Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties.

C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B), are potent positive regulators of endochondral bone growth, making the CNP pathway one of the most promising therapeutic targets for the treatment of growth failure. However, the administration of exogenous CNP is not fully effective, due to its rapid clearance in vivo. Modification of CNP to potentially druggable derivatives may result in increased resistance to proteolytic degradation, longer plasma half-life (T1/2), and better distribution to target tissues. In the present study, we designed and evaluated CNP/ghrelin chimeric peptides as novel CNP derivatives. We have previously reported that the ghrelin C-terminus increases peptide metabolic stability. Therefore, we combined the 17-membered, internal disulfide ring portion of CNP with the C-terminal portion of ghrelin. The resultant peptide displayed improved biokinetics compared to CNP, with increased metabolic stability and longer plasma T1/2. Repeated subcutaneous administration of the chimeric peptide to mice resulted in a significant acceleration in longitudinal growth, whereas CNP(1-22) did not. These results suggest that the ghrelin C-terminus improves the stability of CNP, and the chimeric peptide may be useful as a novel therapeutic agent for growth failure and short stature.

Hiponatremia hipotónica. Diagnóstico diferencial / Hypotonic hiponatremia. Differential diagnosis

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Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide.

BACKGROUND: Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation. METHODS: Chronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK. RESULTS: Participants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05). CONCLUSIONS: The pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.

Efficacy and safety of nesiritide in patients with acute decompensated heart failure.

Acute decompensated heart failure is a common clinical problem with associated poor outcomes. Over the last decade, attention to this area has greatly increased, with a focus on medical therapies that may safely offer improvement in acute symptoms and early outcomes. Previous therapies that focused on increased inotropy have generally failed to improve symptoms without adverse consequences. Thus, attention towards vasodilators and natriuretic peptides, such as nesiritide, has increased owing to nesiritide's symptomatic improvement and unique mechanism of improvement in hemodynamics. However, the pathophysiology of acute decompensated heart failure is complex and the impact of nesiritide on important clinical end points, beyond symptomatic and hemodynamic improvement, is unknown.

Long-term effects of B-type natriuretic peptide infusion after acute myocardial infarction in a rat model.

INTRODUCTION: The effects of exogenous B-type natriuretic peptide (BNP) on postmyocardial infarction (MI) are not known. We tested the hypothesis that in vivo infusion of BNP would improve cardiac function and affect left ventricular (LV) remodeling in an experimental model of MI. METHODS: MI was induced by coronary ligation in rats and confirmed by echocardiography. 19 rats were randomized to 1 of 3 groups: sham (n = 7), MI + saline (n = 5), MI + BNP (400 ng.kg(-1).minute(-1)) (n = 7). Infusions were delivered for 7 days via venous catheters tunneled to an infusion pump. Rats were followed for 8 weeks. Echocardiography, hemodynamics, histology, and in vivo and ex vivo pressure-volume relationships were examined. RESULTS: LV systolic pressure, LV dP/dtmax, and infarct size improved with BNP treatment versus control MI group (132 +/- 4 vs.110 +/- 2 mm Hg, 8097 +/- 317 vs. 5816 +/- 378 mm Hg/s, 19.3% +/- 1.6% vs. 23.3% +/- 1.9%, respectively; all P < 0.05). Ex vivo end-diastolic pressure-volume relationship demonstrated reduced diastolic dysfunction after BNP therapy (P < 0.05 vs. control MI). Serum BNP levels confirmed delivery of BNP. CONCLUSIONS: We demonstrate beneficial effects on LV function and decreased LV remodeling with BNP infusion in an experimental model of acute MI.

Nesiritide for the treatment of decompensated heart failure.

Heart failure is the leading cause of hospitalizations in the USA, and is associated with significant morbidity, mortality and resource utilization. Established therapies for chronic heart failure have been shown to improve outcomes, but treatment for decompensated heart failure remains largely empiric. Nesiritide (Natrecor) is a synthetic analog of human B-type natriuretic peptide, a peptide released by the ventricular myocardium in response to increased wall tension. The physiologic effects of human B-type natriuretic peptide include natriuresis, vasodilation and neurohormonal modulation. In clinical trials, nesiritide has been shown to decrease cardiac filling pressures, increase cardiac index, and improve the clinical status of patients with acute decompensated heart failure. Compared with other available intravenous agents for heart failure, nesiritide is effective, generally well-tolerated with few adverse effects, and does not require invasive monitoring during administration. Nesiritide has proven to be an effective new treatment for patients with decompensated heart failure.

Nesiritide for the treatment of congestive heart failure.

Nesiritide (Natrecor) is a recombinant form of the human B-type natriuretic peptide (BNP) that has been shown, through several studies, to have beneficial natriuretic, diuretic and vasodilatory effects in the treatment of congestive heart failure (CHF). Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in the heart, kidney and vasculature. Nesiritide functions as both a potent venous and arterial vasodilator and has been shown to improve cardiac haemodynamics more rapidly and to a greater extent than intravenous nitroglycerin, as well as having fewer side effects. When compared in an open-label trial, nesiritide has also been shown to be less proarrhythmic than dobutamine. The major adverse effect of nesiritide, as with other vasodilators, is symptomatic hypotension, which occurred infrequently in clinical trials. Overall, nesiritide represents an effective and safe therapeutic option for the treatment of decompensated CHF.

Nesiritide: a new therapy for the treatment of heart failure.

Human BNP serves to compensate for deteriorating cardiac function causing preload and afterload reductions, natriuresis, diuresis, suppression of the renin-angiotensin-aldosterone system (RAAS) and endothelin-1, and lowering of norepinephrine. Based on its unique pharmacologic profile, nesiritide results in clinically significant balanced vasodilation of arteries and veins, and may be well suited for patients presenting with various scenarios of decompensated CHF usually due to volume overload (NYHA classes II-IV). More than 1000 subjects have participated in clinical trials with nesiritide and more than 55,000 patients have been treated with nesiritide since it was approved for use in August 2001. Unlike nitroglycerin, tachyphylaxis did not appear to occur with Natrecor. The complete efficacy profile of nesiritide included preload reduction (PCWP and RAP), reductions in pulmonary artery pressures, afterload reduction (systemic vascular resistance), and increases in cardiac index and stroke volume index (which are dose-dependent and not the result of a direct inotropic effect), without increasing heart rate. Unlike inotropes, the beneficial hemodynamic effects produced by nesiritide do not cause an increase in myocardial oxygen consumption (MVO(2)), an important consideration for patients with acutely decompensated heart failure. Because Nesiritide is not an inotrope, it does not affect myocardial contractility, as does a beta-adrenergic receptor agonist, or a phosphodiesterase III inhibitor. As a result, nesiritide is not arrhythmogenic. Nesiritide should be considered for patients presenting with acutely typical or useful decompensated heart failure, especially those with dyspnea at rest or with minimal activity.

Using BNP to diagnose, manage, and treat heart failure.

A rapid assay for B-type natriuretic peptide (BNP) not only can be used to diagnose heart failure, it can help the clinician evaluate effectiveness of therapy, determine when discharge from the hospital is appropriate, and estimate prognosis. A synthetic formulation of BNP (nesiritide) is used to treat decompensated heart failure, resulting in improved hemodynamics and symptoms.

Nesiritide: a novel approach for acute heart failure.

OBJECTIVE: To review preclinical and clinical information related to nesiritide, a recombinant form of B-type natriuretic peptide approved for treatment of acutely decompensated heart failure. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1966-May 2002) using the key words natriuretic peptide and heart failure, and through secondary sources. Natrecor's document submitted for the Food and Drug Administration (FDA) New Drug Application were obtained from the FDA Web site. STUDY SELECTION/DATA EXTRACTION: Peer-reviewed articles and abstracts of randomized clinical trials in humans were included in this review. DATA SYNTHESIS: Nesiritide has beneficial actions for treatment of heart failure, including arterial and venous dilatation, enhanced sodium and urinary excretion, and suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems. It has been shown to improve hemodynamic parameters, primarily pulmonary capillary wedge pressure, as well as clinical symptoms in patients with acutely decompensated heart failure. Nesiritide produced more rapid hemodynamic improvement and caused significantly fewer adverse effects than intravenous nitroglycerin. The incidence of hypotension, the most common adverse effect, was comparable between nesiritide and nitroglycerin. Additionally, nesiritide is associated with a lower incidence of arrhythmias than dobutamine and has a neutral effect on mortality. CONCLUSIONS: Nesiritide offers an alternative for management of acutely decompensated heart failure. It is considered an option for patients who do not respond to other vasodilators, inotropes, or diuretics and for those at high risk of arrhythmias. Further pharmacoeconomic investigations for nesiritide are warranted.

Nesiritide: a review of its use in acute decompensated heart failure.

UNLABELLED: Nesiritide (Natrecor) is a recombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised with acute decompensated CHF who received nesiritide had significantly greater mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after starting treatment than nitroglycerin or placebo recipients (-5.8 vs -3.8 and -2 mm Hg, respectively); all patients also received standard therapy (e.g. intravenous diuretics). Improvements in other haemodynamic parameters were also seen in nesiritide recipients. In addition, significantly more nesiritide than placebo recipients reported an improvement in dyspnoea after 3 hours' treatment in VMAC, whereas there was no significant difference between nitroglycerin and placebo recipients. Improvements in global clinical status, dyspnoea and fatigue were also seen with nesiritide in another active-comparator study and in a placebo-controlled study. In VMAC, there was no significant difference between nesiritide and nitroglycerin recipients in 6-month mortality. In the other active-comparator trial, 6-month mortality was significantly lower in recipients of nesiritide 0.015 micro g/kg/min than in dobutamine recipients (although mortality was not a prespecified endpoint and this result should be interpreted with caution). In this same study, the 21-day all-cause hospital readmission rate was significantly lower with nesiritide 0.015 micro g/kg/min than with dobutamine and the duration of active drug treatment was significantly shorter with nesiritide than with dobutamine. Nesiritide is generally well tolerated. In VMAC, significantly more adverse events occurred with nitroglycerin than with nesiritide. The most common adverse events reported during the first 24 hours of therapy in nesiritide and nitroglycerin recipients included general pain, abdominal pain, catheter-related pain, headache, nausea, asymptomatic and symptomatic hypotension, nonsustained ventricular tachycardia and angina pectoris. Most episodes of symptomatic hypotension resolved spontaneously or after an intravenous volume challenge of

Nesiritide: a new drug for the treatment of decompensated heart failure.

Nesiritide, a recombinant human B-type natriuretic peptide, is the first in a new drug class for the treatment of decompensated heart failure. The drug binds to receptors in the vasculature, kidney, adrenal gland, and brain, and overcomes resistance to endogenous BNP present in patients with CHF. Nesiritide administration leads to a rapid and balanced vasodilatory effect, which results in a significant decrease in right and left ventricular filling pressures and systemic vascular resistance and at the same time in an increase in stroke volume and cardiac output without a change in heart rate. These early hemodynamic changes result in a rapid improvement in symptoms of heart failure. In addition, nesiritide lowers aldosterone, catecholamines, and endothelin-1 levels and its effect on the kidney leads to an increased natriuresis and diuresis without effect on serum potassium or renal function. Prior to its approval for clinical use, nesiritide was studied in 10 different clinical trials involving 941 patients with moderate and severe CHF, including elderly patients, patients with both systolic and diastolic dysfunction, and patients with arrhythmias, renal insufficiency, and acute ischemic syndrome. In comparative studies with available vasoactive therapies frequently used for treatment of patients with decompensated heart failure, nesiritide was proven comparable in efficacy to inotropic drugs such as dobutamine, but superior in safety. In a recent study, nesiritide was found to be more effective and better tolerated than the vasodilator, nitroglycerin. The most common side effects expected with the use of nesiritide are headaches and decrease in blood pressure. At the recommended dose of nesiritide, headache was reported during the first 24 hours of treatment in 8% of patients and symptomatic hypotension in 4% of patients, compared to 20% and 5% in nitroglycerin-treated patients.

Agmatina: perfil farmacológico y efectos conductuales / Agmatine: pharmacological profile and behavioral effects

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Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.

OBJECTIVE: To study tubular urate transport in Alzheimer's disease (AD) and measure sodium and lithium transport rates in rats exposed to AD plasma. DESIGN: Cross-sectional study in three comparison groups. SETTING: Referral private institution involving outpatient and hospitalized patients. PATIENTS: AD, multi-infarct dementia (MID) and non-demented controls (C) were selected and evaluated by a geriatrician and a psychiatrist according to availability and willingness to participate in the study. Demented patients had brain imaging, categorized according to NINCDS-DSM III criteria, and had Mini-mental status examination (MMSE) scores determined. INTERVENTIONS: Injection of 0.5 mL of plasma I.P. followed 120 minutes later by an IV plasma injection of 0.2 mL priming dose and infusion of 1.8 mL of plasma at 0.01 mL/min in Sprague Dawley rats. MEASUREMENTS: Renal clearance studies were performed in subjects and in rats exposed to the plasma of study subjects. We measured serum urate concentration and fractional excretion (FE) of urate in subjects and FE sodium and FE lithium in rats. RESULTS: Serum urate was lower and FE urate higher in 18 AD patients compared with six patients with MID, P < 0.05 and P < 0.005, and 11 C, P < 0.02 and P < 0.005, respectively. Higher FE sodium and FE lithium were noted in rats given plasma from 19 AD patients compared with 12 with MID, P < 0.005 and P < 0.0025, and 14 C, P < 0.0025 and P < 0.0005, respectively. FE sodium and FE lithium decreased progressively after serial dilutions of three AD plasmas and FE lithium was negatively correlated with MMSE scores only in AD, r = -0.71 and P < 0.0005. CONCLUSIONS: In AD there is defective tubular urate transport and a plasma natriuretic factor(s). FE sodium and/or FE lithium in rats exposed to plasma of demented patients may differentiate AD from MID and estimate the severity of AD.

Pharmacokinetics of brain natriuretic peptide in rats.

The pharmacokinetics of rat brain natriuretic peptide (rBNP) was compared with that of alpha-rat atrial natriuretic peptide (alpha-rANP) in rats. After intravenous infusion in rats (600 pmol min-1kg-1 for 2 min), the disappearance of plasma rBNP was 4-fold slower than that of alpha-rANP. The estimated mean plasma clearance rates for rBNP and alpha-rANP were 45.9 ml min-1kg-1 and 74.4 ml min-1kg-1, respectively. The affinity of rBNP for the clearance receptor or degradation enzyme was considered to be lower than that of alpha-rANP.