Appropriate dosing regimen of allopurinol in Japanese patients.

OBJECTIVE: Approved dosage regimens for prescription drug products are developed with a view to obtaining a favourable therapeutic index in the overall exposed population. The purpose of this study was to examine differences between the approved dosage regimen and the clinically prescribed doses of allopurinol in major hospitals in Japan. METHODS: The prescribing records for allopurinol were scrutinized at five national hospitals in Japan. Prescription information, including mean dose and the distribution of doses, was extracted for each hospital and the data compared with the dosage recommended in the approved labelling for the product. In addition, therapeutic drug monitoring (TDM) data were examined to evaluate relationships between dose administered, serum concentration of oxypurinol, and clinical efficacy. RESULTS: The mean dose of allopurinol prescribed in the five institutions, 131.7 mg/day, was lower than the approved dosage of 200-300 mg/day. There were no differences in the mean dose between the hospitals, and similar dose distributions were seen among the hospitals. Approximately 60-70% of patients were treated with 100 mg/day and 20-30% with 200 mg/day of allopurinol. The most frequent dosage of allopurinol used in clinical practice was 100 mg/day. In the TDM study, the mean trough serum concentrations of oxypurinol were 9.5+/-3.6 microg/mL (50 mg/day), 13.0+/-6.8 microg/mL (100 mg/day), 19.8+/-12.9 microg/mL (200 mg/day) and 15.7+/-7.3 microg/mL (300 mg/day). The mean values of creatinine clearance were 17.0+/-16.4 mL/min (50 mg/day), 33.5+/-32.8 mL/min (100 mg/day), 57.8+/-33.8 mL/min (200 mg/day) and 94.3+/-35.8 mL/min (300 mg/day, in patients with normal renal function), and showed a downward trend together with a reduction of dosage of allopurinol. Allopurinol was given to 91% (91/100) of patients at a daily dose of 100-200 mg, and the oxypurinol trough serum concentration attained (>4.6 microg/mL) was sufficient to maintain a therapeutic effect in 92.3% (84/91) of these patients. A daily dose of 100-200 mg may be enough to obtain therapeutic serum oxypurinol concentrations in most Japanese patients. CONCLUSIONS: Dose of 100-300 mg/day was an effective and commonly used dosing regimen for allopurinol in Japanese patients. The approved dosage range (200-300 mg/day) may be too high for patients with renal dysfunction, suggesting the recommended dosing regimen for allopurinol should be revised to include the lower doses.

Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring.

OBJECTIVE: In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. METHODS: Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. RESULTS: A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. CONCLUSIONS: It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM.

Concomitant use of buffered and enteric-coated low-dose aspirin products and antisecretory drugs.

OBJECTIVE: Buffered and enteric-coated formulations of low-dose aspirin therapy are although expected to avoid gastrointestinal complications, there are reports that these modified products are associated with such complications. One available option for preventing aspirin-induced gastrointestinal complications is the simultaneous use of the agents that inhibit acid secretion such as H(2)-receptor antagonists and proton pump inhibitors. We compared the frequency of prescriptions for antisecretory drugs between users of either buffered or enteric-coated low-dose aspirin. METHODS: Monthly prescriptions at the National Cardiovascular Center for aspirin products and antisecretory drugs were counted from January 1998 to December 2002. Counting was based on information from a prescription database file compiled from a computerized order entry system. Time-series analyses were performed to determine changes in the frequency of prescriptions for low-dose aspirin products and antisecretory drugs. In addition, the frequency of prescriptions for antisecretory drugs was compared in individuals using either buffered or enteric-coated low-dose aspirin. RESULTS: A significant reduction in the frequency of prescriptions for H(2)-receptor antagonists was observed during 2001 in users of enteric-coated low-dose aspirin compared with users of buffered low-dose aspirin users. In contrast, we observed a significant increase in the frequency of prescriptions for H(2)-receptor antagonists in users of enteric-coated low-dose aspirin during 2002. This change in prescribing H(2)-receptor antagonists in users of enteric-coated low-dose aspirin began in the latter half of 2001. Proton pump inhibitors accounted for 0.31% of prescriptions in users of buffered low-dose aspirin and 0.47% in users of enteric-coated low-dose aspirin, with this difference being statistically significant. CONCLUSION: The findings of the present study do not support the notion that enteric-coated low-dose aspirin reduces the risk of gastrointestinal complications and is safer than buffered low-dose aspirin products. However the usual caution about making inferences from observational retrospective data is appropriate.

Physicians' prescribing attitudes to combined therapy with statins and fibrates.

OBJECTIVE: To assess the impact of a package insert revision and a drug-drug interaction warning embedded in a computerized prescription ordering system, on physicians' prescribing of concomitant statins and fibrates. METHODS: Data were obtained using a computerized prescription order entry system before and after administrative intervention advising of potentially adverse effects of this combined therapy. The number of prescriptions for statins and fibrates were counted monthly from January 1998 to June 2002 at the National Cardiovascular Center (NCVC). Counting was based on information from a prescription database file compiled from a computerized order entry system. The total number of prescriptions and frequency of requests for statins and fibrates were compared with the timing of either package insert revision or introduction of the warning on a computerized prescription ordering system. In addition, laboratory testing of renal function using serum creatinine (Scr) assays in patients treated with combined statins and fibrates was obtained from medical records at two stages during the study period (stage 1, January 1998 to June 1998; stage 2, January 2002 to June 2002). RESULTS: There were 204 prescriptions for concomitant statins and fibrates at the beginning and 50 prescriptions at end of the study period. The number of prescriptions began to decrease in the latter half of 1999 with the percentage of concomitant use of statins and fibrates showing an evident downward trend from January 2001. This acceleration in the downward trend coincided with the introduction of the computerized warning message. Scr levels were measured in 43.8% of patients in stage 1 and in 48.3% of patients in stage 2 in the past month. The percentage of patients having Scr levels measured in the past 6 months was 85.3% in stage 1 and 84.5% in stage 2. There was no significant difference in the percentages of patients whose Scr levels had been measured between the two stages. CONCLUSION: Revision of package inserts concerning combined therapy of statins and fibrates led to physicians' prescribing fewer of these combinations. A warning message displayed on a computerized prescription order entry system accentuated this effect.

The stereoselective effects of bucolome on the pharmacokinetics and pharmacodynamics of racemic warfarin.

The objective of this study was to investigate the stereoselective influence of bucolome on the pharmacokinetics and pharmacodynamics of warfarin in Japanese inpatients with heart disease. Thirty patients were administered a fixed-maintenance dose of warfarin alone once a day for at least 7 days. The other 25 patients were concomitantly administered warfarin and a 300 mg dose of bucolome once a day, and blood samples were collected on days 1, 4, 7, 14, or 21 after administration of bucolome. Serum concentration of warfarin enantiomers was measured by a chiral reversed-phase HPLC-ultraviolet detection method. The PT-INR was used as a measure of the pharmacodynamic effect of warfarin. Coadministration of bucolome and warfarin had no effect on serum (R)-warfarin concentration and significantly increased serum (S)-warfarin concentration compared with warfarin alone. The PT-INR of warfarin alone was significantly lower with bucolome cotreatment. These results indicate that the augmented anticoagulant effect of warfarin by bucolome is due to inhibition of (S)-warfarin metabolism in vivo. When bucolome is added to a stabilized regimen of warfarin therapy, the dose of warfarin should be reduced by about 30% to 60%, and caution should be exercised during the first 7 days after coadministration of bucolome.

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

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 6 months 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 200-400 ng/ml was higher than during stage 2 and stage 3. During stage 2, the percentage of samples with a trough level over 400 ng/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.

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 microg/mL. The authors recommend monitoring fluconazole concentrations during high-dose therapy in patients with poor kidney function.

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

OBJECTIVE: A case-control study was carried out to compare the risks of hypoglycemia caused by disopyramide and cibenzoline. 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 75 mg/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. 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 beta-blocking agents in non-diabetic patients were estimated to be lower than those in diabetic patients. CONCLUSION: The use of cibenzoline was significantly correlated with an increased risk of hypoglycemia.

Biodistribution of 3,4-dihydro-5-[11C]methoxy-1(2H)-isoquinolinone, a potential PET tracer for poly(ADP-ribose) synthetase.

Poly(adenosine diphosphate-ribose) synthetase (PARS) is a nuclear enzyme that is activated by deoxyribonucleic acid (DNA) strand breaks and participates in DNA repair. Excessive PARS activation, however, leads to cell death due to depletion of adenosine triphosphate (ATP). To evaluate whether it is possible to detect excessive activation of PARS with positron emission tomography (PET), we examined the pharmacokinetics of 3,4-dihydro-5-[(11)C]methoxy-1(2H)-isoquinolinone ([(11)C]MIQO), a potent poly(ADP-ribose) synthetase inhibitor, in the brain of rats and monkeys. Although the uptake of [(11)C]MIQO in the brain of normal rats was low, [(11)C]MIQO was rapidly incorporated into and then quickly washed out from the brain. The uptake of the radiotracer in the brain of normal monkeys was also low; however, [(11)C]MIQO gave a distribution image that differed from that of cerebral blood flow obtained by [(15)O]water-PET. No localization of [(11)C]MIQO in the brain of normal monkeys was observed. Low accumulation of some radioactivity was also observed in muscles surrounding the brain of monkeys, but did not seem to interfere with measurement of [(11)C]MIQO uptake in the brain with PET. Thus, detection of [(11)C]MIQO uptake with PET may be useful for detecting PARS activity in ischemic injury.

Impairment of mycophenolate mofetil absorption by iron ion.

OBJECTIVE: We sought to evaluate the effect of iron ion on the absorption of mycophenolate mofetil, which is an immunosuppressive agent. The pharmacokinetics of mycophenolic acid were studied. METHODS: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. In the first phase, the volunteers received 1.0 g of mycophenolate mofetil alone (study 1); in the second phase, the volunteers received 1.0 g of mycophenolate mofetil and 2 tablets of iron ion preparations concomitantly (study 2). The serum concentration of mycophenolic acid, which is a pharmacologically active metabolite, was measured by reverse-phase HPLC. RESULTS: The area under the plasma concentration-time curve from 0 to 12 hours and the maximum concentration of mycophenolic acid in study 2 were significantly less than in study 1 (area under the curve, 32.9 +/- 14.7 versus 2.92 +/- 0.883 microg x h/mL, P < .001, maximum concentration, 20.1 +/- 9.21 versus 1.30 +/- 0.367 microg x h/mL, P < .001). CONCLUSIONS: This finding shows that when mycophenolate mofetil and iron ion preparations were administered concomitantly, a remarkable decrease of mycophenolate mofetil absorption was observed. Therefore it seems to be clear that we must avoid the concomitant administration of mycophenolate mofetil and iron ion preparations.

Population pharmacokinetic analysis of mexiletine in adult arrhythmic patients in Japanese population.

We analyzed mexiletine in Japanese patients using population pharmacokinetics. 139 serum concentration data, which were collected for therapeutic drug monitoring from 121 patients, were used for this analysis. We also investigated influence of age and gender on pharmacokinetics, and age was found to be an influential factor on clearance. The final pharmacokinetic parameters are, CL/F=0.580-0.00369 x AGE (l/h/kg) and Vd/F=6.63 (l/kg). These results should be useful for adjusting the dosage to a patient's age for the prevention of an adverse reaction caused by overexposure.

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.

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.

An epidemiological study on the association between the total leukocyte and neutrophil counts, and risk factors of ischemic heart disease by smoking status in Japanese factory workers.

Several epidemiologic studies have shown the association between total leukocyte count and the risk of developing myocardial infarction. The purpose of this study was to assess the association between the total leukocyte and neutrophil counts and risk factors of ischemic heart disease in 1,384 Japanese factory workers. Total leukocyte and neutrophil counts were significantly higher in current smokers than in non-smokers. Among current smokers, the total leukocyte and neutrophil counts were positively associated with the number of cigarettes smoked daily and the duration of cigarette smoking and alcohol consumption. Being independent of smoking habit, the total leukocyte and neutrophil counts were also related to several characteristics recorded at the physical examinations. The total leukocyte and neutrophil counts were positively associated with serum total cholesterol, serum triglyceride and hematocrit levels, and inversely associated with the serum HDL-cholesterol level. No significant associations of the total leukocyte or neutrophil counts were found with the red blood cell count and hemoglobin level. These results suggest that the total leukocyte and neutrophil counts may represent the metabolic condition with a high coronary risk among apparently healthy people.

[Comparative study of sustained-release in theophylline (Slobid, Theolong, Theodur) by pharmacokinetics].

We made a comparative study of three kinds of sustained-release of theophylline compounds by means of analysis of plasma concentrations. The drugs were Slobid (SB) (Up-john) 11 patients (10 men, 1 woman), Theolong (TL) (Eisai) 22 (10 men, 12 women), Theodur (TD) (Nikken chemicals) 34 (18 men, 16 women), who were hospitalized from January 1989 to November 1994. These patients were given oral theophylline, bid at 9:00 and 21:00, plasma concentration of theophylline was determined at 9:00, 12:00, 15:00, 18:00 and 21:00, after plasma concentration reached a plateau. There were no significant differences as to the zero absorption rate, the moment absorption rate, clearance, but there were significant differences to the half life time (T1/2) of SB (18.9) > TL (13.5) > TD (10.1) (p = 0.0061), mean residence time (MRT) of SB (21.3 hr) > TL (16.7) > TD (15.2) (p = 0.0034), by measurements analysis of variance. These results suggest that these sustained-release drugs have different pharmacokinetics judging from the important indices including Cmax-Cmin, T1/2, V, MRT and Tml/2, and that the best one is the SB, the second is the TL, and the third is the TD for RTC therapy.

[Comparative study of sustained-release in theophylline (Slobid, Theolong, Theodur) by pharmacokinetics].

We made a comparative study of three kinds of sustained-release of theophylline compounds by means of analysis of plasma concentrations. The drugs were Slobid (SB) (Up-john) 11 patients (10 men, 1 women), Theolong (TL) (Eisai) 22 (10 men, 12 women), Theodur (TD) (Nikken chemicals) 34 (18 men, 16 women), who were hospitalized from January 1989 to November 1994. Theses patients were given oral theophylline, bid at 9:00 and 21:00, plasma concentration of theophylline was determined at 9:00, 12:00, 15:00, 18:00 and 21:00, after plasma concentration reached a plateau. There were no significant differences as to the zero absorption rate, clearance, the moment absorption rate, but there were significant differences to Cmax-Cmin of SB (3.34 micrograms) < TL (4.22) < TD (5.22) (P = 0.0150), the zero half life time (T1/2) of SB (18.9 hr) > TL (13.5) > TD (10.1) (P = 0.0061), the apparent distribution volume (V) of SB (0.811/ kg) > TL (0.78) > TD (0.55) (P = 0.0309), mean residence time (MRT) of SB (21.3 hr) > TL (16.7) > TD (15.2) (P = 0.0034), the moment half life time (Tm1/2) of SB (13.7 hr) > TL (10.6) > TD (9.55) (P = 0.009), by measurements analysis of variance. These results suggest that these sustained-release drugs have different pharmacokinetics judging from the important indices including Cmax-Cmin, T1/2, V, MRT and Tm1/2, and that the best one is the SB, the second is the TL, and the third is the TD for RTC therapy.