Bioavailability assessment of disopyramide using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

The relationship between the serum concentration and the pharmacological effect of disopyramide was investigated quantitatively to estimate the extent of its oral bioavailability (EBA(p.o.) and to evaluate the drug interaction with miconazole, a CYP3A4 inhibitor. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was used to describe the relationship between the serum concentrations and changes in QT interval (pharmacological data) of disopyramide after intra-vascular infusion for 15 min (i.v. short-term infusion) to rats. A two-compartment model was applied to the pharmacokinetics of disopyramide. The pharmacological data after short-term infusion were well explained using a PK-PD link model. To validate the present PK-PD model. disopyramide was administered intra-vascularly in separate experiments, and the doses were predicted only from the pharmacological data. The model predicted doses were identical to the actual doses, regardless of the dosing rates. This result indicates that the PK-PD model used in the present study is appropriate, and that the relationship between the serum concentrations and changes in QT intervals is independent of the dosing (input) rate. When miconazole was co-administered orally 1 h before disopyramide infusion, the serum disopyramide concentrations were significantly higher than that following disopyramide alone. The raised serum concentrations under miconazole co-administration were well explained by nonlinear elimination clearance. The pharmacological effects of disopyramide under miconazole co-administration, were also greater than those following disopyramide alone. The results of the PK-PD analysis indicated that the enhanced pharmacological response under miconazole co-administration was simply caused by a pharmacokinetic change. The EBA(p.o.) values estimated from the pharmacological effects predicted the observed values reasonably well. In conclusion, we demonstrated following: (1) the pharmacological effect after intra-vascular administration of disopyramide is related quantitatively to the serum concentrations using a PK-PD model; (2) miconazole affects only the elimination clearance of disopyramide to enhance the pharmacological effect; (3) the EBA of disopyramide can estimated reasonably only well from the pharmacological data using the PK-PD model; (4) there is no dosing-rate-dependent or dosing-route-dependent pharmacological effect of disopyramide.

Bioavailability assessment of arginine-vasopressin (AVP) using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

A novel method of assessing the extent of oral bioavailability of arginine-vasopressin (AVP) from pharmacological data was presented. After intravascular administration (i.v. bolus or short-term infusion) of AVP to rats, the relationship between blood concentrations and its effect on both mean arterial pressure (hemodynamic effect) and urinary sodium concentration (anti-diuretic effect) was described on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. A direct model was used for the hemodynamic response, while an indirect response model, rather than a hypothetical link model was used for the anti-diuretic response. A sigmoid Emax model was applied to describe the drug-receptor interaction. Pharmacological responses after intravascular administration of AVP were reasonably described by the PK-PD model. However, PD parameters estimated by the PK-PD analysis suggested that apparent receptor affinity rather than efficacy in i.v. bolus study was significantly higher than that in the short-term infusion study. This fact indicated that PK-PD relationship was influenced by the intravascular input rate of AVP. We then investigated the relationship between plasma concentration and amount of AVP bound to the V2 receptors in the kidney. The result indicated that the amount of AVP bound to the receptors after i.v. bolus injection was always greater than that after short-term infusion. Since the PK-PD relationship after oral administration was almost identical with that after short-term infusion, the PK-PD model obtained in the short-term infusion study was used to assess the extent of oral bioavailability (EBAPp.o.). The EBAp.o. values, estimated from pharmacological effects (hemodynamic effect and anti-diuretic effect) after oral administration of 5 microg/kg of AVP were 0.68% to 0.93% and were almost identical with the actual EBAPp.o. value (0.81%). From these results, we concluded that oral bioavailability of AVP was reasonably predicted by the PK-PD model, provided that appropriate pharmacological effects and appropriate intravascular dosing rate as a reference formulation are available. The method may be an alternative to methods based on plasma concentrations, when drug concentration cannot be measured and when appropriate pharmacological data are available.

Posttraumatic stress and change in lifestyle among the Hanshin-Awaji earthquake victims.

BACKGROUND: In 1995, Japan's Hanshin-Awaji area was severely damaged by a major earthquake. Lifestyle factors, sometimes associated with physical health and mortality, have also been known to be associated with mental health status. This report examines the relationship between the subsequent change in lifestyle and the psychological stress induced by the earth quake. METHOD: An investigation was made of 108 male inhabitants of Awaji Island as to their individual lifestyle before and after the great earthquake, any posttraumatic stress disorder (PTSD) symptoms, and their demographic variables. RESULTS: The mean PTSD score was higher in the worse lifestyle group than in the no/better lifestyle change group. Category B or D of PTSD scores were higher in the worse lifestyle group than in the no/better lifestyle change group. The percentage of subjects who lived in temporary public housing was higher in the worse lifestyle group than in the no/better lifestyle change group. CONCLUSIONS: Worse change in lifestyle might be associated with high PTSD score in victims of Hanshin-Awaji earthquake.

Effects of long workhours on life-style, stress and quality of life among intermediate Japanese managers.

OBJECTIVES: In accordance with international coordination of labor conditions a Japanese campaign advocating less work finally got under way recently in the form of work-reducing policies of the government to prevent occupational and stress-related diseases. However, long workhours among intermediate managers, who are key persons in most organizations in Japanese industry, are still considered to be prevalent. This study was conducted to examine the workhours of intermediate managers and clarify the effects of long workhours on the life-style, subjective stress, and subjective quality of life among them. METHODS: Questionnaires were administered concerning workhours, life-styles, subjective stress, and subjective quality of life to 3870 heads of a division or a section and 2666 foremen in 110 firms in Japan. RESULTS: The prevalence of > or = 10 workhours was 69.7% for the divisional or sectional heads and 53.2% for the foremen. Long workhours had significant effects on the managers' life-style, such as sleeping pattern and regularity of daily life and meals. The divisional or sectional managers with long workhours perceived higher stress [odds ratio (OR) 2.51, 95% confidence interval (95% CI) 2.17-2.90] and lower quality of life (OR 1.17, 95% CI 1.02-1.36) than those who worked relatively short hours. The foremen with long workhours perceived higher stress (OR 2.35, 95% CI 2.01-2.75) and lower quality of life (OR 1.26, 95% CI 1.08-1.46) than those who worked relatively short hours. CONCLUSIONS: Long workhours may be associated with poorer life-style, higher stress, and lower quality of life among managers at the intermediate level.

A comparison of the 8-hydroxydeoxyguanosine, chromosome aberrations and micronucleus techniques for the assessment of the genotoxicity of mercury compounds in human blood lymphocytes.

We compared the mechanism of action of micronuclei (MN), unstable chromosome aberrations, and 8-hydroxydeoxyguanosine (8-OHdG) levels to evaluate the genotoxicity of methyl mercuric chloride (CH3HgCl) and mercuric chloride (HgCl2) in human peripheral lymphocytes. The chromosome aberrations in human peripheral lymphocytes exposed to various concentrations of CH3HgCl or HgCl2 increased in a concentration-dependent manner and were significantly higher than the control when the cells were incubated with 1 x 10(-5) M (HgCl2) or 2 x 10(-6) M (CH3HgCl). The increase in the incidence of micronucleated lymphocytes was significant among the exposed groups, being 2 x 10(-5) M (HgCl2) and 5 x 10(-6) M (CH3HgCl) compared with the control. CH3HgCl was about 4-fold more potent than HgCl2. We determined the 8-OHdG levels in human peripheral blood mononuclear cells(PBMC) and found that they were significantly higher in the exposed groups at 1 x 10(-5) M (HgCl2) and 5 x 10(-6) M (CH3HgCl) compared with the control. A detectable (p < 0.05) increase in the level of 8-OHdG was induced by CH3HgCl at a concentration that was about 50% of the amount of HgCl2 required to produce a similar response. The data confirmed the value of the MN and/or chromosome aberration assays for assessing of HgCl2- and/or CH3HgCl-induced genotoxicity, and indicated that they are about the same concentration as the 8-OHdG assay. The presence of genotoxic effects in peripheral blood lymphocytes exposed to the mercuric compounds indicated by the chromosome aberrations and the MN assays could be partly due either to the disturbance of the spindle mechanism, or to the elevated level of 8-OHdG brought by the generation of reactive oxygen species.

An investigation of the effects of lifestyle on care-seeking behavior using data from health insurance claims.

To clarify the effects of lifestyle on care-seeking behavior, we conducted a questionnaire survey using Morimoto's 8 lifestyle factors and tabulated the medical evaluations at annual medical checkup of 1212 male white-collar employees of a company (aged 21-60 years in 1991), and then extracted the health insurance data for these subjects for the first half of 1992 from the health insurance-carrier computer system. The percentage of employees who visited medical facilities, the number of days of medical care, and the medical fees reported on the health insurance claims were chosen as indices of care-seeking behavior, and the relationship of each index to lifestyle and medical checkup data was examined. The health practice index (HPI), which was obtained by summing the scores for the 8 lifestyle factors was associated with the medical evaluation as expected, but was inversely correlated with the indices of care-seeking behavior. The percentage of employees who visited medical facilities, the number of the days of medical care, and the total medical fees were all higher for the subjects with high HPI scores than for those with low HPIs. Our findings are consistent with those of other researchers who have found an inverse relationship between tobacco smoking and health insurance claims, which has been attributed to the degree of consciousness of health. Compared to smokers, non-smokers have high consciousness of health and tend to consult a doctor more frequently, with resulting increased frequency of medical facility consultation and days of medical care, as well as medical fees. Lifestyle is an important aspect of physical and mental health status.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative assessment of stressors and stress reaction: a review.

To survey methods for assessing stress and to examine the relationship of stress to health and the factors of lifestyle, we reviewed the literature on stressors and stress reactions. Firstly, we reviewed the representative methods for assessing stressors. Secondly, self-report questionnaires based on a theoretical model of occupational stressors were surveyed and factors in work stress were listed. Then, we reviewed stress reactions including physiological, psychological and behavioral reactions. Finally, we examined the relationship of perceived stress measured by a single question to mental health status determined by the General Health Questionnaire (GHQ-28), lifestyles and personality based on the Egogram in Transactional Analysis. It is suggested that we need to assess subjective aspects as well as using objective indices such as data from physical examinations, to evaluate the level of stress and to promote mental health.

Echocardiographic assessment of aneurysm of the aortic valve caused by infective endocarditis--a case report.

No aneurysm of the aortic valve associated with infective endocarditis has yet been reported. This report describes the clinical echocardiographic and pathologic findings in a patient who developed infective endocarditis resulting in aneurysm of the non-coronary cusp with aortic regurgitation. Surgical treatment was performed because of gradual expansion of the aneurysm and gradual thinning of its wall. Two-dimensional and color Doppler echocardiographies proved useful for the initial diagnosis and serial follow-up of this unusual case and for its successful surgical management.

A new HPLC fluorimetric method to monitor urinary delta-aminolevulinic acid (ALA-U) levels in workers exposed to lead.

A new sensitive HPLC method for the determination of urinary delta-aminolevulinic acid (ALA-U) was used to evaluate the relationship between blood-lead (Pb-B) and ALA-U levels in male workers exposed to lead. The differences between the ALA-U levels determined by this method (ALA-U-HP) and by a colorimetric method (ALA-U-CL) are discussed. The HPLC method gave values similar to the ALA-U-CL values at high ALA-U level. However, at low blood-lead levels (58 +/- 22 micrograms/l, n = 23), the mean ALA-U-HP level corrected by urinary creatinine level was one-third of the corrected ALA-U-CL level (0.83 +/- 0.14 and 2.4 +/- 0.5 mg/g creatinine, respectively). A significant increase of the mean corrected ALA-U-HP level was observed at 162 +/- 22 micrograms/l Pb-B (P less than 0.05, n = 26), while that of ALA-U-CL was observed at 245 +/- 30 micrograms/l Pb-B (P less than 0.01, n = 37). The regression equation based on the logistic model fitted well to the relationship data between the Pb-B level and the percentage of the subjects with corrected ALA-U-HP above the cut-off point (1.12 mg/g creatinine) and the expected Pb-B level for 50% response was 270 micrograms/l Pb-B, while it did not fit well to the relationship data between Pb-B level and the percentage of the subjects with corrected ALA-U-CL above the cut-off point (3.5 mg/g creatinine).(ABSTRACT TRUNCATED AT 250 WORDS)