Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential.

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation. Impairment of this signaling system and altered NO-cGMP homeostasis have been implicated in cardiovascular, pulmonary, renal, gastrointestinal, central nervous system, and hepatic pathologies. sGC stimulators, small molecule drugs that synergistically increase sGC enzyme activity with NO, have shown great potential to treat a variety of diseases via modulation of NO-sGC-cGMP signaling. Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models.

The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms. AIMS: To examine abdominal symptom severity and relationships between symptoms and global measures at baseline; compare linaclotide's effect on symptoms in subpopulations with more or less abdominal pain; and assess relationships between symptom improvement and global measures in these two subpopulations. METHODS: In two phase 3 trials, patients meeting modified Rome II CIC criteria were assigned to linaclotide 145 µg, 290 µg, or placebo once daily. Patients rated abdominal and bowel symptoms daily during 2-week pre-treatment and 12-week treatment periods. Linaclotide's effect on symptoms and global measures [constipation severity, health-related quality of life (HRQOL), treatment satisfaction] and their inter-relationships were assessed in post hoc analyses of abdominal pain subpopulations. RESULTS: Of 1271 CIC patients, 23%, 32%, and 43% reported moderate-to-severe abdominal pain, discomfort, and bloating, respectively, during baseline. In more-severe abdominal pain patients, abdominal symptoms were more strongly correlated than bowel symptoms with global measures, but in less-severe abdominal pain patients, abdominal and bowel symptoms were similarly correlated with global measures, at baseline and post-treatment. Linaclotide significantly improved all symptoms and global measures in both subpopulations. CONCLUSIONS: When abdominal pain is present in CIC, abdominal and not bowel symptoms may drive patient assessments of constipation severity, HRQOL, and treatment satisfaction. Linaclotide (145 µg and 290 µg) is an effective treatment for both abdominal and bowel symptoms, even in CIC patients with more severe abdominal pain at baseline. (Clinicaltrials.gov: NCT00765882, NCT00730015).

Innervation of propatagial musculature in a flying squirrel, Glaucomys volans (Rodentia, Sciuridae).

The propatagium of gliding and flying mammals is of both functional and phylogenetic interest. The innervation of the propatagial muscle, platysma II, was studied with the axonal tracer wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) in a flying squirrel, Glaucomys volans. Injections of WGA-HRP into the proximal third of platysma II labeled motoneurons in the lateral part of the medial subdivision of the ipsilateral facial nucleus and in the ipsilateral ventral horn of the brachial enlargement. Injections into distal regions of platysma II labeled motoneurons in the ipsilateral ventral horn of spinal segments C5-C8 but not in the facial nucleus. Injections along the whole length of the muscle labeled afferent axons in the ipsilateral dorsal horn of spinal segments C4-T1. These results demonstrate a mixed facial and spinal motor innervation of propatagial musculature in the flying squirrel and indicate that this pattern of mixed innervation is more widespread among flying and gliding mammals than previously reported. Mixed facial and cervical propatagial innervation, independently derived in different flying and gliding mammals, may represent a common solution in the design of the propatagium. These findings complicate the use of propatagial muscle innervation patterns for the establishment of phylogenetic relationships among flying and gliding mammals.