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Clinical Medicine
Prous Science Solutions
February 13, 2012
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Conivaptan hydrochloride
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Within the diuretic drug class, one of the newer mechanisms of action to emerge in recent years is that of vasopressin antagonists. Vasopressin, a peptide hormone that is also known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and released from the posterior pituitary. There are 2 forms which differ only in the amino acid at position 8: arginine vasopressin (AVP) which is widespread, and lysine vasopressin which is found only in pigs. Circulating AVP is a potent vasoconstrictor, and high levels of AVP may contribute to systemic vasoconstriction and hyponatremia. AVP activity is mediated via V1 (consisting of V1A and V1B subtypes) and V2 receptors. V1A receptors are located on blood vessels, where they exert vasoconstrictor effects, and in the myocardium, where they act as a myocardial stimulant. V2 receptors mediate the effects of AVP on water retention. V1B receptors have only indirect circulatory effects and thus do not constitute an important target.

Late last year, the first vasopressin antagonist was granted marketing approval by the U.S. FDA: Astellas Pharma's Vaprisol® (YM-087, conivaptan hydrochloride), indicated for the intravenous treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan is the first drug specifically indicated for the treatment of euvolemic hyponatremia, a condition that occurs when the body's blood sodium level falls significantly below normal. The drug blocks the activity of AVP, resulting in increased urine output without loss of valuable electrolytes such as sodium and potassium. This aquaresis helps to correct serum sodium levels in patients with hyponatremia due to increased body water. In a randomized, double-blind, placebo-controlled study, intravenous administration of conivaptan hydrochloride (40 mg/day for four days) corrected the balance of sodium and water in hospitalized patients with mild to moderate euvolemic hyponatremia. Significant improvements in serum sodium levels were observed within the first day of treatment. The drug was launched in April 2006. The FDA also issued an approvable letter for conivaptan as a treatment for hypervolemic hyponatremia.

In October 2006, the second vasopressin V2 antagonist -Otsuka's mozavaptan- was launched in Japan, where it is indicated for the treatment of hyponatremia in subjects with inappropriate antidiuretic hormone (ADH) secretion syndrome due to tumors with ectopic ADH production.

*Each month this section highlights a different drug molecule or molecules. Selection is based on the following criteria:
  • the originality of the chemical structure
  • the singularity of the mechanism of action
  • the drug's progression through the R&D pipeline
  • its use in a new indication or where current therapies are inexistent or have proved unsatisfactory.

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