Z-160

The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel.

Acute asthma causes nearly 2 million hospital emergency department (ED) visits in the United States annually, and hospitalization after an ED visit and relapse after ED discharge are common.

To evaluate the adding of therapy with zafirlukast to standardized care for patients with acute asthma in the ED and a 28-day follow-up period.

A total of 641 patients presenting to the ED with acute asthma were randomized to receive either single-dose zafirlukast, 160 mg (Z160) [162 patients], zafirlukast, 20 mg (Z20) [158 patients]), or placebo (321 patients) as adjunct treatment to standard care in this double-blind, multicenter trial. Assessments, including spirometry and symptom scores, were obtained before each albuterol treatment and at 4 h. Patients who were discharged from the ED after 4 h continued outpatient therapy over a 28-day period and received either Z20 bid (276 patients) or placebo (270 patients) in addition to prednisone, albuterol, and their previous asthma medications. FEV(1) was measured at clinic visits on days 10 and 28. Patients recorded outpatient clinical data twice daily on a home diary card.

the effect of zafirlukast on relapse after ED discharge. Other assessments were the rate of extended care (ie, ED stay for > 4 h or hospitalization), FEV(1), and symptoms.

At the end of the outpatient period, 65 of 276 patients (23.6%) treated with zafirlukast and 78 of 270 patients (28.9%) treated with placebo relapsed (p = 0.047; absolute reduction, 5.3%; relative reduction, 18.3%). At the end of the ED period, 16 of 162 patients (9.9%) treated with Z160, 26 of 158 patients (16.5%) treated with Z20, and 48 of 321 patients (15.0%) treated with placebo required extended care (p = 0.052; absolute reduction with Z160 compared to placebo, 5.1%; relative reduction, 34%). These findings were supported by a significant improvement in FEV(1) and dyspnea in the ED with the use of Z160 therapy, and by greater improvement in FEV(1) and symptoms during the outpatient period for patients treated with Z20.

When added to standardized care, therapy with Z20 bid reduced the risk of relapse compared with placebo over a 28-day treatment period. One dose of Z160 in the ED also reduced the rate of extended care.