Open Tibial Fracture Complicated by Wound Botulism: A Case Study.

Botulism is a neuroparalytic disease most commonly caused by foodborne ingestion of neurotoxin types A, B, and E, and is often fatal if untreated. Clinicians should be able to recognize the classic symptoms of botulinum intoxication (12). Owing to its rarity, there are a limited number of studies evaluating the clinical care of patients with wound botulism (10). We present an infected tibial non-union with botulism who underwent a successful radical excision and bone transport. The patient tolerated the procedure well.

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.

Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation.

A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.

Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.

The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.

Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1.

A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.

Aortoiliac reconstruction: the retroperitoneal approach and splenic injury.

Exposure of the abdominal aorta through the left retroperitoneum is a well-accepted technique. Unfortunately, splenic injury is a complication of this approach that rarely occurs through a mid-line transabdominal incision. In this series we evaluate the occurrence of splenic injury during left retroperitoneal aortic surgery. The records of all patients undergoing abdominal aortic reconstruction via the left retroperitoneal approach were reviewed from 1988 to 2001. Indications included either abdominal aortic aneurysm (AAA) or aortoiliac occlusive disease (AIOD). Thoracoabdominal aneurysms and visceral aortic reconstructions were excluded. Those patients that required splenectomy for splenic injury were stratified and analyzed for demographics, indications for operation, and other complications. Chi-square analysis was used to determine statistical significance. Over the 13-year study period, 2889 aortic reconstructions were performed. These consisted of 1773 elective AAA repairs, 357 ruptured or symptomatic AAA repairs, and 759 aortofemoral bypasses for AIOD. Splenectomies were performed after aortic repair in 21 (0.7%) patients. Breakdown by indication totaled 11/1773 (0.6%) for elective AAA repair, 7/357 (2.0%) for rupture or symptomatic AAA repair, and 3/759 (0.4%) for AIOD ( p < 0.05). Mortality for patients undergoing elective AAA without splenectomy was 1.9% (34/1762) and with splenectomy was 9.1% (1/11), while it was 3.2% (24/756) for AIOD patients without splenectomy and 14% (1/7) for AIOD patients with splenectomy (all p = NS). Splenic injury can occur in elective and emergent aortic reconstructions performed through the left retroperitoneum. The surgeon should be prepared for splenectomy whenever intraperitoneal blood or hemodynamic instability is identified. Evaluation of the spleen prior to flank closure may be prudent.