Metolazone is a quinazoline sulfonamide with potent thiazide like diuretic activity on the cortical diluting segment, as well as diuretic action on the proximal tubule. Metolazone (orally) is often employed in patients with severe congestive heart failure (CHF) as a supplement to a loop diuretic, as well as in patients with diuretic resistance to loop diuretics. However, metolazone has not been available for IV administration due to its very poor solubility. An IV formulation would be useful in heart failure patients who invariably have poor oral absorption, in patients unable to take oral medications and in patients with loop diuretic resistance when rapid IV administration is difficult to coordinate with peak loop diuretic action. We have developed a new formulation of metolazone for IV administration at a neutral pH, that we believe is not be phlebitic and is effective in diuretic resistant states. Studies proposed in this grant aim to characterize the new formulation and establish its diuretic action in an animal model, initial steps in obtaining an IND to initiate clinical studies.
Public Health Relevance Statement: Project Narrative Metolazone orally is an effective diuretic in patients with severe edema, congestive heart failure and diuretic resistance to loop diuretics.(1,2,3,4) Diuretic resistance to loop diuretics occurs frequently with large doses administered to patients with severe HF. An IV formulation of metolazone would be useful to treat patients with severe heart failure, and patients with loop diuretic resistance. We had previously developed an IV formulation at pH 9.5 to 10, but the formulation was venous irritating, limiting its utility. A newly developed lipid emulsion formulation at pH 7.4, we believe, will be less phlebitic and effective in diuretic resistant states. The studies proposed aim to characterize the formulation and evaluate the diuretic effects, as well as demonstrating the lack of venous irritation (phlebitis), all requisite steps in the development of a viable product for both adult and pediatric populations.
Project Terms: absorption; Adult; Animal Model; Animals; Blood; Canis familiaris; Childhood; Chronic; Clinical Research; comparative; Congestive Heart Failure; Development; Diuretics; Dose; Ear; Edema; efficacy study; Emulsions; Erythrocytes; Evaluation; Excretory function; FDA approved; Formulation; Furosemide; Grant; Heart failure; Hemolysis; Human Volunteers; In Vitro; Intravenous; irritation; Limb structure; Lipids; man; Measures; Metolazone; Modeling; Oral; Oryctolagus cuniculus; Output; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phlebitis; Population; Preparation; Quinazolines; Resistance; Site; Solubility; Sulfonamides; synergism; thiazide; Urine; Veins; Venous
