Development of a treatment-resistant hypertension (RHTN) depot therapeutics

AbstractResistant hypertensionRHTNis an emerging etiology and was defined as persistent elevation of blood pressure above goal despite concurrent use ofantihypertensive agentseach of unique class with a diuretic included among the treatment regimenand with all drugs at target doseIt has been estimated thatof the hypertensive population in the U Smet the strict definition for RHTNandof these patients are refractory to treatment even withdifferent classes of antihypertensivesRHTN patients have significantly increased risk of all cause mortalitycardiovascular mortalitynonfatal strokeand nonfatal myocardial infarctionWhile the antihypertensive treatment options have increased from just three classes inandaposto over eleven different classes nowphysicians are having difficulties to achieve controlled blood pressure in RHTN patientsIn factthere is scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressureBecause reduction of the blood pressure bymmHg can decrease the risk of stroke byof ischemic heart diseases byand reduce the likelihood of dementia and heart failureclearly there is a substantial unmet medical need of novel therapeutics that can actively improve hemodynamics and endothelial function in RHTN patientsImportantlyan endocrine hormone adrenomedullinADMwas shown to be among the most potent hypotensive hormones and regulators of vascular barrier functionsADM also exhibits neuroprotectiverenoprotectiveand diuresis effects in a variety of cardiovascular disease modelsDespite its promise for treating a variety of cardiovascular diseaseswild type ADM has short half lifeTo overcome this obstaclewe have developed a group of superagonistic ADM peptidomimetics that exhibittofold higher potency on receptor activationBy serendipitywe have also discovered that select super agonists self assemble and form in situ gel depotsTogetherthese data suggested that the ADM analogswhich possess unrivaled super agonistic activity and the novel self assemble depot formation capabilitycould be an ideal drug for sustained activation of ADM signaling in RHTN patientsAccordinglywe propose to investigate the translational potential of the superagonist gels in an RHTN rat modelSuccessful development of the nanomedicine has the potential to drastically improve the care of patients with RHTN or other endothelial dysfunction associated diseases Based on human hormones that play critical roles in the regulation of hemodynamics and vascular integritywe have developed novel therapeutic candidates for the treatment of resistant hypertensionWe will identify a lead candidateand characterize the pharmacokinetics and efficacy of self assemble gel depots made of the selected analogSuccessful development of the proposed therapy has the potential to prevent the progression of resistant hypertension and to reduce mortality resulting from uncontrolled hypertension