Forskolin was found to cause concentration dependent, reversible relaxations of isolated smooth muscle preparations including rat aorta, bovine coronary artery, canine coronary artery, guinea pig taenia caeci and rabbit small intestine. The relaxant effects of forskolin in guinea pig taenia caeci and rabbit small intestine were potentiated by cyclic nucleotide phosphodiesterase inhibitors Ro 20-1724 and MIX. In rabbit small intestine, Ro 20-1724 also potentiated the relaxant effects of isoproterenol but not those of verapamil or 2-chloroadenosine. However, in bovine coronary arteries the phosphodiesterase inhibitors had to be used at concentrations of 100 nM or below because of relaxant effects and did not alter forskolin-induced relaxations. Forskolin caused a concentration dependent activation of adenylate cyclase in broken cell preparations from guinea pig taenia caeci and rabbit small intestine, exceeding the stimulatory effect of 10 mM NaF. These results indicate that relaxations of smooth muscle by forskolin are mediated by cyclic AMP and, in turn, that cyclic AMP may well serve as an intracellular mediator of physiological relaxant stimuli.

No abstract

No abstract

SYN-004 (ribaxamase) delayed release drug product is a multi-particulate, hard capsule for oral delivery of a recombinant β-lactamase enzyme designed to degrade β-lactam antibiotics administered intravenously, and thus prevent colon dysbiosis. Here we describe the development of the SYN-004 enteric coated pellet formulation, which has been tested in multiple clinical trials. Since the SYN-004 drug substance is a buffered liquid, several binder excipients in different ratios were tested to facilitate binding of SYN-004 to sugar spheres. The binding systems were evaluated by droplet pre-evaluation and film casting tests. The most promising formulations were produced in small scale fluidized bed application runs and analyzed by dissolution tests and complementary analytical assays. Hydroxypropyl cellulose was selected as the preferred SYN-004 binding excipient. The formulation included a second, outer coat containing the enteric EUDRAGIT L 30 D-55 polymer-based formulation to achieve gastric protection, and rapid SYN-004 release in the intestinal tract, when the pH rises above 5.5. Additional formulation improvements resulted in an increase in the SYN-004 load compared to a predecessor oral enzyme formulation (Ipsat P1A). Thus, a novel formulation and process for an orally administered enzyme was developed and used to manufacture drug product for clinical trials.

1 Theophylline relaxed isolated strips of guinea-pig stomach fundus in a dose-dependent manner; above 50 to 100 pM responses showed no fade for up to 90 min.2 Relaxant responses to adenosine, adenosine triphosphate (ATPl noradrenaline, and to electric field stimulation of non-adrenergic inhibitory nerves were not affected in a significant manner in the presence of 50 pM theophylline.3 In tissues which showed complete fade of initial responses in the continued presence of 50 pM ATP, the effects of stimulation of non-adrenergic inhibitory nerves remained unaltered, suggesting that the ATP receptor has no function in non-adrenergic inhibitory transmission in this tissue. 4 These findings are opposite to those of Okwuasaba, Hamilton & Cook (1977), who claimed that 50 pM theophylline almost fully inhibited relaxation induced by adenosine, ATP and nerve stimulation and that ATP-induced fade also abolished sensitivity to inhibitory nerve stimulation.