Mikio Masada

Gas chromatographic determination and gas chromatographic-mass spectrometric analysis of chloramphenicol, thiamphenicol and their metabolites

Abstract A rapid and accurate gas chromatographic (GC) method is described for the determination of chloramphenicol, thiamphenicol and their metabolites excreted in human urine. These excretions were pre-treated with diazomethane and N,O-bis(tri-methylsilyl)acetamide, so that they could be easily subjected to GC with satisfactory separation from each other and also from other urinary excretions, and could be determined simultaneously. The structures of the metabolites were confirmed by GC combined with mass spectrometric measurements of the GC peaks. The applicationb of the method to urine specimens enabled more precise results for the amounts of metabolites present to be obtained; the excretion of thiamphenicol glucoronide was not observed.

Efficacy of mometasone furoate nasal spray for nasal symptoms, quality of life, rhinitis-disturbed sleep, and nasal nitric oxide in patients with perennial allergic rhinitis.

Intranasal corticosteroid therapy has exhibited effectiveness for improving nasal symptoms and quality of life (QOL) scores associated with seasonal allergic rhinitis. We prospectively investigated the efficacy of mometasone furoate nasal spray (MFNS) for improving the total nasal symptom score, QOL score, and sleep quality in subjects with perennial allergic rhinitis (PAR). Nasal airway conditions were also objectively assessed by measuring nasal nitric oxide (NO). Fifty-seven patients with PAR were randomized to MFNS or placebo for a 14-day, double-blind, crossover study. The subjects recorded their symptoms on nasal symptom forms and a visual analog scale. QOL and sleep quality were surveyed in accordance with the Japanese version of the Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) and the Japanese version of the Epworth Sleepiness Scale. Nasal NO was measured during a single exhalation using a chemiluminescence analyzer. MFNS treatment achieved significant reductions versus placebo for total nasal symptoms (p < 0.001). There were significant decreases of the usual daily activity domain (p < 0.005), outdoor activities (p < 0.01), social function (p < 0.05), and the overall QOL score (p < 0.05) of JRQLQ with MFNS therapy versus placebo. A significant reduction of the sleepiness scale was also observed in the MFNS group with high sleep disturbance (p < 0.01). A significant decrease of nasal NO was found in the MFNS group (p < 0.01), especially among patients with severe nasal symptoms (p < 0.005). This prospective study indicated that MFNS therapy significantly improves nasal symptoms, QOL, sleep quality, and upper airway condition in Japanese subjects with PAR.

Pharmacoethnicity of docetaxel-induced severe neutropenia: integrated analysis of published phase II and III trials

BackgroundEthnic differences in drug susceptibility and toxicity are a major concern, not only in drug development but also in the clinical setting. We review the toxicity profiles of docetaxel according to dose and ethnicity.MethodsWe analyzed phase II and III clinical trials that included a once-every-3-weeks single-agent docetaxel arm. Logistic regression analysis was applied to identify the significant variables affecting the reported incidence of docetaxel-induced severe neutropenia.ResultsMultivariate logistic regression analysis identified studies conducted in Asia [odds ratio (OR) 19.0; 95% confidence interval (95% CI) 3.64–99.0] and docetaxel dose (OR 1.08; 95% CI 1.03–1.13) as independent variables for the incidence of grade 3/4 neutropenia.ConclusionsThere is a significant difference in the incidence of docetaxel-induced severe neutropenia between Asian and non-Asian clinical studies. Physicians and pharmacists should consider ethnic diversity in docetaxel toxicity when interpreting the results of clinical trials.

Variability in teicoplanin protein binding and its prediction using serum albumin concentrations

The impact of lower serum albumin levels on teicoplanin pharmacokinetics has not been previously determined. The authors assessed the relationship between total and free concentrations of teicoplanin in serum samples obtained from patients receiving teicoplanin therapy for Gram-positive bacterial infections. In addition, the authors determined the contribution of serum albumin concentrations to the unbound fraction of teicoplanin. One hundred ninety-eight serum samples were obtained from 65 patients undergoing routine therapeutic drug monitoring of teicoplanin. Free serum teicoplanin was separated by ultrafiltration, and total and free serum concentrations of teicoplanin were determined by a fluorescence polarization immunoassay. Regression analysis was then performed to build a prediction model for the free serum teicoplanin concentration from the total serum teicoplanin concentration and the serum albumin level using the first 132 samples. The predictive performance of this model was then tested using the next 66 samples. Free serum teicoplanin concentrations (Cf) (μg/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (μg/mL) and albumin concentrations (ALB) (g/dL): Cf = Ct/(1 + 1.78 * ALB). This model could estimate free serum teicoplanin concentrations with a small bias and an acceptable error. The measured free level of teicoplanin will lie between 0.63 and 1.38 times the predicted concentration in 95% of cases. Serum albumin level plays a major role in the variability of the fraction unbound of teicoplanin. This model can reliably estimate free serum teicoplanin concentrations more easily than by using direct measurements.

Inhibitory effect of ciprofloxacin on β-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide

The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β‐glucuronidase‐mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time‐dependent manner from 5 to 60 min in the presence of β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β‐glucuronidase‐mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose‐dependent inhibitory effect on MPA production from MPAG via β‐glucuronidase with a half‐maximal inhibitory concentration (IC50) value of 30.4 µm. While PhePG inhibited the β‐glucuronidase‐mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co‐administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β‐glucuronidase. Copyright

Evaluation of Potential Interaction Between Vinorelbine and Clarithromycin

Background: Myelotoxicity, a major toxicity of vinorelbine, may be related to the degree of ones exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbines pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. To date, macrolide–vinorelbine drug interactions have not been reported. Objective: To estimate the clinical risk of a interaction between vinorelbine and clarithromycin. Methods: In a retrospective cohort study, we searched computerized medical records of patients who had been administered vinorelbine in the University of Fukui Hospital. The study cohort was defined as all patients with non–small-cell lung cancer who received vinorelbine between May 30, 2003, and January 31, 2008. The treatment courses were classified according to whether or not clarithromycin was concomitantly administered with vinorelbine. Nadir neutrophil counts were recorded as the major outcomes. Vinorelbine–clarithromycin interaction was defined as a significant increase in the risk of severe neutropenia when the 2 drugs were administered concomitantly. Results: A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively. Conclusions: Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

Monitoring of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in 1-beta-D-arabinofuranosylcytosine therapy at low and conventional doses.

1‐β‐D‐Arabinofuranosylcytosine (ara‐C) is used empirically at a low, conventional, or high dose. Ara‐C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ara‐C, 1‐β‐D‐arabinofuranosylcytosine 5′‐triphosphate (ara‐CTP). However, ara‐CTP has seldom been monitored during low‐ and conventional‐dose ara‐C therapies because detection methods were insufficiently sensitive. Here, with the use of our newly established method (Cancer Res., 56, 1800‐1804 (1996), ara‐CTP was monitored in leukemic cells from acute myelog‐enous leukemia patients receiving low‐ or conventional‐dose ara‐C [subcutaneous ara‐C administration (10 mg/m2) (3 patients), continuous ara‐C infusion (20 or 70 mg/m2/24 h) (7 patients), 2‐h ara‐C infusion (70 mg/m2) (4 patients), and 2‐h infusion of N4‐behenoyl‐l‐β‐D‐arabinofuranosylcy‐tosine, a deaminase‐resistant ara‐C derivative (70 mg/m2) (6 patients)]. Ara‐CTP could be determined at levels under 1μM. There was a close correlation between the elimination half‐life values of the plasma ara‐C and the intracellular ara‐CTP. The presence of ara‐C in the plasma was important to maintain ara‐CTP. The continuous ara‐C and the 2‐h N4‐behenoyl‐l‐β‐D‐arabinofura‐nosylcytosine infusions maintained ara‐CTP and the plasma ara‐C longer than the subcutaneous ara‐C or the 2‐h ara‐C infusion. They also afforded relatively higher ara‐CTP concentrations, and consequently produced ara‐CTP more efficiently than the 2‐h ara‐C infusion. Different administration methods produced different quantities of ara‐CTP even at the same dose.

Clinical effect of a multidisciplinary team approach to the initial treatment of patients with hospital-acquired bloodstream infections at a Japanese university hospital

BACKGROUND Hospital-acquired bloodstream infections (BSIs) are significant causes of mortality, and strategies to improve outcomes are needed. We aimed to evaluate the clinical efficacy of a multidisciplinary infection control team (ICT) approach to the initial treatment of patients with hospital-acquired BSI. METHODS A before-after quasiexperimental study of patients with hospital-acquired BSI was performed in a Japanese university hospital. The ICT provided immediate recommendations to the attending physician about appropriate antimicrobial therapy and management after reviewing blood cultures, Grams stain, final organism, and antimicrobial susceptibility results. RESULTS The sample included 469 patients with hospital-acquired BSI (n = 210, preintervention group; n = 259, postintervention group). There were no significant differences between the groups in background or microbiologic characteristics. The 30-day mortality was significantly lower and significantly more patients received appropriate antimicrobial therapy in the postintervention group (22.9% vs 14.3%; P = .02 and 86.5% vs 69.0%; P < .001, respectively). Multivariate analysis confirmed that the ICT intervention was significantly associated with appropriate antimicrobial therapy (odds ratio, 2.22; 95% confidence interval, 1.27-3.89) and 30-day mortality (odds ratio, 0.49; 95% confidence interval, 0.25-0.95). CONCLUSIONS A timely multidisciplinary team approach decreases the delay of appropriate antimicrobial treatment and may improve HABSI patient outcomes.

Determination of human immunoglobulin A and secretory immunoglobulin A in bronchoalveolar lavage fluids by solid phase enzyme immunoassay

Solid phase enzyme immunoassay methods for the determination of secretory immunoglobulin A (IgA) and the total amount of serum and secretory IgA in bronchoalveolar lavage fluids (BALF) were developed. The solid phase was prepared by immobilizing rabbit anti-human IgA. Horseradish peroxidase-conjugated goat anti-secretory component or horseradish peroxidase-conjugated goat anti-human IgA (Fc) were used as labeled antibodies. The minimum detectable amounts of secretory IgA and total IgA were 2 and 0.5 ng/well, respectively. These assay methods were successfully applied to the determination of secretory and total IgA levels in BALF samples obtained from 44 subjects including healthy non-smokers, smokers and patients with the following lung diseases: idiopathic pulmonary fibrosis, sarcoidosis and hypersensitivity pneumonitis. The secretory and total IgA levels in BALF collected from healthy non-smokers (n = 9) were 10.5 +/- 3.6 and 25.4 +/- 15.5 (S.D.) micrograms/ml, respectively. In healthy smokers, the secretory IgA concentration was significantly decreased and in idiopathic pulmonary fibrosis, the total IgA was increased. These results indicate that the quantitation of secretory and total IgA may be useful for the investigation of lung disease.

Transient elevation of international normalized ratio during cisplatin-based chemotherapy in patients who are taking warfarin.

Objective: To report 2 cases of a probable interaction between cisplatin and warfarin. Case Summary: Two cases of transient elevation of international normalized ratio (INR) during Irinotecan (60 mg/m2 on days 1, 8, and 15) plus cisplatin (60 mg/m2 on day 1) chemotherapy with concomitant warfarin are presented. In both cases, warfarin dosages were stable at the therapeutic target range prior to initiation of chemotherapy. Granisetron hydrochloride (3 mg on days 1, 6, and 15) and dexamethasone (13.2 mg on day 1 and 6.6 mg on days 2, 3, 8, and 15) were used prior to irinotecan administration in both patients. In addition, aprepitant was administered to both patients for 3–5 days with cisplatin. One of these patients also received aprepitant with irinotecan on days 8 and 15. During chemotherapy, INR was transiently elevated almost 1.5-fold over baseline level on day 3. This variation did not occur in subsequent irinotecan cycles on days 8 and 15. The timing of these increases was similar in each of the cycles. Discussion: Cisplatin was the common drug in the cases presented and therefore could be related to the INR elevations. To our knowledge, these are the first reports of an Interaction between warfarin and irinotecan-cisplatin chemotherapy, but reports of a similar interaction with chemotherapy including platinum derivatives exist. Use of the Horn Drug Interaction Probability Scale indicated a probable interaction between warfarin and cisplatin. Conclusions: Cisplatin might affect the anticoagulation function of warfarin. Careful INR monitoring is necessary during antineoplastic chemotherapy with cisplatin in patients taking warfarin.