In recent years, drug delivery systems (DDS) have been developed, along with anticancer agents for those systems based on the concept of achieving a better clinical response and tolerability. Several clinical trials have shown that these drugs have better clinical effects in the treatment of many cancers, leading to their expanded indications. Liposomal doxorubicin is one DDS agent used to treat AIDS-related Kaposi's sarcoma and ovarian cancer in Japan. In addition to those two indications, the Food and Drug Administration (FDA) approved this drug for the treatment of multiple myeloma in 2007. Another DDS agent approved in Japan is nanoparticle albumin-bound paclitaxel, which has been used in the treatment of breast cancer. Most recently, this drug has been approved for the treatment of non-small cell lung cancer in the U.S.A. Although these DDS agents appear to be less toxic than conventional drugs, DDS-specific side effects such as various skin reactions, hypersensitivity reaction, and peripheral neuropathy sometimes occur. Therefore, medical staff must understand DDS anticancer agents fully, including characteristic side effects, to achieve the desired clinical outcomes.

Busulfan (1,4-butanediol dimethanesulfonate) has been used widely for the treatment of patients with chronic myelogenous leukemia. Busulfan is bifunctional and thus may effectively induce DNA damage, which may play an important role in the cytotoxicity. In this study, we compared the cytotoxicity of bifunctional busulfan with that of monofunctional ethyl methanesulfonate (EMS) in human promyelocytic leukemia HL-60 cells. Busulfan showed a significant inhibitory effect on cell growth, whereas the cells grew in the presence of EMS. To clarify the mechanism of cytotoxicity of busulfan, we investigated DNA damage induced by busulfan using 32P-5'-end-labeled DNA fragments obtained from the human p16 tumor suppressor gene. Busulfan induced DNA damage dose-dependently, whereas EMS caused little DNA damage. DNA-sequencing experiments using piperidine and 3-methyladenine DNA glycosylase indicated that busulfan caused double-base lesions mainly at 5'-GA-3' and, to a lesser extent, at 5'-GG-3' sequences. Time of flight mass spectrometry confirmed that busulfan forms an intrastrand cross-link at the 5'-GA-3' sequence, in addition to mono-alkylation. The mechanism and the role of cross-linking at the 5'-GA-3' sequence are discussed in relation to the cytotoxicity induced by busulfan.

Vancomycin (VCM), a glycopeptide antibiotic, was developed and released in the 1950's for the treatment of aerobic gram-positive infections and has been widely used mainly in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Early reports regarding the possibility of nephrotoxicity and ototoxicity led to concern about the use of VCM and monitor serum VCM concentrations.In general, the purposes of therapeutic drug monitoring (TDM) are to improve clinical effects, to avoid side effects, and to reduce drug costs. In the case of VCM, however, an exhaustive review of the literature revealed that there are no studies analyzing a direct effect of serum VCM concentrations and clinical outcome.1-3) There have been a few studies examining the minimum inhibitory concentration (MIC)/ minimum bactericidal concentration (MBC) ratios and cure rates, 4-6) these studies are not efficient to answer the question what concentration of VCM was required for the successful treatment of infections. Recently, some clinical reports evaluating the TDM of VCM have proposed the following conclusions: 1) TDM is associated with a decreased incidence of VCM-induced nephrotoxicity, indicating that TDM is a cost-effective procedure, 1,[7][8][9] and 2) VCM works most effectively if the concentration at the site of infection is maintained above MIC values throughout the dose interval. So, the clinical efficacy of VCM can usually be obtained if the trough concentration is sufficiently above the MIC at the site of infected organisms. 10,11) Since the MIC values for susceptible organisms were below 5 mg/ml and reported toxicities had occurred most often at drug serum concentrations above 40 mg/ml, clinicians and researchers designated therapeutic trough concentrations at 5-15 mg/ml and peak concentrations at 25-40 mg/ml. 1,[12][13][14] In practice, however, the peak concentration hardly exceeds 40 mg/ml, as long as the trough concentration is kept below 15 mg/ml. 15) For this reason, the policy of monitoring the trough concentration alone for VCM has recently spread worldwide. In Japan, however, both the trough and peak concentrations of VCM are monitored in most of hospitals. Therefore, it would be worthwhile to investigate whether monitoring peak concentration is essential or not.The purpose of the present study was to investigate the clinical utility of the TDM VCM and the relationship between its peak concentrations and clinical effects in MRSAinfected patients. MATERIALS AND METHODS Subjects and Study DesignSubjects (0-86 years of age) in this retrospective study were MRSA-infected patients who received intravenous infusion of VCM (Shionogi & Co., Ltd., Osaka, Japan) from January 1996 to March 2002 and also had confirmed the disappearance of the bacteria thereafter.The incidence of nephrotoxicity, including VCM-induced or MRSA-related nephrotoxicity, was compared between the TDM group (nϭ73) and the non-TDM group (nϭ111). Serum VCM concentrations in the TDM group were monitored within 10 d from the start of VCM ther...

BackgroundThe accuracy, safety and feasibility of, the compounding robot APOTECAchemo were evaluated in the clinical practice of Japan.MethodsAccuracy and precision of robotic preparations by APOTECAchemo was evaluated in 20 preparations of fluorouracil (FU) and cyclophosphamide (CPA) infusions by four pharmacists. Environmental and product contaminations with FU and CPA were evaluated by wipe testing. Robotic performance was compared with manual preparation in a biological safety cabinet. The number of robotic products, total compounding time and total pre-reconstitution time of lyophilized drugs between January 1, 2014 to December 31, 2015 were investigated.ResultsRobotic preparation resulted more accurate and precise (mean absolute dose error and coefficient of variation were 0.83 and 1.04% for FU and 0.52 and 0.59% for CPA) than those of manual preparation (respective values were 1.20 and 1.46% for FU and 1.70 and 2.20% for CPA). Drug residue was not detected from any of the prepared infusion bags with the robotic preparation, whereas FU was detected in two of four analyzed infusion bags with manual preparation. Average total time to make single anticancer drug preparation (compounding plus reconstitution of lyophilized drugs) was 6.11 min in the second half of 2015. During the study period, the highest percentage of production covered by APOTECAchemo was 70.4% of the total inpatient pharmacy activity.ConclusionRobotic preparation using APOTECAchemo should give substantial advantages in drug compounding for accuracy and safety and was able to be successfully worked in Mie university hospital.

A close relationship among postprandial hyperglycemia, advanced age, and hypercholesterolemia is a characteristic of SDM in patients with neurologic diseases. Therefore, monitoring the plasma glucose concentration 2 hours after lunch may be useful to detect SDM in these patients.