Naldemedine. A new option for OIBD

Opioid-induced bowel dysfunction (OIBD) is a common complication in long-term opioid users and abusers. It is a burdensome condition, which significantly limits quality of life and is associated with increasing health costs. OIBD affects up to 60% of patients with chronic non-cancer pain and over 80% of patients suffering from cancer pain and is one of the conditions of the most common symptoms associated with opioid main-tenance. Given the continued use of opioids for chronic pain management in appropriate patients, OIBD is likely to persist in clinical practice in the coming years. We will herein review its underlying pathophysiological mechanisms and the available treatments. In the last years, pharmaceutical research has focused on the opportunity of targeting peripheral mu-opioid receptors without affecting their analgesic activity in the central nervous system, and several peripherally acting mu-opioid receptors antagonists (PAMORAs) drugs have been approved. We will mainly focus on naldemedine, discussing its pharmacological properties, its clinical efficacy and side effects. Head-to-head comparisons between naldemedine and the other PAMORAs are not available yet, but some considerations will be discussed based on the pharmacological and clinical data. As a whole, the available data suggest that naldeme-dine is a valid treatment option for OIBD, as it is a well-tolerated drug that alleviates constipation without affecting analgesia or causing symptoms of opioid withdrawal

Genetic lesions disrupting calreticulin 3′-untranslated region in JAK2 mutation-negative polycythemia vera

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The effect of opiates on bone formation and bone healing

Purpose of Review: Opioids have been shown to be associated with an increased risk of fracture. The purpose of this paper is to review recent research into the effects of opioids on bone formation and bone healing in animal models and in human studies. Recent Findings: Most opioids, such as morphine and fentanyl, negatively affected bone remodeling and bone healing in animal models. Conversely, remifentanil has been recently shown to promote in vitro osteoblast differentiation and to inhibit differentiation and maturation of osteoclasts, therefore reducing bone resorption. According to the possible negative role of opioids in bone healing, opioid antagonists have been shown to enhance bone mineralization, suggesting a possible therapeutic role in the future for osteoporosis. Other neuropeptides, such as the vasoactive intestinal peptide (VIP) and the neuropeptide Y (NPY), have been proved to promote osteogenesis. The increased risk of fractures among opioid users may be related to their central nervous system side effects or to the reduced bone density, partly due to their endocrine effects, and partly to their direct activity on bone cells. Clinical data strongly suggested a potential negative effect of opioids in bone healing. The risk of nonunion fracture is significantly increased in opioid users, and bone mass density was reduced in patients under long-term opioid treatment. Summary: The direct effects of opioids on bone remodeling appears evident from these reports. Not all opioids have the same potential for negatively impacting bone healing. Opioid antagonists may increase bone density and could represent a possible future treatment for low bone mass density pathologies. However, further trials are warranted to clarify the clinical relevance of these emerging findings from animal studies

Overview of T-cell depletion in haploidentical stem cell transplantation

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Transplantation in the onco-hematology field: Focus on the manipulation of αβ and γδ T cells

γ/δ T cells represent a subset of T cells expressing a T cell receptor (TCR) variant composed of gamma and delta chains. The γ/δ TCR is expressed by 2-10% of all T cells in human peripheral blood, whereas the majority of T cells express α/β TCRs. γ/δ T cells display a range of innate effector functions including rapid secretion of chemokines and cytokines, as well as target cell lysis. Recent interest has focused on the function of γ/δ T lymphocytes in allogeneic transplantation in the onco-hematology field. Several studies, in vitro and in vivo, suggest that γ/δ T lymphocytes are potential beneficial effector cells in the context of hematopoietic stem cell transplantation (HSCT). In addition, in this review, we discuss the depletion of α/β T lymphocytes in the graft for allogeneic transplantation. In fact, an efficient TCR α/β cell depletion potentially reduces the risk of GvHD. Furthermore, TCR α/β T cell depletion, especially with immunomagnetic negative selection, retains other potential beneficial effector cells in the graft, such as γ/δ T cells, NK cells, and stem cells. These "facilitating" cells might facilitate engraftment, exert GvL effects, and reduce the risk for infections

T(reg) cells: collection, processing, storage and clinical use

T regulatory cells are fundamental in the maintenance of immune homeostasis and self-tolerance. Experimental models suggest the existence of two functional types of T(reg) cells designated naturally occurring and induced. Interest in T(reg) cells increased with evidence from experimental mouse and human models demonstrating that the immunosuppressive potential of these cells can be utilized in the treatment of various pathological conditions. The existence of a subpopulation of suppressive T cells was the subject of significant controversy among immunologists for many years. T regulatory cells limit immune activation through a variety of direct and indirect interactions, many of which are yet to be determined. Fully understanding T(reg) cells biology will lead us to harnessing the capacity of these cells in order to develop strategies to prevent autoimmune disorders and tolerance to transplantation. Efficient isolation, expansion and cryopreservation strategies that comply with Good Manufacturing Practice (GMP) guidelines are prerequisites for the clinical application of human CD4+ CD25+ CD127(low) FOXP3+ regulatory T cells

Postoperative opioid consumption after orthopedic surgery using sublingual patient controlled analgesia. Effects of different anesthetic techniques

Background and Aims: Acute postoperative pain after total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been reported as moderateto- severe. Aim of this study was to evaluate the effects of different anesthetic techniques on post-operative analgesic opioid consumption in patients who underwent THA and TKA and received Sufentanil Sublingual Tablet System Zalviso® (SSTS) for post-operative pain. Methods: Adults aged ≥18years, who had undergone THA and TKA, received SSTS for the first 72 hours after surgery. Patients were grouped according to the kind of surgery and the type of anesthesia. THAwas performed under spinal anesthesia (SA) or general balanced anesthesia (GA). TKA was conducted under SA or single-shot peripheral nerve block (PNB). Data were collected at baseline (T0) and from day 1-3 after surgery. Results: Twenty-eight patients were included after THA (n=17; 60.7%) and TKA (n=11; 39.3%). 3 patients prematurely interrupted treatment. In THA, SA and GA were associated with a similar postoperative opioid consumption, 25.3 vs 22.5 doses respectively. Similarly, in TKA, no differenceswere observed in total opioid consumption in patients undergoing PNBs and SA, which resulted in 32.5 vs 30 doses, respectively (Figure 1). Timing for the first SSTS dose was similar in patients undergoing SA (75.9 vs 74 min, in THA and TKA respectively). Conversely, it was significantly shortened by GA in THA (27.5 min) and delayed in PNB in TKA (216.7 min)

Patients' perspective in postoperative pain management: role of sufentanil sublingual tablet system in major orthopedic surgery

Background and Aims: Inadequate post-operative pain management is one of the most common complain after major orthopedic surgery. Limits of iv- PCA have been identified in programming and patients' errors, invasive access, and impairment of mobility. The aim of this study was to evaluate patient' perspective into sufentanil sublingual tablet system Zalviso®(SSTS) evaluation for post-operative pain management after orthopedic surgery. Methods: Adults, who had undergone major orthopedic surgery, with expected postoperative pain ≥4 on a 11-point numeric rating scale, received SSTS 15mcg, with a 20-minute lockout interval, as requested for pain, over the 72-hour study period. Datawere collected at baseline (T0) and 3, 6, 12, 24, 36, 48, 60, 72 hours after surgery. The primary endpoint was the Patient Global Assessment (PGA) on a 5-point categorical scale. Secondary endpointswere analgesic efficacy, need for supplemental rescue doses, and sleep pain interference. Results: 36 patientswere enrolled. 97.2%of patients evaluated the treatment as excellent or very good on PGA. No patients discontinued due to inadequate analgesia or adverse events. Required SSTS doses ranged from 5 to 48 in 72 hours. SSTS doses were significantly higher in TKA (29.8), compared with THA (22). Mean required SSTS doses in different surgeries are shown in Figure 1. Rescue doses were needed in 5.5% of SSTS patients. Quality of sleep was good or very good in 86.1% of patients on the same day of surgery. Conclusions: SSTS was well accepted by patients undergoing major orthopedic surgery and resulted in effective management of moderate-to-severe acute postoperative pain