The Experts below are selected from a list of 1398 Experts worldwide ranked by ideXlab platform
Vicente E. Torres - One of the best experts on this subject based on the ideXlab platform.
-
Vasopressin Receptor Antagonists, Heart Failure, and Polycystic Kidney Disease
Annual review of medicine, 2014Co-Authors: Vicente E. TorresAbstract:The synthesis of nonpeptide orally bioavailable Vasopressin Antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of Vasopressin Receptor subtypes for therapeutic purposes. Vaptans acting on the Vasopressin V2 Receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 Receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.
-
tolvaptan in autosomal dominant polycystic kidney disease three years experience
Clinical Journal of The American Society of Nephrology, 2011Co-Authors: Eiji Higashihara, Vicente E. Torres, Arlene B Chapman, Jared J Grantham, Kyongtae T Bae, Terry Watnick, Shigeo Horie, Kikuo Nutahara, John Ouyang, Holly B KrasaAbstract:Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific Vasopressin Receptor Antagonists delay disease progression in animal models. Design, setting, participants, and measurements This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. Results Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m 2 ) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: 2.1 versus 0.71 ml/min per 1.73 m 2 /yr (P 0.01, LMM group difference 1.1 ml/min per 1.73 m 2 /yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r 0.21, P 0.01). Conclusion ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common. Clin J Am Soc Nephrol 6: 2499–2507, 2011. doi: 10.2215/CJN.03530411
Lise Bankir - One of the best experts on this subject based on the ideXlab platform.
-
Vasopressin a novel target for the prevention and retardation of kidney disease
Nature Reviews Nephrology, 2013Co-Authors: Lise Bankir, Nadine Bouby, Eberhard RitzAbstract:Experimental, epidemiological and clinical studies have demonstrated that Vasopressin contributes to the progression of chronic kidney disease by imposing an increased burden on diseased nephrons, and to autosomal dominant polycystic kidney disease by promoting cyst growth. Vasopressin also has a role in the pathogenesis of diabetes mellitus and metabolic disorders. This Review describes the adverse effects of Vasopressin and provides insights into Vasopressin physiology that may be relevant to the understanding of these adverse effects. After several decades during which little attention was paid to Vasopressin and/or urine concentration in clinical practice, interest in Vasopressin has renewed with the availability of new, potent, orally active Vasopressin-Receptor Antagonists—the vaptans—and with the results of epidemiological studies evaluating copeptin (a surrogate marker of Vasopressin) in large population-based cohorts. Several experimental studies in rats and mice had previously shown that Vasopressin, acting via Vasopressin V2 antidiuretic Receptors, contributes to the progression of chronic kidney disease; in particular, to autosomal dominant polycystic kidney disease. New epidemiological studies now suggest a role for Vasopressin in the pathogenesis of diabetes mellitus and metabolic disorders via activation of hepatic V1a and/or pancreatic islet V1b Receptors. The first part of this Review describes the adverse effects of Vasopressin, as revealed by clinical and experimental studies in kidney diseases, hypertension, diabetes and the metabolic syndrome. The second part provides insights into Vasopressin physiology and pathophysiology that may be relevant to the understanding of these adverse effects and that are linked to the excretion of concentrated nitrogen wastes and associated hyperfiltration. Collectively, the studies reviewed here suggest that more attention should be given to the Vasopressin–thirst–urine concentration axis in clinical investigations and in patient care. Whether selective blockade of the different Vasopressin Receptors may provide therapeutic benefits beyond their present indication in hyponatraemia requires new clinical trials.
-
Sodium excretion in response to Vasopressin and selective Vasopressin Receptor Antagonists.
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Julie Perucca, Pascale Bardoux, Nadine Bouby, Daniel G. Bichet, Lise BankirAbstract:The mechanisms by which arginine Vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a Receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide Receptor Antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 μg/kg but increased it at doses >5 μg/kg, an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous Vasopressin can be predicted to vary largely according to the respective levels of Vasopressin in plasma, renal medulla (acting on interstitial cells), and urine (acting on V1a luminal Receptors). In the usual range of regulation, antidiuretic effects of Vasopressin may be associated with variable sodium retention. Although V2 Antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) Receptor Antagonists on sodium handling in humans needs reevaluation.
Thomas D. Boyer - One of the best experts on this subject based on the ideXlab platform.
-
Vasopressin v2 Receptor Antagonists in patients with cirrhosis ascites and hyponatremia
Therapeutic Advances in Gastroenterology, 2012Co-Authors: Shahid Habib, Thomas D. BoyerAbstract:Hyponatremia is a common problem in patients with advanced cirrhosis. It develops slowly (paralleling the rate of progression of the liver disease) and usually produces no neurological symptoms, although it may exacerbate hepatic encephalopathy. For patients awaiting liver transplantation a low serum sodium level is a strong predictor of pretransplant mortality, independent of the Model for End-stage Liver Disease score (MELD). The pathogenesis of hyponatremia is related to the hemodynamic changes and secondary neurohormonal adaptations that occur in patients with cirrhosis and ascites. The nonosmotic release of arginine Vasopressin is the principle cause of the hyponatremia and Vasopressin-Receptor Antagonists are a new class of drugs recently approved for treatment of cirrhotic hyponatremia. In this article we review the safety and efficacy of V2-Receptor Antagonists in patients with cirrhosis, ascites and hyponatremia.
-
Aquaretics in cirrhotics with hyponatremia
Journal of Gastroenterology and Hepatology, 2004Co-Authors: Thomas D. BoyerAbstract:Hyponatremia develops spontaneously or following diuretic therapy in about one-third of patients with cirrhosis. The development of hyponatremia leads to fluid restriction which is unpopular with patients and limits the usefulness of diuretics. The principle factor that leads to hyponatremia in the cirrhotic is an increase in the non-osmotic release of arginine Vasopressin (AVP) and subsequent impaired clearance of free water by the kidney. The development of Vasopressin Receptor Antagonists and Κ-opioid agonists has led to trials examining their efficacy in the treatment of hyponatremia in cirrhosis. The Vasopressin Receptor Antagonists have been shown to improve free water clearance and raise serum sodium in decompensated cirrhotics in short-term studies. The utility of these agents for the long-term management of hyponatremia and in preventing the development of hyponatremia associated with diuretic usage remains to be determined.
Pere Ginès - One of the best experts on this subject based on the ideXlab platform.
-
effects of a selective Vasopressin v2 Receptor antagonist satavaptan on ascites recurrence after paracentesis in patients with cirrhosis
Journal of Hepatology, 2010Co-Authors: Florence Wong, Hugh Watson, Pere Ginès, Yves Horsmans, Paolo Angeli, Paul J Gow, Pascal Minini, Mauro BernardiAbstract:Background & Aims Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin Receptor Antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a Vasopressin V 2 Receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia. Methods One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg ( n =39), 12.5mg ( n =36), 25mg ( n =40) of satavaptan or placebo ( n =36) for 12weeks. Their Child–Pugh scores were 9.2±1.3, 8.7±1.7, 8.8±1.3, and 9.0±1.5, respectively. Results Median time to first paracentesis was 23, 26, and 17days with satavaptan 5, 12.5, and 25mg, respectively, versus 14days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly ( p 0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82±0.48L/week for placebo versus 2.12±0.40, 2.14±0.33, and 2.06±0.40L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan. Conclusions Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.
-
effects of satavaptan a selective Vasopressin v2 Receptor antagonist on ascites and serum sodium in cirrhosis with hyponatremia a randomized trial
Hepatology, 2008Co-Authors: Pere Ginès, Slobodan Milutinovic, Luis Ruiz Del Arbol, Hugh Watson, Florence Wong, Dan OlteanuAbstract:Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin Receptor Antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective Vasopressin V2 Receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium ≤130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [±4.99] for placebo versus +0.15 kg [±4.23], −1.59 kg [±4.60] and −1.68 kg [±4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 ± 4.2, 4.5 ± 3.5, 4.5 ± 4.8, and 6.6 ± 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. Conclusion: The V2 Receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment. (HEPATOLOGY 2008.)
Cesare Orlandi - One of the best experts on this subject based on the ideXlab platform.
-
the efficacy and safety of lixivaptan in outpatients with heart failure and volume overload results of a multicentre randomized double blind placebo controlled parallel group study
European Journal of Heart Failure, 2012Co-Authors: Cesare Orlandi, William T AbrahamAbstract:Aims Volume overload is the dominant feature of decompensated heart failure (HF) and it often results in adverse clinical outcomes. Vasopressin Receptor Antagonists such as lixivaptan may provide effective volume unloading. This study assessed weight loss after 1 day and 8 weeks of treatment with lixivaptan in outpatients with HF and volume overload. Methods and results This phase II, 8-week, multicentre, double-blind, parallel-group study randomized participants (2:1) to receive lixivaptan 100 mg or placebo once daily (in addition to standard HF therapy). Body weight and cardiovascular assessments were made at baseline, Day 1 (not cardiovascular), Weeks 1, 2, 4, and 8, and 7 days post-treatment. The Trail-making Test, part B (TMT-B) and the Medical Outcomes Survey 6-item cognitive function scale (MOS-6) were assessed at baseline and Week 4. The study randomized 170 participants (lixivaptan, n = 111; placebo, n = 59). Most (97.1%) were receiving pharmacological therapy for HF at baseline. Demographic characteristics were generally similar between the two groups. Body weight decreased significantly from baseline to Day 1 with lixivaptan vs. placebo (least-square mean change ± standard error: − 0.38 ± 0.08 kg vs. +0.13 ± 0.11 kg; P < 0.001) and at Weeks 1, 2, and 4 (P < 0.01). Cardiovascular changes were generally similar in both groups, though orthopnoea and dyspnoea improved in the lixivaptan group vs. placebo. The TMT-B and MOS-6 showed no significant differences between groups. Lixivaptan was well tolerated—thirst and polyuria occurred more frequently vs. placebo. Conclusions In outpatients with HF and volume overload, lixivaptan 100 mg once daily, when added to standard therapy, reduced body weight, improved dyspnoea and orthopnoea, and was well tolerated. Trial registration: NCT01055912
-
a multicenter randomized double blind placebo controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction
Journal of Cardiac Failure, 2011Co-Authors: James E Udelson, Cesare Orlandi, Martin S Bilsker, Paul J Hauptman, Rafael F Sequeira, Ignatius Thomas, Terrence X Obrien, Christopher Zimmer, Marvin A KonstamAbstract:Abstract Background Increased Vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the Vasopressin V2 Receptor. The presence of background diuretic therapy may confound evaluations of Vasopressin Receptor Antagonists (VRA). Methods and Results Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the Vasopressin V2 Receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of −1.37 ± 1.61, −0.54 ± 1.59, and −1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline ( P = .0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P P P P Conclusions In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and β-blockers.