The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Jalal K Ghali - One of the best experts on this subject based on the ideXlab platform.
-
Evaluation of Lixivaptan in euvolemic and hypervolemic hyponatremia and heart failure treatment
Expert opinion on drug metabolism & toxicology, 2013Co-Authors: Hammam D Zmily, Anas Alani, Jalal K GhaliAbstract:Introduction: Lixivaptan is a selective vasopressin type 2 (V2) receptor antagonist that induces aquaresis, the electrolytes sparing excretion of water. Its ability to correct hyponatremia has been demonstrated in experimental animal studies as well as in clinical trials in humans. Recently, three Phase III, double-blind, randomized, placebo-controlled studies have been completed. In two studies, patients with euvolemic hyponatremia were enrolled, one in the inpatient and the other in the outpatient setting and the third study involved patients with hypervolemic hyponatremia hospitalized for decompensated heart failure (HF). The trials confirmed the efficacy of Lixivaptan in raising serum sodium but raised concern about its safety in patients hospitalized with decompensated HF. Areas covered: The authors review original publications on Lixivaptan and summarize their findings. Specifically, the authors present information regarding its structure, pharmacodynamics and kinetics, metabolism as well as its eff...
-
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: Jalal K Ghali, 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
-
Abstract 15858: The Aquaretic Effect of Lixivaptan in Patients With Heart Failure and Volume Overload
Circulation, 2011Co-Authors: Jalal K Ghali, Cesare OrlandiAbstract:Introduction: Lixivaptan is a selective, orally active V2 receptor antagonist with potent aquaretic effect. Hypothesis: Patients with heart failure (HF) and volume overload will benefit from the aq...
-
The potential role for Lixivaptan in heart failure and in hyponatremia
Expert opinion on investigational drugs, 2011Co-Authors: Hammam D Zmily, Suleiman Daifallah, Nazia S Khan, Jalal K GhaliAbstract:Introduction: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V2) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. Areas covered: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on Lixivaptan, a selective V2 receptor antagonist. Expert opinion: The available experience of Lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia a...
-
Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia.
IDrugs : the investigational drugs journal, 2010Co-Authors: Jalal K Ghali, Hammam Zmily, Jareer Farah, Suleiman DaifallahAbstract:Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, Lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of Lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, Lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of Lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of Lixivaptan in the management of hyponatremia, especially when associated with heart failure.
Cesare Orlandi - One of the best experts on this subject based on the ideXlab platform.
-
Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia
Kidney International, 2012Co-Authors: William T Abraham, Richard C. Josiassen, Daniel G. Bichet, Johannes Hensen, Peter Gross, Deodatta S Chafekar, Cesare OrlandiAbstract:Hyponatremia is a common electrolyte disorder associated with increased morbidity and mortality, particularly in the elderly. Lixivaptan, a new selective vasopressin V2-receptor antagonist, safely corrected serum sodium concentrations in phase II studies of patients with euvolemic hyponatremia. Here our multinational, double-blind, placebo-controlled, phase III study assessed the effect of Lixivaptan on serum sodium concentrations in 106 initially hospitalized patients with euvolemic hyponatremia (serum sodium less than 130mmol/l). Of them, 52 were randomized to receive placebo and 54 received 50mg Lixivaptan once daily and were then titrated to receive 25–100mg once daily depending on serum sodium concentration. Fluid restriction was at the investigator's discretion. Initial titration occurred in a monitored inpatient setting; patients were then treated as outpatients for a total of 30 days. The primary end point was the change in serum sodium concentration from baseline to day 7. Lixivaptan significantly increased the serum sodium concentration from baseline to day 7 (the primary end point) by 6.7mmol/l compared with placebo (4.5mmol/l; P =0.034). Importantly, the serum sodium concentration was normalized safely and more rapidly in patients receiving Lixivaptan than placebo ( P =0.004) and was well tolerated. After drug discontinuation, serum sodium concentrations decreased to near-baseline levels within 7 days. Thus, Lixivaptan safely and effectively corrects serum sodium concentrations in patients with euvolemic hyponatremia.
-
Oral Lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia
Kidney international, 2012Co-Authors: William T Abraham, Guy Decaux, Richard C. Josiassen, Yoram Yagil, Nelson Kopyt, Hemant P. Thacker, Massimo Mannelli, Daniel G. Bichet, Cesare OrlandiAbstract:Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral Lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25–100mg per day Lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8mmol/l), the serum sodium concentration significantly increased by 3.2mmol/l from baseline to day 7 (primary efficacy endpoint) with Lixivaptan treatment. A significantly greater proportion of patients that received Lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, Lixivaptan was considered safe and well-tolerated. Thus, oral Lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.
-
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: Jalal K Ghali, 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
-
Assessment of Exposure of Metabolites in Preclinical Species and Humans at Steady State from the Single-Dose Radiolabeled Absorption, Distribution, Metabolism, and Excretion Studies: A Case Study
Drug metabolism and disposition: the biological fate of chemicals, 2012Co-Authors: Chandra Prakash, Cesare Orlandi, Lewis J. KlunkAbstract:The exposure of a drug candidate and its metabolites in humans and preclinical species during drug development needs to be determined to ensure that the safety of drug-related components in humans is adequately assessed in the standard toxicology studies. The in vivo radiolabeled studies in preclinical species and human volunteers provide the total fate of the drug-derived radioactivity including the relative abundance of metabolites. Here, we describe how the single-dose radiolabeled human studies could provide the exposure of circulating metabolites at steady state using a case study of an extensively metabolized drug, Lixivaptan. After an oral dose of [(14)C]Lixivaptan to humans, a total of nine metabolites were detected in the systemic circulation; eight of them exceeded 10% of the parent exposure (2-41% of total radioactivity). The plasma samples were profiled for all subjects at each time point by high-performance liquid chromatography, and metabolites were quantified using a radioactive detector. On the basis of single-dose area under the concentration-time curve (AUC) values, exposure of six human metabolites was greater at least in one preclinical species used in toxicology evaluation. On the basis of the t(1/2) of Lixivaptan and two major metabolites from a single dose in humans, their AUC and C(max) values were simulated at the steady state. The simulated exposure (C(max) and AUC) values of parent drug and the two most abundant metabolites were similar to those from a 7-day clinical study obtained using a validated liquid chromatography-mass spectrometry assay, suggesting that a well designed single-dose radiolabeled human study can help in addressing the metabolites in safety testing-related issues.
-
Abstract 15858: The Aquaretic Effect of Lixivaptan in Patients With Heart Failure and Volume Overload
Circulation, 2011Co-Authors: Jalal K Ghali, Cesare OrlandiAbstract:Introduction: Lixivaptan is a selective, orally active V2 receptor antagonist with potent aquaretic effect. Hypothesis: Patients with heart failure (HF) and volume overload will benefit from the aq...
Guy Decaux - One of the best experts on this subject based on the ideXlab platform.
-
urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline
Kidney International, 2015Co-Authors: Fabrice Gankam Kengne, Bruno Couturier, Alain Soupart, Guy DecauxAbstract:Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, Lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with Lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or Lixivaptan. This included breakdown of the blood–brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by Lixivaptan or hypertonic saline.
-
Oral Lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia
Kidney international, 2012Co-Authors: William T Abraham, Guy Decaux, Richard C. Josiassen, Yoram Yagil, Nelson Kopyt, Hemant P. Thacker, Massimo Mannelli, Daniel G. Bichet, Cesare OrlandiAbstract:Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral Lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25–100mg per day Lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8mmol/l), the serum sodium concentration significantly increased by 3.2mmol/l from baseline to day 7 (primary efficacy endpoint) with Lixivaptan treatment. A significantly greater proportion of patients that received Lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, Lixivaptan was considered safe and well-tolerated. Thus, oral Lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.
-
non peptide arginine vasopressin antagonists the vaptans
The Lancet, 2008Co-Authors: Guy Decaux, Alain Soupart, Gilbert VassartAbstract:Arginine-vasopressin is a hormone that plays an important part in circulatory and water homoeostasis. The three arginine-vasopressin-receptor subtypes--V1a, V1b, and V2--all belong to the large rhodopsin-like G-protein-coupled receptor family. The vaptans are orally and intravenously active non-peptide vasopressin receptor antagonists that are in development. Relcovaptan is a selective V1a-receptor antagonist, which has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhoea, and tocolysis. SSR-149415 is a selective V1b-receptor antagonist, which could have beneficial effects in the treatment of psychiatric disorders. V2-receptor antagonists--mozavaptan, Lixivaptan, satavaptan, and tolvaptan--induce a highly hypotonic diuresis without substantially affecting the excretion of electrolytes (by contrast with the effects of diuretics). These drugs are all effective in the treatment of euvolaemic and hypervolaemic hyponatraemia. Conivaptan is a V1a/V2 non-selective vasopressin-receptor antagonist that has been approved by the US Food and Drug Administration as an intravenous infusion for the inhospital treatment of euvolaemic or hypervolaemic hyponatraemia.
William T Abraham - One of the best experts on this subject based on the ideXlab platform.
-
Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia
Kidney International, 2012Co-Authors: William T Abraham, Richard C. Josiassen, Daniel G. Bichet, Johannes Hensen, Peter Gross, Deodatta S Chafekar, Cesare OrlandiAbstract:Hyponatremia is a common electrolyte disorder associated with increased morbidity and mortality, particularly in the elderly. Lixivaptan, a new selective vasopressin V2-receptor antagonist, safely corrected serum sodium concentrations in phase II studies of patients with euvolemic hyponatremia. Here our multinational, double-blind, placebo-controlled, phase III study assessed the effect of Lixivaptan on serum sodium concentrations in 106 initially hospitalized patients with euvolemic hyponatremia (serum sodium less than 130mmol/l). Of them, 52 were randomized to receive placebo and 54 received 50mg Lixivaptan once daily and were then titrated to receive 25–100mg once daily depending on serum sodium concentration. Fluid restriction was at the investigator's discretion. Initial titration occurred in a monitored inpatient setting; patients were then treated as outpatients for a total of 30 days. The primary end point was the change in serum sodium concentration from baseline to day 7. Lixivaptan significantly increased the serum sodium concentration from baseline to day 7 (the primary end point) by 6.7mmol/l compared with placebo (4.5mmol/l; P =0.034). Importantly, the serum sodium concentration was normalized safely and more rapidly in patients receiving Lixivaptan than placebo ( P =0.004) and was well tolerated. After drug discontinuation, serum sodium concentrations decreased to near-baseline levels within 7 days. Thus, Lixivaptan safely and effectively corrects serum sodium concentrations in patients with euvolemic hyponatremia.
-
Oral Lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia
Kidney international, 2012Co-Authors: William T Abraham, Guy Decaux, Richard C. Josiassen, Yoram Yagil, Nelson Kopyt, Hemant P. Thacker, Massimo Mannelli, Daniel G. Bichet, Cesare OrlandiAbstract:Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral Lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25–100mg per day Lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8mmol/l), the serum sodium concentration significantly increased by 3.2mmol/l from baseline to day 7 (primary efficacy endpoint) with Lixivaptan treatment. A significantly greater proportion of patients that received Lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, Lixivaptan was considered safe and well-tolerated. Thus, oral Lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.
-
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: Jalal K Ghali, 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
-
Rationale and design of the treatment of hyponatremia based on Lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study.
Clinical and translational science, 2010Co-Authors: William T Abraham, Stephen S Gottlieb, Marrick Kukin, Juan M. Aranda, John P. Boehmer, Uri Elkayam, Edward M. Gilbert, Gerd Hasenfuβ, Brian D. Lowes, John B. O’connellAbstract:Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of Lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations
-
aquaretic effect of Lixivaptan an oral non peptide selective v2 receptor vasopressin antagonist in new york heart association functional class ii and iii chronic heart failure patients
Journal of the American College of Cardiology, 2006Co-Authors: William T Abraham, Alireza A Shamshirsaz, Kim Mcfann, Ron M Oren, Robert W. SchrierAbstract:Objectives The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure. Background Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure. Methods We examined the effects of the oral, non-peptide, selective V2 receptor antagonist Lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day −1 (baseline) and double-blind study medication (placebo [n = 12] or Lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. Results At all but the 10-mg dose, Lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg Lixivaptan dose (p Conclusions These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist Lixivaptan may be a promising therapeutic agent for the treatment of heart failure.
Brett A Howell - One of the best experts on this subject based on the ideXlab platform.
-
comparison of the hepatotoxic potential of two treatments for autosomal dominant polycystic kidney diseaseusing quantitative systems toxicology modeling
Pharmaceutical Research, 2020Co-Authors: Jeffrey L Woodhead, L. Pellegrini, Lisl K M Shoda, Brett A HowellAbstract:Autosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V2 receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury. In prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathematical model of drug-induced liver injury. In the current study, we evaluated Lixivaptan, another proposed ADPKD treatment and vasopressin V2 receptor antagonist, using DILIsym®. Simulations were conducted that assessed the potential for Lixivaptan and its three main metabolites to cause hepatotoxicity due to three injury mechanisms: bile acid accumulation, mitochondrial dysfunction, and oxidative stress generation. Results of these simulations were compared to previously published DILIsym results for tolvaptan. No ALT elevations were predicted to occur at the proposed clinical dose for Lixivaptan, in contrast to previously published simulation results for tolvaptan. As such, Lixivaptan was predicted to have a markedly lower risk of hepatotoxicity compared to tolvaptan with respect to the hepatotoxicity mechanisms represented in DILIsym. These results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity.
-
Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling
Pharmaceutical Research, 2020Co-Authors: Jeffrey L Woodhead, L. Pellegrini, Lisl K M Shoda, Brett A HowellAbstract:Purpose Autosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V_2 receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury. Methods In prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathematical model of drug-induced liver injury. In the current study, we evaluated Lixivaptan, another proposed ADPKD treatment and vasopressin V_2 receptor antagonist, using DILIsym®. Simulations were conducted that assessed the potential for Lixivaptan and its three main metabolites to cause hepatotoxicity due to three injury mechanisms: bile acid accumulation, mitochondrial dysfunction, and oxidative stress generation. Results of these simulations were compared to previously published DILIsym results for tolvaptan. Results No ALT elevations were predicted to occur at the proposed clinical dose for Lixivaptan, in contrast to previously published simulation results for tolvaptan. As such, Lixivaptan was predicted to have a markedly lower risk of hepatotoxicity compared to tolvaptan with respect to the hepatotoxicity mechanisms represented in DILIsym. Conclusions These results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity.