Mineralocorticoid receptor blocker eplerenone improves endothelial function and inhibits Rho-associated kinase activity in patients with hypertension.

Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow-up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension.

Heating properties of a new hyperthermia system for deep tumors without contact.

In this paper, heating properties of the proposed hyperthermia system for non-invasive treatment of deep tumors are discussed. Our heating system is composed of a large size resonant cavity applicator. In this heating method, a human body is placed between the two inner electrodes. It is heated by electromagnetic fields stimulated in the cavity without contact between the surface of the human body and the applicator. First, we presented the experimental results of heating a cylindrical agar phantom and a cylindrical fat-agar phantom using the proposed system. From the thermal images of the heated phantoms, the center of the agar was locally heated to maximum temperature. Second, we presented the experimental results of heating a mini pig. In the heating experiment, temperature measurements were performed by using fiber-optical thermometers inserted in four locations inside the mini pig. From the results, the deepest region of the liver was heated to the highest temperature 43.3 °C.

A new heating method with dielectric bolus using resonant cavity applicator for brain tumors.

In this paper, we discuss a new method of controlling heating location in the proposed resonant cavity applicator. A dielectric bolus was used to non-invasively treat brain tumors. We have already confirmed that our heating system using resonant cavity is useful to non-invasively heat brain tumors. In order to heat tumors occurring at various locations, it is necessary to control the heating area with our heating system. First, we presented the proposed heating method and a phantom model to calculate temperature distributions. The results of temperature distributions were discussed. Second, a 3-D human head model constructed from 2-D MRI images was presented. The results of specific absorption rate distributions were discussed. From these results, it was found that the proposed heating method was useful to non-invasively treat brain tumors.

Heating properties of coaxial needle applicator made of SMA for hyperthermia treatments.

This paper describes heating properties of the developed coaxial needle applicator made of a shape memory alloy (SMA) for brain tumor hyperthermia treatments to avoid undesirable hotspots. We estimated the temperature distribution inside an agar phantom by the finite element method (FEM) and heated the agar phantom with the developed needle applicator.

SAR analysis of a re-entrant resonant cavity applicator for brain tumor hyperthermia treatment with a 3-D anatomical human head model.

A re-entrant resonant cavity applicator system for non-invasive brain tumor hyperthermia treatments was presented. We have already confirmed the effectiveness of the heating properties of this heating system with cylindrical agar phantoms and with computer simulations.

Heating properties of the re-entrant type cavity applicator for brain tumor with several resonant frequencies.

We have proposed the re-entrant resonant cavity applicator system for non-invasive brain tumor hyperthermia treatment. In this method, a human head is placed in the gap of the inner electrodes. A brain tumor is heated with the electromagnetic field stimulated in the cavity without contact between the human head and the applicator. We have already presented the effectiveness of the heating properties of this system with cylinder-type agar phantoms and by computer simulations. This paper discusses the heating properties of the developed system with the human head-type agar phantom for brain tumor hyperthermia treatment. First, in order to heat deep brain tumors, we tried to heat the human head-type agar phantom by using several electromagnetic field patterns of the resonant frequency. We found that the temperature distributions can be controlled inside the agar phantom by changing the resonant frequencies. Second, to heat local and deep areas of the agar phantom, we tried to achieve heating using the two different resonant frequencies. We found distinct heating properties by changing the electromagnetic field patterns of resonant frequencies. From these results, it was found that our developed heating system can be applied to hyperthermia treatments of deep-seated brain tumors. Further, by changing resonant frequency, treatment can very correspond to the size and the position of a tumor.

Heating properties of the needle type applicator made of shape memory alloy by 3-D anatomical human head model.

Since the human brain is protected by the skull, it is not easy to non-invasively heat deep brain tumors with electromagnetic energy for hyperthermia treatments. Generally, needle type applicators were used in clinical practice to heat brain tumors. To expand the heating area of needle type applicators, we have developed a new type of needle made of a shape memory alloy (SMA). In this paper, heating properties of the proposed SMA needle type applicator were discussed. Here, in order to apply the SMA needle type applicator clinically. First, we constructed an anatomical 3-D FEM model from MRI and X-ray CT images using 3D-CAD software. Second, we estimated electric and temperature distributions to confirm the SMA needle type applicator using the FEM soft were JMAG-Studio. From these results, it was confirmed that the proposed method can expand the heating area and control the heating of various sizes of brain tumors.

Acute effect of pimobendan and furosemide on the circulating renin-angiotensin-aldosterone system in healthy dogs.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. HYPOTHESIS: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. ANIMALS: Nine healthy laboratory dogs were used in this study. METHODS: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2 mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. RESULTS: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy.

Heating properties of re-entrant resonant cavity applicator for brain tumor with simple head model.

We have already confirmed the effectiveness of the re-entrant resonant cavity applicator system with non-invasive experiments of heating cylindrical agar phantoms and computer simulations. This paper discusses the heating properties of the developed heating system with a human head model made of agar for brain tumor hyperthermia treatment. First, we present the results of heating a uniform agar head model with the developed heating system. In the experiments, the temperature rise at the center of the agar was about 8 degrees C, it was found that the center of the agar is heated to maximum temperature non-invasively. Second, we present the results of heating a non-uniform agar head model having an oral cavity and a nasal cavity. We found that the center of the agar can be heated to maximum temperature as well as uniform agar head model. From these results, it is confirmed that the possibility of effective hyperthermia for various types of deep-seated brain tumors.

Finite element analysis of the needle type applicator made of shape memory alloy.

In this paper, we propose a new heating method in which we use shape memory alloy (SMA) in a needle type applicator for brain tumor hyperthermia. In order to expand the heating area of a needle type applicator and to control the heating pattern for various sizes of tumors, some kinds of SMA needle type applicators were developed. To apply the proposed heating method safely to clinical hyperthermia, it is necessary to make appropriate thermal distribution to the region of the brain tumor. However, it is not easy to predict the three dimensional temperature distribution during the human brain tumor hyperthermia. Therefore, we estimated the temperature distribution inside the agar phantom by the finite element method (FEM). Here, first, the computer simulation results of temperature distributions under the different heating times are discussed. Second, a comparison of the heating properties obtained by using the needle type electrodes made of different shaped SMA is discussed. From these results, it is confirmed that the proposed heating method can expand the heating area and control the heating pattern for the various sizes of brain tumors.

Improvement of needle type applicator made of shape memory alloy.

This paper discusses radio frequency (RF) interstitial hyperthermia for brain tumors with a developed needle type applicator made of a shape memory alloy (SMA). The problem with the heating method of interstitial hyperthermia is the small heating area. So, we proposed a new heating method using a needle type electrode made of SMA which consists of nickel (Ni), copper (Cu) and titanium (Ti) for expanding the heating area. Here, we proposed the heating method that the leading end of needle type electrode was divided into four parts and the leading end spreads in four directions with a temperature rise. First, the proposed RF interstitial hyperthermia system with the SMA needle was presented. Second, the results obtained by the experimental heating of the agar phantom by using the developed SMA needle type applicator were presented. Third, comparing experimental results, we discussed the heating properties of the developed system. Finally, from these results, it is confirmed that the developed needle type applicator made of SMA is useful for wide heating by invasive hyperthermia.

Heating properties of developed needle type applicator made of shape memory alloy.

This paper discusses radio frequency (RF) interstitial hyperthermia for a brain tumor with a needle type applicator made of a shape memory alloy (SMA). In this method, it is necessary to make appropriate thermal distribution to the region of the brain tumor. However, it is not easy to predict the thermal distribution during the heating. We estimated the temperature distribution inside an agar phantom by the finite element method (FEM), and heated the agar phantom with the developed needle type applicator. Here, first, the developed RF interstitial hyperthermia system with the SMA needle was presented. Second, the results obtained by the computer simulation and the experimental heating results of the agar phantom by using the developed SMA needle type applicator were presented. Comparing computer simulation results and experimental results, we discussed the heating properties of the developed system. Finally, from these results, it is confirmed that the developed needle type applicator made of SMA is useful for wide heating of invasive hyperthermia.

Finite element analysis of the re-entrant type resonant cavity applicator for brain tumor hyperthermia.

In this paper, we have proposed a new heating method in which high frequency electric fields in a re-entrant type resonant cavity are used for the heating of deeply seated tumors. In this method, a human head is placed between the gap of the inner re-entrant cylinders, and is heated with electromagnetic fields stimulated in the cavity without contact between the surface of the human head and the applicator. Here, we proposed a new method to control the heating area. In this method, the resonant frequency inside the cavity was changed, then we use the TM010-like mode and the TM012-like mode from various types of the resonant frequency. First, the computer simulation results of electric and magnetic field patterns are presented. Second, a comparison of the heating properties of TM010-like mode and TM012-like mode are discussed. The heating area of the center of agar phantom is more concentrated by using TM012-like mode than that of using TM010-like mode. From these results, it is confirmed that the proposed method can be controlled to heat the various sizes of deep tumors.

Heating properties of re-entrant resonant applicator for brain tumor by electromagnetic heating modes.

This paper discusses a new method to control the heating area of a re-entrant resonant cavity applicator for brain tumor hyperthermia treatment non-invasively. We have already discussed about the effectiveness of a developed system with experiments of heating an agar phantom and computer simulations. Here, in order to heat a deep brain tumor, we propose the heating method of using several electromagnetic heating modes which are transverse magnetic (TM) modes. In this method, TM010-like and TM012-like modes obtained by selecting resonant frequencies can be used to heat the deep brain tumors. To control the heating area of the modes the agar phantom is used in the heating experiments by the developed system. From these results, we found that the heating area of the agar phantom by using TM012-like mode is about 50% of the heating area of TM010-like mode. It is found that the proposed heating system can be applicable to the hyperthermia treatment of brain tumors corresponding to the size and the position where it occurred.

Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use.

Kampo (Japanese traditional herbal) medicines have been produced by combining multiple crude drugs, almost all of plant origin but with some of animal or mineral origin, and contain a great many substances. Their effect is a combination of the various interactions of the constituent substances, whether they are enhancing, synergistic or suppressive. Kampo medicine has an overall effect that is different from the combined effects of individual crude drugs, and several side effects such as anorexia, slight fever and nausea have been reported in the treatment of certain disorders and disease states with Kampo medicines. Among 210 medical formulations used in Japan, some relevant information on the clinical uses, pharmacology and toxicology of six manufactured Kampo medical formulations, Shosaikoto, Daisaikoto, Saikokeishito, Hochuekkito, Saibokuto and Saireito, containing Bupleurum root are reviewed. Studies of some potential interactions between Kampo medicine and western drugs are also considered.

Induction of apoptosis in HL-60 cells treated with medicinal herbs.

In order to develop a new apoptosis inducer, we screened 22 crude drugs for their apoptosis-inducing activity. It was found that Glycyrrhiza uralensis, Cynomorium songaricum, Eucommia ulmoides, Phellodendron amurense, Cinnamomum cassia and Paeonia lactiflora induced the death of HL-60 cells. To investigate the mechanism of apoptosis induced by these six crude drugs, the mitochondrial transmembrane potential and the activity of caspase-3 were measured. Reduced mitochondrial transmembrane potentials within 12 hours after the administration of Glycyrrhiza uralensis, Cynomorium songaricum, Phellodendron amurense and Paeonia lactiflora, and within 24 hours after the administration of Eucommia ulmoides and Cinnamomum cassia were observed. All of the six apoptosis-inducing crude drugs increased caspase-3 activity within 12-36 hours after administration. After further examining the apoptosis-inducing activity of berberine, palmatine, panelofuroline and glycyrrhizin, which were the ingredients obtained from Phellodendron amurense, Glycyrrhiza uralensis and Paeonia lactiflora, it was found that only berberine could induce apoptosis. From these results, it was concluded that the apoptosis induced by the six crude drugs (Glycyrrhiza uralensis, Cynomorium songaricum, Eucommia ulmoides, Phellodendron amurense, Cinnamomum cassia and Paeonia lactiflora) occurred via the mitochondrial route and that the apoptosis-conducting mechanism acted through a cascade involving caspase-3.

Effect of whole body hyperthermia on ischemia and reperfusion injury of rat intestine: real-time ATP change studied using (31)P-MRS.

We studied the effect of hyperthermia pretreatment on subsequent small intestinal ischemia and reperfusion (I/R) injury in the rat. Systemic hyperthermia has been reported to induce heat shock proteins (HSPs) in several organs [1-6]. We examined the expression of HSP72 in the small intestinal mucosa using Western blotting and immunohistochemistry. We monitored energy metabolism using magnetic resonance spectroscopy continuously during a 60-min ischemia and the following 120 min of reperfusion. Expression of HSP72 in the small intestine was significantly increased at 6-8 h after hyperthermia. Intestinal ischemia was induced by clamping the superior mesenteric artery. Heating of the rat conferred substantial resistance to the I/R injury. In the untreated rats, beta-ATP decreased during ischemia (37.1 +/- 15.5% of the pre-ischemic value) and recovered on reperfusion, but reached only approximately 50% of the pre-ischemic value after 120 min of reperfusion. However, beta-ATP in the pretreated rats was maintained during ischemia at significantly higher levels and on reperfusion reached approximately 80% of the pre-ischemic value. These results indicate that hyperthermia protects the rat intestine from the I/R injury by unknown mechanisms which may include the induction of HSPs.

Reversibility of n-3 fatty acid deficiency-induced alterations of learning behavior in the rat: level of n-6 fatty acids as another critical factor.

Rats fed a semipurified diet supplemented with 3% (w/w) safflower oil [Saf, n-3 fatty acid deficient, high linoleic acid (18:2n-6)] through two generations exhibit decreased correct response ratios in a brightness-discrimination learning test compared with rats fed 3% perilla oil [Per, high alpha-linolenic acid (18:3n-3)]. This is associated with a decreased DHA (22:6n-3)-to-arachidonic acid (20:4n-6) ratio in brain lipids. In the first set of experiments, dietary oil was shifted from Saf to a mixture of 2.4% safflower oil plus 0.6% DHA after weaning (Saf-DHA), but all parameters measured in the learning test were essentially unchanged. Brain 22:6n-3 content of the Saf-DHA group reached that of the Per group but the levels of 20:4n-6 and docosatetraenoic acid (22:4n-6) did not decrease to those of the Per group at the start of the test. In the second set of experiments, dietary oil was shifted to a mixture of 0.6% safflower oil plus 1.2% oleic acid (OA) plus 1.2% DHA (Saf-OA-DHA group) with 18:2n-6 content comparable to that of the Per group. The Saf-OA-DHA group exhibited a learning performance similar to that of the Per group; brain 22:6n-3, 20:4n-6, and 22:4n-6 contents were also comparable to those of the Per group. These results indicate that the altered learning behavior associated with a long-term n-3 fatty acid deficiency is reversed by supplementing 22:6n-3 after weaning, when the levels of competing n-6 fatty acids in the diet and brain lipids are limited.

Effects of docosahexaenoic acid on annular lipid fluidity of the rat bile canalicular plasma membrane.

The role of docosahexaenoic acid (DHA) in the fluidity of the annular lipid regions and their associated membrane-bound proteins is still not as well understood as that in the global (bulk) lipid regions. We therefore studied the effects of dietary DHA on the relationship between annular and global lipid fluidity and membrane-bound enzymes such as 5'-nucleotidase and Mg(2)+-ATPase in the rat bile canalicular membrane. Dietary DHA caused significant increases in 5'-nucleotidase and Mg(2)+-ATPase activity and in global and annular lipid fluidity, a higher increase in fluidity in the annular lipids than the global lipids, and a decrease in the cholesterol-to-phospholipid molar ratio in the canalicular membrane. Plasma total cholesterol and LDL cholesterol decreased, and fecal cholesterol increased in the DHA-fed rats. No changes were observed in oxidative markers, but glutathione peroxidase increased in the liver with DHA feeding. Annular lipid fluidity, but not global lipid fluidity, correlated remarkably well with DHA, synchronously with the activities of 5'-nucleotidase and Mg(2)+-ATPase. The data indicate that the DHA-induced increase in annular lipid fluidity is responsible for the increases observed in the enzyme activity. We therefore concluded that the increased activity of membrane-bound enzymes and transporters induced by DHA and the concomitant increase in annular lipid fluidity comprise one of the mechanisms involved in DHA-induced clearance of plasma cholesterol.

Adjuvant therapies using biliary stenting for malignant biliary obstruction.

The aim of this study was to analyze the patency of expandable metallic stents in malignant biliary obstruction and to evaluate the efficacy of adjuvant therapy accompanied by biliary stenting. We analyzed 29 patients in whom bile duct stenting was performed for malignant biliary obstruction. Their types of disease were: hilar ductal carcinoma (n = 8), gallbladder carcinoma (n = 11), and pancreatic carcinoma (n = 10). Initially, 46 expandable metallic stents were placed in 29 patients. In 23 of the 29 patients, adjuvant therapy was administered. Seventeen patients underwent radiotherapy, and 16 patients received various systemic chemotherapies. In principle, hyperthermia was performed twice a week, simultaneously with radiotherapy. Patient survival and the probability of stent patency were calculated using actuarial life table analysis. There was no significant difference in stent patency among the patients according to type of disease. Hyperthermia did not influence the stent patency rate. The median stent patency time was significantly greater in the chemo-radiation group than in the no-adjuvant therapy group: 182 days versus 68 days, respectively (P = 0.017). Moreover, a significant increase was seen in the median survival time in the chemo-radiation group: 261 days versus 109 days (P = 0.0337). Complications occurred in 9 patients (31.0%). Stent occlusion occurred in 6 patients (20.7%), with all of these patients managed successfully using a transhepatically placed new expandable metallic stent, employing the stent-in-stent method. Stent migration occurred in 2 patients after radiotherapy. Adjuvant therapies such as radiotherapy and systemic chemotherapy, in combination with stent insertion, resulted in an increase in the patency period of expandable metallic stents and in increased patient survival time.