Efficacy of methylnaltrexone for the treatment of opiod-induced constipation: a meta-analysis and systematic review

Objective: Constipation is a common adverse effect in patients requiring long-term opioid therapy for pain control. Methylnaltrexone, a quaternary peripheral mu-opioid receptor antagonist, is an effective treatment of opioid induced constipation (OIC) without affecting centrally mediated analgesia. Our objective was to conduct a review and meta-analysis to evaluate the efficacy of methylnaltrexone for treatment of OIC, as well as to provide a clinical discussion regarding newly developed alternatives and provide the current treatment algorithm utilized at our institution.

Methods: We performed a systematic review and meta-analysis of randomized control trials using Cochrane Collaboration Databases and MEDLINE from 2007-present. Literature related to methylnaltrexone, opioids, opioid receptors, opioid antagonists, opioid-induced constipation were reviewed. A meta-analysis was completed with the primary outcome of rescue-free bowel movement (RFBM) within four hours of administration. All pooled analyses were based on random-effects models.

Results: 1239 patients were analyzed; 599 received methylnaltrexone and 640 received placebo. With a 95% CI calculated, the true risk difference is between 0.267 and 0.385, demonstrating a statistically significant difference in RFBM between treatment and placebo groups (p < 0.0001). Both the 0.15 mg/kg, 0.30 mg/kg doses every other day, and 12 mg/day dose were found to have increased risk of RFBM compared to placebo.

Conclusion: Results support the use of methylnaltrexone. Furthermore, the use of methylnaltrexone to induce laxation may decrease use of health care resources, increase work productivity, and improve cost utilization. New treatments have been made available; however, controlled clinical studies are needed to demonstrate long–term efficacy, safety and cost–effectiveness. Possible limitations of this study include the relatively small number of randomized, placebo-controlled trials investigating the efficacy of methylnaltrexone versus placebo. There is also the possibility of publication bias, which may lead to overestimating the efficacy of methylnaltrexone in treating OIC.     

An evidence-based medicine review of lymphadenectomy extent for gastric cancer

Background

Several studies in the literature have investigated the possible role of the extent of lymphadenectomy in gastric cancer treatment failure. The current study attempted to determine the effectiveness and safety of lymphadenectomy with gastrectomy for the treatment of gastric cancer.

Methods

Randomized controlled trials (RCTs) were identified by means of MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and Chinese Biomedical Database, as well as by selecting references from relevant articles.

Results

Overall, 14 RCTs (3,432 patients) were included in the meta-analysis. Of the D1 and D2 surgery groups, the operative mortality and postoperative morbidity were higher in the D2 group than in the D1 group, but the 3- and 5-year survival rates were not statistically different. Also the operative time was shorter in D1 compared to D2. In the D2 versus the D3 surgical group, the operative mortality, percentage of postoperative complications, operative time, and hospital stay were not significantly different.

Conclusions

The results suggest that D2 and D3 surgery may not offer specific advantages for gastric cancer and instead may lead to disadvantages for patient outcomes.     

Control of surface free energy in titanium doped phosphate based glasses by co-doping with zinc

To significantly improve the biocompatibility of titanium doped phosphate based glasses, codoping with zinc has been attempted. This study investigated the effect of doping a quaternary 15Na(2)O:30CaO:5TiO(2):50P(2)O(5) glass with zinc oxide (1, 3, and 5 mol %) on bulk, structural, surface, and biological properties; the results were compared with glasses free from ZnO and/or TiO(2). ZnO as adjunct to TiO(2) was effective in changing density, interchain bond forces, degradation behavior, and ions released from the degrading glasses. Incorporation of both TiO(2) and ZnO in T5Z1, T5Z3, and T5Z5 glasses reduced the level of Zn(2+) release by two to three orders of magnitude compared with glasses containing ZnO only (Z5). (31)P NMR results for T5Z1, T5Z3, and T5Z5 glasses showed the presence of Q(3) species suggesting that the TiO(2) is acting as a network former, and the phosphate network becomes slightly more connected with increasing ZnO incorporation. Regardless of their relative lower hydrophilicity and surface reactivity compared with the control glass free from TiO(2) and ZnO (T0Z0), these glasses have significantly higher surface reactivity compared with Thermanox. This has been also reflected in the maintenance of >98% viable Osteoblasts, proliferation rate, and expression level of osteoblastic marker genes in a comparable manner to Thermanox and T5 glasses, particularly T5Z1 and T5Z3 glasses. However, T0Z0 and Z5 glasses showed significantly reduced viability compared to Thermanox. Therefore, it can be concluded that ZnO doped titanium phosphate glasses, T5Z1 and T5Z3 in particular, can be promising substrates for bone tissue engineering applications.     

Relationships among severity of osteonecrosis, pain, range of motion, and functional mobility in children, adolescents, and young adults with acute lymphoblastic leukemia

BACKGROUND AND PURPOSE: Up to 38% of children receiving treatment for acute lymphoblastic leukemia (ALL) develop osteonecrosis, often without symptoms. Little is known about the association between the degree of osteonecrosis and functional mobility in this population. The purpose of this study was to examine relationships among the degree of osteonecrosis, pain, range of motion (ROM), and functional mobility in people with ALL. SUBJECTS: Thirty-three subjects aged 5 to 27 years with ALL and osteonecrosis participated. METHODS: The extent of osteonecrosis was determined by magnetic resonance imaging (MRI) of the hip and knee according to 2 classification systems, including the Association Research Circulation Osseous (ARCO) and a knee staging scale. Pain, hip and knee ROM, and the Timed Up and Down Stairs (TUDS) Test were used as measures. RESULTS: Correlations were observed between ARCO and hip pain (r=.34), between hip flexion ROM and hip pain (r=-.34), and between knee pain and time on the TUDS Test (r=-.35). DISCUSSION AND CONCLUSION: Physical therapists should consider that people with ALL may have hip or knee osteonecrosis without clinical symptoms. This notion supports the need for MRI in addition to a comprehensive examination of functional mobility.     

ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonists

Interaction between von Willebrand factor (VWF) and platelet GP Ib-IX-V is required for hemostasis, in part because intracellular signals from VWF/GP Ib-IX-V activate the ligand-binding function of integrin alphaIIbbeta3. Because they also induce tyrosine phosphorylation of the ADAP adapter, we investigated ADAP's role in GP Ib-IX-V signal transduction. Fibrinogen or ligand-mimetic POW-2 Fab binding to alphaIIbbeta3 was stimulated by adhesion of ADAP+/+ murine platelets to dimeric VWF A1A2 but was significantly reduced in ADAP-/- platelets (P<.01). alphaIIbbeta3 activation by ADP or a Par4 thrombin receptor agonist was also decreased in ADAP-/- platelets. ADAP stabilized the expression of another adapter, SKAP-HOM, via interaction with the latter's SH3 domain. However, no abnormalities in alphaIIbbeta3 activation were observed in SKAP-HOM-/- platelets, which express normal ADAP levels, further implicating ADAP as a modulator of alphaIIbbeta3 function. Under shear flow conditions over a combined surface of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and alphaIIbbeta3, respectively, ADAP-/- platelets displayed reduced alphaIIbbeta3-dependent stable adhesion. Furthermore, ADAP-/- mice demonstrated increased rebleeding from tail wounds. These studies establish ADAP as a component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to alphaIIbbeta3 activation.