COX-inhibiting nitric oxide donators (CINODs) - a new paradigm in the treatment of pain and inflammation.

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.

Effects of NAD-299, a new, highly selective 5-HT1A receptor antagonist, on bladder function in rats.

5-HT is involved in micturition control. In the rat, stimulation of the 5-HT(1A) receptor excites, whereas 5-HT(1A) receptor antagonism inhibits micturition. The present study examined the effects of a new, highly selective, 5-HT(1A) receptor antagonist, NAD-299, on micturition in rats. Comparisons were made with WAY100635, a well-characterised antagonist at the 5-HT(1A) receptor. Female Sprague-Dawley rats, conscious or anaesthetised, were used for cystometric studies. Intravenous (i.v.), intraarterial (i.a.), intrathecal (i.t.) or intracerebroventricular (i.c.v.) catheters were implanted for drug administration. In vitro, rat bladder strips were contracted by carbachol or electrical stimulation of nerves. The effects of NAD-299, WAY100635 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT(1A) receptor agonist) on cystometric parameters and contraction of bladder strips were recorded. In conscious rats, i.v. NAD-299 and WAY100635 at 1 micro mol kg(-1) increased bladder capacity (24+/-13% and 27+/-19% respectively) and decreased micturition pressure (16+/-8% and 12+/-10% respectively). Given i.a., 5-HT 0.25 micro mol kg(-1) and 8-OH-DPAT 0.37 micro mol kg(-1) stimulated micturition. The effect of 8-OH-DPAT, but not those of 5-HT, was blocked by i.a. NAD-299. 8-OH-DPAT 0.03 micro mol given i.t. or i.c.v. stimulated micturition, an effect blocked by WAY100635 0.1 micro mol, given i.t or i.c.v. NAD-299 or WAY100635 (0.1 micro mol i.t.) were without significant effects, but given i.c.v. at 0.1 micro mol both drugs increased bladder capacity (34+/-12% and 22+/-13% respectively). Neither NAD-299 nor WAY100635 up to 10(-5) M had effects on electrically- or carbachol-induced contractions of rat bladder strips. NAD-299 1 micro mol kg(-1) i.v. suppressed oxyhaemoglobin-induced detrusor over-activity. It is concluded that NAD-299, acting at a supraspinal site, can inhibit micturition in the rat.