Efficacy and Safety of Oral Conivaptan: A V<sub>1A</sub>/V<sub>2</sub>Vasopressin Receptor Antagonist, Assessed in a Randomized, Placebo-Controlled Trial in Patients with Euvolemic or Hypervolemic Hyponatremia

Ghali, Jalal K.; Koren, Michael; Taylor, James R.; Brooks-Asplund, E. M.; Fan, Kaisheng; Long, Walker; Smith, Neila

doi:10.1210/jc.2005-2287

Cited by 188 publications

(161 citation statements)

References 19 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…All agents of this class are inhibitors of the cytochrome P450 3A4 (CYP3A4) system, but conivaptan appears to be the most potent in this regard. Although the drug is orally active, 109 to minimize the possibility of drug interactions, the FDA has restricted its distribution to a parenteral form for shortterm (4-day) in-hospital use only. The remaining V 2 R antagonists appear to have more limited CYP3A4 interactions and are currently being developed for long-term oral use.…”

Section: Development Of Vasopressin Receptor Antagonistsmentioning

confidence: 99%

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Verbalis

Goldsmith

Greenberg

et al. 2007

The American Journal of Medicine

523

498

View full text Add to dashboard Cite

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. Hyponatremia is the most common disorder of electrolytes encountered in clinical practice, occurring in up to 15% to 30% of both acutely and chronically hospitalized patients. 1 Although most cases are mild and relatively asymptomatic, hyponatremia is important clinically because: (1) acute severe hyponatremia can cause substantial morbidity and mortality; (2) mortality is higher in patients with hyponatremia who have a wide range of underlying diseases; and (3) overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death.Despite knowledge of hyponatremia since the mid-20th century, this common disorder remains incompletely understood in many basic areas because of its association with a plethora of underlying disease states, and its multiple etiologies with differing pathophysiologic mechanisms. 2 Optimal treatment strategies have not been well defined, both for these reasons and because of marked differences in symptomatology and clinical outcomes based on the acuteness or chronicity of the hyponatremia. 3 Vasopressin receptor antagonists have long been anticipated as a more effective method to treat hyponatremia by virtue of their unique aquaretic effect to selectively increase solute-free water excretion by the kidneys. 4 The recent approval of the first such agent, conivaptan, for clinical use by the US Food and Drug Administration (FDA) heralds the beginning of a new era in the management of hyponatremic disorders. However, effective therapy with these agents will require intelligent guidelines for their use. To this end, a panel of experts in hyponatremia convened to review current therapies for hyponatremia and to evaluate the situations in which aquaretic agents should be considered as alternatives or supplements to accepted current therapies. This review is a summary of the conclusions of this panel.

show abstract

Section: Development Of Vasopressin Receptor Antagonistsmentioning

confidence: 99%

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Verbalis

Goldsmith

Greenberg

et al. 2007

The American Journal of Medicine

523

498

View full text Add to dashboard Cite

show abstract

“…In several double-blind, placebo-controlled clinical trials, conivaptan has been effective in improving serum sodium concentrations [91]. Serum sodium is improved by 6.3 mmol/L with a 40 mg daily dose, and by 9.0 mmol/L with an 80 mg daily dose [92][93][94]. Importantly, despite the properties of conivaptan as a V1a-receptor antagonist, it had no effect on systolic blood pressure or pulse rate.…”

Section: Vasopressin Receptor Antagonistmentioning

confidence: 99%

Novel Treatment Targets for Cerebral Edema

2012

View full text Add to dashboard Cite

Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(−) co-transporter (NKCC1) and the SUR1-regulated NC Ca-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A-and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis.Keywords Cerebral edema . Hyponatraemia . Osmotherapy . NKCC1 . SUR1/TRPM4 . Vaptan . Glyburide Overview of Perturbations in Brain Fluid HomeostasisCerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [5][6][7], and traumatic [8,9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance...

show abstract

“…1), 18 trials met the eligibility criteria or reported data for an eligible subgroup. Two trials assessed conivaptan, 13,14 four assessed lixivaptan, [15][16][17][18] three assessed satavaptan [19][20][21] and nine assessed tolvaptan. [22][23][24][25][26][27][28][29] There were no RCTs published assessing other known interventions such as urea, sodium tablets or mannitol.…”

Section: Resultsmentioning

confidence: 99%

“…Otsuka (manufacturer of tolvaptan and funder of this review) provided information for six trials of tolvaptan vs placebo and the authors of two further trials responded. 14,20 A summary of the characteristics of the included trials is presented in Table 1. All 18 trials were randomized multicentre trials.…”

Section: Resultsmentioning

confidence: 99%

Untitled

2017

Clinical Endocrinology

View full text Add to dashboard Cite

International and national guidelines on the treatment of chronic nonhypovolaemic hypotonic hyponatraemia differ; therefore, we have undertaken this systematic review and metaanalysis to investigate the efficacy and safety of interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia. Following registration of the review protocol with PROSPERO, systematic literature searches were conducted to identify randomized and quasi-randomized controlled trials assessing any degree of fluid restriction or any drug treatment with the aim of increasing serum sodium concentration in patients with chronic nonhypovolaemic hypotonic hyponatraemia. Where appropriate, outcome data were synthesized in a meta-analysis. A total of 45 716 bibliographic records were identified from the searches and 18 trials (assessing conivaptan, lixivaptan, tolvaptan and satavaptan) met the eligibility criteria. Results suggest that all four vasopressin receptor agonists ("vaptans") significantly improve serum sodium concentration. Lixivaptan, satavaptan and tolvaptan were associated with greater rates of response versus placebo. There was no evidence of a difference between each of the vaptans compared with placebo for mortality, discontinuation and rates of hypernatraemia. No RCT evidence of treatments other than the vaptans for hyponatraemia such as oral urea, salt tablets, mannitol, loop diuretics demeclocycline or lithium was identified. Vaptans demonstrated superiority over placebo for outcomes relating to serum sodium correction. Few trials documented the potential benefit of vaptans on change in health-related quality of life as a result of treatment. There was also a lack of high-quality RCT evidence on the comparative efficacy of the vaptans and other treatment strategies for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia.

show abstract

Efficacy and Safety of Oral Conivaptan: A V_1A/V₂Vasopressin Receptor Antagonist, Assessed in a Randomized, Placebo-Controlled Trial in Patients with Euvolemic or Hypervolemic Hyponatremia

Abstract: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na(+)] in hyponatremia.

Cited by 188 publications

References 19 publications

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Novel Treatment Targets for Cerebral Edema

Untitled

Contact Info

Product

Resources

About

Efficacy and Safety of Oral Conivaptan: A V1A/V2Vasopressin Receptor Antagonist, Assessed in a Randomized, Placebo-Controlled Trial in Patients with Euvolemic or Hypervolemic Hyponatremia

Abstract: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na(+)] in hyponatremia.

Cited by 188 publications

References 19 publications

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Novel Treatment Targets for Cerebral Edema

Untitled

Contact Info

Product

Resources

About

Efficacy and Safety of Oral Conivaptan: A V_1A/V₂Vasopressin Receptor Antagonist, Assessed in a Randomized, Placebo-Controlled Trial in Patients with Euvolemic or Hypervolemic Hyponatremia