Population pharmacokinetic investigation for optimization of amiodarone therapy in Japanese patients.

BACKGROUND: Optimal use of amiodarone (AMD) requires information regarding the drug's pharmacokinetics and the influence of various factors on the drug's disposition. This study was conducted to establish the role of patient characteristic in estimating doses of AMD using nonlinear mixed effects modeling in Japanese patients treated with oral therapy. METHODS: Serum concentrations of AMD were determined by high-performance liquid chromatography. The 151 serum trough concentrations from 23 patients receiving repetitive oral AMD were collected. Analysis of the pharmacokinetics of AMD was accomplished using a 1-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on AMD disposition was investigated. RESULTS: Estimates generated by nonlinear mixed effects modeling indicated that the clearance of AMD was influenced by the demographic variables: total body weight (TBW), daily dosage of AMD (DD), body mass index (BMI), gender (GEN), duration of AMD dosing (DUR), and patient clearance factor (Conc(θ); Conc = serum trough concentration of AMD). The final pharmacokinetic parameters were CL/F (L/h) = 0.072·TBW·Conc(-1.01)·1.95(DD≥200)·0.931(BMI≥25)·1.37(GEN)·DUR(-0.016), and Vd/F (L) = 78.4·TBW, where CL is total body clearance and Vd is volume of distribution. As all doses were given orally, it was impossible to assess the bioavailability (F). DD ≧200 is an indicator variable that has a value of 1 if the patient is receiving more than 200 mg daily dosage of AMD, and 0 otherwise. BMI ≧25 is an indicator variable that has a value of 1 if the BMI is 25 kg/m² and over, and 0 otherwise. GEN is an indicator variable that has a value of 1 if the patient is woman, and 0 otherwise. CONCLUSIONS: The authors developed new population pharmacokinetic parameters. Clinical application of the findings in the present study to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect.

Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination.

BACKGROUND: The mortality and morbidity rates of various cardiovascular diseases differ between Western countries and Japan. The age- and gender-specific prevalence rate of atrial fibrillation (AF) in the general population of Japan was determined using the data from periodic health examinations in 2003. METHODS: Data of 630,138 subjects aged 40 years or more (47% were men and 34% were employees of companies and local governments) were collected from northern to southern Japan. The prevalence of diagnosed AF in each 10-year age group of both men and women was determined. Based on these prevalence rates and the Registry of Residents, the number of people having AF in Japan was estimated. RESULTS: The prevalence rate of AF increased as both male and female subjects aged, and it was 4.4% for men but only 2.2% for women aged 80 years or more (p<0.0001). As a whole, the AF prevalence of men was three times that of women (1.35 versus 0.43%, p<0.0001). There may be approximately 716,000 people (95% confidence interval (CI), 711,000-720,000) with AF in Japan, an overall prevalence of 0.56%. The number of people having AF was projected to be 1.034 (95% CI, 1.029-1.039) million, an overall prevalence of 1.09%, in 2050. CONCLUSIONS: The prevalence of AF increased in Japan as the population aged, as in Western countries. The overall prevalence of AF in Japan is approximately two-thirds of that in the USA. The projected increase in the number of people having AF is modest in Japan in 2050.

Impact of metabolic syndrome on the long-term survival of patients with acute myocardial infarction: potential association with C-reactive protein.

BACKGROUND: Population-based cohort studies demonstrate that metabolic syndrome (MeS) is associated with increased risk for cardiovascular diseases and related mortalities. The present study was designed to investigate the prognostic impact of MeS in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The study group was 461 AMI patients without a history of previous myocardial infarction. On the basis of the National Cholesterol Education Program Adult Treatment Panel III criteria, MeS was defined having at least 3 of the following 5 conditions: dysglycemia (impaired fasting glucose, current use of insulin or oral hypoglycemic drugs), hypertriglyceridemia, low high-density lipoprotein-cholesterol level, hypertension and obesity. The prevalence of MeS was 37% (n=172). C-reactive protein (CRP) levels increased with the increase in the number of conditions of MeS. During follow-up at a median of 17.6 months, the incidence of major adverse cardiovascular events (MACE) was significantly different between patients with and without MeS. Furthermore, after adjustment of predictive factors (age, sex, Killip class, multivessel coronary artery disease, low ejection fraction and high CRP level), MeS was an independent risk factor for MACE. CONCLUSIONS: In patients with AMI, MeS is associated with systemic inflammation and is an important predictor for MACE, which suggests the need for early identification and medical intervention for secondary prevention of MeS.

Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation.

BACKGROUND: The present study was conducted to investigate the relation between the accumulation of the risk factors of thromboembolism and the levels of hemostatic markers in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Five hundred ninety-one NVAF patients and 129 control subjects were categorized into low, moderate or high risk of thromboembolism, according to CHADS(2) index. One point each was given to patients with advanced age (> or =75 years), hypertension, congestive heart failure, and diabetes mellitus, and 2 points, to those with prior ischemic stroke or transient ischemic attack. Patients with CHADS(2) score of 0, 1 or 2, and > or =3 were classified as low, moderate and high risk, respectively. Levels of hemostatic markers (platelet factor 4, beta-thromboglobulin, prothrombin fragment F1+2 and D-dimer) were determined. RESULTS: Of 591 patients with NVAF, 302 were treated with warfarin (mean international normalized ratio 1.88). D-dimer levels increased as the risk level increased irrespective of warfarin use. Particularly, NVAF patients without receiving warfarin (n=289) had significantly higher D-dimer levels than control patients (e.g., for high risk patients, 175+/-144 vs 75+/-87 ng/ml, p<0.001), while NVAF patients receiving warfarin had intermediate levels (136+/-156 ng/ml). F1+2 levels increased as the risk level increased, and were significantly suppressed by warfarin. Levels of markers of platelet activation (platelet factor 4 and beta-thromboglobulin) were increased in NVAF patients but not affected by the risk level. CONCLUSION: Coagulation and fibrinolytic activity is increased along with the accumulation of the risk factors of thromboembolism in NVAF patients.

Two cases of short QT interval.

BACKGROUND: The epidemiology of short QT interval remains unclear. We attempted to determine the incidence and clinical characteristics of short QT interval in a longitudinal cohort study. METHODS: A total of 19,153 subjects (7,525 male, 11,628 female) were enrolled in the study and all available electrocardiograms (ECGs) were investigated longitudinally from 1958 through 2003. We defined short QT interval as QTc of less than 350 ms. RESULTS: Of the 19,153 subjects, two met the criteria of short QT interval and allowed for prevalence and incidence estimates for short QT interval as 0.01% and 0.39/100,000 person-years, respectively. Both cases had neither a family history of sudden cardiac death, nor a history of drug use that might have affected for QT interval. Case 1 was a female with history of ischemic heart disease. Case 2 was a 60-year-old male who exhibited a short QT interval for the first time when he was 26 years of age. He had sick sinus syndrome as an underlying heart disease. CONCLUSIONS: Of the 19,153 subjects in this study, none were identified as having the short QT syndrome, with associated high risk of ventricular tachyarrhythmia, atrial fibrillation, and sudden death. Two subjects were identified as having QTc of less than 350 ms, and allowed prevalence and incidence estimates to be made of short QT interval. There observations were suggestive of clinical relationships between short QT interval and organic or electrophysiological heart disease.

Bedtime administration of cilnidipine controls morning hypertension.

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.

Fatty liver and uric acid levels predict incident coronary heart disease but not stroke among atomic bomb survivors in Nagasaki.

Relationships between fatty liver and coronary heart disease (CHD) and stroke risk remain ill defined. We investigated whether fatty liver is a predictor of CHD and stroke risk. Until December 2000 we followed 2,024 atomic bomb survivors (775 men: 62.0 +/- 9.9 years old; 1,249 women: 63.2 +/- 8.4 years old) who had basic examinations between November 1990 and October 1992 for clinical and laboratory CHD risk factors and fatty liver and who were initially free of CHD and stroke. Forty-nine cases of CHD and 84 cases of stroke were observed. At the time of the baseline examinations, significant clinical associations were found between fatty liver and obesity (p<0.001), hypertension (p<0.001), dyslipidemia (p<0.001), and glucose intolerance (p<0.001). A slight but nonsignificant association was found between fatty liver and hyperuricemia (p=0.07) as well. By using multiple Cox regression analyses, age (relative risk [RR] 1.05, 95% confidence interval [CI] 1.01-1.08), smoking (RR 2.20, 95% CI 1.02-4.74), hyperuricemia (RR 2.30, 95% CI 1.08-4.89), and fatty liver (RR 2.53, 95% CI 1.06-6.06) were shown to be significant predictors of CHD, whereas age (RR 1.08, 95% CI 1.06-1.10), smoking (RR 2.06, 95% CI 1.14-3.72), and hypertension (RR 2.14, 95% CI 1.38-3.30) predicted stroke risk. Fatty liver, which clusters clinical and laboratory CHD risk factors, is an independent predictor of CHD, but not of stroke. Fatty liver should be followed as a feature of metabolic syndrome, with the aim of preventing CHD.

Aldosterone induces circadian gene expression of clock genes in H9c2 cardiomyoblasts.

We examined mRNA expression of the clock genes (Per1, Per2, and Bmal1) and PAI-1 (plasminogen activator inhibitor-1) after aldosterone treatment every 4 h up to 48 h in H9c2 cardiomyoblasts by reverse transcription-polymerase chain reaction. To block the MR (mineralocorticoid receptor), the MR antagonist, spironolactone, was added to the medium 1 h before aldosterone treatment. Aldosterone induced an initial increase and rhythmic expression of Per1, while spironolactone attenuated the acute increase in Per1 mRNA induced by aldosterone. On the other hand, aldosterone did not increase the Per2 mRNA in the acute phase, but thereafter induced a rhythmic expression of Per2. Aldosterone also induced rhythmic expression of Bmal1, a positive element of the clock genes. The rhythm of Bmal1 mRNA was anti-phase of that of Per2 mRNA. Aldosterone induced an acute increase in PAI-1 mRNA, but did not induce rhythmic expression of PAI-1. The present study demonstrated first that aldosterone regulates expression of the clock genes Per1, Per2, and Bmal1, and increases PAI-1 expression in H9c2 cardiomyoblasts. Second, an acute increase in Per1 mRNA after aldosterone treatment is mediated through MR. Third, clock genes are not related to PAI-1 expression in H9c2 cardiomyoblasts.

Marked improvement with sildenafil in a patient with idiopathic pulmonary arterial hypertension unresponsive to beraprost and sarpogrelate.

We report a 16-year-old man with severe heart failure due to idiopathic pulmonary arterial hypertension (IPAH). The patient was initially treated with a combination of beraprost, a prostacyclin analog, and sarpogrelate, a serotonin receptor inhibitor. However, he was unresponsive to the treatment. We then changed the treatment to sildenafil, and his condition dramatically improved. Sildenafil has an immediate pulmonary vasodilator effect in patients already receiving vasodilators for IPAH.