Haruko Yokoyama

Influence of non-steroidal anti-inflammatory drugs on antiplatelet effect of aspirin

What is known and Objective:  It has been reported that ibuprofen interferes with the antiplatelet effect of low‐dose aspirin. This interaction is ascribed to steric hindrance at the active site of cyclooxygenase‐1 by ibuprofen, when aspirin is administered after ibuprofen. However, whether other non‐steroidal anti‐inflammatory drugs (NSAIDs) interact with aspirin similarly is not well defined. The aim of this study was to assess the influence of nine NSAIDs on the antiplatelet effect of aspirin.

Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists

BackgroundThe aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT3 receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT3 receptor occupancies, based on receptor occupancy theory.MethodsWe analyzed interindividual differences of 5-HT3 receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT3 receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron.ResultsThe interindividual difference between maximum and minimum 5-HT3 receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%.ConclusionInterindividual differences in the clinical effects of 5-HT3 receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.

エトポシド(VP-16)注射液の持続注入時に発生したポリウレタン製カテーテル亀裂の要因に関する検討

We studied the cause of cracking of a clinically used polyurethane (PU) catheter during the constant infusion of etoposide (VP-16) injection (Lastet), administered without dilution to patients as a part of combination high-dose chemotherapy. After VP-16 injection was infused into the PU catheter at a constant infusion rate (30 ml/h) for 24 h, a decrease in the elasticity (36% of untreated) and on increase in the length of the catheter (3.7%) were observed. These changes were significantly higher than those treated with the control saline. The similar changes of the PU catheter were observed after treatment with a basal solution containing polyethylene glycol 400 (PEG 400), polysorbate 80 and ethanol, which is the vehicle of the VP-16 injection, and with ethanol alone. Moreover, obvious degeneration of the internal wall (occurrence of spots like melting) and cutting face (micro-cracking) of the catheter was observed with an electron microscope after treatment with the vehicle. On the other hand, the elasticity or extension of the PU catheter were not changed after treatment with saline or PEG 400. From these findings, it was suggested that the degeneration and subsequent cracking of the PU catheter during the infusion of VP-16 injection was caused by ethanol contained in its injection solution. No cracking or morphological changes of polyvinyl chloride (PVC) and silicone catheters were found after treatment with the vehicle solution. However, since it has been reported in previous reports that di(2-ethylhexyl)phthalate was leached from PVC bags, the high dose chemotherapy with the dilution-free VP-16 injection should be achieved safely and effectively using a silicon catheter, rather than the PU catheter.

Effects of tumor necrosis factor α-857C/T polymorphism on the expression of tumor necrosis factor α

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 Crohns 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.

Prediction of Antiplatelet Effects of Aspirin In Vivo Based on In Vitro Results

The aim of this study was to establish a method to predict the antiplatelet effects of aspirin in vivo based on in vitro results. Aspirin in 5 different concentrations was added to the platelet-rich plasma samples, and the rates of platelet aggregation induced by collagen were determined in vitro. In addition, platelet aggregation and plasma drug concentration values were determined in vivo before and after the administration of aspirin (162 mg). The 50% effective concentration (EC50) values obtained from the in vivo and in vitro experiments were shown to have relevance, because the EC50 ratio for each subject was the same (0.23 ± 0.03). The actual and predicted values for the rate of inhibition of platelet aggregation were well correlated (P < .0001, r = .95) when the predicted rate was determined using the present method. Our results suggest that the antiplatelet effects of aspirin can be predicted using blood samples obtained before its administration.

Single nucleotide polymorphisms of 17β‐hydroxysteroid dehydrogenase type 7 gene: Mechanism of estramustine‐related adverse reactions?

Objectives:  To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17β‐hydroxysteroid dehydrogenase (HSD17B7) gene.

Impact of holding position during inhalation on drug release from a reservoir-, blister- and capsule-type dry powder inhaler

ABSTRACT Objective: To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs). Methods: 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. Results: 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°. Conclusion: The position in which the DPI is held may affect drug delivery, especially when using BZH.

Prediction of distribution volume of vancomycin in critically ill patients using extravascular lung water and pulmonary vascular permeability indices.

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.