Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases.

PURPOSE: This study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ. METHODS: The medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline. RESULTS: Among the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 [12.6%] vs 7/159 [4.4%], P = 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached; P = 0.024). CONCLUSION: The results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.

Observational retrospective single-centre study in Japan to assess the clinical significance of serum daptomycin levels in creatinine phosphokinase elevation.

WHAT IS KNOWN AND OBJECTIVE: Daptomycin-induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough ; breakpoint of 24.3 µg/mL). However, even with high-dose treatment (ie, > 8 mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of Ctrough above 24.3 µg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3 µg/mL. In this study, we retrospectively evaluated the significance of Ctrough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records. METHODS: Patients who had received daptomycin treatment for > 4 days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including Ctrough and peak (Cpeak ), were measured by high-performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients' characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system. RESULTS AND DISCUSSION: A total of 52 therapeutic cases for 46 patients were identified; of these, Ctrough and Cpeak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68 years (range: 19-88 years), and 14 patients initially had an estimated creatinine clearance of less than 30 mL/min. Seven cases indicated a Ctrough of above 24.3 µg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured Ctrough (of 10.9 µg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured Ctrough levels; these were 8.6 and 8.1 µg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3 µg/mL. In this study, two patients receiving high-dose daptomycin (ie, 9.4 and 10.0 mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin < 9 mg/kg. WHAT IS NEW AND CONCLUSIONS: The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3 µg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher Ctrough levels than 24.3 µg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high-dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved.

Evaluation of pharmaceutical intervention in direct-acting antiviral agents for hepatitis C virus infected patients in an ambulatory setting: a retrospective analysis.

BACKGROUND: Direct-acting antivirals (DAAs) are known to improve tolerability and have higher efficacy and shorter treatment durations compared with conventional interferon (IFN)-based treatments for hepatitis C virus (HCV) infection. Management of drug interactions and maintenance of patient adherence are important to achieve adequate therapeutic effects, sustained virological response (SVR). In order to maximize the benefits of oral DAA therapy, we established an ambulatory care pharmacy practice, a model of integrated collaboration between physicians and pharmacists, for patients receiving IFN-free DAA therapy. In this study, we evaluated pharmaceutical intervention for patients visiting the ambulatory care pharmacy practice. METHODS: HCV-infected outpatients who visited our ambulatory care pharmacy practice between September 2014 and May 2017 were eligible for inclusion in the study. When IFN-free DAAs were first prescribed, the physicians recommended all patients to visit the ambulatory care pharmacy practice after their clinical examination. Subsequently, at the second visit or later, the patients visited the pharmacy service before the physician's examination. The primary endpoint was SVR, defined as HCV RNA below the lower limit of quantification after the completion of treatment. We also evaluated the adherence rate to DAAs, suggestions to the physicians by the pharmacists, and questions from the patients. All data were obtained retrospectively using an electronic medical record system. RESULTS: Among the 401 study subjects, 386 patients completed the IFN-free DAA therapy. A total of 365 patients have reached 12 or 24 weeks after completing the treatment. The overall SVR rate was 98.1% (358/365). The proportion of patients with adherence ≥90% was 99.3% (398/401). Two-hundred and sixty-seven (84%) among 318 suggestions of prescription made by the pharmacists mainly to manage the adverse events were accepted by the physicians. The pharmacists received and answered 1072 questions on DAA therapy from the patients. CONCLUSIONS: This study indicates that the pharmaceutical intervention may contribute to enhanced adherence to DAAs and higher SVR rates in comparison with previous reports. This study also demonstrates that collaboration between physicians and pharmacists in an ambulatory setting provides favorable outcomes for patients receiving IFN-free DAAs.

Effect of Hyperglycemia on Antitumor Activity and Survival in Tumor-bearing Mice Receiving Oxaliplatin and Fluorouracil.

BACKGROUND/AIM: Diabetic patients are at a higher risk of carcinogenesis and death from cancer, including colorectal cancer, than healthy individuals. The efficacy of cancer chemotherapy in the diabetic condition remains unclear. In this study, we investigated the efficacy of anticancer agents oxaliplatin and fluorouracil in streptozotocin (STZ)-treated hyperglycemic mice. MATERIALS AND METHODS: Starting 7 days after transplantation of colonic adenocarcinoma colon-26 cells, STZ-treated and control mice were intraperitoneally administered oxaliplatin, fluorouracil, and levofolinate (FOLFOX) every 2 weeks. RESULTS: Tumor growth was delayed in STZ-treated mice compared to control mice. The tumor volume was significantly smaller after treatment with FOLFOX in control mice, but not in STZ-treated mice. Despite delayed tumor growth, and regardless of whether they received treatment, survival was shorter in STZ-treated mice than in control mice. CONCLUSION: Cancer chemotherapy with oxaliplatin and fluorouracil was less effective and survival was shorter in hyperglycemia.

[Evaluation of Research Experience Based on the Type of Degree Completed for the Development of Pharmacist-Scientists].

  "Pharmacist-scientists" are needed in the clinical setting. However, research competency, including logical thinking, differs among pharmacists. This difference stems from the varying experience of research during university and graduate school. Thus, to ascertain the research experience within different educational systems, we evaluated pharmacists in Kobe City Medical Center General Hospital. In most instances, there was a direct correlation between the duration of research (in the laboratory at university or graduate school), and research experience gained, such as independent thinking and presentations at seminars or academic conferences. Respondents who graduated from the recently introduced 6-year pharmaceutical science course had less research experience than those who graduated with a combination 4-year degree and subsequent master's course. Conversely, the number of presentations at academic conferences and the number of published papers postgraduation were independent of research experience during university and graduate school. These results indicate that there is a considerable difference in the research experience during university and graduate school among pharmacists, and this is likely to impact their pharmaceutical skills.

Reduction in gastrointestinal bleeding by development and implementation of a protocol for stress ulcer prophylaxis: a before-after study.

BACKGROUND: The implementation of a protocol has been associated with improvements in the processes of care in clinical settings. Although stress ulcer prophylaxis is recommended for critically ill patients at high risk, there is currently no consensus on its use. Therefore, we herein developed a protocol for stress ulcer prophylaxis, and evaluated therapeutic outcomes in a before-after study. METHODS: The protocol was developed by considering the effectiveness, disadvantages (including adverse events) and cost of each agent based on previous findings. Patients who were admitted to the 8-bed emergency intensive care unit (ICU) of our hospital for more than 24 h during the year before and after implementation of the study were eligible. Each investigation item was evaluated retrospectively. RESULTS: There were 211 and 238 study patients before and after implementation of the protocol, respectively. The baseline characteristics of patients on/during ICU admission were similar in the two groups. The proportion of medicated patients was 79.6 % before and 84.5 % after protocol implementation. Before implementation of the protocol, 4.3 % of patients developed clinically important gastrointestinal bleeding, and this incidence decreased significantly to 0.8 % after its implementation (P = 0.019). The frequency at which medication was discontinued due to adverse events was slightly lower after implementation of the protocol. No significant differences were observed in the costs of stress ulcer prophylactic agents or mortality in the ICU. CONCLUSIONS: The results of the present study indicated that the development and implementation of a protocol for stress ulcer prophylaxis, for which there are currently no criteria, improved a main outcome, clinically important gastrointestinal bleeding.

Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice.

Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and the removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes.

Development of bone-targeted catalase derivatives for inhibition of bone metastasis of tumor cells in mice.

Removal of hydrogen peroxide by delivering catalase to the vicinity of metastasizing tumor cells is a promising approach for inhibiting tumor metastasis. To inhibit bone metastasis, catalase was conjugated with 3,5-di(ethylamino-2,2-bisphosphono)benzoic acid (Bip), a derivative of bone-seeking bisphosphonates, polyethylene glycol (PEG), or both. Bip-conjugated catalase derivatives, that is, catalase-Bip and PEG-catalase-Bip, exhibited a higher affinity for bone matrix as compared with their counterparts without Bip. The tissue distribution of (111) In-labeled catalase derivatives indicated that the accumulation of radioactivity in bones was increased by conjugation of either Bip or PEG with catalase. An experimental bone metastasis model was developed by injecting male C57BL/6 mice with murine melanoma B16-BL6/Luc cells, which stably express firefly luciferase into left ventricle. Repeated injections of catalase to tumor-bearing mice had no significant effect on the number of melanoma cells in tibiae and femurs, whereas injections of catalase-Bip, PEG-catalase, or PEG-catalase-Bip significantly reduced the number. These results indicate that targeted delivery of catalase to the bones can be achieved by conjugating the enzyme with either Bip or PEG, and this delivery is effective in inhibiting the bone metastasis of tumor cells.

Improvement of insulin resistance by removal of systemic hydrogen peroxide by PEGylated catalase in obese mice.

Insulin resistance, a condition in which insulin action is impaired, is one of the characteristic features of type 2 diabetes. Excessive amounts of reactive oxygen species (ROS) interfere with the insulin signaling pathway, which leads to the progression of insulin resistance. To examine whether removal of systemic hydrogen peroxide is effective in improving insulin resistance, polyethylene glycol-conjugated catalase (PEG-catalase), a derivative with a long circulation half-life, was repeatedly injected into leptin-deficient ob/ob or high fat diet-induced obese mice for 16 or 10 consecutive weeks, respectively. Although ob/ob mice gradually gained weight with time irrespective of the treatment, repeated intraperitoneal injections of PEG-catalase significantly reduced glucose levels in the fed state. Glucose and insulin tolerance tests also showed PEG-catalase significantly improved glucose tolerance and insulin sensitivity in ob/ob mice, respectively. Similar but less marked results were obtained in the diet-induced obese mice. Treatment of 3T3-L1 adipocytes with glucose oxidase (GO) increased lipid hydroperoxide formation and reduced insulin-stimulated Akt phosphorylation. Addition of catalase or PEG-catalase significantly inhibited the GO-induced changes in adipocytes. These findings indicate that systemic removal of hydrogen peroxide by PEG-catalase activates the insulin signaling pathway and improves insulin resistance in obese mice.

Prevention of pulmonary metastasis from subcutaneous tumors by binary system-based sustained delivery of catalase.

Catalase delivery can be effective in inhibiting reactive oxygen species (ROS)-mediated acceleration of tumor metastasis. Our previous studies have demonstrated that increasing the plasma half-life of catalase by pegylation (PEG-catalase) significantly increases its potency of inhibiting experimental pulmonary metastasis in mice. In the present study, a biodegradable gelatin hydrogel formulation was used to further increase the circulation time of PEG-catalase. Implantation of (111)In-PEG-catalase/hydrogel into subcutaneous tissues maintained the radioactivity in plasma for more than 14 days. Then, the effect of the PEG-catalase/hydrogel on spontaneous pulmonary metastasis of tumor cells was evaluated in mice with subcutaneous tumor of B16-BL6/Luc cells, a murine melanoma cell line stably expressing luciferase. Measuring luciferase activity in the lung revealed that the PEG-catalase/hydrogel significantly (P<0.05) inhibited the pulmonary metastasis compared with PEG-catalase solution. These findings indicate that sustaining catalase activity in the blood circulation achieved by the use of pegylation and gelatin hydrogel can reduce the incidence of tumor cell metastasis.

SOD derivatives prevent metastatic tumor growth aggravated by tumor removal.

Although surgical removal is the most aggressive strategy to treat removable tumors, it sometimes aggravates tumor growth in metastatic sites. Because surgical procedures generate reactive oxygen species (ROS), known promoters of tumor metastasis and growth, we examined whether the growth of micrometastasis is inhibited by superoxide dismutase (SOD) derivatives after surgical removal of tumors in mice. Murine melanoma B16-BL6 cells were inoculated into the footpad to establish spontaneous pulmonary metastasis. The removal of the footpad tumor significantly (P < 0.05) increased the level of plasma lipoperoxides and the number of tumor cells in the lung. An intravenous injection of SOD or its pegylated-SOD derivative significantly (P < 0.05) inhibited the peroxidation and metastatic tumor growth. It also extended the survival period of mice undergoing removal of the footpad tumor. These findings indicate that the removal of tumor produces ROS, which then aggravates the growth of tumor cells in micrometastases. SOD derivatives can effectively prevent this metastatic tumor growth by detoxifying ROS.

Cationized catalase-loaded hydrogel for growth inhibition of peritoneally disseminated tumor cells.

A previous study demonstrated that ethylenediamine-conjugated catalase (ED-catalase) inhibits peritoneal dissemination of tumor cells in mice. To increase its inhibitory effects by sustained release, a hydrogel formulation of ED-catalase was prepared using a biodegradable hydrogel consisting of an acidic gelatin with an isoelectric point of 5.0. Although intraperitoneally injected ED-catalase solution rapidly disappeared from the cavity, more than 10% of ED-catalase remained even at 14 days after implantation of ED-catalase/hydrogel into the cavity. Then, the effect of ED-catalase/hydrogel on peritoneal dissemination of tumor cells was evaluated by measuring the luciferase activity of abdominal organs after intraperitoneal inoculation of colon26/Luc, a colon adenocarcinoma stably expressing luciferase. ED-catalase/hydrogel showed a significantly (P<0.05) greater effect on inhibiting the growth of tumor cells than ED-catalase solution, demonstrating the importance of the retention of ED-catalase within the cavity as far as inhibition is concerned. Serial in vivo images of luciferase activity revealed that the ED-catalase/hydrogel significantly (P<0.05) retarded the growth rate of tumor cells. Survival of tumor-bearing mice supported the findings obtained with the luminescence-based analyses. These findings indicate that the sustained release of ED-catalase from hydrogels into the cavity is highly effective in inhibiting the growth of peritoneally disseminated tumor cells.

Inhibition of peritoneal dissemination of tumor cells by cationized catalase in mice.

To inhibit peritoneal dissemination of tumor cells by destroying hydrogen peroxide, ethylenediamine-conjugated catalase (ED-catalase), a cationized derivative, was injected into the peritoneal cavity of mice. ED-catalase had about a 6-fold longer retention time within the cavity than unmodified catalase. Peritoneal dissemination was evaluated after intraperitoneal inoculation of B16-BL6/Luc, a melanoma clone stably expressing firefly luciferase, by measuring luciferase activity. An intraperitoneal injection of ED-catalase just before tumor inoculation significantly reduced the number of tumor cells in peritoneal organs. Catalase was less effective, confirming the importance of the retention of the enzyme within the cavity for the inhibition. ED-catalase injected 3 days after tumor inoculation was also effective in inhibiting tumor growth. A real-time quantitative PCR analysis revealed that ED-catalase significantly suppressed the expression of intercellular adhesion molecule-1. Daily dosing of ED-catalase for 7 days significantly prolonged the survival of tumor-bearing mice. These findings indicate that ED-catalase, which is retained for a long time within the peritoneal cavity, is highly effective in inhibiting the adhesion and proliferation of peritoneally disseminated tumor cells, and in increasing the survival of tumor-bearing mice.