NSAIDS: Design and Development of Innovative Oral Delivery Systems

Recently, different technologies have been used to transform active pharmaceutical ingredients (APIs) into new dosage forms. Engineered drug delivery systems may modify biopharmaceutical properties of the API achieving either immediate or delayed release according to specific therapeutic needs. Particularly, preprogrammed release of oral formulations delivering the drug at expected times may be useful in chronotherapy of early morning pathologies. The conventional approach when dealing with such diseases is to administer NSAIDs two to three times daily. This approach does not allow to fit drug release with symptoms onset resulting in inefficient therapy and poor patient compliance. NSAIDs may be very effective if administered at least 4–6 h before the pain reaches its peak in the early morning. The solution could be to design delayed drug delivery systems allowing one administration before going to sleep acting in the early morning. This chapter highlights new approaches in developing controlled delivery systems of NSAIDs potentially useful to treat both acute and chronic inflammation. The chapter illustrates the versatility of laminar jet break‐up technology (prilling) to produce gel beads able to control rate and time of drug delivery. A special focus will be on particle‐engineering strategies, i.e., prilling and prilling technique in tandem with microwave or supercritical fluid‐assisted drying

Prognostic value of diabetes and metformin use in a real-life population of head and neck cancer patients

Introduction: Head and neck carcinoma (HNC) is a disease with a poor prognosis despite currently available treatments. The management of patients with this tumor is often complicated by several comorbidities. Among these, diabetes is the second most frequent and its influence on the prognosis is not known.Methods: In this work, we collected data on progression free survival (PFS) and overall survival (OS) of one hundred twenty-three patients with HNC who received biweekly cetuximab maintenance treatment after first-line chemotherapy. We then compared the survival of nondiabetic patients versus diabetics' one.Results: Surprisingly, both PFS (4 vs. 5 months, HR 2.297, p < 0.0001) and OS (7 vs. 10 months, HR 3.138, p < 0.0001) were in favor of diabetic patients, even after excluding other clinical confounding factors. In addition, we also studied survivals in patients taking metformin, a widely used oral antidiabetic drug that has demonstrated antitumor efficacy in some cancers. Indeed, diabetic patients taking metformin had better PFS and OS than those not taking it, 7 vs. 5 months (HR 0.56, p = 0.0187) and 11 vs. 8.5 months (HR 0.53, p = 0.017), respectively.Discussion: In conclusion, real-world outcomes of biweekly cetuximab maintenance remain comparable to clinical trials. The prognostic role of diabetes and metformin was confirmed to be significant in our series, but further prospective studies are needed for a definitive evaluation

On the detectability of gravitational waves background produced by gamma ray bursts

In this paper we discuss a new strategy for the detection of gravitational radiation likely emitted by cosmological gamma ray burst. Robust and conservative estimates lead to the conclusion that the uncorrelated superimposition of bursts of gravitational waves can be detected by interferometric detectors like VIRGO or LIGO. The expected signal is predicted to carry two very distinctive signatures: the cosmological dipole anisotropy and a characteristic time scale in the auto correlation spectrum, which might be exploited, perhaps with ad hoc modifications and/or upgrading of the planned experiments, to confirm the non-instrumental origin of the signal.Comment: 9 pages, 2 figures, LATEX2e, Accepted for pubblications as a Letter to the Editor in Journal of Physics G: Nuclear and Particle Physic

Increased carotid intima-media thickness and stiffness in obese children

Summary (Abstract not available):Obesity in childhood increases the risk of atherosclerotic disease and death in adulthood. We studied 100 children with obesity and 47 healthy age-mathced control subjects, mean age 10 years of both groups. Biochemical parameters describing lipoprotein and glucose metabolism were measured. Quantitative B-mode ultrasound examination of common carotid arteries was performed. Carotid thickness and stiffness were significantly increased in obese children as compared to nonobese ones, independently of traditional cardiovascular risk factors. Obesity should be regarded as a disease with vascular implications even in young age

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

Càncer colorectal metastàtic; Oxaliplatina; Trifluridina/TipiracilCáncer colorrectal metastásico; Oxaliplatino; Trifluridina/TipiracilMetastatic colorectal cancer; Oxaliplatin; Trifluridine/tipiracilBackground In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.The study was funded jointly by Servier, France and Taiho Pharmaceutical, Japan

Direct peroral cholangioscopy in the management of difficult biliary stones: a new tool to confirm common bile duct clearance. Results of a preliminary study

Background and aims: Endoscopic sphincterotomy (ES) with stone extraction is the standard treatment for choledocholithiasis. After stone retrieval, balloon-occluded cholangiography is generally performed to confirm bile duct clearance but can miss residual stones particularly in patients with residual small-sized stones, a large bile duct or pneumobilia. In addition, difficult common bile duct (CBD) stones requiring advanced endoscopic techniques for retrieval are a potential risk factor for choledocholithiasis recurrence. Methods: We performed a retrospective evaluation of a prospectively maintained procedures database. From July 2016 to December 2017, all patients with difficult CBD stones who underwent endoscopic retrograde cholangiopancreatography (ERCP) with papillary balloon dilation-assisted stone retrieval and subsequent direct per-oral cholangioscopy (DPOC) using standard gastroscopes to confirm CBD clearance were analyzed. Results: Thirty-six patients who underwent ERCP and DPOC were included. Technical success, defined as deep intubation of CBD with hepatic hilum visualization, was achieved in 31 of 36 patients (86%). During DPOC, residual CBD stones were visualized and removed in 7 of 31 patients (22.5%). After a mean of 241 +/- 56 days of follow-up post-DPOC, no serious adverse events were reported, and there was no evidence or suspicion of recurrent choledocholithiasis. Conclusions: Direct per-oral cholangioscopy immediately following difficult CBD stone removal was safe, feasible and accurate. In this setting, DPOC at the time of ERCP appears to be a very useful tool to achieve complete clearance of choledocholithiasis.info:eu-repo/semantics/publishedVersio

Endoscopic Ultrasound Guided Biliary Drainage in Malignant Distal Biliary Obstruction

Malignant biliary obstruction (MBO) is a challenging medical problem that often negatively impacts the patient’s quality of life (QoL), postoperative complications, and survival rates. Endoscopic approaches to biliary drainage are generally performed by ERCP or, in selected cases, with a percutaneous transhepatic biliary drainage (PTBD). Recent advances in therapeutic endoscopic ultrasound (EUS) allow drainage where previous methods have failed. EUS has evolved from a purely diagnostic technique to one that allows a therapeutic approach in the event of ERCP failure in distal MBO. Moreover, the introduction of dedicated accessories and prostheses for EUS-guided transmural biliary drainage (EUS-BD) made these procedures more successful with regard to technical success, clinical outcomes and reduction of adverse events (AEs). Finally, lumen-apposing metal stents (LAMS) have improved the therapeutic role of the EUS. Subsequently, the electrocautery enhanced tip of the LAMS (EC-LAMS) allows a direct access of the delivery system to the target lumen, thereby simplifying and reducing the EUS-BD procedure time. EUS-BD using LAMS and EC-LAMS has proven effective and safe with a low rate of AEs. This review aims to evaluate biliary drainage techniques in malignant obstruction, focusing on the role of EUS biliary drainage by LAMS