Metformin therapy in patients with chronic kidney disease

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open‐label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.     

Care of the critically ill patient in a military unique environment: a program of research

The goal of the Air Force Nursing Research Program at WHMC is to conduct research on topics unique to Air Force and military nursing. The nine stressors of flight and the military environment of care have been used as a conceptual model to guide the development of research studies. The studies conducted to date describe how the environment affects practice and when the environment directly affects the patient. The studies conducted are examples of the numerous military nursing research projects supported by funding from the TSNRP. The research funded by TSNRP contributes to the body of nursing knowledge by supporting scientific research, particularly knowledge that is unique to the military. As our nation faces the threat of chemical and biologic attacks, terrorism, and increased deployment of soldiers to battlefields in remote locations throughout the world, it is more important than ever that we ensure the advancement of military nursing research. Supporting research that advances healthcare in peace and in war is critical to the care of our military members and their families. This will require that research funds continue to be available to support military nursing research, that a strong infrastructure to provide resources in support of nursing research programs continues to exist, and that the military nursing corps continues to attract, train, and retain PhD prepared nurse researchers. Given the results of the research completed to date, the following evidence-based practice can be applied to the care of the patient described at the beginning of this article: The nurse positions the patient in the center of the cargo compartment, away from the bulkhead, toward the front of the aircraft, the warmest location during flight. While enroute, the patient will need to be positioned on an aerovac mattress, repositioned frequently, and have his/her heels elevated at all times. Additional padding may be needed for areas adjacent to the litter cross members to reduce pressure on the skin in areas prone to pressure ulcer formation. Should the patient need endotracheal suctioning, the nurse knows that hyperoxygenation-hyperinflation is effective in preventing suctioning-induced hypoxemia. In addition, the suction pressure will need to be increased to account for the effects of altitude without exceeding the pressure limits on the transport ventilator and causing catastrophic ventilator failure. Because there is not enough room on the litter for the chest tube drainage tubing to lay straight, it will be coiled and should dependent loops develop, they should be drained every 15 minutes. This is Air Force nursing research in practice.     

Enhanced selective cellular uptake and cytotoxicity of epidermal growth factor-conjugated liposomes containing curcumin on EGFR-overexpressed pancreatic cancer cells

Pancreatic cancer is one of the most malignant cancers with a high mortality rate. Some types of pancreatic cancer cells overexpress epidermal growth factor receptor (EGFR), which is a potential target for anticancer agents. In this study, we examined the effect of epidermal growth factor (EGF)-conjugated liposomes containing curcumin (EGF-LP-Cur) on three different EGFR-expressed human pancreatic cancer cell lines, BxPC-3, Panc-1 and Mia Paca-2. We have demonstrated that it is feasible to prepare liposomal vesicles of EGF-LP-Cur and that it is stable in the liquid vehicle at ambient conditions for three weeks. In addition, the formulation of curcumin had higher cytotoxicity on BxPC-3 than on any other cells. It is also shown that the cellular uptake of curcumin on BxPC-3, which is essential for the cytotoxicity, is associated with EGFR-mediated mechanism of action. In summary, our results have showed that targeting EGFR with EGF-conjugated curcumin liposomes enhanced the antitumor activity of curcumin against human pancreatic cancer cells.     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Inhibition of Cathepsin K Increases Modeling‐Based Bone Formation,and Improves Cortical Dimension and Strength in Adult Ovariectomized Monkeys

Treatment with the cathepsin K (CatK) inhibitor odanacatib (ODN) protects against bone loss and maintains normal biomechanical properties in the spine and hip of ovariectomized (OVX) preclinical models. Here, we characterized the effects of ODN on the dynamics of cortical modeling and remodeling, and dimension and strength of the central femur in adult OVX‐rhesus monkeys. Animals were treated with vehicle or ODN (6 or 30 mg/kg, once per day [q.d., p.o.]) in prevention mode for 21 months. Calcein and tetracycline double‐labeling were given at 12 and 21 months, and the femoral cross‐sections were subjected to dynamic histomorphometric and cement line analyses. ODN treatment significantly increased periosteal and endocortical bone formation (BFR/BS), accompanied with an increase in endocortical mineralizing surface (102%, p < 0.01) with the 6 mg/kg dose. ODN at both doses reduced remodeling hemiosteon numbers by 51% and 66% (p < 0.05), respectively, and ODN 30 mg/kg numerically reduced activation frequency without affecting wall thickness. On the same endocortical surface, ODN increased all modeling‐based parameters, while reducing intracortical remodeling, consistent with the observed no treatment effects on cortical porosity. ODN 30 mg/kg markedly increased cortical thickness (CtTh, p < 0.001) and reduced marrow area (p < 0.01). Lastly, ODN treatment increased femoral structural strength (p < 0.001). Peak load was positively correlated with the increases in bone mineral content (BMC) (r² = 0.9057, p < 0.0001) and CtTh (r² = 0.6866, p < 0.0001). Taken together, by reducing cortical remodeling‐based and stimulating modeling‐based bone formation, ODN significantly improved cortical dimension and strength in OVX monkeys. This novel mechanism of CatK inhibition in stimulating cortical formation suggests that ODN represents a novel therapeutic approach for the treatment of osteoporosis. © 2014 American Society for Bone and Mineral Research.