A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

Thin-layer chromatography and mass spectrometry were used to isolate and identify cyclophosphamide metabolites present in blood of mice. Blood was removed 5, 15, 30 and 45 minutes after intraperitoneal administration and extracted with chloroform followed by methanol. Thin-layer chromatography of the two extracts and the residual solid with or without prior methylation, collection of resulting alkylating components, determination of radioactivity and mass spectral analysis, served to identify cyclophosphamide, 4-ketocyclophosphamide, alcophosphamide, N-dechloroethylcyclophosphamide, carboxyphosphamide, phosphoramide mustard and nor-HN2. The absence of detectable levels of 4-hydroxycyclophosphamide or aldophosphamide in the blood of cyclophosphamide-treated mice suggests that cyclophosphamide is converted rapidly in the liver to carboxyphosphamide, 4-ketocyclophosphamide, phosphoramide mustard and nor-HN2. Direct administration of synthetic 4-hydroxycyclophosphamide to mice and extraction of blood with chloroform demonstrated the recovery of this metabolite in vivo. Analysis of extracts of blood from mice treated with phosphoramide mustard indicated the presence of nor-HN2, 3-(2-chloroethyl)-1,3-oxazolidin-2-one and unchanged drug. Consideration of blood levels, cytotoxicity and alkylating activity of metabolites identified, in or inferred from, this study, implicates phosphoramide mustard as a leading condidate for the biologically active form of cyclophosphamide.

All patients greater than 50 years of age (N = 96) admitted with a pre- or postoperative diagnosis of acute appendicitis from 1971 to 1980 were reviewed. A comparative series of 91 patients aged 25 to 50 years was similarly reviewed. Noninflammatory diseases of the appendix and incidental appendectomies were excluded. Detailed study of symptoms, clinical presentation, laboratory evaluation, radiographic evaluation, concomitant diseases, hospital course, surgical findings, complications, and mortality were completed. Comparison of patients aged 25 to 50 to patients older than 50 years revealed a statistically significant increased incidence of perforation in the older group (p less than 0.0001). Sixty-five per cent of the older group showed greater incidence of perforation. Further analysis of this series yields the hypothesis that the increased incidence of perforation is related to a significant decrease in the frequency of classic presentation in the greater-than-50 age group, a significant decrease in frequency of correct admission diagnosis and a significant delay between admission and surgical procedure in the older group. A more rapid pathophysiologic progression of appendicitis with increasing age was noted. A much higher percentage of older patients was undiagnosed until the surgical procedure. In this group, there was a longer duration of symptoms, less frequent classic presentation, and decreased frequency of right lower quadrant guarding and tenderness as compared to patients with correct diagnosis prior to surgery. Complications were much more frequent in older patients and higher still in those with perforation. Analysis of findings by decade of life revealed an anticipated high incidence of perforated appendicitis in patients greater than 50, but also showed a continuation of the high incidence of perforation into the decade 40 to 50. There were three deaths in the entire study group (1.6%) all occurring in the older age group with postoperative sepsis.

Implementation of protocols according to IDSA guidelines may result in cost savings to institutions wishing to reduce the economic burden associated with treating hospitalised patients for CAP.

Background: Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit. Methods: The GLP-1-and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and shamoperated male mice. Results: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. Conclusion: Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R andThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.