Establishment of a new initial dose plan for vancomycin using the generalized linear mixed model.

BACKGROUND: When administering vancomycin hydrochloride (VCM), the initial dose is adjusted to ensure that the steady-state trough value (Css-trough) remains within the effective concentration range. However, the Css-trough (population mean method predicted value [PMMPV]) calculated using the population mean method (PMM) often deviate from the effective concentration range. In this study, we used the generalized linear mixed model (GLMM) for initial dose planning to create a model that accurately predicts Css-trough, and subsequently assessed its prediction accuracy. METHODS: The study included 46 subjects whose trough values were measured after receiving VCM. We calculated the Css-trough (Bayesian estimate predicted value [BEPV]) from the Bayesian estimates of trough values. Using the patients' medical data, we created models that predict the BEPV and selected the model with minimum information criterion (GLMM best model). We then calculated the Css-trough (GLMMPV) from the GLMM best model and compared the BEPV correlation with GLMMPV and with PMMPV. RESULTS: The GLMM best model was {[0.977 + (males: 0.029 or females: -0.081)] × PMMPV + 0.101 × BUN/adjusted SCr - 12.899 × SCr adjusted amount}. The coefficients of determination for BEPV/GLMMPV and BEPV/PMMPV were 0.623 and 0.513, respectively. CONCLUSION: We demonstrated that the GLMM best model was more accurate in predicting the Css-trough than the PMM.

Development of the Virtual Physical Assessment Learning Material That Allows the Learners to Check Drug Efficacy and Early Detection of Adverse Effects through Virtual Experience.

We utilized the information and communication technology to develop the physical assessment (PA) learning materials in the virtual experience type. This learning material consists of two parts which include case learning and basic learning. We created example scenarios about various conditions that a pharmacist may experience in medical scenes such as in a hospital ward, community pharmacy, home, and drugstore. Illustrations of a virtual patient's avatar before and after taking the medicines were incorporated in the learning materials. The virtual training includes a stethoscope that was used in examining sounds (heart, pulmonary and bowel sounds) that served as evidences in the confirmation of drug efficacy and its possible adverse effects. In addition, we included the images of each body part, the 24 format question items, the palpation (rate and rhythm) of the radial artery, brachial artery and pedal artery, the clinical data obtained from several medical equipment, the pupillary reflex, and the urine dipstick test. This way, learners are able to experience PA with reference to the subjective and objective data from patient reception and questions. The virtual patient's avatar displayed on the monitor features auscultatory sounds on the stethoscope. It also features clinical data obtained from other medical equipment that can give the learners an interactive way of learning about various medical conditions. For evaluation, we gave out questionnaires on the virtual PA to pharmacy students. As a result, a high evaluation was reflected in terms of the degree of usefulness for both case learning and basic learning.

Physical Assessment Education Using Various Simulators.

Pharmacists are in demand not only because of their knowledge of medical therapy but also due to their skills in basic physical assessment and emergency care as medical personnel. Pharmaceutical education has developed using patient simulators in bedside training, seminars in hospital pharmacies, and physical assessment practice at the Kyushu University of Health and Welfare School of Pharmaceutical Sciences. We first explain the outline of the method to confirm basic vital signs with simulators and then demonstrate some simulations to enable the reproduction of drug misadministration/changes in condition. In addition, we check students' knowledge of and skill in the advanced objective structured clinical examination through practical examinations to test their technical ability in physical assessment. Furthermore, we conduct case study exercises in which students perform physical assessments and collect basic information on patient background. The Stan, Heart SIM, and Physico simulators are used. As examples of drug misadministration, the reproduction of asystole from fatal arrhythmia after the rapid intravenous injection of potassium preparations and ventricular fibrillation from tachycardia after an overdose of insulin are presented to student pharmacists utilizing the simulators. The simulation of anaphylactic shock and hyperglycemia is also possible as examples of changes in condition. Overall, pharmaceutical simulation education provides pharmacy students and pharmacists with experience in the types of medical treatment performed by various healthcare professionals, leading to explorations of the new roles of pharmacists in team medical care.

A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid.

Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.

[Necessity of research of pharmaceutical departments in the creation of new pharmaceutical skills through technical education of physical assessment].

Physical assessment skills are now being more widely accepted by pharmacists and pharmaceutical departments than in the past. This is explained by the realization that pharmacists can prevent serious adverse effects and evaluate drug efficacy for their patients through assessment, thus providing effective medical care. However, is that all physical assessment can provide to pharmacists and pharmaceutical students? These students, in turn, should recognize the "need for skill" and the "pleasure to be gained in acquiring that skill" through the physical assessment performed by doctors. They should also recognize the importance of medical devices (e.g., stethoscope, electrocardiograph and endoscope) and take responsibility for creating their own techniques for their use. Here they will consider valuable pharmaceutical skills. "Yaku-jutsu" is a pharmaceutical diagnosis to determine the time required to achieve maximum beneficial effects and effective drug administration based on that diagnosis. Pharmacists cannot gain public trust unless they relieve a patient's pain using Yaku-jutsu which has been made available to them by the research support of a pharmaceutical department.

Albumin-binding of diclofenac and the effect of a site II inhibitor in the aqueous humor of cataract patients with the instillation of diclofenac.

Diclofenac instillation has been used widely in cataract surgery to prevent postoperative inflammation. Since diclofenac binds strongly to albumin in the circulation, it does not have a sufficient effect on patients in whom diclofenac binds strongly to albumin in the aqueous humor. A decrease in diclofenac binding and an increase in free diclofenac levels are necessary in these patients. The binding of diclofenac to albumin was investigated in the aqueous humor. In a diclofenac binding assay with albumin in the aqueous humor of individual patients, diclofenac was extracted from aliquots of the aqueous humor, and its total levels were measured using ultra high performance liquid chromatography (UHPLC). Free diclofenac levels were measured using ultrafiltration and UHPLC. The albumin-binding fraction of diclofenac was 0.8 or higher in the aqueous humor of some patients. Ibuprofen significantly inhibited diclofenac binding to site II of albumin in mimic aqueous humor, but not in pooled aqueous humor. This difference may have been due to the weak binding of diclofenac to site II in the pooled aqueous humor. Flurbiprofen was used instead of diclofenac. Flurbiprofen has been shown to bind more strongly than diclofenac to the same site of albumin. Thus, the inhibitory effect of ibuprofen on the binding of flurbiprofen to albumin was investigated in pooled aqueous humor. The results indicated that ibuprofen significantly inhibited the flurbiprofen binding. An effective diclofenac administration method may be established for clinical application by the instillation of an appropriate inhibitor of binding to the albumin site II.

An advanced objective structured clinical examination using patient simulators to evaluate pharmacy students' skills in physical assessment.

OBJECTIVE: To implement an advanced objective structured clinical examination (OSCE) in the curriculum and to evaluate Japanese pharmacy students' skills in physical assessment such as measuring pulse and blood pressure, and assessing heart, lung, and intestinal sounds. DESIGN: An advanced OSCE was implemented in a hospital pharmacy seminar as a compulsory subject. We programmed patient simulators with 21 different patient cases in which normal and abnormal physiological conditions were produced. The virtual patients were then used to evaluate the physical assessment skills of fifth-year pharmacy students. ASSESSMENT: Significant differences were observed between the average of all the detailed evaluations and the mean results for the following skills: pulse measurement, blood pressure measurement, deflating the cuff at a rate of 2-3 mmHg/sec, listening to heart sounds, and listening to lung sounds. CONCLUSION: Administering an advanced OSCE using virtual patients was an effective way of assessing pharmacy students' skills in a realistic setting. Several areas in which pharmacy students require further training were identified.

[Implementation of bedside training and advanced objective structured clinical examination (OSCE) trial to learn and confirm about pharmacy clinical skills].

Bedside training for fourth-year students, as well as seminars in hospital pharmacy (vital sign seminars) for fifth-year students at the Department of Pharmacy of Kyushu University of Health and Welfare have been implemented using patient training models and various patient simulators. The introduction of simulation-based pharmaceutical education, where no patients are present, promotes visually, aurally, and tactilely simulated learning regarding the evaluation of vital signs and implementation of physical assessment when disease symptoms are present or adverse effects occur. A patient simulator also promotes the creation of training programs for emergency and critical care, with which basic as well as advanced life support can be practiced. In addition, an advanced objective structured clinical examination (OSCE) trial has been implemented to evaluate skills regarding vital signs and physical assessments. Pharmacists are required to examine vital signs and conduct physical assessment from a pharmaceutical point of view. The introduction of these pharmacy clinical skills will improve the efficacy of drugs, work for the prevention or early detection of adverse effects, and promote the appropriate use of drugs. It is considered that simulation-based pharmaceutical education is essential to understand physical assessment, and such education will ideally be applied and developed according to on-site practices.

A diclofenac suppository-nabumetone combination therapy for arthritic pain relief and a monitoring method for the diclofenac binding capacity of HSA site II in rheumatoid arthritis.

Diclofenac suppository, a non-steroidal anti-inflammatory drug (NSAID), is used widely in rheumatoid arthritis (RA) patients with severe arthritic pain. As the binding percentage of diclofenac to serum proteins is high, its free (unbound) concentration after rectal administration is low. To increase temporarily the free concentration of diclofenac and to enhance its analgesic effect by inhibiting the protein binding of diclofenac, the analgesic effect of diclofenac was examined before and after the start of an inhibitor administration to RA patients with insufficient control of arthritic pain, and the protein binding capacity of diclofenac was evaluated. Binding experiments were performed by ultrafiltration, and arthritic pain was recorded by the face scale. Free fractions of diazepam and diclofenac were augmented by increasing 6-methoxy-2-naphthylacetic acid (6-MNA; the active metabolite of the NSAID nabumetone) concentrations. The free fraction of diazepam increased after the start of nabumetone administration to RA patients, and arthritic pain relief was observed. These results suggest that 6-MNA has an inhibitory effect on the protein binding of diclofenac and the free fraction of diazepam can be used to evaluate the binding capacity of diclofenac. It is considered that diclofenac suppository-nabumetone combination therapy and the method for protein binding monitoring by diazepam can positively benefit RA patients with insufficient control of arthritic pain.

Preparation of simulation programs regarding excess-dose drug administration and acute-phase condition changes and its evaluation by students.

Vital-sign checks and physical assessment have been performed by physicians and nurses among medical staff in particular. However, pharmacists must also have basic skills of vital-sign checking and physical assessment to evaluate the patient condition/drug efficacy or prevent adverse reactions to drugs. To promote the acquisition of these skills, we prepared simulation programs with an emergency-care simulator, which facilitate the reproduction of excess-dose drug administration/condition changes. We used an emergency-care simulator equipped with a personal computer. General condition was established using the blinking velocity, cardiac/respiratory sounds and blood pH as parameters. As a results, concerning drug administration, the simulation programs facilitated the reproduction of symptoms related to the excess-dose insulin administration. With respect to changes in the condition, it facilitated the reproduction of asthma, hyperglycemia, and hemorrhage. This facilitated the palpation-, visual perception-, and auditory perception-mediated understanding of changes in the patient condition through fingertips and warnings/alarms on the monitor. Evaluation of the student for these program contents increased significantly (p<0.01). These programs can be downloaded via the Internet. Experience regarding excess-dose drug administration/condition changes with an emergency-care simulator is useful for checking patients' vital signs, evaluating the drug efficacy, and confirming adverse reactions to drugs. By the practice of these programs, we can teach pharmacy students how to check for vital signs (pulse palpation, auscultation, blood pressure measurement, and electrocardiography) in a school setting, not a hospital setting. Mastering these techniques may allow pharmacy students to determine the efficacy of a drug and adverse reactions.

Vital sign monitoring using human patient simulators at pharmacy schools in Japan.

OBJECTIVE: To develop, implement, and assess an experience-based education program using human patient simulators to instruct pharmacy students in monitoring vital signs to identify drug treatment effects and adverse events. DESIGN: Medical emergency care programs using human patient simulators were prepared and facilitated practical clinical training in resuscitation, which required selecting drugs while monitoring changes in blood pressure, pulse, and arterial blood oxygen saturation. Training encompassed the monitoring of routes of drug administration, drawing of simulated blood, vital-sign monitoring based on a pharmaceutical universal training model, vital-sign monitoring devices and simulators, and medical emergency education using biological simulators. ASSESSMENT: Before and after bedside training, students were asked to complete a questionnaire to assess their understanding of vital sign monitoring and emergency care. Students successfully learned how to monitor routes of drug administration, vital signs, and pathological conditions. There was a significant increase in students' recognition of the importance of vital-sign monitoring. CONCLUSION: Experienced-based training using patient simulators successfully prepared pharmacy students to monitor vitals signs and identify drug treatment effects and adverse events.

[Survey of student pharmacists' attitudes toward new procedures expected for future pharmacists].

Bedsides conventional bedside training the Department of Pharmacy of Kyushu University of Health and Welfare covers advanced practices focused on new procedures expected for future pharmacists. A questionnaire survey was conducted among the 4th year students of the 6-year curriculum of the department in order to retrospectively evaluate their attitudes toward basic life support, and the necessity and feasibility of items related to the training. Sixty-nine percent of the students responded that they would provide appropriate treatment under a situation where basic life support was needed. The item regarded as most necessary and feasible before training was "treatment for basic life support--cardiopulmonary resuscitation." After training, however, "checking vital signs," "physical assessment," and "pharmacist's assistance in medication" were the items rated as equal to or higher than "treatment for basic life support--cardiopulmonary resuscitation." The lowest ranked item in terms of necessity and feasibility both before and after training was "intramuscular/subcutaneous injection," followed by "intravenous injection" and "normal intravenous collection of blood" in that order. The results of this attitude survey demonstrated that many students were willing to perform such operations as part of checking vital signs and physical assessment.

[Life-support training to improve the clinical competence of pharmacy students].

Life-support (particularly, advanced life-support) training is not included in pharmacist education; however, the life-support should be mastered since a pharmacist is a medical professional. We consider it to be important to master other skills before the life-support practicing, because a pharmacist does not check a patient to assess their clinical condition and administer drugs (suppository, intravenous injection etc.) The pharmacist prepares medicines, but does not administer medicines to treat the patient. Furthermore, the pharmacist is not interested in the vital signs of the patient receiving the medicines (the pharmacist has not identified the patient has complaint from changes in vital signs), which is why pharmacists can not develop themselves as medical professionals. Based on this observation, life-support training should be considered. In other words, to foster pharmacists with high clinical competence, pharmacy students should receive life-support training after training in drug administration and vital sign checks in a bedside training room. Drug administration using a pharmacy system versatile-type training model and pharmacy training model, vital signs check and auscultation using a physical assessment model and a cardiac disease disorder simulator in our bedside practice are useful for advanced life-support using a high-performance care simulator (monitoring vital signs, adrenalin administration and oxygen inhalation for ventricular fibrillation (VF). These training skills can improve the clinical competence of pharmacy students.

Adsorption of irinotecan onto oral adsorbent AST-120 (Kremezin) for preventing delayed diarrhea.

PURPOSE: One of the significant dose-limiting toxicities of irinotecan hydrochloride (CPT-11) is severe diarrhea due to impairment of the intestinal membrane induced by the excreted CPT-11 and its metabolites. AST-120 (Kremezin) is a prominent oral adsorbent that consists of porous spherical carbonic particles. To evaluate whether Kremezin can prevent the diarrhea induced by CPT-11, we investigated the adsorption characteristics of CPT-11 and its metabolites onto Kremezin in vitro and in vivo. METHODS: For in vitro studies, Kremezin was added to each solution containing one of the camptothecin drugs (CPT-11, SN-38, and SN-38-glucuronide), and adsorption activities were determined under various conditions. For in vivo studies, CPT-11 was consecutively administered, and the occurrence of diarrhea was compared between Kremezin-treated and non-treated rats. RESULTS: Kremezin drastically adsorbed the camptothecin drugs in vitro, and the adsorption percentages of the camptothecin drugs for 60 min were more than 85%. In addition, the frequency of diarrhea in Kremezin-treated rats decreased by approximately half of that in the non-treated rats. CONCLUSION: Kremezin showed potent adsorption capacities for the camptothecin drugs and mitigated the symptoms of diarrhea in rats. These results suggest that Kremezin is useful to prevent the diarrhea in clinical CPT-11 chemotherapy.

Transient inhibition of cyp3a in rats by star fruit juice.

Star fruit juice is a potent in vitro inhibitor of CYP3A; however, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Therefore, in this study, we investigated the CYP3A-mediated star fruit-drug interaction in vivo. The effect of star fruit juice on carbamazepine pharmacokinetics was examined in rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.3-fold greater when star fruit juice (2 ml) was orally administered 1 h before the oral administration of carbamazepine (50 mg/kg). In contrast, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the administration of star fruit juice. These results suggest that star fruit juice impairs the function of enteric CYP3A, but not of hepatic CYP3A. In addition, we evaluated the time course of recovery of CYP3A activity that was reduced after the treatment with star fruit juice. The inhibition by star fruit juice was recovered within approximately 24 h. These data suggest that the effect of star fruit juice is mainly reversible and transient. Thus, we discovered that star fruit juice alters the carbamazepine pharmacokinetics in rats.

Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats.

In this study, we investigated whether components of pomegranate could inhibit CYP3A-mediated drug metabolism. The ability of pomegranate to inhibit the carbamazepine 10,11-epoxidase activity of CYP3A was examined using human liver microsomes, and pomegranate juice was shown to be a potent inhibitor of human CYP3A. Addition of 25 microl (5.0% v/v) of pomegranate juice resulted in almost complete inhibition of the carbamazepine 10,11-epoxidase activity of human CYP3A (1.8%). The inhibition potency of pomegranate juice was similar to that of grapefruit juice. In addition, we investigated the in vivo interaction between pomegranate juice and carbamazepine pharmacokinetics using rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.5-fold higher when pomegranate juice (2 ml) was orally injected 1 h before the oral administration of the carbamazepine (50 mg/kg). On the other hand, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the injection of pomegranate juice. These data suggest that pomegranate juice component(s) impairs the function of enteric but not hepatic CYP3A. Thus, we discovered that a component(s) of pomegranate inhibits the human CYP3A-mediated metabolism of carbamazepine. Furthermore, pomegranate juice alters the carbamazepine pharmacokinetics in rats.