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Circulation Journal : Official Journal... 2014Fluid management is of paramount importance in the treatment strategy of heart failure (HF), but the therapeutic efficacy of loop diuretic-based treatment for HF... (Review)
Review
Fluid management is of paramount importance in the treatment strategy of heart failure (HF), but the therapeutic efficacy of loop diuretic-based treatment for HF patients is limited by insufficient response and adverse effects. Clinical data establishing the efficacy and safety of tolvaptan, a selective oral vasopressin V2 receptor antagonist that induces aquaresis, have recently been accumulated over 3 years of daily clinical experience in Japan. Intravenous infusion of carperitide, a synthetic α-human atrial natriuretic peptide, has also been widely used as acute-phase therapy for acute decompensated HF in Japan. Combination therapy using loop diuretics, tolvaptan, and carperitide with differing and complementary mechanisms of action may maximize therapeutic activity, to minimize the dosage of loop diuretics and thereby reduce the adverse effects not only for volume removal but also for the stability of cardiorenal hemodynamics.
Topics: Antidiuretic Hormone Receptor Antagonists; Atrial Natriuretic Factor; Benzazepines; Diuretics; Heart Failure; Humans; Japan; Receptors, Vasopressin; Tolvaptan
PubMed: 25008484
DOI: 10.1253/circj.cj-14-0592 -
European Journal of Heart Failure Aug 2023In the SHIFT (Systolic Heart failure treatment with the I inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure...
AIMS
In the SHIFT (Systolic Heart failure treatment with the I inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF.
METHODS AND RESULTS
The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days.
CONCLUSION
Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.
Topics: Humans; Ivabradine; Heart Failure; Stroke Volume; Heart Rate; Treatment Outcome; Heart Failure, Systolic; Bradycardia; Benzazepines; Cardiovascular Agents
PubMed: 37092340
DOI: 10.1002/ejhf.2870 -
Kidney International Apr 2013The treatment of hyponatremia, an exceedingly common electrolyte disorder, has been a subject of controversy for many years. The advent of vasopressin antagonists... (Review)
Review
The treatment of hyponatremia, an exceedingly common electrolyte disorder, has been a subject of controversy for many years. The advent of vasopressin antagonists (vaptans) has added to the treatment arsenal. This review focuses on why hyponatremia should be treated and the role of these antagonists in the treatment. Upon analysis of the available literature, we conclude that there is presently no role for vaptans in acute symptomatic hyponatremia. Although numerous therapeutic approaches are available for chronic symptomatic hyponatremia, vasopressin antagonists provide a simpler treatment option. Vaptans are efficacious in raising serum sodium in long-standing 'asymptomatic' hyponatremia. However, the cost of the only Food and Drug Administration-approved oral agent (tolvaptan) makes its use prohibitive for most patients in this setting.
Topics: Acute Disease; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biomarkers; Chronic Disease; Drug Costs; Hormone Antagonists; Humans; Hyponatremia; Receptors, Vasopressin; Sodium; Tolvaptan; Treatment Outcome
PubMed: 23254896
DOI: 10.1038/ki.2012.402 -
Molecular Neurobiology Dec 2023N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for...
N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain.
Topics: Ligands; Receptors, N-Methyl-D-Aspartate; Benzazepines; Exons; Learning
PubMed: 37542648
DOI: 10.1007/s12035-023-03526-1 -
Expert Review of Neurotherapeutics Feb 2007Varenicline is a selective alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist and the first non-nicotine-containing medication developed with the sole... (Review)
Review
Varenicline is a selective alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist and the first non-nicotine-containing medication developed with the sole purpose of treating nicotine addiction. To date, four published clinical trials have demonstrated the efficacy and safety of varenicline for smoking cessation in healthy adults who were ready to make a quit attempt. One additional trial found that extended use of varenicline effectively reduced relapse to smoking. One trial to date published as a poster documented the 1-year safety of the drug. Varenicline was more efficacious than bupropion 24 weeks after randomization to a 12-week treatment course and 1 year after randomization in an identical trial. It has no contraindications except hypersensitivity and is well tolerated. This article reviews the available information on varenicline and discusses its clinical use.
Topics: Benzazepines; Humans; Quinoxalines; Receptors, Nicotinic; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Varenicline
PubMed: 17286546
DOI: 10.1586/14737175.7.2.121 -
Canadian Family Physician Medecin de... Jan 2011
Topics: Benzazepines; Bupropion; Humans; Nicotinic Agonists; Nortriptyline; Quinoxalines; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Varenicline
PubMed: 21252131
DOI: No ID Found -
Nefrologia : Publicacion Oficial de La... 2014The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of hyponatremia in a hospital setting. However, detailed protocols and...
INTRODUCTION
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of hyponatremia in a hospital setting. However, detailed protocols and algorithms for its management are lacking. Our objective was to develop 2 consensus algorithms for the therapy of hyponatremia due to SIADH in hospitalized patients.
MATERIAL AND METHODS
A multidisciplinary group made up of 2 endocrinologists, 2 nephrologists, 2 internists, and one hospital pharmacist held meetings over the period of a year. The group worked under the auspices of the European Hyponatremia Network and the corresponding Spanish medical societies. Therapeutic proposals were based on widely-accepted recommendations, expert opinion and consensus guidelines, as well as on the authors’ personal experience.
RESULTS
Two algorithms were developed. Algorithm 1 addresses acute correction of hyponatremia posing as a medical emergency, and is applicable to both severe euvolemic and hypovolemic hyponatremia. The mainstay of this algorithm is the iv use of 3% hypertonic saline solution. Specific infusion rates are proposed, as are steps to avoid or reverse overcorrection of serum sodium levels. Algorithm 2 is directed to the therapy of SIADH-induced mild or moderate, non-acute hyponatremia. It addresses when and how to use fluid restriction, solute, furosemide, and tolvaptan to achieve eunatremia in patients with SIADH.
CONCLUSIONS
Two complementary strategies were elaborated to treat SIADH-induced hyponatremia in an attempt to increase awareness of its importance, simplify its therapy, and improve prognosis.
Topics: Algorithms; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Humans; Hyponatremia; Inappropriate ADH Syndrome; Saline Solution, Hypertonic; Tolvaptan
PubMed: 25036057
DOI: 10.3265/Nefrologia.pre2014.Apr.12220 -
BMC Public Health Dec 2006Smoking remains the leading preventable cause of premature deaths. Several pharmacological interventions now exist to aid smokers in cessation. These include Nicotine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Smoking remains the leading preventable cause of premature deaths. Several pharmacological interventions now exist to aid smokers in cessation. These include Nicotine Replacement Therapy [NRT], bupropion, and varenicline. We aimed to assess their relative efficacy in smoking cessation by conducting a systematic review and meta-analysis.
METHODS
We searched 10 electronic medical databases (inception to Sept. 2006) and bibliographies of published reviews. We selected randomized controlled trials [RCTs] evaluating interventions for smoking cessation at 1 year, through chemical confirmation. Our primary endpoint was smoking cessation at 1 year. Secondary endpoints included short-term smoking cessation (approximately 3 months) and adverse events. We conducted random-effects meta-analysis and meta-regression. We compared treatment effects across interventions using head-to-head trials and when these did not exist, we calculated indirect comparisons.
RESULTS
We identified 70 trials of NRT versus control at 1 year, Odds Ratio [OR] 1.71, 95% Confidence Interval [CI], 1.55-1.88, P =< 0.0001). This was consistent when examining all placebo-controlled trials (49 RCTs, OR 1.78, 95% CI, 1.60-1.99), NRT gum (OR 1.60, 95% CI, 1.37-1.86) or patch (OR 1.63, 95% CI, 1.41-1.89). NRT also reduced smoking at 3 months (OR 1.98, 95% CI, 1.77-2.21). Bupropion trials were superior to controls at 1 year (12 RCTs, OR1.56, 95% CI, 1.10-2.21, P = 0.01) and at 3 months (OR 2.13, 95% CI, 1.72-2.64). Two RCTs evaluated the superiority of bupropion versus NRT at 1 year (OR 1.14, 95% CI, 0.20-6.42). Varenicline was superior to placebo at 1 year (4 RCTs, OR 2.96, 95% CI, 2.12-4.12, P =< 0.0001) and also at approximately 3 months (OR 3.75, 95% CI, 2.65-5.30). Three RCTs evaluated the effectiveness of varenicline versus bupropion at 1 year (OR 1.58, 95% CI, 1.22-2.05) and at approximately 3 months (OR 1.61, 95% CI, 1.16-2.21). Using indirect comparisons, varenicline was superior to NRT when compared to placebo controls (OR 1.66, 95% CI 1.17-2.36, P = 0.004) or to all controls at 1 year (OR 1.73, 95% CI 1.22-2.45, P = 0.001). This was also the case for 3-month data. Adverse events were not systematically different across studies.
CONCLUSION
NRT, bupropion and varenicline all provide therapeutic effects in assisting with smoking cessation. Direct and indirect comparisons identify a hierarchy of effectiveness.
Topics: Benzazepines; Bupropion; Humans; Nicotine; Quinoxalines; Smoking Cessation; Treatment Outcome; Varenicline
PubMed: 17156479
DOI: 10.1186/1471-2458-6-300 -
Revista Espanola de Enfermedades... Apr 2023Tolvaptan (TVP) is a selective antagonist of vasopressin receptors, approved for the treatment of hyponatremia in SIADH, congestive heart failure (CHF) and cirrhosis. We...
Tolvaptan (TVP) is a selective antagonist of vasopressin receptors, approved for the treatment of hyponatremia in SIADH, congestive heart failure (CHF) and cirrhosis. We retrospectively reviewed all cases where TVP was used in a tertiary hospital (January 2012- January 2017). Our aim was to study the use of TVP in real life practice in patients with portal hypertension (PHT) (past history of non-malignant ascites or variceal bleed).
Topics: Humans; Tolvaptan; Antidiuretic Hormone Receptor Antagonists; Retrospective Studies; Benzazepines; Hyponatremia; Hypertension, Portal
PubMed: 36093979
DOI: 10.17235/reed.2022.9145/2022 -
Drug Metabolism and Pharmacokinetics Feb 2017Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug development. The rarity and multifactorial nature of iDILI makes it difficult to predict and... (Review)
Review
Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug development. The rarity and multifactorial nature of iDILI makes it difficult to predict and explain. Recently, human leukocyte antigen (HLA) allele associations have provided strong support for a role of an adaptive immune response in the pathogenesis of many iDILI cases; however, it is likely that an adaptive immune attack requires several preceding events. Quantitative systems pharmacology (QSP), an in silico modeling technique that leverages known physiology and the results of in vitro experiments in order to make predictions about how drugs affect biological processes, is proposed as a potentially useful tool for predicting and explaining critical events that likely precede immune-mediated iDILI, as well as the immune attack itself. DILIsym, a QSP platform for drug-induced liver injury, has demonstrated success in predicting the presence of delayed hepatocellular stress events that likely precede the iDILI cascade, and has successfully predicted hepatocellular stress likely underlying iDILI attributed to troglitazone and tolvaptan. The incorporation of a model of the adaptive immune system into DILIsym would represent and important advance. In summary, QSP methods can play a key role in the future prediction and understanding of both immune-mediated and non-immune-mediated iDILI.
Topics: Animals; Benzazepines; Chemical and Drug Induced Liver Injury; Chromans; Drug-Related Side Effects and Adverse Reactions; Humans; Models, Biological; Thiazolidinediones; Tolvaptan; Troglitazone
PubMed: 28129975
DOI: 10.1016/j.dmpk.2016.11.008