Relationship between insulin resistance and accumulation of coronary risk factors.

We examined correlations between the frequency of insulin resistance and the accumulation of coronary risk factors in residents of rural comities in Japanese, using simple criteria for determination of insulin resistance based on evaluation by the euglycaemic-hyperinsulinaemic glucose clamp (GC) method. The subjects were 376 men and 589 women living in two rural communities in Japan. We measured body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), HDL cholesterol (HDL), and homeostasis model assessment (HOMA-R). Correlations between HOMA-R and those parameters were examined. To assess the existence of insulin resistance in these subjects, we used a practical index based on the GC method. The subjects with value of HOMA-R >or= 1.73 have insulin resistance. In addition, the HOMA-R was divided into five quantiles based on the frequency distribution (0.60 or below, from 0.61 to 0.82, from 0.83 to 1.18, from 1.19 to 1.69, and 1.70 or higher), to examine the concentration of risk factors in each group. In total, 74 (19.6%) of the men and 119 (20.3%) of the women had insulin resistance (HOMA-R >or= 1.73). It was found that the higher the HOMA-R, the higher was the number of coronary risk factors, such as hypertension, obesity, hypertriglyceridaemia and hypo HDL cholesterolaemia. The number of coronary risk factors was particular high in subjects with HOMA-R >or= 1.70. HOMA-R in the case of no glucose loading is a useful and practical index for evaluation of insulin resistance and coronary risk factors in the epidemiological study.

Structure-activity relationships of quinazoline derivatives: dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation.

We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-alpha production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound la. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-alpha production.

Synthesis and biological evaluation of CX-659S and its related compounds for their inhibitory effects on the delayed-type hypersensitivity reaction.

In order to find novel nonsteroidal compounds possessing an inhibitory activity against delayed-type hypersensitivity (DTH) reactions, we conducted random screening using a picryl chloride (PC)-induced contact hypersensitivity reaction (CHR) in mice, and found compound 1 as a lead compound. Then we synthesized and evaluated an extensive series of 5-carboxamidouracil derivatives focused on both the uracil and the antioxidative moieties. Among them, we found that the hindered phenol moiety was necessary to exhibit the activities; especially, compounds 28a-28c having the partial structure of vitamin E were found to exert potent activities against the DTH reaction by both oral and topical administration. And compound 28c showed antioxidative activity against lipid peroxidation with an IC50 of 5.9 microM. Compound 28c (CX-659S) was chosen as a candidate drug for the treatment of cutaneous disorders such as atopic dermatitis and allergic contact dermatitis.

Impaired myocardial accumulation of 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid in a patient with hypertrophic cardiomyopathy and exercise-induced ischemia due to vasospasm.

We encountered a patient with hypertrophic cardiomyopathy complicated with exercise-induced myocardial ischemia. Exercise-stress 99mTc-tetrofosmin imaging demonstrated reversible ischemia in the lateral wall, whereas resting fatty acid imaging with a new beta-methyl branched fatty acid analogue, I-123-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (123I-9-MPA), showed impaired uptake and accelerated washout kinetics in the inferoapical and posteroseptal walls but not in the ischemia-related region. These findings suggest that the metabolic derangement is closely related to cardiomyopathy per se rather than exercise-induced myocardial ischemia in this patient with hypertrophic cardiomyopathy and a spastic coronary lesion so that myocardial perfusion and 123I-9-MPA imagings may contribute to clarifying the etiological background of impaired myocardial fatty acid metabolism.

Relationship between blood pressure level and mortality rate: an 18-year study conducted in two rural communities in Japan.

BACKGROUND: There have been very few studies on life prognosis of cardiovascular disease according to blood pressure stratification in the Japanese. Therefore, in Japan, although treatment of hypertension is possible, albeit at times difficult, due to the availability of various antihypertensive medications, the appropriate time at which treatment should be started remains a problem. OBJECTIVE: To investigate the long-term prognosis of cardiovascular disease in the Japanese general population according to blood pressure stratification in the Japanese. DESIGN: A community-based prospective cohort study of 1996 men and women between the ages of 40 and 64 years at the baseline examination was conducted over an 18-year period. Information on death was obtained from local public health nurses and death certificates. The causes of death were clarified by questionnaires sent to doctors in the hospital in which the deceased was hospitalized, and the causes of death were analysed in each blood pressure category at baseline examination. RESULTS: Mortality from cardiovascular disease increased with increases in the level of blood pressure and was significantly higher in > or = 140 mmHg group in systolic blood pressure and > or = 90 mmHg group in diastolic blood pressure, adjusted for age, sex and other cardiovascular risk factors in the Japanese general population. However, mortality risk from cardiovascular disease did not have a J-shaped relationship with systolic and diastolic blood pressure. CONCLUSION: We conclude that the optimum time for starting treatment in Japanese people is when blood pressure is 140/90 mmHg or less.

[Prevalence of glucose intolerance in Japan--from the National Circulatory Disorders Basic Survey, 1990].

The prevalence of glucose intolerance was surveyed in 8,063 people over 30 years old from the general population of Japan. The data used in the analysis were from the Fourth National Circulatory Disorders Basic Survey, which was conducted in 1990. Survey items included history of diabetes mellitus, body mass index (BMI) and daily life activity. Blood and urine were also examined, and the blood glucose levels, presence or absence of sugar in urine, and levels of glycohemoglobin (HbA1c) were determined. Glucose intolerance was identified from the blood glucose level, HbA1c level and history of diabetes mellitus. The frequency of glucose intolerance was 8.6% in all subjects (11.9% in men and 6.3% in women). The frequency was higher in older people: 1.7 times higher in men over 65 years old and 2.5 times higher in women over 65 years old. Among people over 40 years old, glucose intolerance was significantly more prevalent in men than in women. It was also significantly more prevalent in men living in big cities than in men living in rural areas. Among obese male subjects and men with a low level of activity in daily life, the frequency of glucose intolerance was higher than in normal male subjects. The level of activity in daily life tended to be lower for people living in big cities than for those in rural areas. The results suggest that the prevalence of glucose intolerance depends on the environment in which people live. The results also indicate that raising the level of activities in daily life might help prevent diabetes mellitus.