Methods for administration and methods for treating cardiovascular diseases with resiniferatoxin

#The present disclosure provides a method for administration of a formulation of resiniferatoxin (RTX) to provide cardiac sympathetic afferent denervation when in an amount and concentration sufficient to chemically denervate vanilloid 1 receptor (TRPV1)-expressing CSAR (cardiac sympathetic afferent reflex) afferents. The present disclosure further provides a method for treating heart failure or hypertension and its related indications selected from the group consisting of increased sympatho-excitation, cardiac hypertrophy, increased left ventricular end diastolic pressure (LVEDP), lung edema, and combinations thereof, comprising administering an effective amount of RTX directly to a tissue site selected from the group consisting of epicardium, dorsal root ganglion T1-T4 and intrathecally to the T1-T4 region of the spinal column.

#Chronic heart failure (CHF) is a serious and debilitating condition with poor survival rates and an increasing level of prevalence. Exaggerated sympatho-excitation, that is a hallmark of CHF, is a critical factor in the development and progression of CHF. Sympatho-excitation targets multiple organs and causes long-term effects that contribute to disease progression. The mechanism(s) by which sympathetic excitation occurs in the CHF state are not completely understood.

#Myocardial ischemia causes the production and release of several metabolites including bradykinin, prostaglandins and protons that stimulate sympathetic afferent nerve endings. This leads to increases in arterial pressure (AP), heart rate (HR) and sympathetic nerve activity (Wang and Zucker, Am. J. Physiol. 1996, 271:R751-R756; Wang and Ma, Heart Fail Rev. 2000; 5:57-71; and Longhurst et al. Ann. N Y Acad. Sci. 2001; 940:74-95). In CHF, the CSAR is sensitized and cardiac sympathetic afferents are tonically activated (Wang and Zucker, Am. J. Physiol. 1996 271:R751-R756; Gao et al. Hypertension. 2005; 45:1173-1181; and Wang and Ma, Heart Fail Rev. 2000; 5:57-71).

#FIG. 1A-E show, (A) an original hemodynamic and neural recording, (B) and mean data showing the cardiovascular and (C) sympathetic responses to epicardial application of either capsaicin or bradykinin (10 μg/ml) in sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats (n=8-12/each group). Scale bar in A represents 30 seconds. D and E, basal cardiac (n=6-8/each group) and renal sympathetic nerve activity (n=8-12/each group) and urinary NE secretion (E, n=6/each group) in sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats. Values are mean±SE. *P<0.05 vs. sham+vehicle; †, P<0.05 vs. CHF+vehicle.

#FIG. 2A and B shows representative recordings (A) and mean data (B) showing basal dp/dtmax and diastolic dp/dtmin as well as the dose-dependent responses to beta-adrenergic receptor stimulation with ISO (0.01, 0.1 and 1.0 μg/kg, 0.2 ml). Values are mean±SE. n=6/each group. *P<0.05 vs. sham+vehicle; †, P<0.05 vs. CHF+vehicle.

#FIG. 3A shows representative sirus red stain (top) and mean data (bottom right) showing that RTX reduces cardiac fibrosis induced by myocardium infarction (MI); bottom left, Masson's trichrome staining showing similar infarcted size between CHF+Vehicle and CHF+RTX rats in top panel. Black arrows point to the sirius red-positive staining.

#We performed epicardial application of RTX at the time of coronary ligation; MI surgery in rats in order to 1) investigate potential beneficial effects of selective deletion of TRPV1-expressing CSAR afferents on autonomic dysfunction and 2) determine whether the CSAR control of sympathetic nerve activity (especially cardiac sympathetic nerve activity; CSNA) plays a critical role in deleterious cardiac remodeling in CHF. Furthermore, we investigated the effects of CSAR afferent desensitization on cardiac morphological and hemodynamic function in rats with CHF. Epicardial administration of RTX comprises delivering RTX formulation to the epicardial surface, for example by using pericardiocentesis as a means for RTC delivery. Pericardiocentesis administration of RTX thereby selectively ablates cardiac sympathetic afferents in CHF patients. Therefore, the present disclosure shows that RTX-induced CSAR deafferentation prevents cardiac remodeling and reduces cardiovascular dysfunction in CHF rats and has high translational potential.

#The term “subarachnoid space” or cerebral spinal fluid (CSF) space incorporates the common usage refers to the anatomic space between the pia mater and the arachnoid membrane containing CSF.

#The term “intrathecal administration” is the administration of a composition directly into the spinal subarachnoid space.