ABSTRACT
BACKGROUND: ENaC inhibition has long been an attractive therapeutic target for the treatment of cystic fibrosis. However, previous attempts at developing ENaC inhibitors have been unsuccessful due to complications arising from systemic circulation of the compounds. Here, we describe the preclinical toxicology assessment of a new inhaled peptide promoter of ENaC internalization delivered as a nebulized aerosol. METHODS: Preclinical assessment of SPX-101 safety was determined using an in vitro hERG assay, bolus injection of SPX-101 in a canine cardiovascular and respiratory safety pharmacology model and 28-day inhalation toxicology studies of nebulized drug in rats and dogs. RESULTS: SPX101 had no effects on the respiratory, cardiac or central nervous systems. The 28-day inhalation toxicology studies of nebulized SPX-101 in rats and dogs revealed no drug-related adverse events. Plasma levels of SPX-101 peaked less than 1 h after the end of treatment in rats and were below the limit of detection in canine models. CONCLUSIONS: SPX-101, a novel peptide promoter of ENaC internalization, elicited no adverse effects at doses up to the MFD and in excess of the highest preclinical efficacious and expected clinical doses. In contrast to channel blockers like amiloride and derivative small molecules, SPX-101 does not achieve significant systemic circulation, thus doses are not limited due to toxic side effects like hyperkalemia and weight loss.
Subject(s)
Peptides/toxicity , Administration, Inhalation , Animals , Cystic Fibrosis/drug therapy , Dogs , ERG1 Potassium Channel/physiology , Epithelial Sodium Channels/metabolism , Female , Glycoproteins , HEK293 Cells , Humans , Lung/drug effects , Lung/metabolism , Male , Peptides/blood , Peptides/pharmacokinetics , Peptides/pharmacology , Phosphoproteins , Rats, Sprague-Dawley , Toxicity Tests, SubacuteABSTRACT
INTRODUCTION: This study was designed to provide a comprehensive nonclinical respiratory safety pharmacology assessment using respiratory inductance plethysmography (RIP) concomitant with a standard cardiovascular (CV) safety assessment in non-human primates (NHP) in a single cardiorespiratory study. METHODS: RIP calibration data were generated in conscious, ketamine-sedated, or propofol-anesthetized NHP to determine the most appropriate method. Calibration accuracy was assessed using a CO(2) rebreathe maneuver. Regardless of the technique, the RIP system reliably demonstrated accurate assessment of the CO(2) rebreathe response when expressed as a percent change with respect to control. Four male NHP were given single oral doses of vehicle, 1.25 and 5 mg/kg test article followed by 20 mg/kg repeatedly for 7 days. Telemetry-derived cardiovascular parameters (PR, QRS, QT, heart rate corrected QT (QTcR) intervals, blood pressure [BP], and heart rate [HR]) and RIP-derived respiratory parameters (respiration rate [RR], tidal volume [TV], and minute volume [MV]) were determined for 24 h pretest, 2 h predose and 24 h postdose. RESULTS: A single dose of the test article at 5 or 20 mg/kg was associated with slight increases in HR, BP, RR, and MV at 2 to 7 h postdose, followed by decreases in HR, RR, TV, and MV at 5-23 h postdose. Decreases in HR, RR, TV, and MV were observed following 7 days of dosing at 20 mg/kg. Slight QTcR prolongation at 1 to 11 h postdose was observed following a single dose of 20 mg/kg. CONCLUSION: These data show that the integrated assessment of cardiovascular and respiratory parameters in NHP is achievable continuously for at least 24 h postdose. The use of RIP as a method to assess the effects of a novel compound on the respiratory system complements, but does not interfere with, the cardiovascular assessment of new drugs.
Subject(s)
Cardiovascular Physiological Phenomena/drug effects , Cardiovascular System/drug effects , Drug-Related Side Effects and Adverse Reactions , Haplorhini/physiology , Animals , Animals, Laboratory , Calibration , Consciousness , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Hemodynamics/drug effects , Male , Models, Animal , Plethysmography , Pulmonary Ventilation/drug effects , Pulmonary Ventilation/physiology , Telemetry/methods , Tidal Volume/drug effects , Tidal Volume/physiologyABSTRACT
BACKGROUND: There have been few trials in which dogs with mitral regurgitation (MR) have been treated with various cardioactive drugs to determine effects on left ventricular (LV) function. HYPOTHESIS: Four classes of cardiovascular drugs may improve LV function in dogs with MR without increasing MR. ANIMALS: Nine mature dogs were included in the study. METHODS: MR was produced in 9 dogs. Five months later under butorphanol narcosis, parameters of LV function and left atrial dimension (LAD) were monitored by LV micromanometry and echocardiography/Doppler. Dogs were given (in random order) enalaprilat, nitroglycerine, ouabain, milrinone, and placebo. RESULTS: Nitroglycerin produced no significant change; milrinone and ouabain increased contractility; ouabain decreased heart rate; and there was evidence that enalaprilat and milrinone decreased LAD. Milrinone and ouabain decreased isovolumetric contraction time and therefore the time available for MR. There was no evidence that a positive inotrope increased MR despite increasing LV contractility and stroke volume. CONCLUSION AND CLINICAL IMPORTANCE: This study contradicts the hypotheses that (1) strengthening the left ventricle may increase MR and (2) treatment of MR (even before symptoms of heart failure develop) may decrease LAD. It is reasonable that strengthening the force of LV contraction should increase the driving pressure for MR; however, this effect did not appear to increase MR. Although some investigators believe that treating dogs with MR with afterload reducers and decreasing hindrance to ejection of blood from the LV to aorta may lengthen life by decreasing MR, there did not appear to be a reduction in MR, at least in response to the angiotensin-converting enzyme (ACE) inhibitor.
