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A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells. After two or three rounds of selection, 7.5% of randomly picked clones were GLP1R/GCGR co-agonists, and a further 1.53% were agonists of a single receptor. The phages were sequenced and 35 corresponding peptides were synthesized. 18 peptides were potent co-agonists, 8 of whom showed EC 50  ≤ 30 pM on each receptor, comparable to the best rationally designed co-agonists reported in the literature. Based on literature examples, two sequences were engineered to stabilize against dipeptidyl peptidase IV cleavage and prolong the in vivo half-life: the engineered peptides were comparably potent to the parent peptides on both receptors, highlighting the potential use of phage-derived peptides as therapeutic agents. The strategy described here appears of general value for the discovery of optimized polypharmacology paradigms across several metabolically-related hormones.

Aim: The increase in the average life led an increase of diseases, acute and chronic, not only cardiovascular and respiratory system, but also gastrointestinal. Likewise we see an increase in neoplastic lesions, sometimes diagnosed in advanced stage of disease, not susceptible to radical therapy. The purpose of this work is to evaluate the usefulness, reliability and security of colonoscopy in elderly patients, age 75 years or more. MATHERIALS END METHODS: We analysed 2407 colonoscopies, performed from January 2005 to December 2006 in Unit of Digestive Endoscopy of Gastrointestinal Surgery ("Federico II" University of Naples) and in Unit of Digestive Endoscopy of "Villa Maria Clinica" (Mirabella Eclano). Of these four hundred and sixty-nine patients (19.5%), 276 men and 139 women, were 75-years-old or more. Were considered indications to endoscopy completeness of the examination, findings, presence of any complications. In all patients were performed premedication with midazolam, 2,5-5 mg and floroglucina biidrata, 40-80 mg. The patients were constantly monitored with pulsiossimetro., Results: The colonoscopy was completed in 432/469 patients (92%). In 19 cases (4%) there was a neoplastic stenosis; other reasons for the failure of cecal intubation were the poor intestinal preparation (2.5%) and intolerance of the patient (1.5%). Were excluded patients in follow-up to previous surgery or polypectomy (33.5%). Other indications in the investigation were, in descending order, abdominal pain (32.8%), presence of anaemia (22.4%), rectal bleeding (19.2%), diarrhea or constipation (18.4%), presence of abdominal mass (72%). There were no complications observed, or local (perforation/bleeding), or general (cardio-respiratory or neurological). Most frequent findings were: diverticoular disease (34.4%), polyps (22.4%), cancer (12.8%), find colitis also aspecific (10.4%), hemorrhoids (8.8%). In 11.2% of patients colonoscopy was negative., Conclusion: The endoscopic examination of the gastrointestinal tract is now practiced daily in almost all hospitals. The advanced age of patient, with the possible presence of diseases associated is not, in our opinion, a controindication. Although present in the literature trials that emphasize the possibility of a higher incidence of complications in elderly patients, our experience shows how this control is quite safe, if executed in appropriate and correct manner, thanks also to appropriate preparation/sedation and monitoring of the patient. Compared to other diagnostic methods, such as air contrast barium enema, the computed tomography and virtual colonoscopy, "traditional" colonoscopy has the undoubted and decisive advantage of being able to run biopsies, and complete removal of the lesion, as in the case of polypectomy. In our case we have seen a high number of elderly patients, well 469/2407, equivalent to 19.5%. A neoplastic lesion was found in 165 patients (35.2%) and of these over 80% has successfully received curative treatment (surgery or polipectomy).