V1 D -2 Lab, Screen, EKG, UA
V2 D 1 (Predose) Baseline, EKG, UA, Hold Drug if Na increases greater than 8/24 H or greater than 12/48H
V3 D 1 Dispense Lixivaptan, Hold Drug if Na increases greater than 8/24 H or greater than 12/48H
V4 D 2 Lab, EKG
V5 D 3 Lab, EKG
V6 D 8 Lab, EKG
V7 D 15 Lab, EKG, UA
V8 D 22 Lab, EKG
V9 D 29 Lab, EKG, UA
V10 W 8 Lab
V11 W 12 Lab, EKG
V12 W 15 Dispense Lixivaptan, Phone weekly to check general health & weight
V13 W 18 Lab, EKG
V14 W 22 Dispense Lixivaptan, Phone weekly to check general health & weight
V15 W 26 Lab, EKG, UA
V16 W 27 Lab
V17 W 30 Lab, EKG, UA
20 August 2007
VERSION: 1 2 3 4 5 6 7 8 9
Euvolemic Hyponatremia
http://www.cardiokine.com/lixivaptan.asp
Lixivaptan is a highly potent, non-peptide, selective vasopressin V2 receptor antagonist. Lixivaptan antagonizes the action of vasopressin (also known as antidiuretic hormone, ADH) on the V2 receptors in the kidney collecting duct, causing a decrease in renal water reabsorption and urine osmolality and an increase in urine volume.
The pharmacologic activity of Lixivaptan is expected to be of benefit in the treatment of disease states associated with water retention, such as congestive heart failure (CHF), cirrhosis and syndrome of inappropriate antidiuretic hormone (SIADH ).
Because of its ability to cause the elimination of water with reduced sodium loss, Lixivaptan is expected to benefit patients by removing the excessive free water, while elevating plasma sodium, thus relieving signs and symptoms of hyponatremia and water retention.
Vasopressin is a nine amino acid, cyclic peptide hormone, synthesized in the hypothalamus and stored in the posterior pituitary. The actions of vasopressin are mediated by three subtypes of cell membrane receptors—V1a, V1b (also known as V3), and V2—which are distinguished by being linked to different signaling pathways and by the cell type specificity of their expression. The V1a and V1b receptors are linked to the phosphatidylinositol (1P3) and 1, 2-diacylglycerol (DAG) signaling pathway, and the V2 receptors are linked to the adenylate cyclase signaling pathway.
As a result of its action at the V2 receptors, vasopressin plays a pivotal role in the regulation of extracellular fluid volume. The principal physiological stimulus for the release of vasopressin into circulation is an increase in plasma osmolality above the normal physiological range. Severe hypovolemia with hypotension is also a powerful stimulus for vasopressin release.
Vasopressin acts on the vasopressin V2 receptors in the kidney to open renal water channels, leading to the reabsorption of water. Thus, an increase in plasma osmolality leads to stimulation of vasopressin release, causing an increase in renal water reabsorption and a decrease in plasma osmolality back to normal. By this mechanism, vasopressin secretion, in conjunction with the thirst regulating mechanism, maintains plasma osmolality within a narrow normal range.
The V 1a subtype of cell membrane receptors is present on vascular smooth muscle cells, hepatocytes, blood platelets, lymphocytes and monocytes, type II pneumocytes, brain, reproductive organs, retinal epithelium, and renal mesangial cells. These receptors mediate cell contraction and the proliferation of vascular smooth muscle, platelet aggregation, coagulation factor release (factor VIII and tissue plasminogen activator), and glycogenolysis. The hemodynamic effect of vasopressin results from its action on V1a receptors in the vasculature.
Stimulation of the V1a receptors results in a potent vasoconstriction and provides homeostatic control of blood pressure and circulatory volume. Stimulation of the V1a receptors occurs at plasma vasopressin levels significantly greater than that required for antidiuretic activity. Vasopressin also acts at V1b, receptors in the pituitary to potentiate the action of corticotrophin releasing hormone and participate in the release of ACTH.
There is an AVP (ADH) antagonist on the market already in IV form called Vaprisol (Conivaptan). See: http://www.vaprisol.com