Shigeru Takechi

Evaluation of pH-independent sustained-release granules of dipyridamole by using gastric-acidity-controlled rabbits and human subjects

The solubility of dipyridamole at pH 2.5 was about 6000-fold greater than that at pH 7.0. A commercial powder of dipyridamole showed pH-dependent dissolution. Two kinds of sustained-release granules of dipyridamole were prepared. The release rate of pH-dependent sustained-release granules was controlled by ethylcellulose (EC) and decreased with increasing medium pH. The release rate of pH-independent sustained-release granules was regulated by carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose (TC-5) and Eudragit RS100, and was not influenced by varying pH of the medium. We used gastric-acidity-controlled rabbits to evaluate the variability in absorption after oral administration of these formulations. An extremely large difference in bioavailability between the high and low gastric acidity groups was observed after oral administration of the commercial powder. There were no statistically significant differences in the values of Cmax, Tmax, AUC0–12h and MRT between the high and low gastric acidity groups after administration of pH-independent sustained-release granules, while statistically significant differences in Cmax and AUC0–12 h were found between the two groups after administration of pH-dependent sustained-release granules. Furthermore, this pH-independent sustained-release granule preparation was administered orally to human subjects and compared with the commercial powder. There was no significant difference in the AUC0–12 h between the two preparations. It was also shown that the Cmax for the granules was about 50% of that for the commercial powder and that the plasma levels after oral administration of the granules were maintained over a longer duration than those of the commercial powder. It was found that the bioavailability was not influenced by variations in gastric acidity in rabbits and high bioavailability was achieved in human subjects after oral administration of the pH-independent sustained-release granule preparation, indicating that this preparation should be a useful dosage form for the potential reduction of interindividual variabilities in absorption.

Recovery of cardiac norepinephrine concentration and tyrosine hydroxylase activity by the central α2-adrenoceptor agonist guanabenz in rats with aortic constriction

Depletion of cardiac norepinephrine has been reported in cardiac hypertrophy. This depletion causes less support for cardiac output in response to sympathetic nerve activation. The central nervous system is thought to be involved in this abnormality. Correction of this abnormality is expected to restore proper support for the heart. Clipping of the ascending aorta or a sham operation was performed in 10-week-old rats. At 4 weeks after the operation, the left ventricular norepinephrine concentration in clipped rats decreased (p<0.01). The clipped rats and sham-operated rats were treated with either guanabenz (1 mg/kg) or a vehicle for 4 weeks starting from fifth postoperative week. The level of left ventricular norepinephrine increased more in clipped rats treated with guanabenz (469+/-37 ng/g) than in clipped rats treated with a vehicle (325+/-28 ng/g). The norepinephrine concentration in the left ventricle recovered significantly after the treatment with guanabenz (p<0.001). Tyrosine hydroxylase activity in the left ventricle also recovered after treatment with guanabenz (p<0.01). Modulation of sympathetic nerve tone by the alpha2-adrenoceptor agonist restored cardiac norepinephrine concentration and tyrosine hydroxylase activity. This could be a new approach to the treatment of heart failure.

Effects of short- and long-acting calcium channel blockers on the relationship between blood pressure and physical activity

Calcium channel blockers are widely used as antihypertensive drugs. However, there is some controversy as to how they should be used. Our first aim was to clarify how the dihydropyridine calcium channel blocker, benidipine, affects the quantitative relationship between blood pressure (BP) and physical activity. The second aim was to determine whether there is a relationship between systolic blood pressure (SBP) and physical activity in patients with hypertension when treating with a short-acting (nifedipine) or long-acting (benidipine) calcium channel blocker. In Study 1, ambulatory BP and physical activity were measured simultaneously in 27 patients with hypertension before and after 6 months with benidipine. In Study 2, ambulatory BP and physical activity were measured simultaneously in 16 patients with hypertension before (placebo) and after 6 weeks of crossover treatment with nifedipine and benidipine. In Study 1, there was no difference in the SBP change caused by physical activity between the pre- and posttreatment periods. In Study 2, SBP was significantly related to physical activity in the placebo (16/16) and benidipine (16/16) groups but not in the nifedipine (12/16) group. The lowest BP during day-time and nighttime in the nifedipine group were significantly lower than those in the benidipine group. Plasma renin activity (ng/mL/h) was significantly higher in the nifedipine group (1.20+/-1.05) than in the placebo (0.57+/-0.59) and benidipine (0.75+/-0.78) groups. These findings indicate that nifedipine might interfere with the adaptation mechanism of BP changed by physical activity and that the activated renin-angiotensin system might cause cardiac events.

Rationale and design of the Japanese Heart Failure Outpatients Disease Management and Cardiac Evaluation (J-HOMECARE)

BACKGROUND Although many studies have demonstrated the efficacy of disease management programs on mortality, morbidity, quality of life (QOL), and medical cost in patients with heart failure (HF), no study has focused on psychological status as an outcome of disease management. In addition, very little information is available on the effectiveness of disease management programs in other areas than the USA and Europe. METHODS The Japanese Heart Failure Outpatients Disease Management and Cardiac Evaluation (J-HOMECARE) is a randomized controlled trial in which 156 patients hospitalized with HF will be randomized into usual care or a home-based disease management arm receiving comprehensive advice and counseling by visiting nurses during the initial 2 months and telephone follow-up for the following 4 months after discharge. This study evaluates depression and anxiety (Hospital Anxiety and Depression Scale), mortality, readmission due to HF, and QOL (Short Form-8). Data are collected during index hospitalization and then 2, 6, and 12 months after discharge. This study started in December 2007, and the final results are expected in 2011. CONCLUSION The J-HOMECARE will provide important information on the efficacy of disease management for psychological status as well as the effective components of disease management for patients with HF. (ClinicalTrials.gov number, NCT01284400).

Cardiac acetylcholine concentration in the rat.

Varying values for the acetylcholine (ACh) concentration in the rat heart have been reported. The possibility that the method of sampling may influence prompted a comparison of heart levels of ACh obtained by two different procedures for sacrificing animals. One method was by microwave irradiation in vivo and the others being in vitro on the irradiated heart removed after decapitation. There were significant differences found in cardiac ACh concentration between the in vivo irradiated group and the decapitation groups. In decapitated animals, the cardiac ACh concentration became increasingly lower on standing. We also measured the ACh concentration of right atrium, left atrium, right ventricle and left ventricle. They were 4.62 +/- 1.57 nmol/g (mean +/- SD), 2.58 +/- 1.01, 2.76 +/- 1.00 and 2.12 +/- 0.70, respectively. We conclude the microwave irradiation in vivo is a more appropriate method for determining the cardiac ACh concentration.

Excretions of urinary albumin and various proteins increase in hypertension

Aims. Hypertension causes proteinuria and is an important factor in the progress of renal dysfunction. Increases in various proteins in urine are caused by malfunction of the glomerulus and the renal tubules. In the present study, the effects of hypertension on urinary excretion levels of various proteins were investigated to show the tubular cell malfunction in hypertensive patients. Methods and subjects. The subjects included 55 non‐diabetic hypertensive patients without previous treatment and 42 normotensive individuals without microalbuminuria. Total urinary protein/creatinine ratio was measured, and urinary proteins were analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). Findings. Total urinary protein/creatinine ratio was higher in hypertensive patients than in normotensive individuals (122.0±11.0 vs. 60.6±3.1 mg/gCr; p<0.001). SDS–PAGE resolved 15 protein fractions from the urine of both groups. Thirteen fractions were more intensely stained in samples from the hypertensive than from the normotensive. Two fractions did not differ between the groups. Hypertension increased the urinary excretion of various proteins including proteins of less than 40 kDa, called tubular proteins, in addition to albumin. Conclusions. Hypertension differently influenced the excretion of each urinary protein fraction. Tubular malfunction should be considered in hypertensive patients in addition to glomerular malfunction.

High-sodium diets in Japanese evacuation centers increase blood pressures of evacuees

Aims: High blood pressure after a natural disaster is tentatively considered to be due to elevation of sympathetic nerve activity. A volcano in Japan erupted on March 31, 2000, and people living in the vicinity of the volcano were evacuated to safe shelters. We found that many evacuees developed high blood pressure while staying at evacuation centers. The aim of this study was to investigate why their blood pressures stayed elevated. Methods and Subjects: Sixty‐five evacuees, who were staying evacuation centers for 4 months, were examined for blood pressure, urinary sodium excretion, urinary potassium excretion, and plasma and urinary catecholamines. Results: Associations were found between systolic blood pressure and sodium excretion (r = 0.311, p < 0.05) and between systolic blood pressure and the ratio of urinary sodium to urinary potassium (r = 0.320, p < 0.05). However, no association was found between blood pressure and plasma and urinary catecholamines (NE, DHPG and MHPG). Conclusion: High sodium consumption was thought to be an important factor in the elevation of blood pressure of the evacuees after acute phase reactions.

Cardiac acetylcholine concentration in the mouse

We measured cardiac acetylcholine (ACh) in mice using four different methods. The mice in the in vivo irradiation group received microwave irradiation and then the hearts were removed. The animals in the in vitro irradiation group were decapitated and only the hearts were irradiated. The animals in the non-frozen group were decapitated and ACh was measured soon after the removal of the heart. The animals in the frozen group were decapitated and the hearts were frozen. There were significant differences in ACh concentrations between the in vivo irradiation group and the other groups. We also measured the ACh concentrations in both atria and ventricles after the mice were irradiated while alive. The atrial ACh concentration 1.70 +/- 0.70 nmol/g (mean +/- SD) was significantly higher than the ventricle concentration 1.07 +/- 0.30. We concluded the microwave irradiation of animals was suitable method of sacrifice for the measurement of cardiac ACh.

Carvedilol improves uptake-1 in patients with systolic congestive heart failure.

Background The sympathetic nervous system (SNS) of the whole body, including cardiac sympathetic nerves, is activated in patients with severe congestive systolic heart failure (CHF). Carvedilol can improve clinical status in such patients. This study aimed to determine how carvedilol acts on the SNS to improve CHF. Methods and Results Ten subjects (New York Heart Association criteria III) were treated using carvedilol at 2.5 mg/d for 1 week. Before and after treatment, subjects walked on a treadmill for 6 minutes, and plasma concentrations of carvedilol, norepinephrine, and 3,4-dihydroxyphenyl glycol were measured. After treatment, norepinephrine was decreased at rest (3.2 ± 0.3 pmole/mL to 2.1 ± 0.4 pmole/mL, P < 0.05), while standing (5.4 ± 1.2 to 3.3 ± 0.7 pmole/mL, P < 0.01) and during exercise (6.5 ± 1.3 pmole/mL to 5.1 ± 1.1 pmole/mL, P < 0.05). Regression lines for percentage changes in norepinephrine and 3,4-dihydroxyphenyl glycol were compared before and after treatment, showing steeper slopes after treatment (P < 0.05). Plasma carvedilol concentrations (1.8 ± 0.3 ng/mL) did not reach &bgr;-adrenoceptor–blocking levels of effect. Conclusions Carvedilol is considered to improve function of uptake-1 for the whole-body SNS, including the cardiac SNS, and does not seem to block adrenoceptors at such low doses in CHF patients. However, both effects seem to work at high doses in clinical settings.