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For providing appropriate pharmacotherapy, "Doing the right things, and doing things right" are necessary. Additionally, vigilance is required for the appropriate use of pharmaceuticals. Evidence-based medicine has been a common approach to healthcare, and many guidelines have been published. In addition, risk management plans (RMPs) are developed upon the approval of new drugs. Therefore an environment to provide the best healthcare based on scientific evidence has been developed. When putting RMPs into practice, it is necessary to understand and utilize regulatory science (RS). If pharmaceuticals are not used, no adverse drug reactions will occur; at the same time, diseases will not be cured or symptoms controlled. We should exploit RS to use drugs appropriately. RS is not meant to limit the use of drugs in pharmacotherapy but to indicate the rules for their appropriate use. Pharmacists should ensure that patients receive maximum benefit from prescribed drugs in every case and should determine the best ways to minimize risk.

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 μg/ml, but it increased during S-1 therapy, reaching 22.9 μg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 μg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.

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.

Sentinel lymph node biopsy (SLNB) has recently been accepted as a standard diagnostic procedure in the treatment of early breast cancer.However,since there are no dyes for this diagnostic technique on the market in Japan,we conducted a survey of the situation of dye use and preparations for SLNB in regional cancer treatment centers.We sent a questionnaire to 286 institutions for which the response rate was 75.2%.The results showed that 80.9% of the institutions had already introduced SLNB and the dye-guided method was used by more than 90% of them.The most common indication for SLNB was breast cancer.Patent blue prepared by hospitals and indigo carmine and indocyanine green (both off-label use) were commonly used dye preparations for SLNB.Although patent blue is the most satisfactory dye and has the highest identification rate,problems were reported with hospital preparations.There were also differences between institutions regarding storage conditions,validity dates,preparation standards and annual use of this dye.The survey also revealed that 74.4% of institutions wanted dyes for SLNB to be marketed and there were numerous opinions on which types of patent blue preparation should be available.In conclusion,the present study indicated that there was a need for SNLB dye preparationsinclinicalpracticeandthatitwould be beneficial to make such preparations available on the market.

As the effect of the filling process of portable pumps on the homogeneity of drug concentrations had not been investigated,in this study,we examined the influence of the filling process of the anticancer agent 5-fluorourcil (5-FU) and saline in this respect.We used 3 types of pump and filled the pump in 3 different ways (5-FU first and then saline,saline first and then 5-FU,and mixing 5-FU and saline beforehand and then filling).There was a significant variation in the 5-FU concentration when 5-FU and saline were added separately but the drug concentration did not vary when 5-FU and saline were mixed before filling the pumps.The result also varied with the type of pump.Our findings suggested that the drug and saline were not mixed uniformly in some types of pump when 5-FU and saline were added separately.Therefore,it is important to mix the drug and saline well before filling pumps.

During cancer chemotherapy,myelosuppression is a frequently observed toxicity manifestation which may sometimes cause severe infections.In this regard,though leukopenia-induced infections are more closely related to neutrophil counts than leukocyte counts,it is important to evaluate both leukocyte counts and neutrophil counts as markers of myelosuppression.Neutrophil counts,however,are sometimes estimated to be half leukocyte counts without conducting differential leukocyte counts.In the present study,the authors evaluated the necessity of differential leukocyte counts during cancer chemotherapy using pooled laboratory data at the University of Fukui Hospital.Variation in the percentage of neutrophils in leukocytes was observed in each leukocyte range,with the neutrophil count decreasing in pace with decreases in the leukocyte count.As an alternative index to the neutrophil count,the utility of the leukocyte count is thus considered to be low in cancer chemotherapy.There was also a divergence between adverse event grade between neutrophil and leukocyte numbers.In addition,neutrophil counts in 14.8% of the patients (26)were less than 1000/μL in spite of the fact that their leukocyte counts were higher than 3000/μL,and it was noted that 23 of them had undergone a paclitaxel-containing regimen.These results suggested that leukocyte differential counts should be measured during cancer chemotherapy,especially during the nadir period and when receiving chemotherapy containing paclitaxel.

The purpose of this study was to evaluate the quality of the original and 3 generic formulations of Iopamidol injection.To do this,the free iodine concentration and osmotic pressure were measured.In addition,impurities were tested for using high performance liquid chromatography-tandem mass spectrometry.There were no major differences between the original and generic formulations as regards free iodine concentration and osmotic pressure measurements,though one lot of the original formulation failed the free iodine concentration test.However,in the HPLC analysis,some substances not present in the original product were detected in the generic formulations.One of them was identified as DM 1/2,a substance related structurally to Iopamidol.

The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. β-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the β-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-D-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the β-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC50 ) value of 83.8 μM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal β-glucuronidase-mediated SN-38-G deconjugation.

We previously reported that the protocols of bioequivalence studies on generic pravastatin sodium had not been standardized. The bioequivalence of generic drugs is confirmed by crossover studies using healthy volunteers. In this study, we examined protocols for bioequivalence studies on generic itraconazole (ITCZ) formulations which show poor absorption.Based on pharmacokinetic parameters obtained from pharmaceutical companies, we evaluated the protocols for studies on 5 generic formulations and the results of these studies. The sampling schedule, number of subjects and food intake status were found to be different for each study and there were also differences in the intra-individual variation index for Cmax and AUCt.In conclusion, it is difficult to accurately evaluate the quality of bioequivalence studies only on the basis of mean and standard deviation values that have been made publicly available.

We examined differences in adverse drug reactions reported in trials for new drug applications and those reported in early post-marketing phase vigilance (EPPV) for drugs approved between October, 2001 and July, 2003. In EPPV reports, we found that the proportion of adverse drug reactions noted from blood tests (e.g. drug-induced hepatitis, hematology adverse reactions, electrolyte metabolism disorders, and renal dysfunction) was less than that of other adverse drug reactions. We consider that this was because blood tests were not conducted regularly enough and the reason that such reactions are severe when discovered.Since EPPV is considered as phase IV of drug testing, regular blood tests are still required and we feel that it is necessary to carry out pharmacovigilance more thoroughly to ensure the safety of drugs after they have been marketed.

The equivalencies of generic drugs are assessed by biological equivalency tests. These tests are conducted on healthy subjects by the crossover method in comparison with the original product, which makes them a useful method for comparing bioequivalencies among generics. However, since a large variation in the results is sometimes observed, we decided to determine what causes this.We requested 28 companies to provide biological equivalency test results for pravastatin sodium tablet (23 products) and compared pharmacokinetic parameters among them. There was a large variation in pharmacokinetic parameters, especially in maximum serum drug concentration, area under the serum concentration to time curve and elimination half-life, though there were no differences between the original product and generic product in each test.On comparing individual parameters from two tests that were carried out according to nearly the same protocol, there was a marked difference in the distribution of data among subjects, indicating that this was a factor causing parameter differences between tests. Thus, when pharmacists are thinking of using a generic drug, it is important for them to notonly consider average parameter values but also the process by which these values have been obtained.

In the treatment of infectious diseases, the antimicrobial susceptibility test is an important laboratory test in the selection of appropriate antimicrobial agents. In most hospitals, the antimicrobial susceptibility test is carried out by the method stipulated by NCCLS (National Committee for Clinical Laboratory Standards), a U.S. organization, and thus the standard (break point) used for interpreting the result is based on dosage regimens in that country. In the present study, we calculated time above MIC (T >MIC) for the dosage regimen indicated by Japanese drug packages inserts for ceftazidime (CAZ) and piperacillin (PIPC). T >MIC is a PK/PD parameter related to the effect of beta-lactams and is calculated using Japanese serum concentration measurement data for them. We determined that this parameter covered the full range judged by the susceptibility test to be sensitive (S) and concluded that, based on T >MIC, sufficient efficacy might not be achieved under the Japanese dosage regimen even though the result had been S in the susceptibility test. This is because there are many differences in dosage regimens between Japan and the U.S.Despite the fact that Japan has its own dosage regimens, the break point used is the one in NCCLS, which is based on dosage regimens in the U.S., and thus the results of susceptibility tests in Japan may cause susceptibility to be overestimated.

We investigated the situation of early post-marketing phase vigilance reports prepared by pharmaceutical companies for medical institutions. To do this we collected reports prepared by pharmaceutical companies for this purpose and investigated their contents during the period October 2001 to April, 2003. The number of medicines targeted by our investigation was 51.We found that most pharmaceutical companies were preparing final reports for medical institutions a few months after the early post-marketing phase vigilance was over. However, reports differed greatly regarding such aspects as contents, items reported and analysis methods and information on important adverse effects was difficult to understand. We thus feel that there is a need to standardize the format of early post-marketing phase vigilance reports to make the information in them more useful.

Aim St John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined. Methods Thirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day−1) or placebo for 14 days. The study was performed in a randomized, placebo-controlled, cross-over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14. Results SJW decreased the plasma quazepam concentration. The Cmax and AUC0-48 of quazepam after SJW were significantly lower than those after placebo [Cmax; −8.7 ng ml−1 (95% confidence interval (CI) −17.1 to −0.2), AUC0-48; −55 ng h ml−1 (95% CI −96 to −15)]. The urinary ratio of 6β-hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85–3.4)). Quazepam, but not SJW, produced sedative-like effects in the VAS test (drowsiness; P

In Japan, no report has so far been published which evaluates drug use for scabies. We surveyed the prevalence of scabies and its management. The result showed that scabies is not a rare contagious parasitic skin infection. Since there is no effective and safe drug for scabies on the market, the following medications were found to be used for its treatment : crotamiton (unlabeled use), Benzyl benzoate formulation (compounded), γ-BHC formulation (compounded). Adverse events associated with those drugs were also reported. In most case, the patients did not receive adequate counseling regarding their drug therapy.Physicians and other health care professionals have been frustrated by the lack of effective preventive and therapeutic intervention for scabies. It is therefore necessary to approve a drug to treat scabies and to also establish clear guidelines for the treatment and management of scabies.

In 25 cancer patients treated with slow-release oral morphine (MS Contin® in 12 patients and Kadian® in 13 patients) and in 10 cancer patients treated with continuous infusion of morphine, plasma steady-state concentrations of morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) were determined by HPLC. Blood samples were withdrawn at 0 hr, 2 hr, 6 hr after oral administration in patients treated with slow-release oral morphine and once or twice a day in patients treated with continuous infusion of morphine. In 4 cancer patients treated with continuous infusion of morphine, in order to analyze chronopharmacokinetic variability, M-3-G/M ratio was observed at 12: 00 h and 24: 00 h.No significant changes were observed in M-3-G/M ratios and M-6-G/M ratios at 0, 2, and 6 hr after administration of oral morphine. There was no difference between Kadian® and MS Contin®.The M-3-G/M ratio (38.6±25.7) in the oral morphine group was significantly higher than that (15.3±12.9) of the continuous infusion group (p

A heparin lock is technique performed in order to prevent blood coagulation in the needle detained in the vessel, or a catheter. In Japan, when we perform a heparin lock, a heparin injection is diluted with physiological salt solution before use. We need to use prefilled syringes with diluted heparin. We received a sample of this product. We investigated the user-friendliness of the product. From our results, the prefilled syringe with the diluted heparin was found to be useful. Furthermore, when we use the prefilled syringe with diluted heparin, patient safety is increased.

1-beta-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-beta-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 myelogenous leukemia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg / m(2) ) (3 patients), continuous ara-C infusion (20 or 70 mg / m(2) / 24 h) (7 patients), 2-h ara-C infusion (70 mg / m(2) ) (4 patients), and 2-h infusion of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine, a deaminase-resistant ara-C derivative (70 mg / m(2) ) (6 patients)]. Ara-CTP could be determined at levels under 1 microM. 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 N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine 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.

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

As DDS drugs with various drug delivery functions are often prescribed under in conbination with a widerange of concurrent drug therapies, drug information closely related to its clinical usage is required to guarantee the appropriate multiple pharmaceutical functions of DDS drugs: We surveyed the actual concurrent therapy of lipo-PGE1 (Palux® inj. and Liple®), a targeting-type DDS, with various aqueous infusions at both Okayama University Hospital and Fukui Medical School Hospital. The term of the survey, which was done by evaluating the prescription records, and the total number of prescriptions were 14 months and 1, 005 prescriptions, respectively. Lipo-PGE1 was scarcely administered without any concurrently prescribed infusions. Although lipo-PGE1 was mostly diluted with Glucose Injection or Isotonic Sodium Chloride Solution, some electrolyte infusions were also concurrently prescribed with Lipo-PGE1 in some cases. The magnification of the dilution and the administration route seemed to be related each other. The data revealed in this report ave considered to be useful for a clinical usage-based assessment system to obtain further information guaranteeing the drug delivery function of Lipo-PGE1 from both a pharmaceutical and pharmacodynamic viewpoint one word.

The protective effect of α-glucosidase inhibitor (GI) by once a day administration against the increase of postprandial blood glucose (ΔPBG) was examined. Using a control group of 5 hospitalized patients with non-insulin-dependent diabetes mellitus (NIDDM) consisting who received only dietary treatment, we demonstrated the effect of GI while considering the influence of an inproved of living environment during hospitalization. The effects on the blood glucose level were studied using the GI treatment group, which consisted of 8 hospitalized NIDDM patients who received medical treatment with GI, and compared the findings before and after GI treatment. In addition, we also compared two GI treatment groups, one which received treatment 3 times a day and the other which was treated only once a day. Blood samples were obtained at 30 min before and 2h after each meal, before sleep and early the next morning. The increase in the postprandial blood glucose levels decreased significantly by the once a day administration of GI, but no significant changes were observed in the control group. The in crease in (ΔPBG) level was also reduced by the once a day administration of GI, and the effect was also similar to that after the 3 times a day administration.Our findings in this small group of patients suggest that good glycemic control can be obtained all day long by the once a day administration of GI.

Cyclosporine A (CyA), an immunosuppressive drug, has shown a potency in pure red cell aplasia (PRCA). However, the effective blood level is not known in PRCA treatment. In a PRCA patient (53-year-old male) who responded to CyA, we carefully monitored CyA trough levels over a 4-year period. In the first 6 months, the hemoglobin level was about 11 g/dl and the CyA trough level was over 150 ng/ml ; the dose of CyA was then tapered to prevent renal toxicity. The trough level was controlled between 100 and 150 ng/ml, and he remained in continuous remission for the subsequent year. However, after that time, the hemoglobin level gradually decreased and PRCA recurred. We then increased the CyA trough level to over 150 ng/ml and his anemia improved. This case report illustrates that a CyA trough level of at least 150 ng/ml is necessary to maintain remission.

In Japan, pharmacists who are in consultation with doctors independently prepare medications in an attempt to meet the needs of patients in the hospital. In particular, the need for hospital preparations to treat cancer is high and diverse. However, unlike gov]ernment-approved medications, independently and individually prepared hospital preparations raise concerns about their effectiveness, safety, economic efficiency, quality control, etc. One way to address these concerns is to commercialize these preparations and to understand the difference between necessity and demand from various points of view. We have conducted nation-wide utilization surveys and evaluated the literature on hospital preparations. On the basis of the findings of this survey, we have concluded that pharmaceutical companies and the government need to implement the commercialization of hospital preparations in clinical practice. In this report, we discuss the significance of commercialization of hospital preparations, concerns regarding pharmaceutical preparations, and our recent efforts on cancer treatment. We hope to continuously contribute to society and to medical care by improving individualized care and by commercializing medications needed in clinical practice.

We performed a pharmacoepidemiological study on triazolam dependence with typical doses in out-patients of Fukui Medical School Hospital. We investigated the prescriptions (duration of treatment and total dose prescribed) for patients administered triazolam.The patients were classified according to the prescription pattern of this drug, Group 1: patients who had been prescribed triazolam daily, Group 2: those who had been allowed to take triazolam when they cannot sleep.Approximately 40% of all the patients had been prescribed triazolam for 8 months or longer, and were judged to be normal dose dependence. The prevalence of this dependence was apparently higher in group 1 than in group 2.

We performed a pharmacoepidemiological study on the effect of different types of questionnaires on coughing and the prevalence of this symptom in out-patients taking angiotensin converting enzyme inhibitors (ACEI) in Fukui Medical School Hospital.The following three types of quentionnaires were prepared:Type 1 ; Questionnaire asking whether the patient has a cough or no after implying that ACEI might cause this symptom.Type 2 ; Questionnaire on the general adverse effects of ACEI, including coughing.Type 3 ; Questionnaire on the general adverse effects of ACEI other than coughing.All questionnaires included a blank space in which the patients were asked to write any adverse effects. The patients were randomly divided into three groups. Each group was given one of the three questionnaires. In the type 3 questionnaire, no patient com-plained of coughing. The prevalence of cough was higher in type 1 questionnaire than in type 2 quetionnaire patients. These results indicate that the prevalence of adverse effects varies greatly depending the type of questions in the questionnaire.

We investigated the influence of pharmacokinetics on the dilution of isosorbide (ISOBIDE®) in three healthy male volunteers. They received both undiluted ISOBIDE® and 5-times-diluted ISOBIDE®. Gas chromatodraphy was used to measure the serum concentration and excretion rate of isosorbides in urine.The results showed thet the pharmacokinetic parameters did not significantly differ between to undiluted ISOBIDE® and 5-times-diluted ISOBIDE® (elimination rate constant of 0.101 hr-1 and 0.106 hr-1, distribution volume of 0.660 1/kg and 0.660 1/kg, half-life of 6.84 hr and 6.57 hr, and excretion amount in urine of 79% and 80%). Therefore, these results indicate that the effect of pharmacokinetics on 5-times-diluted isosorbide remains unchanged.

A new prediction method of vancomycin (VCM) pharmacokinetics has been developed using the modified Bayesian forecasting method involved in time-dependent pharmacokinetics in clearance. We investigated to evaluate the usefulness of this new prediction method compared with that of the ordinary Bayesian forecasting method. Serum samples, obtained from 4 patients at least 3 different days during the period for the VCM treatment were assayed by fluorescence polarization immunoassay. VCM pharmacokinetic parameters and predicted serum VCM concentrations were calculated using this new method and the ordinary one according to the one-compartment model. The precision of the predicted serum VCM concentrations by these two methods at the third experimental day were evaluated with the mean prediction error (ME), mean absolute prediction error (MAE) and root mean squared error (RMSE). The most precise and least-bias prediction of serum VCM concentrations were observed using this new prediction method (ME: -0.36 +/- 1.40, MAE: 1.13 +/- 0.82 and RSME: 1.37). The time-dependent decrease of VCM clearance was observed in all patients. Therefore, the fitting of the actual serum VCM concentrations obtained using the ordinary method produced less precise results than that using this new method. These results suggest the usefulness of this new prediction method considering time-dependent changes in VCM clearance.

In a pharmacoepidemiological study, the response to norfloxacin and ofloxacin (duration of treatment and total dose prescribed) was analyzed in order to determine whether norfloxacin and ofloxacin in combination with metal cation-containing prepara tions have an effect on the outcome of treatment.The treatment duration and total dose prescribed were significantly greater (p

We performed a pharmacoepidemiological study of the response to norfloxacin (duration of treatment and total dose prescribed) in order to determine whether norfloxacin in combination with metal cation containing preparations has an effect on the outcome of treatment. The treatment duration and total dose prescribed were significantly greater (p

Ethnic 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. We 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. Multivariate 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. There 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.

For the purpose of obtaining liposomes with long circulation time in blood, we synthesized 1-O-palmityl-D-glucuronic acid (PGlcUA) and incorporated it into the liposomal membranes. The clearance of the PGlcUA-liposomes composed of dipalmitoylphosphatidylcholine (DPPC), cholesterol, and PGlcUA (40:40:20 as a molar ratio) from blood and their tissue distribution were compared with those of dipalmitoylphosphatidylglycerol (DPPG)-liposomes (DPPC/cholesterol/DPPG = 40:40:20). When [3H]inulin-loaded PGlcUA-liposomes and DPPG-liposomes were intravenously injected into rats, the half-life of the PGlcUA-liposomes in the blood appeared to be 1.7-fold longer than that of DPPG-liposomes. Radioactivities present in plasma and various tissues were measured 22 h after administration of these liposomes, and radioactivity remaining in the plasma was 2.5-fold greater when PGlcUA-liposomes were injected. The distribution pattern of [3H]inulin in PGlcUA-liposomes was similar to that in DPPG-liposomes. The radioactivity recovered in urine was 25% lower in rats treated with PGlcUA-liposomes than in those treated with DPPG-liposomes. Since both PGlcUA- and DPPG-liposomes exhibited similar size distribution and zeta-potential, glucuronic acid, rather than negative charge, on the liposomal surface appears to endow liposomes with a longer circulation time in the bloodstream.

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) (mug/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (mug/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.

We have developed a simple, sensitive and reliable assay procedure for cyclosporin A (CyA), a modified fluorescence polarization immunoasay method incorporating fat emulsion (FE-FPIA), to determine the CyA content in rat skin. The conventional fluorescence polarization immunoassay (FPIA) method for CyA using a commercially available FPIA kit, TDX[○!R] cyclosporine monoclonal whole blood, was modified. A fat emulsion for intravenous infusion, Intralips[○!R], was incorporated for dissolving the CyA extracted from the skin tissue, and a mixture of MeOH/purified water was used as the sample pretreatment medium instead of the precipitation reagent in the conventional FPIA kit intended for whole blood samples. These modifications enabled us to produce a reliable and the sensitive assay of CyA in skin tissue. The reproducibility (coefficient of variation), detection limit, and assay time for FE-FPIA were below 2%, 25 ng/ml, and about 24 min/24 samples, respectively, and were comparable with those for the whole blood samples determined by the conventional FPIA. Pre-purification of samples required by the HPLC assay is not needed in the FE-FPIA method. The usefulness of the FE-FPIA method in evaluating the topical pharmacokinetics of CyA in skin is discussed.