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Neoadjuvant or induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) is regarded as one of the most promising regimens for locally advanced esophageal squamous cell carcinoma (ESCC), but has a high incidence of adverse events. We retrospectively evaluated adverse events in patients with ESCC who received DCF. Between December 2009 and May 2012, 57 patients with Stage II to IV locally advanced ESCC received three cycles of DCF (docetaxel 70–75 mg/m2, day 1; cisplatin 70–75 mg/m2, day 1; 5-fluorouracil, 750 mg/m2, days 1–5) as neoadjuvant or induction chemotherapy in a single institution. Adverse events of DCF were evaluated retrospectively. The median age of the subjects was 65 years (range 41–74). Fifty-four patients (95 %) received three cycles of DCF as scheduled. Dose modifications were made for 34 patients (60 %). There were no treatment delays or unplanned admissions. Grade 3 or 4 neutropenia developed in 53 patients (93 %), including 18 (32 %) with febrile neutropenia. Other grade 3 or 4 toxic effects were hyponatremia in 15 patients (26 %), hypokalemia in 10 (18 %), oral mucositis in 9 (16 %), diarrhea and hypocalcemia in 8 (14 %) each, fatigue in 4 (7 %), and vomiting, anorexia, hiccups, hypoalbuminemia, and elevations of alanine aminotransferase in 1 (2 %) each. No treatment-related deaths occurred within 30 days after completion of DCF. For patients with locally advanced ESCC, neoadjuvant or induction chemotherapy with DCF is tolerable. DCF is a viable treatment option for fit patients with locally advanced ESCC.

Background Epinephrine can potentially worsen the neurotoxic effects of local anesthetics when used for spinal or epidural anesthesia. The vasoconstrictive property of epinephrine reduces dural blood flow, which in turn reduces the clearance of local anesthetics from the subarachnoid space. This study examined the histological and neurofunctional effects of intrathecally administered lidocaine combined with epinephrine in rats. Methods Sixty-two rats were divided into 9 treatment groups: 5% or 7.5% lidocaine in 10% glucose solution with or without 0.1 or 0.5 mg/mL epinephrine, or epinephrine alone at 0.1 or 0.5 mg/mL in 10% glucose, or 10% glucose alone. Hind-limb motor function was evaluated immediately after drug injection by walking behavior. Sensory function was assessed by the response to radiant heat stimulation at just before and 1 week after the injection. Seven days after the injection, L3 spinal cord with anterior and posterior roots, the dorsal ganglion, and cauda equina were harvested and examined histologically. Results Histological lesions were limited to the posterior root just at entry into the spinal cord in rats injected with 7.5% lidocaine, with and without epinephrine. No histological abnormalities were noted in other areas or other groups. There was no significant change in sensory threshold in all groups. Significantly, prolongation of gait recovery time was noted in 5% and 7.5% lidocaine with epinephrine groups compared with 5% or 7.5% lidocaine alone. Conclusions Intrathecal epinephrine prolonged the action of intrathecal lidocaine but did not worsen lidocaine-induced histological damage and functional impairment.

Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CL(fenta) (L/h) = 3.53 × (15 - Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Voriconazole (VRCZ) reportedly possesses a broad spectrum of antifungal activity against Aspergillus spp. and Candida spp., and the blood concentration of VRCZ is correlated with both the efficacy and the adverse effects of this drug. Monitoring of the blood concentration target level of VRCZ has not yet been widely adopted in the medical field, and no evidence concerning this target level has been reported. Accordingly, we used a meta-analysis to investigate the optimal blood concentration of VRCZ. Using data from 12 reports, we found that the success rate for fungal infection treatment increased significantly at VRCZ levels greater than 1.0 μg/ml when a graded cutoff value within the range of 1.0–3.0 μg/ml was used as the VRCZ trough blood concentration [odds ratio (OR) 7.23, 95% confidence interval (CI) 2.84–18.37, P < 0.0001]. Concerning the safety evaluation, the incidence of adverse neurological effects increased significantly at a cutoff value of 4.0 μg/ml when a graded cutoff value within the range of 3.0–6.0 μg/ml was used (OR 2.23, 95% CI 1.12–4.46, P = 0.02). However, in all 12 literature sources, an increasing incidence of liver dysfunction was reported at higher blood concentrations, and no accurate cutoff values were obtained. Consequently, a VRCZ trough blood concentration more than 1.0 μg/ml from the perspective of efficacy and less than 4.0 μg/ml from the perspective of safety is recommended.

In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA.

Liposomal amphotericin B (L-AMB), a lipid-based amphotericin B formulation, has been used in Japan since June 2006 to treat fungal infection. In the 3 years since L-AMB was launched, few reports have been made on its status. To ensure its appropriate use, we restrospectively reviewed its efficacy and safety in treating fungal infections. 25 subjects with fungal infection treated with L-AMB from April 2007 until February 2008. Of those, 16 showed clinical improvement. Elevated serum creatinine occurred in 1 and decreased serum potassium in 6. We found a positive relationship between the serum potassium decrease and L-AMB dose. Logistic regression analysis of this relationship showed that serum potassium tended to fall on day 5 to 6 of L-AMB administration. While L-AMB appears highly effective in fungal infection, it requires serum potassium monitoring to ensure patient safety.

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dose x serum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.

Elcatonin injection is used for the treatment of osteoporosis in Japan.In order to compare the original product with generic versions, we measured the elcatonin content and amounts of impurities in both using high performance liquid chromatography, and observed changes in content with time under the conditions of light exposure and shaking.We found that elcatonin content and amounts of impurities varied among the generics and that changes in content with time under the above conditions for some generics were greater than the changes for the original product.These results suggest that some generic products should not be considered to be equivalent to the original product.

Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLC-electrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V(d)=226.7+/-105.5 l (mean+/-S.D.), CL=37.9+/-25.1 l/h, t(1/2)=4.1+/-1.9 h. Hydrocotarnine; V(d)=276.8+/-237.2 l, CL=95.1+/-64.3 l/h, t(1/2)=2.0+/-0.7 h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.

Following is the Otorhinolaryngology Department report, by Kitasato University Hospital, on the use of arbekacin sulfate (ABK) and vancomycin hydrochloride (VCM) for treating methicillin-resistant Staphylococcus aureus (MRSA). From March 2005 to February 2006, we performed retrospective research on 13 cases treated with either ABK or VCM. The subjects were 13 cases in which MRSA was detected in this institute's Otorhinolaryngology Department. The cases were evaluated for effectiveness, safety and economy. VCM treatment tended to show superior efficacy over ABK treatment, but safety was found to be equal. Anti-MRSA agents were administered for 8.6 days to the ABK group, and for 10.2 days to the VCM group. The ABK group costs tended to be lower. Considering patient background, the dosage, administration period, and other relevant factors, we concluded that either ABK or VCM may be equally recommended for the initial treatment of MRSA patients.

It has been reported that fentanyl is released from transdermal fentanyl at a constant rate,the concentration reaches a steady state within 24 hours,and a constant serum concentration of the drug can be maintained through repeated patch application at 72-hour intervals.However,we have encountered a number of patients who experienced pain on the third day after application of the patch,and who were not able to gain satisfactory pain relief even when the dosage was increased.In the current study,serum concentrations of fentanyl were determined to elucidate the relationship between fentanyl concentration and transdermal fentanyl dosage,and intra-individual variability in fentanyl serum concentration after fetanyl patch application in patients with cancer pain.Blood samples were collected from 38 patients at 24,48,and 72 hours since the second or later application of the fentanyl patch.A good correlation was obtained between the dose of transdermal fentanyl and the fentanyl serum concentrations(r=0.9565,0.8785 and 0.9351 at 19-30,45-55 and 65-79 hours,respectively,after patch application).When the intra-individual variabilities in serum concentrations were examined,significant differences were noted between 45-52 and 19-25 hours,between 65-72 and 19-25 hours,and between 65-72 and 45-52 hours after application of patches in a paired analysis of variance(P =0.0038,P

アセトアミノフェン(APAP)坐薬の成分含量は1個200mgが最大で, がん性疼痛患者に用いる場合, 海外における用量(4000mg/日上限)を目安に投与するケースがあるため, 一回に3～4個挿入しなければならない. そこで, 今回, 1個600～800mgの坐薬を調製し, その有用性について検討した. 方法は, APAP経口投与患者と直腸内投与患者の血中トラフ濃度を測定し, 副作用についても比較検討した. その結果, APAP経口投与群と直腸内投与群の血中濃度は, ほぼ同等な値を示した. また, APAP使用1週間後のAST, ALTおよび総ビリルビン値に異常値は認められなかった. さらに, APAPを経口投与から直腸内投与に切り替えた症例で, 切り替え前後でNRSに変化がなく, 血中濃度もほぼ同等な値を示していた. 以上のことから, 今回, 調製した高用量APAP坐薬はがん性疼痛患者において血中濃度と安全性に問題なく使用可能であると考えられた.

Cyclosporine (CyA) is the most commonly used immunosuppressive agent in patients who undergo kidney transplantation. Dosage adjustment of CyA is usually based on trough levels. Recently, trough levels have been replacing the area under the concentration-time curve during the first 4 h after CyA administration (AUC(0-4)). The aim of this study was to compare the predictive values obtained using three different methods of AUC(0-4) monitoring. AUC(0-4) was calculated from 0 to 4 h in early and stable renal transplant patients using the trapezoidal rule. The predicted AUC(0-4) was calculated using three different methods: the multiple regression equation reported by Uchida et al.; Bayesian estimation for modified population pharmacokinetic parameters reported by Yoshida et al.; and modified population pharmacokinetic parameters reported by Cremers et al. The predicted AUC(0-4) was assessed on the basis of predictive bias, precision, and correlation coefficient. The predicted AUC(0-4) values obtained using three methods through measurement of three blood samples showed small differences in predictive bias, precision, and correlation coefficient. In the prediction of AUC(0-4) measurement of one blood sample from stable renal transplant patients, the performance of the regression equation reported by Uchida depended on sampling time. On the other hand, the performance of Bayesian estimation with modified pharmacokinetic parameters reported by Yoshida through measurement of one blood sample, which is not dependent on sampling time, showed a small difference in the correlation coefficient. The prediction of AUC(0-4) using a regression equation required accurate sampling time. In this study, the prediction of AUC(0-4) using Bayesian estimation did not require accurate sampling time in the AUC(0-4) monitoring of CyA. Thus Bayesian estimation is assumed to be clinically useful in the dosage adjustment of CyA.

We studied the quality and stability of generic sodium ozagrel solution products for injection. Through the use of inspection apparatus, we noted exfoliation of the surface layer of glass ampoules filled with sodium ozagrel solution drug products for injection. Also, foreign insoluble matter, such as oil droplets, which was assumed to be silicone that had been applied to the internal surface of syringe barrels, was observed in pre-filled syringe products. In a stability study performed under accelerated conditions (40°C/75% RH) the generic sodium ozagrel solutions yielded a degradation product that was not detected in the lyophilized original product. The degradation product content of some of the generic products was over 16 mg/mL of sodium ozagrel, exceeding the specification for the original lyophilized product. These results indicate that some of the generic products are inferior in quality and stability to the original lyophilized drug.

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin ( n = 41), vancomycin ( n = 19), or panipenem ( n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution ( V ) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL arbekacin = 0.0238 × BW/serum creatinine level for PCAs of arbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, V arbekacin = 0.54 liters/kg, CL vancomycin = 0.0250 × BW/serum creatinine level for PCAs of vancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, V vancomycin = 0.66 liters/kg, CL panipenem = 0.0832 for PCAs of panipenem = 0.179 × BW for PCAs of ≥33 weeks, and V panipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of

The aim of this study was to devise a Drug Compliance Instruction Program (DCIP) for patients with type 2 diabetes taking oral hypoglycemic agents (OHA) and to assess its effectiveness. The new program was devised to improve levels of understanding and implementation in drug therapy for diabetes with the aims of contributing to and evaluating the effectiveness of such therapy. As its major features, the program uses the level of drug therapy implementation as an indicator of drug compliance and gives patients instructions on several occasions to ensure that they continue to be effective. Subjects were 109 type 2 diabetes outpatients who had HbA1c levels of 7% or more and were taking OHA. To study the effectiveness of the instructions, patients were randomly assigned to two groups : a single instruction group (n=66), and a multiple instruction group (n=43), whose subjects received instructions at least twice.DCIP significantly improved the levels of understanding (p=0.001) and implementation (p=0.033) of the drug therapy. The status of glycemic control based on HbA1c levels was used as an indicator in the evaluation of instructions, whose educational effect was significantly higher in the multiple instruction group than in the single instruction group (p=0.042). By enhancing levels of understanding and implementation in drug therapy for diabetes, DCIP significantly improved glycemic control, and this was maintained when instructions were given on several occasions.

Objectives: Tibolone (KB-889) is a novel compound that possesses tissue-specific hormonal effects. We investigated the pharmacokinetics of tibolone in postmenopausal women in four pharmacokinetic studies, namely a dose linearity study, a multiple dose study, a study in fasted condition, and a study in elderly. In this report, the results obtained from the above four studies are summarized.Methods: In the dose linearity study, a single dose of 0.5 mg, 1 mg and 2 mg of tibolone was administered to 6 postmenopausal women using a 3-period crossover method with at least a 7-day wash-out period between treatments. In the multiple dose study, 2 mg of tibolone was administered once daily for 4 days to 6 postmenopausal women. In the study in fasted condition, a single dose of 2 mg of tibolone was administered to 6 postmenopausal women after overnight fasts. In the study in elderly, a single dose of 2 mg of tibolone was administered to 6 elderly women aged 65 or older. Plasma and urine concentrations of tibolone and its metabolites were measured.Results and Conclusion: Plasma concentrations of the 3α-OH and 3β-OH metabolites of tibolone were measured, since the levels of tibolone and its Δ4-isomer were under or near the detection limits. After single dose administration of 0.5, 1 and 2 mg of tibolone, the means of Cmax and AUC0-12h of plasma 3α-OH metabolite were 2.3, 3.5 and 6.5 ng/mL and 10.2, 18.5 and 36.7 ng·Eh/mL, respectively, and those of 3β-OH metabolites were 0.9, 1.7 and 3.1 ng/mL and 4.6, 8.8 and 17.7 ng·Eh/mL, respectively. The means of Tmax and T1/2 (6-12h) of plasma 3α-OH and 3β-OH metabolites were between 3.7 and 5.7 h, and between 3.2 and 4.4 h, respectively. The pharmacokinetic properties of tibolone were considered to be linear within the dose range of 0.5 mg to 2 mg. In the multiple dose study, no accumulation was found. When comparing the pharmacokinetic parameters obtained from the study in fasted condition with those of day 1 of the multiple dose study, the absorption of tibolone was rapid under fasted condition, but AUC was not influenced by food intake. [The means of Tmax of 3α-OH and 3β-OH metabolites were 1.17 and 1.33 h in fasted condition, and 3.83 and 4.00 h on day 1 of multiple dose.] Finally no difference in pharmacokinetics was found between postmenopausal women and elderly women in the comparison of the pharmacokinetic parameters obtained from the study in the elderly and those of day 1 of the multiple dose study.

Postoperative nausea and vomiting (PONV) with morphine therapy develops in more than 60% of patients after surgery, markedly reducing patient QOL. The prophylactic effect of several antiemetics has already been studied, but evaluations, and even those using the same drug, are not uniform. The present research involved a meta-analysis of randomized controlled trials on prophylactic drug therapy for PONV in patients receiving morphine for the treatment of postoperative pain. The efficacy of the prophylactic administration of the drugs was examined. As a result, meta-analysis of five drugs was possible and the evidence of efficacy was shown for three drugs ranked in order of an increasing odds ratio (OR) and confidence interval (CI): dexamethasone (OR: 0.23, 95% CI: 0.15-0.35, p < 0.00001), droperidol (OR: 0.27, 95% CI: 0.21-0.34, p < 0.00001), and metoclopramide (OR: 0.48, 95% CI: 0.30-0.75, p < 0.001). These results suggest that the three drugs are effective in prophylactic treatment for PONV. Of them, dexamethasone used as a prophylactic drug for PONV provided the best results. Dexamethasone was shown to reduce the incidence of PONV from 66-80% to 16-50% with a dose of 1.25 to 10 mg and to be suitable as a first drug of choice.

Two-step conversions of myo-inositol into (±)-2,3,4,5,6- and 1,3,4,5,6-penta-O-benzyl-myo-inositols are described. Starting from these monohydroxy derivatives of myo-inositol, O-β-L-arabinopyranosyl-(1 → 2)-sn-myo-inositol from Japanese green tea [SENCHA], Camellia sinensis, and O-α-D-galactopyranosyl-(1 → 3)-sn-myo-inositol (galactinol) as well as its homolog, O-α-D-galactopyranosyl-(1 → 6II)-galactinol, were synthesized by way of the in situ activating glycosylation procedure.

Four tri-O-benzyl derivatives of 2-deoxy-2-(2,4-dinitroanilino)-D-glucopyranose were synthesized. Glycosylation using 3,4,6-tri-O-benzyl-2-deoxy-2-(2,4-dinitroanilino)-D-glucopyranose as glycosyl donor and a reagent mixture of p-nitrobenzenesulfonyl chloride, silver trifluoromethanesulfonate, and triethylamine produced β-glycosides with complete selectivity. Starting from benzyl 3,6-di-O-benzyl-2-deoxy-2-(2,4-dinitroanilino)-β-D-glucopyranoside as acceptor, O-α-D-galactopyranosyl-(1→4)-O-β-D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranose, the human blood-group P1-antigenic determinant, was synthesized.

The effects of co-administration of antacid (Maaloxreg; 15ml) and sucralfate (1g) on the pharmacokinetic actions of roxatidine acetate (75mg), a typical histamine H2 antagonist, were evaluated in six healthy volunteers following a meal. After the coadministration of roxatidine and sucralfate or antacid, no significant difference was demonstrated in the pharmacokinetics of roxatidine. However, when sucralfate administered together with roxatidine before the meal, the pharmacokinetic actions of roxatidine were significantly decreased compared to roxatidine alone. There was no effect in the absorption of roxatidine, when Maaloxreg; and sucralfate were taken by oral administration.

We have reviewed the Japanese literature on patients mistakenly ingesting the plastic press through packages (PTP) together with the tablets or capsules, surveyed the current situation at Kitasato University East Hospital and Kitasato University Hospital (our hospital), and discuss preventive measures.The literature during the past 10-year period reported about 23.9 cases/year of patients mistakenly ingesting PTP. At our hospital, an average of 5.6 cases were treated annually. When cases not reported in the literature are included, the member may by considerably greater. The reasons for mistaken ingestion include: “took the drug too hastily” “took the drug while talking” and “took the drug mixed with other drug”, suggesting that the patients attention was directed to other factors during the ingestion of the tablets/capsules in many cases.To prevent the misingestion of PTP, measures are necessary from the drug manufacturer, hospital, and the patient. At Kitasato University East Hospital, an explanatory leaflet for preventing mistaken ingestion of PTP was produced and distributed to patients. After distribution, 75.4% of the patients polled replied that they now realize the danger associated with misingestion and will be more careful from now on. The production and distribution of such explanatory leaflets may by useful for preventing the mistaken ingestion of the PTP by patients.

This study was designed to clarify the pharmacokinetics of prophylactically administered cefmetazole in serum, intestinal tissue, and subcutaneous adipose tissue in patients who underwent surgery for colorectal cancer.Cefmetazole sodium (1 g) was given intravenously during the induction of anesthesia, followed by a 1-g dose after 3 hours. Blood samples were taken at the start of surgery, immediately before administration of the additional dose of cefmetazole, at the time of lesion resection, and at the time of wound closure. Tissue samples were obtained immediately after lesion resection and at the time of wound closure. Concentrations of cefmetazole in serum and tissue were measured by high performance liquid chromatography using an internal standard for calibration. Minimum inhibitory concentrations (MIC80) of cefmetazole for Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis were measured, and pharmacokinetics were evaluated.In subcutaneous adipose tissue, cefmetazole concentrations were maintained higher than the MIC80's for E. coli and K. pneumoniae, but were low in all patients regardless of the time of measurement.The low transition rate of cefmetazole into subcutaneous adipose tissue indicates the need for additional measures, such as high-pressure washing of the subcutaneous wound tissue.

Methyl and benzyl 2,3,4-tri-O-benzyl-D-glucopyranuronates, prepared from D-glucurono-6,3-lactone, afforded selectively the corresponding α-glucopyranosiduronates by the aid of the condensing reagent system composed of p-nitrobenzenesulfonyl chloride, silver trifluoromethanesulfonate, and triethylamine. Using this method, O-α-D-glucopyranuronosyl-(1→3)-O-α-L-arabinofuranosyl-(1→3)-D-xylopyranose, one of the minimal component units in the structure of plantago-mucilage A from the seeds of Plantago asiatica Linne constituting a Chinese medicine : chegianzi [].

With a recent progress in biotechnology, mass production of various kinds of cytokines became possible. At present, recombinant human granulocyte-colony stimulating factor, rhG-CFG is widely applied to clinical areas, and its good efficacy has been confirmed.rhG-CSF is administered by drip infusion or by subcutaneous injection, which is chosen depending on the indications. We previously indicated that the adsorption of rhG-CSF onto an end-line filter used for preventing compromised hosts from the infection or the infusion route was a serious problem for its use, because the administration dose was extremely low, in an order of μg.Since we obtaind a newly developed filter (PDl), we made a comparative study on the adsorption of rhG-CSF to two kinds of filters which are frequently used for infusion; ELD-096LL and IVEX-II.The drug was used at a half of the ordinary adult dose of 150μg/100ml. The adsorption of rhG-CSF was found for the conventional filters but almost not for the new fluter tested. Its adsorption to the infusion route was estimated to be 10-20%.

Glycogen-storage-disease-relating linear tetra-, hexa-, and octasaccharides of D-glucose having α(1→4) and α(1→6) linkages were synthesized using a stereoselective dehydrative glycosylation with a reagent mixture of p-nitrobenzenesulfonyl chloride, silver trifluoromethanesulfonate, N,N-dimethylacetamide, and triethylamine. A cross-condensation of a quasi-stoichiometric amount of a donor and an acceptor of an octasaccharide, followed by deprotection, afforded a glucohexadecasaccharide.

There are a limited number of reports that compare the clinical efficacy of anti-MRSA agents such as arbekacin (ABK), vancomycin (VCM), teicoplanin (TEIC) and linezolid (LZD). There is a tendency for these four agents to show variation in the inflammatory response parameters, in C-reactive protein (CRP) and in white blood cell count (WBC), depending on the administration period. There was no significant difference among the agents in analysis of variance (ANOVA) in the group of days 1-3 (p = 0.0536) but there was some significant difference in the group of days 4-7, as well as days 8-14 (p0.001, p0.01) in relative variation rate of CRP. Furthermore, we compared in more detail the groups of LZD, VCM and ABK, with a significant decrease of CRP, each of which showed more decrease in comparison with the group of TEIC in the period days 4-7 (p0.01). We took 1-hr serum level after days 3-4, with the ABK treatment as the peak concentration (C(peak)). Having made nonlinear logistic regression analysis of CRP and C(peak)/MIC, we concluded that the decrease rate estimable by early inflammatory effect could be decreased to some 40%, assuming that C(peak)/MIC shows the high value within 4 days after ABK treatment.

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Purpose To determine the mechanism of intraoperative floppy-iris syndrome (IFIS) by examining the binding affinity of tamsulosin and silodosin to α-receptors and melanin pigment using control and α 2 -blocker chronically administered in rabbit models. Setting Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan. Design Experimental study. Methods The study was performed in isolated albino and pigmented rabbit iris dilators using pharmacologic and morphologic examinations. Results For pharmacologic examinations, the mean p K B values (p K B = −log K B , where −log K B is the equilibrium dissociation constant of the antagonist–receptor complex) of tamsulosin in albino and pigmented rabbits were 9.10 and 8.08 and those of silodosin, 10.3 and 8.11, respectively. The p K B values of tamsulosin and silodosin in albino rabbits were significantly higher than in pigmented rabbits. In the isolated rabbit iris dilator, the maximum contraction evoked by 10 −3 mol/L phenylephrine gradually decreased by repetitive application in the chronic α-blocker–administered models. For morphologic examinations, the sizes of the pigment granules of pigment epitheliums for the α-blocker–administered models were irregular. The shape of shared nucleus of dilator muscles and pigment epitheliums changed to lobular, and the dilator muscle layer was thinner than in the control. Conclusions The high affinity of α-blockers for α 1 -adrenoreceptors is important in the analysis of the mechanism of IFIS. However, IFIS should not be attributed to long-term binding with receptors alone; the drug–melanin interaction causing dilator muscle atrophy is probably the other important factor in the mechanism of IFIS. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

The pain experienced by cancer patients can be managed in 70-90% of cases by the World Health Organisation protocol for cancer pain. However, cancer pain treatment in Japan is not sufficiently effective. To use medicine safely and effectively, various problems must be solved. Therefore, in this study, appropriate usage of cancer pain treatment was examined. We were able to use acetaminophen suppositories (800 mg each) in cancer pain patients. It was suggested that high serum concentrations of oxycodone and hydrocotarnine might be observed in geriatric patients or in the state of decreased hepatic blood flow, making dose adjustment is necessary for such patients. We also clarified that the conversion ratio from oral oxycodone to intravenous ocycodone/hydrocotarnine was 0.71±0.12. In addition, we clarified the pharmacokinetics of controlled-release oxycodone in patients with cancer pain. Moreover, the findings of our study indicate that in the steady state, the serum concentrations of fentanyl are not maintained at a constant level for 3 days following the use of transdermal fentanyl. We established a method of appropriately passing a nasal duct for sustained release of fine granules of morphine sulfate. Resolution of the clinical problems associated with cancer pain treatments is anticipated to allow the proper use of cancer pain treatments in Japan.

A new type of nonionic surface-active agents containing sugars as the hydrophilic group were synthesized and evaluated for their antimicrobial activity. Methyl 6-deoxy-3-O-dodecyl-6-halo-D-glucopyranoside derivatives showed powerful antimicrobial activity, but no significant differences were observed on the activity with regard to the kinds of anomers as well as halogen atoms.

A series of 3-O-alkyl-1,2-O-isopropylidene-alpha-D-glucofuranoses (3-7), 6-deoxy-3-O-dodecyl-6-halo-1,2-O-isopropylidene-alpha-D-glucofuranose s (9-11), and 6-deoxy-3-O-dodecyl-6-halo-D-glucopyranoses (12-14) were prepared from 1,2; 5,6-di-O-isopropyridene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds having C12 and C14 alkylchains at C-3 of 1,2-O-isopropylidene glucoses were the most effective in vitro antibacterial screening, of which the structure-activity relationships are also discussed.

A series of 3-O-alkyl and 3-O-haloalkyl-D-glucoses were prepared from 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds with C12 and C14-alkyl chains were the most effective in vitro antibacterial screening, among 3-O-alkyl and 3-O-haloalkyl derivatives. The 3-O-alkyl derivatives were more effective than 3-O-haloalkyl derivatives.

Oxinorm powder is a rapid-release preparation of oxycodone hydrochloride for oral administration recently marketed for the first time in Japan. Administration of a powdered drug through a nasal tube is known to involve the risk of tube obstruction by the drug. For narcotic preparations like oxinorm powder, it is desirable from the perspective of drug control, that the drug administered be unlikely to remain in the cup, syringe or catheter used, and that the drug be dispensable in precise amounts. The present study was undertaken to identify problems associated with administration of oxinorm powder through a nasal tube and to determine an appropriate method for its administration. First, the solubility of the powder in various solvents was evaluated macroscopically to select initially appropriate solvents. Then, the drug dissolved in each of these solvents was administered through 3 types of catheters with different raw materials and forms, to simulate drug administration through a nasal tube. Percent residual drug remaining on/within the cup, syringe, and catheter was measured by HPLC, to evaluate the adhesiveness of the drug. When dissolved in distilled water, black vinegar, or milk, the drug was easy to administer through the catheter, with a low percentage of drug remaining on the cup, syringe, and catheter, suggesting that these fluids can be used as solvents for oxinorm powder. Semidigested nutrients such as Ensure.H were found to be unsuitable solvents for oxinorm powder.

Occasionally, pain control with the fentanyl patch may lead to overdose at an initial dose of 2.5 mg, as well as during dose increase from 2.5 to 5.0 mg. Respiratory depression and other adverse drug reactions associated with fentanyl overdose have been observed in several of our patients. We developed a procedure for applying one-half of the fentanyl patch formulations and evaluated the new mode of application by examining the fentanyl concentration in 32 patients with cancer-related pain who had been using the fentanyl patch for pain control. While some patients were treated with the full-sized 2.5-, 5.0-, or 7.5-mg formulations, others were treated with the half-sized 2.5-mg formulation. The fentanyl patch was equally divided by drawing a line on the side on which the product name and dose were written. Tegaderm was applied to the patient's skin, and after detaching from the protective liner, half of the patch was applied to overlap Tegaderm along the line and the other half applied directly to the skin. Blood samples were collected 48-72 h after patch application. The mean serum concentration of fentanyl given in the half-sized 2.5-mg formulation was 0.286 ng/ml, which was approximately one-half of the concentration of the full-sized 2.5-mg formulation, 0.544 ng/ml. Therefore the 2.5-mg fentanyl patch, applied using the one-half procedure we developed, is clinically useful.

The demand for oxycodone increases in the treatment of patients with cancer pain, but there is no injection formulation containing oxycodone as a single ingredient in Japan. Instead, we have an oxycodone/hydrocotarnine compound product. Long ago, hydrocotarnine was added to enhance the analgesic effect of oxycodone. However, the mechanism of hydrocotarnine is unclear, and few studies have mentioned the conversion ratio between intravenous and oral oxycodone. In the present study, in order to define the conversion ratio between them, we investigated 18 patients treated by intravenous or oral oxycodone and changed to another administration route during their treatment. We surveyed the change in pain level and adverse effects before and after changing the administration route. The conversion ratio from oral oxycodone to intravenous oxycodone/hydrocotarnine was 0.71+/-0.12 (mean+/-S. D.), and no obvious change in adverse effect was observed.

Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

Cyclosporine (CyA) is the most commonly used immunosuppressive agent in patients who undergo kidney transplantation. Dosage adjustment of CyA is usually based on trough levels. Recently, trough levels have been replacing the area under the concentration-time curve during the first 4 h after CyA administration (AUC(0-4)). The aim of this study was to compare the predictive values obtained using three different methods of AUC(0-4) monitoring. AUC(0-4) was calculated from 0 to 4 h in early and stable renal transplant patients using the trapezoidal rule. The predicted AUC(0-4) was calculated using three different methods: the multiple regression equation reported by Uchida et al.; Bayesian estimation for modified population pharmacokinetic parameters reported by Yoshida et al.; and modified population pharmacokinetic parameters reported by Cremers et al. The predicted AUC(0-4) was assessed on the basis of predictive bias, precision, and correlation coefficient. The predicted AUC(0-4) values obtained using three methods through measurement of three blood samples showed small differences in predictive bias, precision, and correlation coefficient. In the prediction of AUC(0-4) measurement of one blood sample from stable renal transplant patients, the performance of the regression equation reported by Uchida depended on sampling time. On the other hand, the performance of Bayesian estimation with modified pharmacokinetic parameters reported by Yoshida through measurement of one blood sample, which is not dependent on sampling time, showed a small difference in the correlation coefficient. The prediction of AUC(0-4) using a regression equation required accurate sampling time. In this study, the prediction of AUC(0-4) using Bayesian estimation did not require accurate sampling time in the AUC(0-4) monitoring of CyA. Thus Bayesian estimation is assumed to be clinically useful in the dosage adjustment of CyA.

We developed an HPLC procedure using electrochemical detection for the quantitation of oxycodone and hydrocotarnine in cancer patients serum. An eluent of methanol:acetonitrile:5 mM pH 8 phosphate buffer (2:1:7) was used for the mobile phase. The calibration curve was linear in the range from 10 ng/mL to 100 ng/mL. The recovery of oxycodone and hydrocotarnine was 97.2% and 90.5%, respectively. The relative standard deviations within-runs and between-runs for the assay of oxycodone or hydrocotarnine were less than 4.8%. The method developed here was better than the method reported previously.

Japanese Pharmacopoeia (J. P.) requires that the pyrogen test is essential for parenteral solutions. But, in hospital pharmacy, it is practically impossible to perform the official test because of the difficult control of test animals, limited laboratory facilities and timeconsuming procedures. In the study for a simplified checking, a method better than the J. P. pyrogen test was found. The method requires Limulus Lysate, a blood component of Limulus, which is presently applied for the quantitative analysis of endotoxin. The result of this study indicates the possibility of checking pyrogens in parenteral solutions prepared at a hospital pharmacy.

The metabolism of lipids in the intestines was studied in vitro on their surface. Interfacial tension between lipids and water is depressed by adsorption of bile salts at the lipid-water interface. During triglyceride hydrolysis, the fraction of monoglyceride at this interface increases, leading to additional depression of interfacial tension and the formation of a fine lipid dispersion. The interfacial tension of lipid-water is minimum at optimum HLB (hydrophile lipophile balance) of mixed emulsifiers. With further hydrolysis, the monoglyceride fraction at the interface becomes larger, leading in turn to greater interfacial tension. Fine emulsion droplets produced on decreasing the interfacial tension to 0.50.3mN·m-1, may be adsorbed on the intestinal wall when the HLB of the adsorbed amphiphile layer becomes lipophilic. This is because an amphiphile aggregate disperses water when it is hydrophilic, but forms an amphiphile phase when the hydrophile lipophile property is balanced or lipophilic. After absorption of emulsion droplets, triglyceride may form by esterification of glycerides. Thus, the HLB of mixed amphiphiles may become hydrophilic, and bile salts may dissolve into the blood and recirculate.