Masahiko Shibakawa

Impairment of Absorption of Digoxin by Acarbose

This study was conducted to determine the effect of acarbose on serum concentrations of digoxin in healthy male volunteers. A randomized crossover design with three phases was used. In phase 1 participants received 0.5 mg of digoxin alone. In phase 2 they received 0.5 mg of digoxin 0.5 hours after a 200‐mg dose of acarbose. In phase 3 they received 100 mg of acarbose 0.5 hours before each meal three times daily for 3 days. On the fourth day, they received 0.5 mg of digoxin 0.5 hours after a 100‐mg dose of acarbose. Area under the concentration—time curve (AUC0–48) and mean maximum concentration (Cmax) were significantly lower and tmax significantly increased in phases 2 and 3 compared with phase 1. These results indicate that the absorption of digoxin is reduced by administration of acarbose, and that one of the major mechanisms of this interaction may be due to the pharmacodynamics of acarbose.

Fluconazole-induced convulsions at serum trough concentrations of approximately 80 microg/mL.

On the basis of two case reports it is suggested that serious convulsions may occur in patients treated with flucoazole when serum trough concentrations exceed 80 &mgr;g/mL. The authors recommend monitoring fluconazole concentrations during high-dose therapy in patients with poor kidney function.

Efficacy of therapeutic drug monitoring in prevention of hypoglycemia caused by cibenzoline

Abstract.Objective: The purpose of this study was to evaluate the efficacy of our therapeutic drug monitoring (TDM) services in cibenzoline therapy using the risk of hypoglycemia as an end point. Methods: The TDM services of cibenzoline were introduced in March 1998. If the serum concentrations of cibenzoline deviated from the therapeutic range, adjustment of dosage was recommended. In addition, the physicians were recommended to pay attention to the hypoglycemia induced by cibenzoline. A series of case-control studies were performed before and after introduction of TDM services. After introduction of TDM services of cibenzoline, four case-control studies were performed every 6xa0months between March 1998 and February 2000 (stage 2 between March 1998 and August 1998; stage 3 between September 1998 and February 1999; stage 4 between March 1999 and August 1999; stage 5 between September 1999 and February 2000) using the same method as in the previous study which had been performed between September 1997 and February 1998 (stage 1). The TDM data of inpatients and outpatients between March 1998 and February 2000 were reviewed. Results: A significantly increased risk of hypoglycemia was observed for users of cibenzoline during stage 1 [crude odds ratio (OR) 10.4; 95% confidence interval (CI) 2.7–40.3], stage 2 (crude OR 3.1; 95% CI 1.0–9.0), and stage 3 (crude OR 3.8; 95% CI 1.2–12.7). However, during stage 4 and stage 5, no significantly increased risk of hypoglycemia was observed. There was no significant difference between the mean doses during stage 1 and stage 5. However, there was a significant difference in the distributions of the trough levels among the four stages. During stage 4 and stage 5, the percentage of samples with a trough level of 200–400xa0ng/ml was higher than during stage 2 and stage 3. During stage 2, the percentage of samples with a trough level over 400xa0ng/ml was 42.9%. Furthermore, the risk of hypoglycemia associated with cibenzoline use decreased together with the increase in the percentage of outpatients whose serum concentrations of cibenzoline had been measured in the past. The risk of hypoglycemia associated with cibenzoline use decreased after introduction of TDM of cibenzoline. Conclusion: Dose adjustment based on TDM and the physicians increased recognition of hypoglycemia associated with cibenzoline use were beneficial for those patients treated with cibenzoline in order to prevent hypoglycemia.

Lack of Pharmacokinetic Interaction between Mexiletine and Omeprazole

OBJECTIVE: To investigate the effect of omeprazole on the pharmacokinetics of mexiletine. METHODS: Nine healthy male Japanese volunteers participated in a crossover study. On day 1, the subjects received mexiletine 200 mg. On days 2–7, they received omeprazole 40 mg, and on day 8 they received mexiletine 200 mg and omeprazole 40 mg concomitantly. Serum concentrations of mexiletine were determined just before drug administration and at 1, 2, 3, 4, 6, 8, 12, and 24 hours on day 1 and day 8. RESULTS: No differences in mexiletine concentrations were observed between the two phases of the study. The mean AUCs after administration of mexiletine alone and in combination with omeprazole 40 mg/d were 6.26 and 6.20 ng·h/L, respectively. CONCLUSIONS: These findings suggest that omeprazole does not affect mexiletine metabolism. OBJETIVO: Investigar el efecto de omeprazole en la farmacocinética de mexiletine. MÉTODOS: Nueve hombres japoneses saludables participaron en forma voluntaria en un estudio cruzado. En el primer día, los voluntarios recibieron mexiletine 200 mg solamente. Desde el segundo al séptimo día, los sujetos recibieron omeprazole, y en el octavo día recibieron mexiletine y omeprazole 40 mg concomitantemente. Los concentracions séricas de mexiletine fueron tomadas justo antes de la administración del medicamento en la 1, 2, 3, 4, 6, 8, 12, y 24 hora después de la administración del medicamento en el día 1 y en el día 8. RESULTADOS: En las concentraciones de mexiletine no fueron observadas diferencias entre los dos fases del estudio. El área promedio bajo la curva de concentración versus tiempo despues de la administración de mexiletine solo y en combinación con omeprazole 40 mg/día fueron 6.26 y 6.20 ng·h/L, respectivamente. CONCLUSIONES: Los hallazgos sugieren que omeprazole no afecta el metabolismo de mexiletine. OBJECTIF: Évaluer linfluence de loméprazole sur la pharmacocinétique de la mexilétine. MÉTHODES: Neuf volontaires sains ont participé à cette étude. Tous les individus étaient dorigine Japonaise et de sexe masculin. Dans un premier temps, les individus ont reçu une dose unique de 200 mg de mexilétine. Puis ils ont reçu 40 mg doméprazole pendant 6 jours. La huitième journée de létude, on leur a administré 40 mg doméprazole accompagné de 200 mg de mexilétine. Des prélèvements sanguins ont été effectués immédiatement avant ladministration de mexilétine et après 1, 2, 3, 4, 6, 8, 12, et 24 heures. Les concentrations de mexilétine étaient mesurées par chromatographie liquide haute performance. RÉSULTATS: Aucune différence na été noté entre les concentrations de mexilétine au jour 1 et celles au jour 8. Les surfaces sous la courbe moyennes étaient de 6.26 et 6.20 ng · h/L, respectivement. CONCLUSIONS: Les résultats suggérent que loméprazole naffecte pas le métabolisme de la mexilétine.

The relationship between risk of hypoglycemia and use of cibenzoline and disopyramide

AbstractObjective: A case-control study was carried out to compare the risks of hypoglycemia caused by disopyramide and cibenzoline.nn Methods: We selected 91 subjects with hypoglycemia from among 14,156 outpatients who consulted the National Cardiovascular Center (NCVC) and received drug therapy between September 1997 and February 1998. We used the fasting blood sugar (FBS) level of 75u2009mg/dl or less as the cut-off level to screen for hypoglycemia. For each case, five controls matched for gender and age were selected from the clinical division consulted by relevant subjects.nn Results: Ninety-one cases and 455 controls were enrolled in this study. Of 91 cases with hypoglycemia, 8 (8.8%) were treated with cibenzoline and 3 (3.3%) with disopyramide. The percentage of cases treated with cibenzoline was greater than that in the controls (1.5%), and the prescription frequency of cibenzoline during the study period was 2%. With adjustment for potential confounding factors using conditional logistic regression, hypoglycemia was significantly correlated with the use of cibenzoline [OR 8.0 (95% CI 1.7–36.8)], insulin [OR 48.4 (95% CI 8.8–267.2)], and thyroid agents [OR 13.0 (95% CI 1.1–160.4)]. An increased risk of hypoglycemia associated with the use of sulfonylureas was not detected. In additional logistic regression analysis, including the variables with individual sulfonylureas, glibenclamide but not gliclazide significantly increased the risk of hypoglycemia. The use of disopyramide did not affect the risk of hypoglycemia. In separate analyses for diabetic and non-diabetic patients, the risks of hypoglycemia associated with the use of drugs other than β-blocking agents in non-diabetic patients were estimated to be lower than those in diabetic patients.nn Conclusion: The use of cibenzoline was significantly correlated with an increased risk of hypoglycemia.

Lack of kinetic interaction between digoxin and voglibose

We have studied the ex80ect of voglibose, a disaccharidase inhibitor [1, 2], on serum digoxin concentration in eight healthy men (mean age 29.6 years, range 26±45 years; mean weight 64.0 kg, range 58±70 kg). A randomized two-way crossover design was used, each phase being separated by a 2-week washout period. In phase 1, the subjects took digoxin 0.25 mg alone with 200 ml of water after breakfast for 8 days. In phase 2, the subjects took 0.2 mg of voglibose 0.5 h before each meal three times a day and 0.25 mg of digoxin after breakfast for 7 days; on day 8, they took 0.2 mg of voglibose at 0630 hours with 100 ml of water and 0.25 mg of digoxin at 0700 hours with 100 ml of water; they then took 0.2 mg of voglibose half an hour before each meal three times for another day. On the 8th day of both phases, the subjects fasted overnight for at least 10 h before taking digoxin and continued to fast for 6 h afterwards. They were instructed not to take any other medications or drink alcoholic beverages for 1 week before and throughout the study period. Blood was collected on day 8 just before the administration of digoxin and 1, 2, 4, 8 h, and 24 h afterwards. The serum digoxin concentration was measured by ̄uorescence polarization immunoassay (FPIA; Dainabott, Tokyo, Japan). The minimum detectable concentration of digoxin was 0.2 ng á ml and the coex81cients of variation were <5%. The peak serum concentration (Cmax) and the time to reach Cmax (tmax) were obtained from the actual values. The area under the serum concentrationtime curve (AUC) was calculated from 0 to 24 h by the linear trapezoidal method. The clearance (CL/F) of digoxin was calculated from CL/F = dose/AUC. Statistical analysis was performed using paired Students t-tests (Statistical Analysis System, Version 6.12). The pharmacokinetic parameters are summarized in Table 1. There were no signi®cant dix80erences in AUC, Cmax, or CL/F, but the tmax was signi®cantly longer in phase 1 (P < 0.05). Thus, the absorption of digoxin was not ax80ected by voglibose, except for a small delay in tmax. The ex80ect was too small to be of clinical signi®cance. We have shown elsewhere that acarbose also delays the tmax of digoxin [3]. Acarbose is an a-glucosidase inhibitor, which delays digestion by sucrose and maltose, and it has been reported that when digoxin and acarbose were coadministered, the absorption of digoxin was decreased [3, 4]. Serrano et al. [4] suggested that the mechanisms of the interaction of digoxin and acarbose involved a disturbance of gastrointestinal transit with loose stools due to bacterial gas products from nonabsorbed carbohydrate, interference with the hydrolysis of digoxin before its absorption, and adsorption of digoxin by acarbose. However, Holt et al. [5] reported that acarbose had no ex80ect on the digoxin-metabolizing enzyme in the colon. On the other hand, acarbose inhibits not only a-glucosidase but also a-amylase, while voglibose inhibits only a-glucosidase. Acarbose causes abdominal distension and marked gastrointestinal enlargement by inhibition of a-amylase, and a low dose of voglibose has a constant inhibitory ex80ect on postprandial hyperglycemia without bringing on gastrointestinal symptoms such as diarrhea and abdominal distension. Eur J Clin Pharmacol (1999) 55: 79±80 Ó Springer-Verlag 1999

Evaluation of Mexiletine Clearance in a Japanese Population

OBJECTIVE: To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition. METHODS: Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC. RESULTS: Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed. CONCLUSIONS: The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.

POPULATION PHARMACOKINETIC ANALYSIS OF PIRMENOL IN HEALTHY VOLUNTEERS AND PATIENTS WITH ARRHYTHMIA

Pirmenol is a class Ia antiarrhythmic agent and is reported to be ex80ective for premature ventricular contractions [1±3]. Pirmenol is mainly eliminated by hepatic metabolism, although more than 23% of the dose is excreted in urine in an unchanged form [4]. However, at present only limited information is available, based on small-scale pharmacokinetic studies. Thus, we studied the population pharmacokinetics of pirmenol in patients and investigated the ex80ects of demographic or clinical factors on the pharmacokinetic parameters. Data were obtained from 90 subjects during phase 1 or 2 clinical trials [5±7] and post marketing study. Thirty-eight of the subjects were patients at Maizuru Kyosai Hospital and they received pirmenol in a post marketing study; only one concentration was measured per patient (Table 1). All subjects provided informed consent before enrolling onto the study, which was approved by the institutional ethics committee of Maizuru Kyosai Hospital. Plasma pirmenol concentrations were determined by HPLC [8]. No subjects received rifampicin, which enhances pirmenol elimination because of the induction of hepatic drug-metabolizing enzymes [9]. The time course of pirmenol was described using a one-compartment open model without absorption because the absorption phase could not be clearly seen. Bioavailability was assumed to be complete in the normal state. All data from all subjects were ®tted simultaneously with NONMEM (Version IV) [10]. The ex80ects of gender, body weight, age and creatinine clearance on total clearance (CL), volume of distribution (Vd) and relative bioavailability were investigated. The signi®cance of those factors was tested by a likelihood ratio test with a signi®cance level of P < 0.05. The ®nal population pharmacokinetic model with signi®cant covariates was as follows: CL x85l hÿ1 kgÿ1x86 x88 0:240 x891ÿ0:00563 age (years)x8a; Vd x85l kgÿ1x86 x88 2:06. No statistically signi®cant ex80ect on either volume of distribution or relative bioavailability was found. The interindividual variations in CL and Vd were 62.0% and 27.0%, respectively. The residual variation was 32.1%. In this study, it was shown that CL was negatively correlated to age, which might be caused by hepatic and/ or renal dysfunction. The relationships between each subjects age and CL estimated by the Bayesian method is shown in Fig. 1. Two regression lines using data from Eur J Clin Pharmacol (1999) 55: 77±78 Ó Springer-Verlag 1999

Study on Awareness of Adverse Drug Reactions in Hospitals-ADR Awareness Investigated through Questionnaire Sent to National Hospitals, and Situation at National Cardiovascular Center-

Up till now, the major drug information-related activity of hospital pharmacists has been to disseminate drug safety information issued by the Ministry of Health, Labour and Welfare. However, another important activity of pharmacists is noting adverse drug reactions (ADR) occurring in their own hospital and informing other medical staff about them. This information should also be reported to the Ministry of Health, Labour and Welfare so that the adverse reactions may be widely known among the medical community. In order to investigate the extent that pharmacists actually conduct such activities, a questionnaire survey was sent to 62 national hospitals and the number of ADR reports to the Ministry of Health, Labour and Welfare from 189 national hospitals in fiscal 2003 was investigated. The results indicated that most hospitals were insufficiently aware of the ADRs that occurred. A major reason for this was considered to be the lack of systems for collecting and reporting adverse reactions. Pharmacists were found to be involved in 78% of ADR reports. For the National Cardiovascular Center, the survey showed that the introduction of an ADR collecting system in which pharmacists played a leading role had significantly increased the number of ADR reports to the Ministry of Health, Labour and Welfare. Moreover, 3% of the reported ADRs were related to safety information from the Ministry of Health, Labour and Welfare. The survey results also suggested that providing safety information to physicians is effective in improving safety in the use of drugs. Although medical staff were only aware of about 3% of the ADRs, the crucial role of pharmacists in collecting and reporting ADRs was recognized.

Evaluation of the Optimal Dosage of Alopurinol in Japanese Patients.

Allopurinol is often used for the treatment of patients suffering from gout and hyperuricemia. However, adverse effects due to the accumulation of oxipurinol, the main active metabolite of allopurinol, have been reported in patients with renal insufficiency. Therefore, in order to prevent such adverse effects, some guidelines for the optimal dosage of allopurinol have been advocated. To evaluate these guidelines, the serum oxipurinol concentration in 101 patients with hyperuricemia treated with allopurinol was measured by HPLC. The serum oxipurinol concentration/dosage increased (p< 0.01) as the creatinine clearance level decreased. In addition, to evaluate the optimum dosage based on the renal function, Ccr was classified into three groups (Ccr≤30mL/min, 30mL/min<Ccr≤50mL/min, Ccr< 50mL/min).A positive correlation was observed between the dosage of allopurinol and the serum oxipurinol concentration in each group (Ccr≤30mL/min, Ccr< 50mL/min : p< 0.01 30mL/min< Ccr : ≤50mL/min : p< 0.05).Regarding the serum oxipurinol concentration/dosage in each group, it increased as the creatinine clearance level decreased (p< 0.05).Based on our findings, the optimal dosages of allopurinol in each group in Japanese are considered to be as follows : 1) Ccr≤30mL/min : 50mg/day2) 30mL/min< Ccr≤50mL/min : 100mg/day3) Ccr< 50mL/min : 200mg/day