Synchronous perforation of sigmoid diverticula: a rare presentation.

Diverticular disease affects more than 50% of the population over the age of 60 years in the west and becomes even more common as the population ages. Diverticulitis is one of the complications of diverticular disease and can culminate into colonic perforation. Though perforated diverticular disease is not uncommon, synchronous colonic perforations in diverticulitis is rare. Our patient was admitted with acute abdomen and exploratory laparotomy revealed two side-by-side perforations of the sigmoid colon. A Hartmann's procedure was performed. Macro- and microscopic evaluation confirmed the presence of two perforated sigmoid diverticula due to diverticulitis. Simultaneous perforation of two abreast sigmoid diverticula is uncommon; thus, a cautious surgeon should always take into account such a probable diagnosis.

Gallbladder perforation in a patient on steroid therapy.

Gallbladder perforation is a serious clinical condition. A definitive diagnosis is contentious before surgery. We discuss a case where a young patient with Crohn's disease taking oral steroids presented with an acute abdomen. CT scan demonstrated a perforated gallbladder without evidence of gallstones. The patient underwent an emergency cholecystectomy and peritoneal lavage. The history and clinical findings of this patient are reviewed to highlight perforation of the gallbladder in relation to steroid therapy.

Diverticular abscess presenting as a strangulated inguinal hernia: case report and review of the literature.

Potentially life threatening diseases can mimic a groin hernia. We present an unusual case of diverticulitis with perforation and a resulting abscess presenting as a strangulated inguinal hernia. The features demonstrated were not due to strangulation of the contents of the hernia but rather pus tracking into the hernia sac from the peritoneal cavity. The patient underwent sigmoid resection and drainage of retroperitoneal and pericolonic abscesses. Radiological and laboratory studies augment in reaching a diagnosis. The differential diagnosis of inguinal swellings is discussed.

Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.

1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction.

A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.

Synthesis and evaluation of 3-aryl piperidine analogs as potent and efficacious dopamine D4 receptor agonists.

A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.

Synthesis and functional activity of (2-aryl-1-piperazinyl)-N-(3-methylphenyl)acetamides: selective dopamine D4 receptor agonists.

Diaryl piperazine acetamides were identified as potent and selective dopamine D(4) receptor agonists. Our strategy is based on an amide bond reversal of an acid sensitive, dopamine D(4) receptor partial agonist, PD 168077. This reversal provided compounds with excellent potency and improved stability. Systematic evaluation of the substitution on the aryl piperazine portion revealed a significant effect on functional activity. The synthesis and biological activity of these new dopamine D(4) agonists is discussed.