Evaluation of Digoxin Concentration After Loading Dose in Patients With Renal Dysfunction.

Evaluation of digoxin concentration after loading dose in patients with renal dysfunction.

Can J Hosp Pharm. 2013 Mar; 66(2): 104-9
Pawlosky N, Macdonald E, Patel R, Kanji S

Loading dose recommendations for digoxin are based on the volume of distribution, which is proportional to lean body weight, whereas maintenance dose recommendations depend on renal function. The volume of distribution of this drug is demonstrably reduced in severe renal dysfunction, but the threshold at which a reduction in loading dose is warranted remains unknown.To describe the practice of digoxin loading at The Ottawa Hospital and to determine the proportion of patients, categorized by degree of renal function, who experienced digoxin toxicity after a loading dose.Data were collected retrospectively from charts of patients who had received a digoxin loading dose between May 2008 and January 2012, with a blood sample drawn for determination of digoxin concentration 6 to 24 h later. Patients were categorized into 4 groups according to creatinine clearance.The mean loading dose of digoxin (± standard deviation) was 9.8 ± 4.1 ?g/kg among patients with creatinine clearance below 15 mL/min, 14.4 ± 5.4 ?g/kg for those with creatinine clearance between 15 and 29 mL/min, 16.0 ± 5.6 ?g/kg for those with creatinine clearance between 30 and 59 mL/min, and 14.0 ± 3.7 ?g/kg for those with creatinine clearance 60 mL/min or above. Degree of renal dysfunction, particularly creatinine clearance below 60 mL/min, predicted the likelihood of experiencing a toxic serum concentration of digoxin after the loading dose, after adjustment for dose and weight (odds ratio 2.60, 95% confidence interval 1.55-4.39).Patients with creatinine clearance below 60 mL/min were more likely than those with creatinine clearance of 60 mL/min or greater to experience toxic serum digoxin concentrations with current loading dose strategies. It is recommended that loading doses be reduced (to 6-10 ?g/kg) for these patients. Prospective trials are required to determine the clinical implications of these findings and to determine if greater reductions in loading dose are required for patients with severe renal dysfunction (i.e., creatinine clearance below 30 mL/min). HubMed – drug

IL-17-mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-related Osteonecrosis of the Jaws.

Clin Cancer Res. 2013 Apr 24;
Zhang Q, Atsuta I, Liu S, Chen C, Shi S, Shi S, Le AD

PURPOSE: Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of IL-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). EXPERIMENTAL DESIGN: The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma (MM)-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease. RESULTS: Increased Th17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, Laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-gamma-induced M1 polarization through augmenting STAT-1 phosphorylation while suppressed IL-4-mediated M2 conversion via inhibiting STAT-6 activation. CONCLUSIONS: These findings have established a compelling linkage between activated IL-17-mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models. HubMed – drug

Blinding the Monocytes to Protect the Heart.

Circulation. 2013 Apr 24;
Charo IF

Despite the impressive success of HMG-CoA reductase inhibitors (statins) in lowering cholesterol levels, atherosclerotic heart disease remains the leading cause of death in the Western world. Although a central role for cholesterol, particularly LDL-cholesterol in atherogenesis is undisputed, other contributing factors likely include diabetes mellitus, triglycerides, oxidation of proteins and/or lipids, and immune responses to self or bacterial antigens. Whatever the precise agents, an expanding body of evidence strongly implicates inflammation as a final common pathway leading to formation of unstable atherosclerotic plaques, plaque rupture, and acute myocardial infarction(1,2). Consistent with the hypothesis that inflammation plays an important role in plaque instability, a large prospective clinical trial found that elevated levels of hsCRP were a strong predictor of future major cardiovascular events, even in patients who met current American Heart Association guidelines for LDL-cholesterol levels(3). Clinical trials are now testing the hypothesis that potent anti-inflammatory drugs, such as methotrexate(4) or IL-1b(5), can reduce the risk of major cardiovascular events in patients who have suffered myocardial infarctions. Ideally, however, one would prefer a drug that more specifically targets vascular inflammation. In this regard, biological insights into the pathogenesis of atherosclerosis have focused attention on circulating blood monocytes. HubMed – drug

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells.

J Nucl Med. 2013 Apr 24;
Rae C, Tesson M, Babich JW, Boyd M, Sorensen A, Mairs RJ

Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the antitumor efficacy of external-beam ?-irradiation and (131)I-metaiodobenzylguanidine ((131)I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. METHODS: The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The synergistic interaction between disulfiram and radiotherapy was evaluated by combination-index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice. RESULTS: Escalating the disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 ?M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 ?M was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of (131)I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. CONCLUSION: The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of (131)I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy. HubMed – drug

The Growing Impact of Bioorthogonal Click Chemistry on the Development of Radiopharmaceuticals.

J Nucl Med. 2013 Apr 24;
Zeng D, Zeglis BM, Lewis JS, Anderson CJ

Click chemistry has become a ubiquitous chemical tool with applications in nearly all areas of modern chemistry, including drug discovery, bioconjugation, and nanoscience. Radiochemistry is no exception, as the canonical Cu(I)-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, inverse electron demand Diels-Alder reaction, and other types of bioorthogonal click ligations have had a significant impact on the synthesis and development of radiopharmaceuticals. This review will focus on recent applications of click chemistry ligations in the preparation of imaging agents for SPECT and PET, including small molecules, peptides, and proteins labeled with radionuclides such as (18)F, (64)Cu, (111)In, and (99m)Tc. HubMed – drug