The purpose of this study was to identify risk factors and initial symptoms of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). From the CARPIS (Case Reports of Adverse Drug Reactions and Poisoning Information System) database, which contains 35,000 case reports of adverse drug reactions (ADRs), we selected 101 cases (case group) matching the criteria for TEN/SJS provided by the Japanese Ministry of Health, Labour and Welfare. We also selected 590 controls (control group) who had also taken the drugs suspected of causing TEN/SJS in the case group. Various data were compared between the case group and the control group and analyzed statistically. A comparison between the case group and the control group based on logistic regression analysis yielded 2 factors that were associated with a significant elevation of TEN/SJS risk : infectious diseases (OR=1.84, 95% CI=1.18-2.86) and collagen disease (OR=2.58, 95% CI=1.14-5.44). In addition, age (OR=0.38, 95% CI=0.15-0.94) and history of allergy or ADRs (OR=0.48, 95% CI=0.25-0.87) were associated with a significant reduction in the risk. Based on logistic regression analysis of the initial symptoms, itching (OR=0.17, 95% CI=0.07-0.34) was associated with a significant reduction in the risk of TEN/SJS, and sore throat (OR=3.15, 95% CI=1.44-6.60) with a significant elevation of the risk. The present study thus uncovered some risk factors for TEN/SJS that would be helpful in preventing severe drug reactions.
Compatibility between risperidone and soft drinks was examined by means of isothermal titration microcalorimetry, and the interaction of risperidone with tea tannin- (-)-epigallocatechin, (-)-epicatechin, theaflavin and their gallates-was investigated thermodynamically. Risperidone exothermically bound to tea tannin monomers with a binding affinity of 103-104 M-1 in aqueous solution to form an insoluble complex at a 1:1 molar ratio. The binding reaction was characterized by small enthalpy and entropy changes, reflecting hydrophobic and van der Waal's interactions. After mixing Risperdal® liquid (1 mg/mL risperidone oral solution) with soft drinks containing tannin-such as green tea, black tea and oolong tea, there was an immediate decrease in the risperidone content and the mixtures became cloudy. The heat effect of risperidone titrated into these soft drinks was exothermic and proportional to the quantity of the complex formed in the mixture. However, no significant heat effect was noted when risperidone was titrated into drinks in PET bottles that do not contain tea tannin, such as mineral water and an infusion of parched barley. Isothermal titration microcalorimetry is thus a rapid and effective method for evaluating the compatibility and physico-chemical interactions of drugs.
The inappropriate use of antimicrobials results in the creation of resistant organisms and increases the overall costs of health care. In 2004, the Ministry of Health, Labour and Welfare in Japan issued a report on the current state of hospital infection control in Japan. The report mentioned that though 99.8% of 1,364 hospitals in Japan had an active infection control team, only 30.9% of them had guidelines for the appropriate use of antimicrobials. We investigated the roles of infection control pharmacists (ICPs) at Nagoya University Hospital (NUH) in Japan and compared them with those of ICPs at Cedars Sinai Medical Center (CSMC) in the US with the aim of pinpointing activities of ICPs in Japan that need improvement. NUH is a 1,035-bed national acute tertiary care teaching hospital and CSMC a 900-bed private nonprofit acute tertiary care teaching hospital. The main duties of ICPs at CSMC are the development and implementation of guidelines for the use of antimicrobials, which are approved by the hospital's Executive Committee. The duties of ICPs at NUH are mostly the same as those at CSMC, and they also work on the prevention of nosocomial infection. However, there is still no approval system for the guidelines they draw up. In many hospitals in the US, such guidelines have resulted in cost benefits, and decreases in antimicrobial resistance and length of hospital stays. US systems will serve as a useful model for Japanese ICPs.
Clinical research coordinators (CRCs) play an important role in ensuring to that clinical trials are conducted in accordance with the new GCP guidelines. In Shimane University Hospital, the clinical trial coordination system was officially introduced in April 2002. In the present study, we carried out a survey on protocol derogation cases before (from April 1997 to March 2002) and after (from April 2002 to March 2005) the introduction of the system to evaluate the effectiveness of CRCs in improving the quality of clinical research in our hospital. In doing this, we investigated the details of the protocol derogation cases and the reasons for derogation. We also looked at the extent of adoption of the per protocol set (PPS) and full analysis set (FAS) by clinical trial sponsors. After the introduction of the CRC system, the following improvements were observed. The incidence of protocol derogation dropped to 1/3, a significant decrease. Patient noncompliance had accounted for 1/3 of all derogation cases before the introduction of the system but after introduction, there were no more cases of noncompliance. There were also no more of the violations of enrollment criteria, which was related to the extent of adoption of FAS and PPS. Adoption rates of FAS and PPS increased from 97.2% to 100% and from 88.9% to 93.4%, respectively. Any noncompliance cases that resulted in exclusion from PPS after introduction of the system were due to adverse events and other unavoidable causes. These results indicate that the activities of CRCs raised the quality of clinical trials in our hospital.
To determine a pharmacodynamic model for warfarin under thrombo-test (TT) monitoring, we examined the correlation between steady state TT values, warfarin dosage and serum concentration in patients receiving warfarin treatment. Based on the results, we developed a pharmacodynamic model relating TT values to free warfarin concentrations. We studied 19 cardiac patients receiving warfarin anticoagulant therapy in whom warfarin serum concentrations and TT values were considered to be in a steady state. While no correlation was observed between steady-state TT values and either warfarin dosage per kilogram body weight or total warfarin concentration, a significant negative correlation was observed between steady-state TT values and free warfarin concentrations (r=-0.561, p<0.05). We then developed a pharmacodynamic model expressing the relationship between steady-state TT values and free warfarin concentrations using nonlinear least-squares fitting. The AIC (Akaike's Information Criterion) of the sigmoid Emax model was 171.2, a value less than the AICs of the linear, log-linear and Emax models. In conclusion, a sigmoid Emax model expressing the relationship between TT values and free warfarin concentration is an appropriate pharmacodynamic model for warfarin when TT values are used as an indicator of coagulability.
Interest in dietary fiber has been growing due to the many benefits it has for health. It is well known that dietary fiber reduces the risk of developing health problems such as obesity, hypertension, constipation, type 2 diabetics and hyperlipidemia. However, dietary fiber is also known to reduce the bioavailability of minerals, nutrients and certain drugs, though the interaction between dietary fiber and drugs is still poorly understood. In this study, we examined the adsorption of drugs (theophylline, acetaminophen, metoprolol, chlorpromazine, imipramine, amitriptyline and diclofenac sodium) onto several types of dietary fiber (cellulose, chitosan, pectin, sodium alginate and glucomannan) at pH 3 and pH 7 in order to determine the in vitro adsorption characteristics of dietary fiber. Our findings indicated that adsorption of drugs onto dietary fiber ranged from 0 to 96%, varying with the types of dietary fiber and drugs, and pH. Chlorpromazine, imipramine and amitriptyline showed particularly marked adsorption onto sodium alginate and glucomannan. We considered that ionic bonding was one of the reasons for adsorption. These findings indicate the possibility of the bioavailability of drugs being reduced when they are taken with dietary fiber due their adsorption onto dietary fiber.
At the time of rotating medical staff it was necessary for pharmacists to carry a list of updated prescriptions so that they could inform nurses and other medical staff of changes in prescriptions in the sequence of patient wards. We developed a new computer system for recording updates to prescriptions, and it is linked with existing computer systems used by all medical staff. At the time of staff rotation, a list of the latest changes in the prescriptions can be printed out making it easy for ward pharmacists to inform doctors and nurses of these changes. This facilitates good pharmaceutical care for inpatients and helps ensure that patients take the drugs prescribed to them properly. By doing this, we pharmacists have gained further respect from other medical staff and inpatients.
In recent years, intravesical chemotherapy has been performed for bladder cancer after transurethral resection of bladder tumors (TUR-Bt). The initial intravesical treatment with chemotherapeutic agents is performed during hospitalization, and further intravesical treatments are administered in the outpatient clinic. The intravesical agents are usually BCG (Bacillus Calmette-Guérin) which is given as a course of 8 treatments once weekly and pirarubicin which is given as a course of 10 treatments once weekly. To obtain information on subjective adverse effects for these intravesical chemotherapy regimens, a retrospective investigation comparing the subjective adverse effects per number of treatments, and the accomplishment rate and achievement rate for one course of therapy with BCG (n=9) or pirarubicin (n=21) was conducted over a two-year period using medical records and nursing records. While the accomplishment rate for pirarubicin therapy was higher than that for BCG therapy, there was no significant difference in the achievement rate between the two chemotherapy regimens. Some patients receiving BCG therapy developed fever but none on pirarubicin therapy did. Information on patients' subjective symptoms such as headache, nausea and constipation was obtained directly from the patients using an outpatient guidance sheet on which they checked the subjective adverse effects due to the intravesical chemotherapy. It seemed that the outpatient guidance sheet had made a positive contribution to the management of intravesical chemotherapy for bladder cancer.
In 1996, research was conducted at the National Cardiovascular Center to determine prescribing trends for drugs used in the treatment of myocardial infarction (MI). Since much evidence was collected and clinical guidelines for the treatment of MI were established, we thought that the prescribing trends might have changed in the following years so in 2004, we conducted research to determine what changes had occurred in the period from 1996 to 2004. The frequency of prescribing platelet aggregation inhibitors, β-adrenergic antagonists, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) was higher in 2004, when platelet aggregation inhibitors were prescribed for 91.6% of the patients with MI, and aspirin was prescribed for 86.4% of the patients. The frequencies of prescribing multiple drugs for ischemic heart disease was high in both 1996 and 2004, and β-adrenergic antagonists had become the predominant drugs in multiple drug therapy in 2004. β1-selective adrenergic antagonists without intrinsic sympathetic activity and αβ-adrenergic antagonists were major drugs among the β-adrenergic antagonists. Among calcium antagonists, the frequency of amlodipine use showed an upward trend in this eight-year period. In conclusion, our findings indicate that standard pharmacotherapy for MI based on the evidence and clinical guidelines has been introduced at NCVC.
Telbans®DS 20% (TEL) is a sustained-release theophylline dry syrup. In order to observe the effect of various foods and drinks on its dissolution, we compared theophylline dissolution rates from the dry syrup preparation when various foods and drinks were used as the suspension medium. The following seven foods and drinks were chosen as suspension mediums based on the results of a questionnaire survey on the method of administration of the preparation : purified water, deglutition aid jelly, ice cream, yoghurt, orange juice, a sports-drink and reconstituted powdered milk. The reference standard (control) for comparison of dissolution rates was a TEL suspension in purified water immediately after preparation. In the case of using freshly prepared suspensions, the dissolution rate for powdered milk was significantly lower than that of the control at 30 minutes and thereafter. For suspensions that were freshly prepared and kept still for 30 minutes, there was a significant difference in dissolution rates among water, deglutition aid jelly and orange juice from 2 to 10 minutes after starting the experiment. However, in the case of ice cream, yoghurt and reconstituted powdered milk, dissolution rates were significantly lower than that of the control at 30 minutes and thereafter. From these test results, we concluded that TEL suspensions made with purified water, deglutition aid jelly, ice cream, yoghurt, and orange juice should be taken shortly after preparation, and we felt that reconstituted powdered milk is not an appropriate medium for TEL suspensions.
The goal of the present study was to determine the feeling of pediatric patients and their guardians towards commercial pharmaceutical preparations and to examine the effect of breaking up or crushing four kinds of commercial pharmaceutical tablets on their bitterness using an artificial taste sensor and human gustatory sensation tests. We interviewed children between 3 and 5 years old together with their guardians to obtain their views on taking tablets. More than half of the children and their guardians showed a positive attitude toward taking tablets, although they had little experience of taking any. The four kinds of tablets evaluated for bitterness were clarithromycin, azithromycin, telithromycin, and amantadine, which are all naturally bitter, and bitterness was compared among intact, broken up and crushed tablets. The breaking up and crushing of tablets produced a significant increase in bitterness scores obtained with both the artificial taste sensor and human gustatory sensation tests. Thus, in case of drugs in tablet form which are very bitter, if available, pediatric tablets are preferable to breaking up or crushing adult tablets for children.