Blood pressure control status and effects of pravastatin on cardiovascular events occurrence in patients with dyslipidaemia.

Dyslipidaemia is often associated with hypertension, and many clinical trials have shown that lipid-lowering therapy and strict blood pressure (BP) control are important for preventing cardiovascular disease (CVD). However, few reports describe the effect of statins on CVD occurrence in relation to long-term BP control. In the present analysis, we investigated the effects of baseline BP and follow-up BP control on the occurrence of CVD in patients enrolled in the MEGA Study. We investigated whether BP values provide more accurate prediction of the occurrence of CVD, including cerebrovascular disease/transischemic attack (CVA/TIA), and the effect of pravastatin on CVA/TIA. The risk for CVA/TIA and other CVD increased significantly (P≤0.001) as the severity of hypertension increased. In contrast, pravastatin reduced the onset of CVA/TIA, regardless of the BP controlled. The mean BP was a more accurate predictor of CVD than a one-time BP value. In patients with mild-to-moderate dyslipidaemia, elevated BP increases the risk for CVA/TIA and other CVD, and rigorous BP control was important for preventing CVD, in particular CVA/TIA. The 12-month mean BP is useful to avoid attenuation to determine the association between CVD and BP. Pravastatin prevented CVA/TIA, regardless of BP controlled.

Primary undifferentiated carcinoma arising from the retroperitoneum: a case report.

A 35-year-old woman, gravida 1, para 1, underwent cesarean section in her 39th week of pregnancy. At the time of operation, multiple retroperitoneal tumors were found. Postoperative computed tomography and magnetic resonance imaging showed multiple solid tumors, each approximately 3-5 cm, in the right pelvic retroperitoneal space. Total resection of the tumors was performed without any macroscopic residual. A systematic workup for the primary tumor from which the retroperitoneal tumors may have metastasized failed to demonstrate any responsible tumor. We therefore assumed it to be a primary retroperitoneal tumor. The histopathologic features of the tumors were consistent with small-cell carcinoma. Two months postoperatively, recurrent tumors in the right inguinal and common iliac regions were detected. Since chemotherapy with irinotecan hydrochloride or paclitaxel did not produce any beneficial effect, a second tumor reduction surgery was performed 8 months after the initial operation. Four months after the second operation, a third operation including total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection in the contralateral iliac region were done. Afterward, a new recurrent tumor appeared along the aorta up to the left supraclavicular node. The patient died 19 months after the first operation.

The preparation of the chronic hyper-endotoxemia experimental animal model by means of a drug delivery system.

A drug delivery system (DDS) consisting of lipopolysaccharide (LPS) as a drug and 2-hydroxyethyl methacrylate (HEMA)-diethylene glycol dimethacrylate (2G) or -polyethylene glycol dimethacrylate (4G, 9G) copolymer was prepared, and used for the efficient preparation of an experimental animal model of chronic hyper-endotoxemia. The release profiles of LPS in the in-vitro test were greatly influenced by the composition of HEMA-2G, 4G, 9G in the copolymer. It was found that LPS release from the DDS continued gradually and constantly throughout 2 weeks. In the in-vivo experiment with rats, the DDS maintained a high blood concentration level of LPS for 3 days. These results strongly suggest the possibility of convenient and reproducible preparation of a chronic hyper-endotoxemia animal model.

Application of a drug delivery system in a novel rat model of chronic hyperendotoxemia.

There has not been an ideal reproducible small-animal model of chronic hyperendotoxemia to date. Our drug delivery system (DDS) is a new technology that can deliver a drug conveniently to a target organ at an optional rate. 2-Hydroxyethyl methacrylate (HEMA) was used as a carrier of lipopolysaccharide (LPS), and diethylene glycol and polyethylene glycol dimethacrylates (2G, 4G, 9G) were used as cross-linking agents. A mixed solution of HEMA and di(poly)ethylene glycol dimethacrylate was charged into a glass tube with or without LPS and polymerized by ultraviolet irradiation. This polymer was cut into DDS tablets of the same size with or without LPS. A mixture with HEMA:4G = 1:3 was the most suitable composition to release a constant concentration of LPS. We also developed a novel rat model of chronic hyperendotoxemia. Four DDS tablets, each containing 15 mg LPS, were implanted into the abdominal cavity of rats in the LPS group. The control group was implanted with four DDS tablets without LPS. Plasma levels of LPS in the study group were maintained at more than 2,000 pg/ml for 72 h after implantation. Weight gain was lower and body temperature was higher in the LPS group than in the control group. Plasma levels of inter leukin (IL)-6 in the LPS group were higher than in the control group only during the initial 12 h after implantation of DDS tablets. The white blood cell count at 24 h and platelet counts at 24, 48, and 72 h in the LPS group were lower than those in the control group. These results indicate that chronic hyperendotoxemia was maintained for 72 h by continuous release of LPS from the DDS. Moreover, the intensity of endotoxemia could be varied by varying the number of DDS tablets. It is concluded that our new rat model using LPS-DDS will be applicable and useful as a model of chronic hyperendotoxemia.

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.

Recovery of cardiac norepinephrine concentration and tyrosine hydroxylase activity by the central alpha2-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.

Changes in the binding capacity of alpha-1-acid glycoprotein in patients with renal insufficiency.

The elevation of alpha-1-acid glycoprotein (AAG) concentration and the binding characteristics of disopyramide (DP) to AAG in patients with renal insufficiency were investigated. The serum AAG concentration and protein binding of DP in patients were significantly greater than those in healthy subjects. However, in both the serum and the purified AAG, Scatchard analysis showed that the number of binding sites per molecule of AAG in patients was significantly lower than that in healthy subjects, although there was no difference in the dissociation constant (Kd). These results suggest that the AAG induced in renal insufficiency is qualitatively different from normal AAG. Moreover, the change of the unbound DP fraction when DP concentration was increased was larger in the patients than in the healthy controls. Therefore, monitoring of the unbound DP would be important for therapeutic drug monitoring in patients with renal insufficiency.

Purification method for alpha-1-acid glycoprotein with subsequent high-performance liquid chromatographic determination of monosaccharides in plasma of healthy subjects and patients with renal insufficiency.

A simple purification method for human plasma alpha-1-acid glycoprotein (AAG) using an ion-exchange and hydroxyapatite column was developed. The recovery of the method was found to be high. We also improved a determination method for N-acetylneuraminic acid and monosaccharides in the carbohydrate moiety of AAG by using an ion-exchange column and pulse-amperometric detection. By this method, a composition analysis of the carbohydrate moiety of AAG (N-acetylneuraminic acid, fucose, N-acetyl glucosamine, galactose and mannose) was possible with 1.0 ml of plasma. We compared these carbohydrate concentrations in the AAG of patients with renal insufficiency with those of healthy subjects. In the AAG of the patients, the concentrations of N-acetylglucosamine, galactose and mannose were significantly higher than those in the AAG of the healthy subjects.

Alpha-1-acid glycoprotein concentration and the protein binding of disopyramide in healthy subjects.

Age- and gender-related changes in serum alpha 1-acid glycoprotein (AAG) concentration and the serum protein binding of disopyramide were examined after intensive medical examination. Based on the clinical chemistry tests over 51 points, 245 subjects were diagnosed as healthy and 71 subjects (22.5%) revealed an abnormal value for at least one item. In the healthy subjects, serum AAG concentration in men was significantly higher than in women (men, 0.78 +/- 0.18 mg/mL, mean +/- SD; women, 0.67 +/- 0.16 mg/mL). In contrast, there were no significant differences in the AAG concentration between age groups for men and women and in the unbound fraction of disopyramide. Gender changes AAG concentration. Age, however, does not change AAG concentration and the protein binding of the basic drug.

[Effect of enalapril on left ventricular hypertrophy and left ventricular function in patients with hypertension].

The aim of this study was to study the effect of enalapril (E) on left ventricular (LV) mass, LV function and blood renin-angiotensin (RA) in patients with hypertension. Sixteen hypertensives were included in this study (WHO I 8, WHO II 8, 49.5 +/- 10.5 yrs). They were examined for blood pressure and heart rate. Chest X-ray film, echocardiography (echo), X-ray computed tomography (CT) and RA before and after about 6 months of E administration were studied. The LV mass was calculated by CT. The LV function was measured by echo. RAS was unchanged during this study. LV mass was significantly reduced after E (121.4 +/- 25.6 vs 104.6 +/- 13.7 g/cm2). The LV systolic function was unchanged after E, but LV diastolic function improved. It was shown that the long-term administration of E improves LV hypertrophy and LV diastolic function without any change of RAS.

[Effects of intravenous injection of ioversol, a nonionic contrast medium, on circulating blood volume: comparison among different combinations of its dose and volume injected].

Effects on circulating blood volume (CBV) of the intravenous injection of a nonionic contrast medium, ioversol, with various doses were assessed in order to find a way of injection with less effects on systemic circulation. Ioversol was injected as a bolus to 20 mongrel dogs at doses of A: 3.75 ml/kg (n = 8) or B: 2 ml/kg (n = 6) of a solution containing 320 mg iodine per ml, or C: 2 ml/kg (n = 6) of a 240 mgI/ml solution. Colloid oncotic pressure (COP) of the bloods drawn before and 1, 2, 3, 5 min after the injection of ioversol was measured by a needle type osmometer, and changes in CBV were calculated using the COP values. Upon injection of ioversol CBV increased rapidly and then gradually returned to the preinjection levels. The change in CBV induced by ioversol was significantly less than those reportedly induced by an ionic contrant medium, iothalamate, and a nonionic medium, iopamidol, and comparable to that by another nonionic medium, iohexol. The degree of increase in CBV and the blood concentration of ioversol were related to the amount, but not the volume, of ioversol injected. Thus, ioversol proved to be one of the low osmotic nonionic contrast media with less effects on CBV. Furthermore, it is suggested that the amount, rather than volume, of contrast medium should be taken into consideration when the angiography of the patients with reduced cardiac function, children or aged patients is performed in whom the contrast medium-induced CBV expansion needs to be as less as possible.

Rapid and simple method for the determination of alpha 1-acid glycoprotein in serum by column liquid chromatography.

A rapid and simple method for the determination of alpha 1-acid glycoprotein (AAG) in serum was developed by using an anion-exchange column for clean-up of serum and a hydroxyapatite column for high-performance liquid chromatography (HPLC). A good correlation was observed between this HPLC method and the conventional radial immunodiffusion method. The method may also be used to determine the AAG concentration in the serum of experimental animals.

[Contrast medium-induced expansion of circulating blood volume: Comparison between nonionic and ionic contrast media].

We assessed whether the osmotic expansion of circulating blood volume (CBV) induced by nonionic contrast medium (NCM) is less than that induced by ionic contrast medium (ICM). Iohexol (Io) (NCM: 795 mO sm/kg H2O), 1.28 g iodine/kg, was injected intravenously into 5 mongrel dogs and blood samples were drawn at certain times. One week later, meglumine iothalamate (MI) (ICM: 1470 mOsm/kgH2O), 1.28 g iodine/kg, was injected into the same dogs. Another 5 dogs received MI first and Io one week later. Colloid oncotic pressure (COP) of the blood samples was measured by a needle osmometer, and changes in CBV were calculated from the COP values. The injection of Io or MI resulted in an immediate decrease in COP, and an increase in CBV at 1 min. MI induced significantly more severe and longlasting changes in COP and CBV than Io. Neither MI nor Io modified COP when they were added to the control blood samples. Thus, although NCM considerably expanded CBV, the magnitude of expansion induced by NCM was less than that induced by ICM. This may explain one of the reasons why NCM causes fewer adverse reactions than ICM.

[Transient abnormal Q waves under acute myocardial infarction in patients with pneumoconiosis].

Abnormal Q waves have been generally considered to be one of the most reliable indicators of permanent myocardial cell death, namely myocardial infarction. Pathological and experimental studies also support this concept. However, some cases of abnormal Q waves disappearing after myocardial infarction have been reported. Recently, we observed acute myocardial infarction with pneumoconiosis. In this case, a patient with abnormal Q waves appeared within 24 hours after the onset of acute myocardial infarction. But, thirteen days later, these abnormal Q waves disappeared on the surface twelve-lead ECG. The precise mechanism for regression or disappearance of abnormal Q waves is not yet well known. Several studies pointed out a relation of this phenomenon to myocardial collateral circulation under ischemia. And, Nonkin et al reported that, patients with chronic lung disease such like pneumoconiosis, had high incidence of collateral circulation to the myocardium. This was due to chronic hypoxic conditions. In our case, cineangiographic study could not be performed, but disappearance of abnormal Q wave (so called Transient abnormal Q waves), following acute myocardial infarction may be related to the presence of chronic lung disease.

[Study of the correlation between severity of hypertension and the left ventricular mass and left ventricular functions].

The correlation between the severity of hypertension and the left ventricular mass and left ventricular functions were studied in normal controls (n = 6) and essential hypertensives (n = 37). And we studied the factors that influence on the severity of hypertension by discriminant analysis. Thirty-seven hypertensives were divided into three groups (WHO I 16, WHO II 16, WHO III 5). The left ventricular mass (LVM) was calculated by X-ray computed tomography. The %fractional shortening (%FS), mean Vcf (mVcf) and ejection fraction (EF) were obtained as left ventricular systolic function by echocardiogram. The left ventricular diastolic posterior wall velocity (PWVd) and left ventricular rapid filling volume/stroke volume (RFV/SV) were obtained as left ventricular diastolic function by echocardiogram. The LVMs (g/m2) of controls, WHO I, WHO II and WHO III were 92 +/- 14, 113 +/- 23, 155 +/- 56 and 237 +/- 38. The LVM were great as the stage of hypertension was deteriorated. The left ventricular diastolic function was impaired as hypertension exacerbated. The left ventricular systolic function was not changed in four groups including controls. The LVM was significantly well correlated with systolic blood pressure (r = 0.48, p less than 0.01), diastolic blood pressure (r = 0.30, p less than 0.05), cardiothoracic ratio (r = 0.36, p less than 0.05), SV1 + RV5 on ECG (r = 0.66, p less than 0.001) and left ventricular diastolic function (PWVd; r = 0.49, p less than 0.01, RFV/SV; r = 0.52, p less than 0.001). But, the LVM was poor correlated with left ventricular systolic function. Depending on the discriminant analysis, the LVM and left ventricular diastolic function had significantly well influence on the severity of hypertension and ECG abnormality. As using the LVM calculated by computed tomography, we have exactly and useful informations of essential hypertension.

[A comparative study of apical hypertrophy with giant negative T waves and non-obstructive hypertrophic cardiomyopathy: evaluation by computed tomography, echocardiography and left ventriculography].

To assess the relationships between patterns of left ventricular hypertrophy and giant negative T waves (greater than 15 mm, GNT), 24 patients with GNT were categorized in two groups: Group A consisted of 12 patients with GNP but without left ventricular hypertrophy (greater than 13 mm at the chorda level of the interventricular septum and/or left ventricular posterior wall by UCG, LVH); and group-B consisted of 12 patients with GNT and LVH. Twelve patients with LVH but no GNT compromised as group-C. Left ventriculography (LVG) was performed, and left ventricular mass (LVM) and apical hypertrophy were assessed by CT. The configurations of the end-diastolic left ventricle by LVG (RAO 30 degrees) were as follows, by group: A: spade in eight patients and papillary muscle hypertrophy (PMH) shape in four. B: spade in five, PMH in four, banana in one and oval in two. C: banana in nine and oval in three. The LVM (g/BSAm2) were as follows; A: 121.5 +/- 14.9, B: 130.5 +/- 14.8, C: 190.6 +/- 42.1 (C greater than A, B, p less than 0.001). The apex/base ratios calculated by CT were as follows; A: 1.43 +/- 0.31, B: 1.21 +/- 0.19, C: 1.09 +/- 0.20 (C greater than A, p less than 0.05). The left ventricular mass in patients with GNT was less than that of those without GNT. Giant negative T waves were most often associated with apical hypertrophy.