Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 (n = 8), control; group 2 (n = 8), control plus placebo; group 3 (n = 8), control plus r-Hu-EPO; group 4 (n = 8), SAH; group 5 (n = 8), SAH plus placebo; group 6 (n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations (P < 0.001), and reduced vasoconstriction of the basilar artery (P < 0.05), ischemic neuronal damage (P < 0.001), and subsequent neurological deterioration (P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.     

Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage?

OBJECT: Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH. METHODS: Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001). CONCLUSIONS: The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.     

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT‐P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT‐P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX‐double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single‐switched from originator IFX to CT‐P13 was performed, before and after an inverse probability of treatment weighting (IPTW)‐based propensity score analysis. Fifty‐two double‐switched patients with IBD were enrolled. The 24‐ and 52‐week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%–100%) and 90% (95% CI 81%–99%), respectively. Four patients experienced a total of five AEs, all graded 1–3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24‐week and follow‐up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double‐switch group with a single‐switch group of 66 patients with IBD; all these results were confirmed by IPTW‐adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT‐P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Biosimilars reduce the direct costs of therapy and facilitate access to high‐cost therapies to patients. Data show that switching from originator infliximab to infliximab biosimilars (CT‐P13 or SB2) is safe and effective. Few data are available on the outcomes of double switch (from biological originator to a first biosimilar and then to a second biosimilar), and caution has been expressed by the European Crohn’s and Colitis Organization (ECCO) and the Italian Group for the study of inflammatory bowel disease (IBD; IG‐IBD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study was aimed to compare the effectiveness and safety of single and double switch of infliximab (IFX) in patients with IBDs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

No differences were found in clinical response and remission as well as adverse events between either single or double IFX switch. Data were consistent with the safety profile of IFX.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Double switch strategy is safe and effective in IBD. These data assume high relevance in terms of cost‐savings strategies.     

Dyspnea following thoracostomy closure after right pneumonectomy: An uncommon echocardiographic diagnosis and therapeutic approach

Dyspnea and hypoxemia are common postoperative problems after pneumonectomy. One of the rarer causes of respiratory distress after right pneumonectomy is the development of a significant right‐to‐left shunt across a patent foramen ovale (PFO), which can evolve at a variable interval of time after the operation. We report here our experience with a patient who underwent right pneumonectomy, followed by several complications, and who presented severe dyspnea 7 months later, after the closure of a right thoracostomy. This report outlines the management of this challenging clinical condition; transesophageal echocardiography (TOE) provided a clear diagnosis and guided an effective percutaneous treatment.     

A new integrative conjugative element detected in Haitian isolates of Vibrio cholerae non-O1/non-O139

The presence of SXT/R391-related integrating conjugative elements (ICEs) in Vibrio cholerae O1 and non-O1/non-O139 isolated from clinical and environmental samples in Haiti in 2010 was studied. The main finding of this work was the identification of the novel ICEVchHai2 among closely related V. cholerae non-O1/non-O139 clinical strains. The mosaic structure of this element confirms the role of ICEs as efficient recombination systems whereby new genetic material can be acquired and exchanged, according V. cholerae strains new accessory functions.     

Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

MRI in Crohn's disease--current and future clinical applications

Crohn's disease is a chronic, disabling disease that, over time, can lead to irreversible bowel damage. MRI can be used to diagnose and assess the activity, severity and complications of Crohn's disease; however, the role of MRI in therapeutic monitoring of changes in disease-related intestinal damage is still to be defined. Objective, validated MRI-based scores have been developed to assess the activity of Crohn's disease; these indices are based on the extent and severity of intestinal inflammation, postoperative recurrence and perianal disease. MRI is accurate, safe, reproducible and can allow repeated evaluations of patients without radiation exposure. Evidence that MRI might be valuable in the therapeutic monitoring of patients with Crohn's disease is increasing and, in combination with endoscopy and surgical history, this imaging technique could enable clinicians to assess Crohn's-disease-related intestinal damage. MRI could, therefore, have a crucial role in a future 'damage-driven' treatment paradigm--in which imaging is used to monitor intestinal damage and medication use is targeted to prevent the accumulation of further damage. This damage-driven therapeutic approach could potentially change the course of Crohn's disease.     

Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials

Introduction: A new pharmacological class, Janus kinases (JAK) inhibitors, has been shown to be effective and safe for the treatment of inflammatory bowel diseases (IBDs). The aim of this review is to provide an overview of the JAK inhibitors currently under investigation in phase I and II clinical trials for patients with Crohn’s disease and ulcerative colitis and the possible future perspectives for the treatment of IBD patients with this class of drugs.

Areas covered: This review describes the JAK–STAT pathway and analyzes the efficacy and safety of new small molecules such as filgotinib, upadacitinib, TD-1473, peficitinib, and Pf-06651600/Pf-06700841, showing data from phase I and II trials.

Expert Opinion: JAK inhibitors, if approved by the regulatory authorities, could represent a novel and intriguing drug class. In the next years, the approach to patients with IBD will become increasingly personalized.