Sex and age differences of major cardiovascular events in patients after percutaneous coronary intervention.

BACKGROUND: Women usually have higher risk after receiving percutaneous coronary interventions (PCIs) than men with coronary artery disease (CAD). The aim of this study was to investigate the association of sex differences with future outcomes in CAD patients undergoing PCI, to assess the role of age, and to extend observed endpoints to stroke and congestive heart failure. METHODS: Six thousand six hundred forty-seven patients with CAD who received successful PCIs. The associations between clinic outcomes and sex were analyzed. The primary outcome was major cardiovascular events (MACE), including cardiac death, nonfatal myocardial infraction, and nonfatal stroke. The secondary outcome was MACE and hospitalization for heart failure (total CV events). RESULTS: During a mean of 52.7 months of follow-up, 4833 men and 1614 women received PCI. Univariate and multivariate analyses showed that women were independently associated with an increased risk of cardiac death (HR, 1.78; 95% CI, 1.32-2.41), hospitalization for heart failure (HR, 1.53; 95% CI, 1.23-1.89), MACE (HR, 1.34; 95% CI, 1.10-1.63), and total CV events (HR, 1.39; 95% CI, 1.20-1.62). In the subgroup analysis, women aged under 60 years had higher cardiovascular risks than men of the same age category. CONCLUSION: Women with CAD after successful PCI had poorer cardiovascular outcomes than men. Additionally, younger women (aged <60 years) were especially associated with a higher risk of developing future adverse cardiovascular outcomes.

Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling.

Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.

Optimal blood pressure for patients with end-stage renal disease following coronary interventions.

Hypertension is a frequent manifestation of chronic kidney disease but the ideal blood pressure (BP) target in patients with coronary artery disease (CAD) with end-stage renal disease (ESRD) (eGFR < 15 ml/min/1.73m2 ) still unclear. The authors aimed to investigate the ideal achieved BP in ESRD patients with CAD after coronary intervention. Five hundred and seventy-five ESRD patients who had undergone percutaneous coronary interventions (PCIs) were enrolled and their clinical outcomes were analyzed according to the category of systolic BP (SBP) and diastolic BP (DBP) achieved. The clinical outcomes included major cardiovascular events (MACE) and MACE plus hospitalization for congestive heart failure (total cardiovascular (CV) event).The mean systolic BP was 135.0 ± 24.7 mm Hg and the mean diastolic BP was 70.7 ± 13.1 mm Hg. Systolic BP 140-149 mm Hg and diastolic BP 80-89 mm Hg had the lowest MACE (11.0%; 13.2%) and total CV event (23.3%; 21.1%). Patients with systolic BP < 120 mm Hg had a higher risk of MACE (HR: 2.01; 95% CI: 1.17-3.46, p = .008) than those with systolic BP 140-149 mm Hg. Patients with systolic BP ≥ 160 mm Hg (HR: 1.84; 95% CI, 3.27-1.04, p = .04) and diastolic blood BP ≥ 90 mm Hg (HR: 2.19; 95% CI: 1.15-4.16, p = .02) had a higher risk of total CV event rate when compared to those with systolic BP 140-149 mm Hg and diastolic BP 80-89 mm Hg. A J-shaped association between systolic (140-149 mm Hg) and diastolic (80-89 mm Hg) BP and decreased cardiovascular events for CAD was found in patients with ESRD after undergoing PCI in non-Western population.

Association between Preoperative Nutritional Status and Clinical Outcomes of Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Malnutrition is associated with poor outcomes in patients with cancer, heart failure and chronic kidney disease. This study aimed to investigate the predictive value of the Controlling Nutritional Status (CONUT) score in coronary artery disease (CAD) patients. METHODS: We recruited a cohort of 3118 patients with CAD undergoing percutaneous coronary intervention (PCI) from 2005 to 2015. Nutritional status was evaluated using the CONUT score, with higher scores reflecting worse nutritional status. RESULTS: After adjustment for comorbidities and medication, an increased CONUT score was independently associated with a higher risk of acute myocardial infarction (AMI) (HR: 1.13; 95% CI: 1.03-1.24), cardiovascular (CV) death (HR: 1.18; 95% CI: 1.07-1.30), congestive heart failure (CHF) (HR: 1.11; 95% CI: 1.04-1.18), a major adverse cardiovascular event (MACE) (HR: 1.14; 95% CI: 1.07-1.22), and total CV events (HR: 1.11; 95% CI: 1.07-1.15). The subgroup analyses demonstrated that the association of the CONUT score existed independently of other established cardiovascular risk factors. In addition, CONUT significantly improved risk stratification for myocardial infarction (MI), cardiac death, CHF, MACEs and total CV events compared to conventional risk factors in CAD patients by the significant increase in the C-index (p < 0.05) and reclassification risk categories in cardiac death and MACEs. Conclusions The CONUT score improved the risk prediction of adverse events compared to traditional risk factors in CAD patients after percutaneous coronary intervention (PCI).

Systemic immune-inflammation index (SII) predicted clinical outcome in patients with coronary artery disease.

BACKGROUND: This study examines the predictive value of a novel systemic immune-inflammation index (SII, platelet × neutrophil/lymphocyte ratio) in coronary artery disease (CAD) patients. METHODS: A total of 5602 CAD patients who had undergone a percutaneous coronary intervention (PCI) were enrolled. They were divided into two groups by baseline SII score (high SII vs low SII) to analyse the relationship between SII groups and the long-term outcome. The primary outcomes were major cardiovascular events (MACE) which includes nonfatal myocardial infarction (MI), nonfatal stroke and cardiac death. Secondary outcomes included a composite of MACE and hospitalization for congestive heart failure. RESULTS: An optimal SII cut-off point of 694.3 × 109 was identified for MACE in the CAD training cohort (n = 373) and then verified in the second larger CAD cohort (n = 5602). Univariate and multivariate analyses showed that a higher SII score (≥694.3) was independently associated with increased risk of developing cardiac death (HR: 2.02; 95% CI: 1.43-2.86), nonfatal MI (HR: 1.42; 95% CI: 1.09-1.85), nonfatal stroke (HR: 1.96; 95% CI: 1.28-2.99), MACE (HR: 1.65; 95% CI: 1.36-2.01) and total major events (HR: 1.53; 95% CI: 1.32-1.77). In addition, the SII significantly improved risk stratification of MI, cardiac death, heart failure, MACE and total major events than conventional risk factors in CAD patients by the significant increase in the C-index (P < .001) and reclassification risk categories by significant NRI (P < .05) and IDI (P < .05). CONCLUSIONS: SII had a better prediction of major cardiovascular events than traditional risk factors in CAD patients after coronary intervention.

Association of variability in uric acid and future clinical outcomes of patient with coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND AND AIMS: Hyperuricemia is independently associated with cardiovascular disease (CVD) and is considered to be one of the major risk factors for CVD. However, the impact of inter-visit uric acid (UA) variability on cardiovascular risk remains undetermined. METHODS: We enrolled 3202 patients with coronary artery disease (CAD), who received successful coronary intervention, in a cohort from Taipei Veterans General Hospital from 2006 to 2015. All post-baseline visits UA measurements using standard deviation (SD) were analyzed to correlate with long-term outcome. The primary outcome was the composite of cardiac death, nonfatal MI, nonfatal stroke (MACE). The secondary event was MACE and hospitalization for heart failure. RESULTS: During an average 65.06 ± 32.1-month follow-up, there were 66 cardiovascular deaths, 175 nonfatal myocardial infarctions, 64 nonfatal strokes, 287 hospitalizations for heart failure, and 683 revascularization procedures. There was a linear association between high UA SD and future adverse events. Compared to the lowest quartile SD, subjects in the highest quartile SD had a higher risk of MACE (HR: 2.53, 95% CI: 1.78-3.59), myocardial infarction (HR: 2.43, 95% CI: 1.53-3.86), cardiovascular death (HR: 6.45, 95% CI: 2.52-16.55), heart failure-related hospitalization (HR: 3.43, 95% CI: 2.32-5.05), and total major CV events (HR: 2.72, 95% CI: 2.09-3.56). Furthermore, compared to the average achieved on-treatment UA value, increasing UA SD had a stronger association of higher risk of developing MACE (HR: 1.51, 95% CI: 1.36-1.68), myocardial infarction (HR: 1.37, 95% CI: 1.38-1.68), ischemic stroke (HR: 1.43, 95% CI: 1.13-1.82), CV death (HR: 1.77, 95% CI: 1.50-2.11), HF (HR: 1.43, 95% CI: 1.29-1.58), and total major CV events (HR: 1.46, 95% CI: 1.34-1.58). CONCLUSIONS: High UA variability is associated with a higher risk of developing future cardiovascular events, suggesting the importance of maintaining stable serum UA levels and avoiding large fluctuations in CAD patients after percutaneous coronary intervention (PCI).

Assessment of spatiotemporal variations in river water quality for sustainable environmental and recreational management in the highly urbanized Danshui River basin.

Rivers are an important urban resource, and water quality influences the use of river water. Thus, analyzing spatiotemporal variations in river water quality is crucial for sustainable use and management of water resources in a highly urbanized region. This study employed river pollution index (RPI) data obtained in 2013 to assess spatiotemporal variations in river water quality for sustainable environmental and recreational management in the highly urbanized Danshui River basin. First, ordinary kriging was adopted to analyze monthly RPI distributions. Subsequently, different percentiles of monthly estimated RPI distributions were probabilistically determined at a river segment. Finally, three measurement methods of local uncertainty, namely-conditional variance, local entropy, and interquartile range-were used to characterize spatiotemporal variations in river water quality in the Danshui River basin. Assessment results revealed that more highly polluted river water quality resulted in higher seasonal variations. Moreover, high and very high seasonal variations were mainly concentrated in urban river segments, whereas low and very low seasonal variations were primarily located in upstream river segments. Thus, to achieve sustainable development goals, artificial wetlands should be established at downstream and midstream urban riverbanks and urban recreational activities should be developed in upstream riverbank parks in the Danshui River basin before the comprehensive improvement of river water quality.

Professional Practice Environment Scale-Chinese Version: Development and Psychometric Testing.

BACKGROUND: The Professional Practice Environment (PPE) scale is widely used to assess the quality of the healthcare environment around the world. No validated Chinese-language scale that is designed to address this issue currently exists. PURPOSE: The present study evaluates the construct validity of the Chinese-version PPE on a sample of 290 healthcare workers in Taiwan. METHODS: Forward and backward translations of the PPE scale of Halcomb et al. were used to ensure semantic equivalence. Further, multiple psychometric properties were examined. RESULTS: The developed scale showed sufficient equivalence. The results of a survey of 290 healthcare providers demonstrated that the developed Chinese-version PPE scale had high reliability (Cronbach's alpha = .88) and validity. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of the present study support the effectiveness and efficiency of the Chinese-version 30-item Halcomb's PPE in assessing the professional practice environment in Taiwan.

Tablet splitting of narrow therapeutic index drugs: a nationwide survey in Taiwan.

BACKGROUND: Tablet splitting or pill splitting frequently occurs in daily medical practice. For drugs with special pharmacokinetic characters, such as drugs with narrow therapeutic index (NTI), unequal split tablets might lead to erroneous dose titration and it even cause toxicity. OBJECTIVE: The aim of this study was to investigate the frequency of prescribing split NTI drugs at ambulatory setting in Taiwan. SETTING: A population-based retrospective study was conducted using the National Health Insurance Research Database in Taiwan. All ambulatory visits were analyzed from the longitudinal cohort datasets of the National Health Insurance Research Database. METHODS: The details of ambulatory prescriptions containing NTI drugs were extracted by using the claims datasets of one million beneficiaries from National Healthcare Insurance Research Database in 2010 in Taiwan. The analyses were stratified by dosage form, patient age and the number of prescribed tablets in a single dose for each NTI drugs. Main outcome measures Number and distinct dosage forms of available NTI drug items in Taiwan, number of prescriptions involved split NTI drugs, and number of patients received split NTI drugs. RESULTS: A total of 148,548 patients had received 512,398 prescriptions of NTI drugs and 41.8 % (n = 62,121) of patients had received 36.3 % (n = 185,936) of NTI drug prescriptions in form of split tablets. The percentage of splitting was highest in digoxin prescriptions (81.0 %), followed by warfarin (72.0 %). In the elderly patients, split tablets were very prevalent with digoxin (82.4 %) and warfarin (84.5 %). CONCLUSION: NTI drugs were frequently prescribed to be taken in split forms in Taiwan. Interventions may be needed to provide effective and convenient NTI drug use. Further studies are needed to evaluate the clinical outcome of inappropriate split NTI drugs.

Impact of a warning CPOE system on the inappropriate pill splitting of prescribed medications in outpatients.

BACKGROUND: Prescribing inappropriate pill splitting is not rare in clinical practice. To reduce inappropriate pill splitting, we developed an automatic warning system linked to a computerized physician order entry (CPOE) system for special oral formulation drugs in outpatient settings. We examined the impact of the warning system on inappropriate prescribing of pill splitting and assess prescribers' responses to the warnings. METHODS: Drugs with extended-release or enteric-coated formulations that were not originally intended to be split were recognized as "special oral formulations". A hard-stop system which could examine non-integer doses of drugs with special oral formulations, provide warnings to interrupt inappropriate prescriptions was integrated in CPOE in a medical center since June 2010. We designed an intervention study to compare the inappropriate splitting before and after the implementation of the warning system (baseline period 2010 January to May vs. intervention period 2010 June to 2011 August). During the intervention period, prescription changes in response to a warning were logged and analyzed. RESULTS: A total of 470,611 prescribed drug items with 34 different drugs with special oral formulations were prescribed in the study period. During the 15-month intervention period, 909 warnings for 26 different drugs were triggered among 354,523 prescribed drug items with special oral formulations. The warning rate of inappropriate splitting in the late intervention period was lower than those in baseline period (0.16% vs. 0.61%, incidence rate ratio 0.27, 95% CI 0.23-0.31, P<0.001). In respond to warnings, physicians had to make adjustments, of which the majority was changing to an unsplit pill (72.9%). CONCLUSIONS: The interruptive warning system could avoid the prescriptions with inappropriate pill splitting. Accordingly, physicians changed their behavior of prescribing special oral formulations regarding inappropriate pill splitting. We suggest the establishment of such system to target special oral formulations with warnings to prevent inappropriate pill splitting.

Prescription trends of immunosuppressive drugs in post-heart transplant recipients in Taiwan, 2000-2009.

PURPOSE: Significantly increasing heart transplantations have been performed in Taiwan in the past decades, but the trends of maintenance immunosuppression for heart transplant recipients have not been well known. In this study, we aimed to explore the trends of maintenance immunosuppressive therapy and common complications for heart transplant recipients. METHODS: We retrospectively analyzed ambulatory prescriptions in 488 heart transplant recipients for the period 2000-2009. Patient complications after heart transplantation were also identified. RESULTS: The annual number of new heart transplant recipients ranged from 18 to 68. The 5-year survival rate was 77.9%. The total number of regimens was 10 in 2000, and increased to 28 in 2009. Most prescriptions were immunosuppressive combinations (95.5%-89.5%). The majority of immunosuppressive regimens were a triple regimen: cyclosporine, mycophenolic acid and corticosteroid in 2009. Cyclosporine was a predominant calcineurin inhibitor with a decreasing trend from 73.9% to 59.1%, whereas the use of tacrolimus significantly increased from 11.9% to 38.4%. Mycophenolic acid was the most frequently used antimetabolite (60.1%-80.3%), while the use of azathioprine was reduced (21.6%-2.3%). From 2008, the launch of everolimus initiated a new era in the utilization of mammalian target of rapamycin inhibitors for maintenance immunosuppression. CONCLUSIONS: Cyclosporine remained the most frequently used calcineurin inhibitors, and tacrolimus increased gradually. Mycophenolic acid was the most popular antimetabolite rather than azathioprine. The rapidly increased everolimus combined regimen may change the patterns of maintenance immunosuppression. The increasing number of combination therapies indicates an active role of everolimus and a tendency of complex tailored individual therapies.

Old habits die hard: a nationwide utilization study of short-acting nifedipine in Taiwan.

BACKGROUND: To investigate the nationwide trend of ambulatory prescriptions of short-acting nifedipine on a PRN (pro re nata) order over a fifteen-year period in Taiwan. METHODS: The systematic sampling claims datasets (0.2% sampling ratio) of ambulatory care visits within Taiwan's National Health Insurance from 1997 to 2011 were analyzed. The prescriptions of short-acting capsule-form nifedipine on a PRN order were stratified by the patient's age, the prescribing physician's specialty, and the setting of healthcare facility for each year. RESULTS: During the study period, 8,189,681 visits were analyzed. While the utilization rate of calcium channel blockers changed with time from 2.8% (13,767/489,636) in 1997 to 5.1% (31,349/614,719) in 2011, that of short-acting nifedipine were from 1.0% (n = 5,070) to 0.2% (n = 1,246). However, short-acting capsule-form nifedipine on a PRN order still existed (from 447 prescriptions in 1997 to 784 in 2011). More than one half of these PRN nifedipines were prescribed by the internists and to the elderly patients; almost four-fifths of PRN nifedipines were prescribed during non-emergent consultations. CONCLUSION: The physicians in Taiwan still had the habit of prescribing short-acting nifedipines for PRN use. The reason for such practices and the impact on patients' health deserve attention.

Association between physician specialty and risk of prescribing inappropriate pill splitting.

BACKGROUND: Prescription errors that occur due to the process of pill splitting are a common medication problem; however, available prescription information involving inappropriate pill splitting and its associated factors is lacking. METHODS: We retrospectively evaluated a cohort of ambulatory prescriptions involving extended-release or enteric-coated formulations in a Taiwan medical center during a 5-month period in 2010. For this study, those pill splitting prescriptions involving special oral formulations were defined as inappropriate prescriptions. Information obtained included patient demographics, prescriber specialty and prescription details, which were assessed to identify factors associated with inappropriate pill splitting. RESULTS: There were 1,252 inappropriate prescriptions identified in this cohort study, representing a prescription frequency for inappropriate pill splitting of 1.0% among 124,300 prescriptions with special oral formulations. Among 35 drugs with special oral formulations in our study, 20 different drugs (57.1%, 20/35) had ever been prescribed to split. Anti-diabetic agents, cardiovascular agents and central nervous system agents were the most common drug classes involved in inappropriate splitting. The rate of inappropriate pill splitting was higher in older (over 65 years of age) patients (1.1%, 832/75,387). Eighty-seven percent (1089/1252) of inappropriate prescriptions were prescribed by internists. The rate of inappropriate pill splitting was highest from endocrinologists (3.4%, 429/12,477), nephrologists (1.3%, 81/6,028) and cardiologists (1.3%, 297/23,531). Multivariate logistic regression analysis revealed that the strongest factor associated with individual specific drug of inappropriate splitting was particular physician specialties. CONCLUSION: This study provides important insights into the inappropriate prescription of special oral formulation related to pill splitting, and helps to aggregate information that can assist medical professionals in creating processes for reducing inappropriate pill splitting in the future.

Disparity of physician specialties in the management of chronic heart failure: trend analysis in Taiwan, 2000 - 2010.

OBJECTIVE: Chronic heart failure (CHF) is a condition that is daily confronted by clinicians in a variety of medical specialties, where physicians routinely seek optimum pharmacotherapy for their outpatients with CHF. We conducted a population- based study on pharmacotherapy for outpatients with CHF in Taiwan from 2000 to 2010, which focused on drug prescription patterns of different physician specialties. MATERIALS AND METHODS: We retrieved records from the National Health Insurance Research Database of patient ambulatory visits with diagnosed chronic heart failure, when cardiovascular drugs were prescribed. For purposes of this study, anti-chronic heart failure drugs were separated into categories: mortality reducing agents (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, spironolactone, hydralazine plus nitrates) and symptom-relieving agents (digoxin, diuretics). Thereafter, the trends of prescription patterns related to different physician specialties were analyzed. RESULTS: From 2000 to 2010, the prescription rate of any mortality-reducing agent for CHF outpatients rose from 61.5% to 76.3% while the concomitant rate for digoxin decreased from 47.3% to 45.4%. Compared to internists and family physicians, cardiologists not only prescribed far more mortality-reducing agents from 2000 to 2010 (53.9 - 72.7%, 54.1 - 64.3%, 74.7 - 84.4%, respectively), but also prescribed two or three mortality-reducing drugs. CONCLUSION: There was a significant improvement of optimal pharmacotherapy for chronic heart failure in Taiwan. We observed that cardiologists were more aggressive than non-cardiologists when deciding whether to prescribe mortality-reducing drugs for heart failure management. However, those factors which influence the prescription patterns of internists and family physicians for their patients with CHF still require additional research.

Transforming growth factor-ß1 level and outcome after catheter ablation for nonparoxysmal atrial fibrillation.

BACKGROUND: Atrial fibrosis plays a role in the development of a vulnerable substrate for atrial fibrillation (AF). Transforming growth factor (TGF)-ß(1) is related to the degree of atrial fibrosis and the recurrence of AF after surgical maze procedures. Whether TGF-ß(1) is associated with the outcome after catheter ablation for AF remains unclear. OBJECTIVE: The purpose of this study was to investigate whether plasma TGF-ß(1) was an independent predictor of AF recurrence after catheter ablation. METHODS: Two hundred consecutive AF patients (154 with paroxysmal AF and 46 with nonparoxysmal AF) underwent catheter ablation. Their TGF-ß(1) levels and clinical and echocardiographic data were collected before ablation. RESULTS: Thirty patients (65%) with nonparoxysmal AF and 57 (37%) with paroxysmal AF had AF recurrence after catheter ablation. Among patients with nonparoxysmal AF, those experiencing recurrence had higher TGF-ß(1) levels than did those who did not experience recurrence (34.63 ± 11.98 ng/mL vs 27.33 ± 9.81 ng/mL; P = .026). In patients with paroxysmal AF, recurrence was not associated with different TGF-ß(1) levels. In patients with nonparoxysmal AF, TGF-ß(1) levels and left atrial diameter (LAD) were independent predictors of AF recurrence after catheter ablation. Moreover, TGF-ß(1) levels had an incremental value over LAD in predicting AF recurrence after catheter ablation (global χ(2) of LAD alone: 6.3; LAD and TGF-ß(1) levels: 11.9; increment in global χ(2) = 5.6; P = .013). Patients with small LAD and low TGF-ß(1) levels had the lowest AF recurrence rate at 11%. CONCLUSION: TGF-ß(1) level is an independent predictor of AF recurrence in patients with nonparoxysmal AF and might be useful for identifying those patients likely to have better outcomes after catheter ablation.

Dimemorfan N-demethylation by mouse liver microsomal cytochrome P450 enzymes.

Dimemorfan (d-3-methyl-N-methylmorphinan), an analogue of dextromethorphan, is commonly used as a non-opioid antitussive. To clarify the contribution of cytochrome P450 (P450) in dimemorfan N-demethylation, effects of selective inducers and inhibitors were studied in ICR mice. Phenobarbital (PB)- and dexamethasone (Dex)-treatments caused 5-fold increases of liver microsomal dimemorfan N-demethylation activity. In untreated mouse liver microsomes, demethylation activity was strongly inhibited by a CYP3A inhibitor, ketoconazole. In PB-and Dex-treated mouse liver microsomes, ketoconazole caused strong inhibition, whereas orphenadrine caused a decrease of less than 20%. Pretreatment of control mouse liver microsomes with anti-CYP3A inhibited demethylation activity, whereas pre-treatment with anti-CYP2B had no effect. In PB-and Dex-treated mouse liver microsomes, the demethylation activity was inhibited by both anti-CYP3A and anti-CYP2B. In control mice, the intrinsic clearance of dimemorfan from N-demethylation was 5.8 microl min(-1)mg protein(-1). In PB- and Dex-treated mice, the correlation coefficient of fitting using one-enzyme and two-enzyme models were similar. The intrinsic clearances of induced mouse liver microsomes were similar. These results revealed that CYP3A played a major role in hepatic demethylation in untreated mice. Both CYP3A and CYP2B were involved in this demethylation in PB- and Dex-treated mice.