Obturator hernia is a rare type of hernia, but it is a significant cause of intestinal obstruction due to the associated anatomy. Correct diagnosis and treatment of obturator hernia is important, be cause delay can lead to high mortality. Twelve patients with obturator hernia were managed during a 11-year period, including 11 women and 1 man with a mean age of 82 years. We compared our expe rience with the previously published data to establish standards for the diagnosis and treatment of this hernia. All 12 patients presented with intestinal obstruction. The median interval from admission to operation was 2 days. The Howship-Romberg sign was positive in 5 patients. A correct diagnosis was made in all 8 patients who underwent pelvic CT scanning. Surgery was performed via an abdominal approach (n=7) or an inguinal approach (n=5). The hernial orifice was closed using the uterine fundus (n=6), a patch (n=5), and direct suture (n=1). Mean follow-up time was 33 months, and no recurrence has been detected. The poor physical condition of patients might have led to a delay in di agnosis and treatment. In troubled patients with nonspecific intestinal obstruction, CT scanning is useful for the early diagnosis of obturator hernia. Correct CT diagnosis of obturator hernia allows us to select the inguinal approach combined with patch repair, which is minimally invasive surgery.
We have previously shown that the
oral administration of the small
molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity
in thyroparathyroidectomized rats. However, 1 was converted
to a reactive metabolite in a human liver microsome assay. In this
article, we report on the modification path that led to an enhancement
of PTHR1 agonistic activity and reduction in the formation of a reactive
metabolite to result in a potent, selective, and orally active PTHR1
agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione
(PCO371, 16c). This compound is currently being evaluated
in a phase 1 clinical study for the treatment of hypoparathyroidism.
During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC of 3.0 μM and EC of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.
The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.
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