Sustained Release Pellets for Antidiuretic Drugs Formulation & Clinical Evaluation

Desmopressin acetate (DDAVP) is an oligopeptide used to treat primary nocturnal enuresis, for example. The low oral bioavailability of DDAVP has expedited the move to other modes of administration such as nasal and oromucosal, with nasal administration resulting in large variations, raising the likelihood of unpleasant side effects. Hyponatremia is common in clinical practice and is mainly caused by renal water retention. Many drugs are thought to be among the different causes of hyponatremia because they either promote the production of arginine vasopressin (AVP) or increase its effect in the kidney. Antidepressants, anticonvulsants, antipsychotics, diuretics, and cytotoxic agents are the most common causes of drug-induced hyponatremia. However, research into the ability of these medicines to boost AVP release from the posterior pituitary gland or raise urine concentration via intrarenal processes is limited. We previously reported that in the absence of AVP, sertraline, carbamazepine, haloperidol, and cyclophosphamide enhanced vasopressin V2 receptor (V2R) mRNA and aquaporin-2 (AQP2) protein and mRNA expression in primary cultured inner medullary collecting duct cells. Tolvaptan, a V2R antagonist, and protein kinase A (PKA) inhibitors both prevented AQP2 upregulation. These observations lead us to the conclusion that the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the primary cause of drug-induced hyponatremia. Previous research has also found that the V2R has a role in chlorpropamide-induced hyponatremia. Several additional drugs, such as metformin and statins, have been shown in animal studies to elicit antidiuresis and AQP2 over expression via diverse V2R-independent routes, but they are not related with hyponatremia while being widely used therapeutically