCLUSIONS: Currently, LVEDV and plasma BNP offer the greatest potential as surrogate end points in heart failure. Further investigation of these measures is required before routine implementation in drug development and clinical practice can be justified.

Atrial Natriuretic Factor↗