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Background Currently, supplementary serological testing for β-D glucan (BDG) is often selected to diagnose deep mycosis in care covered by the health insurance in Japan. The Wako method used by our center has low sensitivity, and different studies have used different cut-off values due to factors that cause false positives and false negatives. One possible cause of false negatives is the use of platelet-rich plasma (PRP) as the sample material. Because phagocytic white blood cells (WBC) are precipitated by centrifugation and only plasma is measured, it seems unlikely that the actual amount of BDG is being measured when using PRP. Further, a frequent cause of false positives is contamination from blood products and gauze containing BDG. To resolve these issues, the blood cell separator, hydroxyethyl starch, is used to precipitate only the red blood cells to obtain leukocyte-rich plasma (LRP). We hypothesized that it might be possible to improve the diagnostic rate of deep mycosis by measuring the BDG content of plasma containing WBC and fungal components and by comparing the BDG content of PRP and LRP measured simultaneously. Materials and methods Healthy human blood, albumin-added blood, wrung-out gauze fluid-added blood, and fungal solution-added blood were prepared, and PRP and LRP were prepared using hydroxyethyl starch. The BDG content of each sample was measured using the Wako method and compared. In addition, PRP and LRP of fungal-added blood were Gram-stained and examined under a microscope, and the number of WBCs and phagocytosed fungi was counted visually and compared. Results Measuring the BDG content of LRP confirmed that there were no false positives with LRP, and in vitro experiments comparing albumin-added false-positive blood to fungal-added blood showed significant differences between PRP and LRP only in the fungal-added blood. Conclusion Calculating the BDG-ratio (LRP/PRP) by measuring both LRP and PRP may eliminate false positives and false negatives of true deep mycosis and improve the diagnostic rate.

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09-0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.

The Pade approximation gives rational functions \(\frac{P(x)}{Q(x)}\) which approximate a given function \(\psi (x)\). From the approximants P(x), Q(x), one can obtain interesting linear differential equations. We explain the derivation of such equations in a simple example.

In the Pade interpolation, one can make various choices for the grid (interpolating points: \(x_0, x_1, x_2, \cdots \)). Here we discuss applications of the Pade interpolation on a q-quadratic grid defined by \(x_s=q^s+c q^{-s}\).

In this chapter, we consider the Pade approximation where the function \(\psi (x)\) is given by certain infinite products and apply it to the q-difference analog of the Painleve/Garnier equations. As we will see later, the discrete analogs of the Pade approximation (Pade interpolations) are a more natural setting in which to approach the discrete Painleve/Garnier equations. Hence the results in this chapter may be considered as a separate case; however, they show that there is a profound interplay between discrete and continuous cases.

We will consider the Pade approximation problem associated with the function \(\psi (x)=(1-x)^\alpha (1-\frac{x}{t})^\beta \), and derive a pair of linear differential equations from it. Since the compatibility condition of the pair is the sixth Painleve equation \(P_\mathrm{VI}\), we obtain special solutions of the \(P_\mathrm{VI}\) equation from the Pade problem.

The 8-parameter elliptic Sakai difference Painlev\'e equation admits a Lax formulation. We show that a suitable specialization of the Lax equation gives rise to the time-independent Schr\"odinger equation for the $BC_1$ 8-parameter 'relativistic' Calogero-Moser Hamiltonian due to van Diejen. This amounts to a generalization of previous results concerning the Painlev\'e-Calogero correspondence to the highest level in the two hierarchies.

This note is intended to provide an introduction to the theory of discrete Painleve equations focusing mainly on the elliptic difference case. The elliptic Painleve equation is the master case of the continuous/discrete Painleve equations in two variables and has the largest affine Weyl group symmetry \(W(E_8^{(1)})\). Various “integrable” nature such as the symmetry of equation, bilinear form, Lax pair and special solutions are explained from a geometric point of view.

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.

We evaluated the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, as well as the severity and outcome of reactions based on analyses of pharmacist involvement in a collaborative approach to medicine. Of 5436 cases with pharmacist involvement, adverse drug reaction prevention was seen in 440, accounting for 8.1%, and exacerbation avoidance in 213, accounting for 3.9%. We concluded that pharmacist involvement contributes to detect adverse drug reactions and avoid exacerbation, and improves pharmacotherapy safety. We also analyzed 131 cases in which the course after intervention was followed. When categorized by adverse drug reaction severity, Grade 1 and 2 were the same at 45.8%, Grade 3 at 8.4%, respectively. Those findings suggested that pharmacist intervention contributes to early detection of an adverse drug reaction. Also, the relationship between clues for detecting adverse drug reactions by a pharmacist and their severity showed that objective evaluations such as clinical laboratory test results, physical assessments and medication history were important for detecting reactions that became more serious. Patients recovered or recovering from an adverse reaction comprised 76.4%, indicating that pharmacist intervention contributed to exacerbation avoidance and improvement. Our findings revealed the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, and for safety improvement of pharmacotherapy. Additionally, we considered it necessary for the future pharmacist intervention to improve skills of assessing an adverse drug reaction objectively.

To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs).Using an inhalation simulator, we measured drug release from Turbuhaler® (TBH), Diskus® (DKS) and Breezhaler® (BZH) at several peak inhaled flow rates (PIFs) while the DPIs were held at level and tilted (80°). Drug release was then measured from all three DPIs at 0, 30, 60 and 90° of tilt, and capsule rotation was also recorded.Drug release from TBH was flow-dependent while that from DKS and BZH was flow-independent. With TBH, the plot of drug release vs. PIF either at level or at tilted position scattered along approximately the same regression lines. With DKS and BZH, drug release at tilted position was significantly lower than that while at level. With DKS the decrease was almost 20%, while with BZH, drug release frequently failed. With BZH, significant reductions in drug release were observed while the device was tilted by 30-90°.The position in which the DPI is held may affect drug delivery, especially when using BZH.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical efficacy and adverse effects of the β-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the β1 and β2 receptors (Фssβ1 and Фssβ2) by these drugs. Thereafter, we examined the relationship between Фssβ1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Фssβ1 value than the others. Therefore, we constructed a model under the assumption that β-blocking agents exert both indirect action of LVEF increase through the β1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of β-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper β-blocking agent and its administration at a reasonable dose for successful heart failure therapy.

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.

We study a quantum (non-commutative) representation of the affine Weyl group mainly of type $E_8^{(1)}$, where the representation is given by birational actions on two variables $x$, $y$ with $q$-commutation relations. Using the tau variables, we also construct quantum "fundamental" polynomials $F(x,y)$ which completely control the Weyl group actions. The geometric properties of the polynomials $F(x,y)$ for the commutative case is lifted distinctively in the quantum case to certain singularity structures as the $q$-difference operators. This property is further utilized as the characterization of the quantum polynomials $F(x,y)$. As an application, the quantum curve associated with topological strings proposed recently by the first named author is rederived by the Weyl group symmetry. The cases of type $D_5^{(1)}$, $E_6^{(1)}$, $E_7^{(1)}$ are also discussed.

It was reported that homozygosity for a lymphotoxin α (LTA) 1-1-1-1 haplotype (LTA NcoI-TNFc-aa13L-aa26) may identify subgroups with a poor response to infliximab in Crohn's disease patients. Previously, we found a genetic polymorphism that linked with the LTA 1-1-1-1 haplotype and noted that it was a tumor necrosis factor (TNF) α-857 T allele. To investigate the effects of the -857C/T (rs1799724) polymorphism on the expression of TNFα, we compared levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The change in transcriptional activity of the -857T allele was higher than that of the -857C allele. Furthermore, the accumulated transcriptional activity of the -857T allele was 1.3-fold higher than that of the -857C allele up to 48 h. The levels of mRNA and protein of the TNFα after stimulation were also shown to be significantly higher in -857C/T as compared to the -857C/C genotype. Our results suggested that TNFα promoter -857T is higher than -857C in the levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The differences in therapeutic effect of TNF inhibitors among individuals can be explained in part by the induction ability of TNFα via the -857C/T polymorphism.

Rasburicase has a strong and fast effect for reducing blood levels of uric acid. However, there have been no reports of theoretical analysis for the rational dose and interval of administration. Thus we constructed a pharmacokinetic and pharmacodynamic model to determine changes in uric acid level after rasburicase administration at various doses and regimens. The time courses of uric acid level predicted using our model were in good agreement with observed data, indicating adequate performance for our model. The therapeutic effects after a single infusion at various rates of generation of uric acid were predicted. The maximum effect was not a large difference, in spite of the generation rate. Then, the therapeutic effects of repeated administrations were predicted. The effect did not change when rasburicase was administered at more than the usual dose. Besides, as the administration interval increased, the difference between minimum and maximum level of uric acid became greater. However, in all doses and regimens, adequate therapeutic effects were obtained. In conclusion, the model was found useful for predicting therapeutic effect of rasburicase and individually determining rational dosage regimen of rasburicase.

Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has not been analysed theoretically. The present study analysed of sequential changes in the Crohn's disease activity index (CDAI) after repeated administrations of adalimumab using a pharmacokinetic and pharmacodynamic model. In addition, we analysed the validity of the dosage regimen, and the potential efficacy gained by increasing the dose and reducing the interval of administration. The sequential changes in CDAI values obtained with our model were in good agreement with observed CDAI values, which is considered to show the validity of our analysis. We consider that our results showed the importance of a loading dose of adalimumab to obtain remission in an early stage of active CD. In addition, we showed that patients who have an incomplete response to adalimumab can obtain similar efficacy from increasing the dose and reducing the dose interval. In conclusion, our results showed that the present model may be applied to predict the CDAI values of adalimumab for CD. They indicate the validity of the dosage regimen, as well as the efficacy of increasing the dose and reducing the dose interval.

It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous vancomycin for a suspected or definitively diagnosed Gram-positive bacterial infection within 72 h after admission to the intensive care unit. The Vd and elimination half-life (t 1/2) of vancomycin values were calculated using the Bayesian method, and we investigated the relationship between them and APACHE II score. There were significant correlations between APACHE II scores and Vd/actual body weight (ABW), as well as t 1/2 (r = 0.58, p

We evaluated the effectiveness of small group discussion (SGD) in association with a drug abuse prevention program for junior high school students. The students first received a lecture about drug abuse prevention, then participated in SGD. The discussion focused on how to take action when tempted to abuse drugs. We gave a questionnaire 3 times; before and after the lecture (before SGD), and after SGD. Seventy-seven students replied to these questionnaires. After the lecture, knowledge about drug abuse was improved and all students answered that they had never abused drugs. However, in answer to a different question, a few students noted that they might use drugs in some situations. We consider it necessary to give more consideration to this problem. After the lecture, 35.5% of the students felt that they had definitely acquired skills for drug abuse prevention, whereas after the SGD this was increased to 73.7%. In addition, more than 75% of the students answered that the SGD program was useful since the opinions of other students could be heard. These results suggest that more students acquired skills to prevent drug abuse by participation in SGD. Our findings showed that SGD was useful and that the students were able to more effectively understand important concepts related to drug abuse prevention.

We study several variants of q-Garnier system corresponding to various directions of discrete time evolutions. We also investigate a relation between the $q$-Garnier system and Suzuki's higher order $q$-Painlev/'e system by using a duality of the $q$-KP system., 20 pages, 1 tables

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Φ ss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Φ ss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Φ ss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Φ ss exceeded 95%. It was thought that a very high Φ ss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Φ ss. It was shown that the K d ratio (K d for mutant/K d for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Φ ss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Φ ss in EGFR-TKI therapy.

In this study, we established a methodology to calculate the rate of overlooking a dispensing error (inspecting error rate) as a new index for the purpose of determining dispensing error and malpractice rates. Using data obtained from analyses of these error rates at our and two other hospitals, an inspecting error rate was calculated for each institution. Our results showed that inspecting errors occurred at a frequency 3-5 times greater as compared to dispensing errors at each of the examined hospitals. We concluded that construction of a higher quality safety management system would be enabled by incorporation of an inspecting error rate as a new index to evaluate medical safety in regard to dispensing of medicines and managing inspection accuracy.

The associations between the efficacy of IgG reagents and the FCGRIIIa-158V/F polymorphism (rs396991) have been investigated. Although the genotype frequencies in healthy Japanese have been reported, those have varied, as one study reported that the proportions of V/V, V/F, and F/F were 59.1%, 38.6%, and 2.3%, respectively, while another study found that they were 4%, 44%, and 52%, respectively. However, there are no known investigations of the association between the antibody-dependent cellular cytotoxicity (ADCC) activity of adalimumab (ADA), an IgG reagent, in combination with FcγRIIIa and the polymorphism. In this study, we analyzed healthy Japanese to clarify genotype frequency using a direct sequence method. In addition, we examined the association between the ADA-mediated ADCC activity and the polymorphism. Our results showed that the frequencies of the V/V, V/F, and F/F genotypes in healthy Japanese were 9.2%, 39.8%, and 51.0%, respectively. The average activity of ADA-mediated ADCC was 25.0%, 19.0%, and 13.3% in the V/V, V/F, and F/F genotypes, respectively. Then, the ADCC activity of V/V was significantly higher than that of F/F (p < 0.05) in therapeutic concentration. The differences in therapeutic effect of ADA among individuals can be explained, in part, by ADCC activity via the FCGRIIIa-158V/F polymorphism.

Considering a certain interpolation problem, we derive a series of elliptic difference isomonodromic systems together with their Lax forms. These systems give a multivariate extension of the elliptic Painlev\'e equation.

Low-dose aspirin-induced gastrointestinal lesions are becoming an important problem in clinical practice. In our investigation of such adverse effects, we obtained 4 important findings considered useful for physicians, as follows; 1) even when aspirin was given at a dose, the incidence rate of gastrointestinal lesions was higher than with other non-steroidal anti-inflammatory drugs (NSAIDs), 2) the odds ratios for gastrointestinal lesions induced by aspirin with a histamine H2 receptor antagonist and proton pump inhibitor were 0.6 and 0.4, respectively, as compared with aspirin alone, 3) it is difficult to administer aspirin, which exerts an antiplatelet effect, without inducing gastrointestinal lesions, and 4) these gastrointestinal lesions appears early, especially within 2 years after administration. We distributed a questionnaire to 41 physicians to confirm our findings, and compared high (n=20) and low (n=21) frequency aspirin prescription groups. The recognition rate of points 1 and 3 noted above in the high group was significantly elevated as compared to the low group, whereas there no significant difference in regard to the information in point 4 between the groups and the rate of recognition was low. Moreover, only 27% of the surveyed physicians were familiar with all 4 points. Prior to receiving this information, 17% of the physicians gave no related instructions their patients, which was reduced to 0% after receiving this information. Furthermore, 98% of those surveyed found the information to be useful. Our results suggest that these 4 points of information regarding potential adverse gastrointestinal effects of low-dose aspirin are useful for physicians.

TNF inhibitors are used as therapeutic agents for rheumatoid arthritis (RA). Each has a different dosage regimen and it is thought that the differences among them have implications on efficacy. However, those differences have not been analyzed in a theoretical manner. In the present study, we tried to explain theoretically the differences. We theoretically analyzed the anti-inflammatory effect of infliximab (IFX), etanercept (ETN), and adalimumab (ADA) for RA by using a pharmacokinetic and pharmacodynamic model. Then, we simulated values for sequential changes of tender joint count (TJC) after repeated administrations of TNF inhibitors by using the model. The sequential changes of TJC obtained with our model were in good agreement with observed TJC ratio data, which was considered to show the validity of our analytical method. The following results were obtained: the onset of clinical response was fastest with IFX, the fluctuation of IFX was greater than that of the others, and the clinical response with ADA was as stable as that with ETN. The present model was useful to analyze theoretically the anti-rheumatic effect of TNF inhibitors. Our results showed that different dosage regimens have implications on the onset and fluctuation of clinical response.

実践的指導力の育成を目的とした教育実践分野におけるPBL教育は、明確な目標のもとに判断・技術を適用していく医学部的なPBL教育ではなく、目的・状況があいまいな中で的確な判断、具体的な対策を打てるように構成されなければならない。本稿では、そのことを踏まえて「対話型の事例シナリオ」の原理・原則を示し、事例シナリオを試作しその作成過程を明らかにした。

Based on the fact that the Painleve equations can be written as Hamiltonian systems with affine Weyl group symmetries, a canonical quantization of the Painleve equations preserving such symmetries has been studied recently. On the other hand, since the Painleve equations can also be described as isomonodromic deformations of certain second-order linear differential equations, a quantization of such Lax formalism is also a natural problem. In this paper, we introduce a canonical quantization of Lax equations for the Painleve equations and study their symmetries. We also show that our quantum Lax equations are derived from Virasoro conformal field theory.

The aim of this study was to establish an appropriate inhalation method with a mometasone furoate dry powder inhaler (MF-DPI). Utilizing a tone-based inhalation training device, we investigated the maximum peak inspiratory flow rate time (Tmax PIFR) and peak inspiratory flow rate (PIFR) to determine whether either had an influence on lung deposition with use of an MF-DPI. A low tone indicated a PIFR of 28 L/min and a high tone that of 40 L/min, while 60 L/min was considered to be the standard. We established an inhalation profile in consideration of a human inhalation pattern, in which Tmax PIFR was set at 0.5 s (Tmax PIFR 0.5 s) and 2.5 s (Tmax PIFR 2.5 s). The reference cut-off value derived with a cascade impactor test was used for evaluation of the rate of delivered dose in the lung, which was the amount of drug from stage 3 to 7 at all PIFRs. We then investigated the relationship of the fine particle fraction (FPF) with the claimed dose at Tmax PIFR of 0.5 s and PIFR. There were no differences among the Tmax PIFR values for the doses emitted from the device or for the rate of delivered doses in stages 3-7. However, FPF for the claimed dose at 40 L/min was significantly lower than that at 60 L/min, which was dependent on PIFR. Our results showed that PIFR but not Tmax PIFR has an effect on lung deposition after inhalation with an MF-DPI.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright © 2016 John WileySons, Ltd.

Objective Alterations in distribution volume affect the concentrations of hydrophilic drugs in plasma and tissues at the time of initial therapy. When the distribution volume of hydrophilic antimicrobials is increased in critically ill patients with a serious infection, antimicrobial concentrations are reduced, which may adversely affect the efficacy of antimicrobial therapy. A transpulmonary thermodilution technique system (PiCCO) enables measurements of pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), which are related to pulmonary edema and pulmonary vascular permeability, respectively. In addition, those indices may also be related to the distribution volume of hydrophilic antimicrobials. The aim of this study was to investigate the relationships of PVPI and EVLWI with the distribution volume of vancomycin (Vss), as well as to establish a method for estimating Vss for planning an appropriate initial dose for individual patients. Methods Seven patients were administered vancomycin intravenously and underwent extended hemodynamic monitoring with the PiCCO system in the intensive care unit (ICU) from April 2009 to March 2011. Vss was calculated using the Bayesian method, and the relationships of PVPI and EVLWI with Vss were investigated. Results The relationship between Vss/actual body weight (ABW) and median EVLWI on days when blood levels were measured was significant (r = 0.900, p = 0.0057), whereas the relationship between Vss/ABW and PVPI was not significant (r = 0.649, p = 0.1112). Conclusion EVLWI determined by the PiCCO system is useful to predict Vss and should lead to more effective vancomycin therapy for critically ill patients at the initial stage.

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.

The urea breath test (UBT) is used widely for assessment of Helicobacter pylori (H. pylori) eradication after treatment. A false-negative UBT is common during administration of anti-ulcer drugs and immediately after their discontinuation. It was thought that the pharmaceutical care by the pharmacists was necessary for the diagnostic accuracy of UBT after H. pylori eradication therapy. Therefore, we investigated the effect of pharmaceutical care on diagnosis based on assessment of UBT. The patients who performed UBT were classified into two groups according to the pharmacists' intervention. From 2008 April to 2009 September, the number of the patients taken pharmaceutical care was 57 (intervention group) and that of the patients taken no pharmaceutical care was 62 (control group). When drugs for H. pylori infection and anamnestic therapy were same, the percentage that avoided administration of double drugs was significantly increased by the pharmaceutical care (93.3% in intervention group versus 21.4% in control group, p

Cross sections of pd breakup reaction at E p = 250 MeV were measured systematically in single-proton detection and in two-proton coincidence detection. Measured cross section is up to two times higher than calculated ones. The enhancement of breakup cross section is similar to reported enhancement in pd elastic scattering cross section. Origins of this enhancement are discussed.

The educational intervention could improve knowledge about rational drug use in the junior high school. Improving knowledge about rational drug use at an early age may be a good way to increase the population's awareness of health, medicines and self-medication. To educate the rational drug use, it is desirable that the school pharmacists participate in this educational program in the junior high school. So we conducted an educational lecture by school pharmacists to promote rational drug use and self-medication in junior high school students. The study compared participant responses before and after a lecture. After the first questionnaire, we lectured the mentioned above to them. Afterward, second questionnaire was conducted. In the second questionnaire, more than 95% of the students understood the contents of the lecture to some extent. After a lecture, students who answered that 'I don't have confidence that I can buy medicines rightly by myself' decreased from 42.7% to 11.7%. And students who answered that 'I don't have confidence that I can use medicines rightly by myself' decreased from 25.2% to 12.6%. It was possible to achieve a favorable modification of attitudes to rational use of medicines in junior high school students. Continuous interventions might allow better effects and could help to fill the gap in health education of the general population.

Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (k on: second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.

It has been reported that non-steroidal anti-inflammatory drugs (NSAIDs) interact with aspirin to influence its antiplatelet effect. For example, there have been reported that the rate of platelet aggregation inhibition associated with aspirin was significantly decreased when ibuprofen was taken before administration of aspirin, as compared with aspirin alone. In this study, we investigated the prescriptions on combination of aspirin with NSAIDs. The subjects were consisted of 1212 patients who were prescribed aspirin in March, 2008 in Tokai University Hachioji Hospital. The patients prescribed combination of aspirin with NSAIDs were 8.1% and 18.6% of those were prescribed in the order of adminstration to induce drug interaction. The pharmacists should provide information about drug interactions of aspirin with NSAIDs to the doctors and patients, and it is necessary to pay attention of these interactions.

Aspirin irreversibly inhibits the enzyme cyclooxygenase-1 and depresses the production of thromboxane A(2), and also exerts antiplatelet effects. On the other hand, it also depresses the production of prostaglandin E(2) (PGE(2)) and induces gastroduodenal lesions, which are often seen in patients taking aspirin. The aim of this study was to clarify the degree of gastroduodenal lesions induced by low-dose aspirin. We investigated the incidence rate of such lesions induced by aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), and performed theoretical evaluations in a retrospective study. The incidence rates of gastroduodenal lesions in the low-dose aspirin (n=1103) and NSAIDs (n=1856) groups were 2.54% and 0.27%, respectively, which was significantly greater in the aspirin group. Furthermore, the calculated value of inhibition rate of gastric PGE(2) was significantly correlated with the actual value after administration of aspirin or NSAIDs (r=0.902, p