Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: Phase 1 trial of GS-9411.

BACKGROUND: Inhaled epithelial sodium channel (ENaC) blockers are designed to increase airway surface liquid volume, thereby benefiting cystic fibrosis patients. This study evaluated the safety, tolerability, and pharmacokinetics of multiple doses of ENaC blocker GS-9411, in healthy participants. METHODS: This randomized, double-blind, placebo-controlled, parallel-group, residential, Phase 1 study evaluated inhaled GS-9411 (2.4, 4.8, and 9.6 mg) or placebo, dosed twice daily for 14 days. RESULTS AND CONCLUSIONS: GS-9411 was well tolerated; 86.1% of treated participants completed dosing (n=31/36). Cough and dizziness (27.8% participants each; most of mild severity) were the most commonly reported adverse events and occurred in both placebo and GS-9411 treatment groups. Arrhythmias were not observed for GS-9411-treated participants, and electrocardiographic changes were not considered clinically significant. Serum potassium levels exceeded the upper limit of normal (>5 mmol/L), 4 hr after the morning dose in GS-9411 (n=16/24) and placebo (n=4/12) treatment groups (38 incidences total). Retesting revealed levels had returned to normal within 2-3 hr. In urine electrolyte analyses, obtained 0-6 hr after the Day 1 morning dose, mean sodium/potassium ratios significantly increased from values 0-6 hr before dosing. Increased urine sodium/potassium ratios corresponded with high urine concentrations of active GS-9411 metabolites, which inhibited sodium reabsorption in the kidney, leading to the observed transient hyperkalemia in these participants. Inhaled GS-9411 was well tolerated except for the emergence of transient clinically significant hyperkalemia; this finding resulted in termination of further clinical development of this drug and will necessitate development of a new generation of ENaC blockers, which provide a sustained improvement in mucociliary clearance, while reducing renal exposure to ENaC blockade. Transient increases in mean urine sodium/potassium ratios appeared to be the first signal of electrolyte imbalances resulting from drug-induced block of ENaC in the kidney. The results of this study strongly suggest that clinical trials of novel ENaC blockers will require intensive measurement of plasma and urine electrolyte levels.

Intracerebroventricular infusions of gp120 inhibit weight gain and induce atrophy in the hippocampus and neostriatum without affecting cognition.

The HIV envelope protein, gp120, has been proposed to be a key agent in the development of AIDS dementia complex (ADC). To elucidate CNS effects that gp120 alone may be inducing in ADC, the present study investigated changes in weight, motor activity, cognitive function and corresponding neuropathology in rats given daily bilateral infusions of gp120 intracerebroventricularly for 7 days. gp120 inhibited weight gain, but had no measurable effects on motor activity or water maze cognitive performance. Nonetheless, gp120 infusions did induce both hippocampal and neostriatal atrophy. Thus, gp120 alone can cause ADC-related neuropathologic and weight changes, but gp120 alone was not sufficient to induce impairments in spatial learning and memory.