Interim Report of a Japanese Phase II Trial for Cardiac Stereotactic Body Radiotherapy in Refractory Ventricular Tachycardia　- Focus on Target Determination.

Background: Cardiac radiotherapy using stereotactic body radiation therapy (SBRT) has attracted attention as a minimally invasive treatment for refractory ventricular tachycardia. However, a standardized protocol and software program for determining the irradiation target have not been established. Here, we report the first preclinical stereotactic radioregulation antiarrhythmic therapy trial in Japan, focused on the target-setting process. Methods and Results: From 2019 onwards, 3 patients (age range 60-91 years) presenting with ischemic or non-ischemic cardiomyopathy were enrolled. Two patients were extremely serious and urgent, and were followed up for 6 and 30 months. To determine the irradiation targets, we aggregated electrophysiological, structural, and functional data and reflected them in an American Heart Association 17-segment model, as per the current recommendations. However, in all 3 patients, invasive electrophysiological study, phase-contrast computed tomography, and magnetic resonance imaging could not be performed; therefore, electrophysiological and structural information was limited. As alternatives, high-resolution ambulatory electrocardiography and nuclear medicine studies were useful in assessing arrhythmic substrates; however, concerns regarding test weighting and multiple scoring remain. Risks to surrounding organs were fully taken into account. Conclusions: In patients requiring cardiac SBRT, the information needed for target planning is sometimes limited to minimally invasive tests. Although there are issues to be resolved, this is a promising option for the life-saving treatment of patients in critical situations.

Antemortem Diagnosis of Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Recurrent Breast Cancer: An Autopsy Case Report.

OBJECTIVE: Herein, we report a case of a patient with recurrent breast cancer who was diagnosed antemortem with pulmonary tumor thrombotic microangiopathy (PTTM) using wedge aspiration cytology of the pulmonary artery after breast cancer surgery. CASE SUMMARY: The patient was a 50-year-old woman who underwent mastectomy and axillary lymph node dissection for stage IIIA (T3N2M0) triple-negative left breast cancer. Postoperative follow-up was performed with radiotherapy and anticancer chemotherapy. Seventeen months after the surgery, the patient was hospitalized for right heart failure and diagnosed with pulmonary arterial hypertension. The patient was diagnosed with PTTM following the detection of malignant cells in the pulmonary artery using wedge aspiration cytology. Anti-pulmonary hypertension therapy was administered; however, the patient did not respond and died 26 days after admission. Autopsy revealed multiple microscopic tumor emboli in the pulmonary artery. In portions of the pulmonary artery without embolization, fibro-cellular intimal hyperplasia and stenosis were observed. Tumor embolism was expressed for CK7+/CK20-, consistent with the primary breast cancer. DISCUSSION: Since the primary pathophysiology of PTTM entails narrowing due to fibro-cellular intimal hyperplasia rather than multiple tumor thrombi, the efficacy of chemotherapy combined with vasodilators is discussed.

Effect of Cardiac Rehabilitation on Glomerular Filtration Rate Using Serum Cystatin C Concentration in Patients With Cardiovascular Disease and Renal Dysfunction.

PURPOSE: Among patients with chronic kidney disease (CKD), little is known about whether the effect of cardiac rehabilitation (CR) on renal function differs across baseline estimated glomerular filtration rate using the serum concentration of cystatin C (eGFRcys). The aim of this study was to evaluate the effect of CR on renal function in patients with CKD. METHODS: We performed a retrospective cohort study of patients with CKD (15 ≤ eGFRcys < 60 mL/min/1.73 m2) who participated in our CR program for cardiovascular disease. First, the patients were divided into three groups according to the baseline severity of the eGFRcys: G3a, G3b, and G4 groups. We compared the eGFRcys before and after the CR in each group. Second, to determine the association of baseline eGFRcys with the effect of CR, we fitted a linear regression model using the percent change in the eGFRcys (%ΔeGFRcys) as an outcome. RESULTS: Of the 203 patients, 122 were in G3a, 60 were in G3b, and 21 were in G4 groups. The mean improvement of eGFRcys in each group was 1.3, 3.1, and 4.8 mL/min/1.73 m2, respectively. The %ΔeGFRcys was larger among patients with lower baseline eGFRcys (0.47% greater improvement of %ΔeGFRcys/one lower baseline eGFRcys; 95% CI, 0.23-0.72%). This association remained significant after adjustment for potential confounders (0.63% greater improvement of %ΔeGFRcys/one lower baseline eGFRcys; 95% CI, 0.35-0.91%). CONCLUSIONS: The effect of CR on renal function was greater in patients with worse renal dysfunction measured by eGFRcys. A CR program could be useful for patients with severe renal dysfunction and it might have a beneficial effect on their renal function.

A Case of Effective Mepolizumab Induction Therapy for Severe Eosinophilic Granulomatosis with Polyangiitis Diagnosed by Eosinophilic Cholecystitis and Interstitial Nephritis.

A 66-year-old man with a history of bronchial asthma and sinusitis was admitted with cholecystitis and peripheral neuropathy. The histopathological findings of the gallbladder revealed necrotic vasculitis and granulomatous inflammation with marked eosinophilic infiltration. Kidney biopsy also showed marked eosinophilic infiltration in the tubulointerstitial area and eosinophilic tubulitis. He was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with corticosteroids. However, he showed no response. Therefore, he was administered mepolizumab 300 mg, which resulted in clinical improvement, including normalization of the eosinophil and CRP levels. We herein describe the first case of successful induction therapy of EGPA using mepolizumab.

Effects of cardiac rehabilitation on physical function and exercise capacity in elderly cardiovascular patients with frailty.

BACKGROUND: The effects of cardiac rehabilitation (CR) on long-term prognosis of cardiovascular disease (CVD) are well known. However, the effect of CR on frail CVD patients has not been fully addressed. METHODS: This study consisted of 89 CVD patients with their age ≥65 years old (68 males, 75 ± 6 years), who participated in the outpatient CR program for 3 months. All the patients underwent cardiopulmonary exercise testing and the physical frailty was assessed using the Japanese Version of the Cardiovascular Health Study Standard before and after CR. Based on the assessment of frailty before CR, the patients were divided into the following two groups: frailty group (n = 23) and non-frailty group (n = 66: robust in 10 and pre-frail in 56 patients). RESULTS: In the frailty group, 20 patients (87%) improved from frail status after CR, and usual walking speed, maximal grip strength, and lower extremity strength were significantly improved (1.06±0.20 vs. 1.20±0.18 m/sec, p<0.001; 21.7 ± 5.5 vs. 23.6 ± 6.3 kg, p<0.01; 0.37±0.09 vs. 0.43±0.11 kgf/kg, p = 0.001, respectively), but peak VO2 did not change after CR (15.9 ± 3.1 vs. 16.2 ± 3.8 ml/min/kg, NS). In the non-frailty group, all these parameters were significantly improved after CR (1.24±0.19 vs. 1.29±0.23 m/sec, p<0.05, 28.7 ± 7.0 vs. 30.2 ± 7.3 kg, p<0.001, 0.50±0.18 vs. 0.54±0.13 kgf/kg, p<0.05, 17.7 ± 4.7 vs 18.5 ± 4.2 ml/min/kg, p<0.01, respectively). CONCLUSION: Short-term CR could obtain the improvement of the physical function, providing the prerequisite step for possibly following improvement of exercise capacity in elderly CVD patients with frailty. It may be inferred that longer duration of CR would be needed to obtain the improvement of exercise capacity in these patients, being the future consideration to be determined.

Quality Evaluation and Characterization of Fractions with Biological Activity from Ephedra Herb Extract and Ephedrine Alkaloids-Free Ephedra Herb Extract.

Previously, we reported that the c-Met inhibitory effect of Ephedra Herb extract (EHE) is derived from ingredients besides ephedrine alkaloids. Moreover, analgesic and anti-influenza activities of EHE and ephedrine alkaloids-free Ephedra Herb extract (EFE) have been reported recently. In this study, we examined the fractions containing c-Met kinase inhibitory activity from EHE and the fractions with analgesic and anti-influenza activities from EFE, and elucidated the structural characteristics of the active fractions. Significant c-Met kinase activity was observed in 30, 40, and 50% methanol (MeOH) eluate fractions obtained from water extract of EHE using Diaion HP-20 column chromatography. Similarly, 20 and 40% MeOH, and MeOH eluate fractions obtained from water extract of EFE were found to display analgesic and anti-influenza activities. Reversed phase-HPLC analysis of the active fractions commonly showed broad peaks characteristic of high-molecular mass condensed tannin. The active fractions were analyzed using 13C-NMR and decomposition reactions; the deduced structures of active components were high-molecular mass condensed tannins, which were mainly procyanidin B-type and partly procyanidin A-type, including pyrogallol- and catechol-type flavan 3-ols as extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9 : 2, and the weight-average molecular weight based on the polystyrene standard was >45000. Furthermore, GPC-based analysis was proposed as the quality evaluation method for high-molecular mass condensed tannin in EHE and EFE.

[The Adverse Effects of Ephedra Herb and the Safety of Ephedrine Alkaloids-free Ephedra Herb Extract (EFE)].

Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia (JP) as the terrestrial stem of Ephedra sinica Stapf., Ephedra intermedia Schrenk et C.A. Meyer, or Ephedra equisetina Bunge (Ephedraceae). The stems of Ephedra Herb contain greater than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). Despite its high effectiveness, Ephedra Herb exert several adverse effects, including palpitation, excitation, insomnia, and dysuria. Both the primary and adverse effects of Ephedra Herb have been traditionally believed to be mediated by these ephedrine alkaloids. However, our study found that several pharmacological actions of Ephedra Herb were not associated with ephedrine alkaloids. We prepared an ephedrine alkaloid-free Ephedra Herb extract (EFE) by eliminating ephedrine alkaloids from Ephedra Herb extract (EHE) using ion-exchange column chromatography. EFE exerted analgesic, anti-influenza, and anticancer activities in the same manner as EHE. Moreover, EFE did not induce adverse effects due to ephedrine alkaloids, such as excitation, insomnia, and arrhythmias, and showed no toxicity. Furthermore, we evaluated the safety of EFE in healthy volunteers. The number of adverse event cases was higher in the EHE-treated group than in the EFE-treated group, although the difference was not significant. Our evidence suggested that EFE was safer than EHE.

Indication for voiding cystourethrography during first urinary tract infection.

BACKGROUND: There is confusion surrounding the precise indications for voiding cystourethrography (VCUG) during the assessment of vesicoureteral reflex (VUR) after a first febrile urinary tract infection (UTI). The aim of this study was to determine the combination of clinical, laboratory and ultrasonography factors correlating with grades IV-V VUR in young children with a first febrile UTI. METHODS: Children 0-24 months of age who were brought to the emergency department at National Center for Child Health and Development with the diagnosis of first time febrile UTI between March 2004 and May 2011, were enrolled. We compared clinical, laboratory and ultrasonography findings between children with grades IV-V VUR (high-grade VUR) and those with no or grades I-III VUR (normal or low-grade VUR). RESULTS: A total of 231 patients were eligible and 19 had high-grade VUR. Poor clinical appearance, presence of a uropathogen other than Escherichia coli, positive blood culture, hydroureter and thickened renal pelvic wall were all independently associated with high-grade VUR. When one or more of these factors were present, sensitivity, specificity, positive or negative predictive value, and positive or negative likelihood ratio were 94.7%, 69.4%, 23.1%, 99.3%, 3.1 and 0.1, respectively. When none of the factors was present, the proportion of high-grade VUR was 0.7%; if one factor, 11.3%; two factors, 55.6%; three factors, 85.7%. CONCLUSIONS: In the absence of five specific factors during the first febrile UTI episode in young children, VCUG is not necessary to detect high-grade VUR. When more than one factor is present, however, VCUG is indicated.

Effect of cardiac rehabilitation on the renal function in chronic kidney disease - Analysis using serum cystatin-C based glomerular filtration rate.

BACKGROUND: Whether an individually determined appropriate level of cardiac rehabilitation (CR) has a favorable effect on the renal function still remains unclarified. The aim of this study was to confirm the effect of CR on the estimated glomerular filtration rate (eGFR) using cystatin C, which is known to be unaffected by physical exercise. METHODS: The study population was comprised of 86 patients (61 males; average age 74 y/o) with a lower-moderate level of chronic kidney disease (CKD) who was admitted to our hospital for treatment of cardiovascular disease (CVD) and who participated in our 3-month CR program. The exercise capacity was assessed by cardiopulmonary exercise testing (CPX) and the eGFR was measured by a formula based on the serum cystatin C concentration (eGFRcys) in each patient both at the beginning and end of the CR. RESULTS: In the CVD patients with CKD, both the peak oxygen uptake (VO2) and peak work rate (WR) improved significantly after CR (15.0 ±â€¯3 to 15.8 ±â€¯3 ml/min/kg, p = 0.002. 65.5 ±â€¯21 to 70.2 ±â€¯25 W, p = 0.001). Regarding the renal function, the eGFRcys improved (45.2 ±â€¯11 to 47.3 ±â€¯13 ml/min/1.73 m2, p = 0.023), however, the eGFR assessed by the serum creatinine (eGFRcr) did not improve after CR (45.1 ±â€¯12 to 44.9 ±â€¯13 ml/min/1.73 m2, p = 0.834). CONCLUSIONS: In CVD patients, a novel CR program significantly improved the exercise capacity. Further, CR was shown to have a favorable effect on the renal function when it was estimated by the eGFRcys.

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias.

Ephedrine alkaloids-free Ephedra Herb extract (EFE) has been developed to eliminate the adverse effects caused by ephedrine alkaloid-induced sympathetic hyperactivation. Previously, we reported that EFE possesses analgesic, anti-influenza, and cancer metastatic inhibitory effects at comparable levels to that of Ephedra Herb extract (EHE). However, it has not yet been demonstrated that EFE is free from the known side effects of EHE, such as excitation, insomnia, and arrhythmias. In this study, the incidence of these adverse effects was compared between mice administered EHE and those administered EFE. Increased locomotor activity in an open-field test, reduced immobility times in a forced swim test, and reduced sleep times in a pentobarbital-induced sleep test were observed in EHE-treated mice, when compared to the corresponding values in vehicle-treated mice. In contrast, EFE had no obvious effects in these tests. In electrocardiograms, atrial fibrillation (i.e., irregular heart rhythm, absence of P waves, and appearance of f waves) was observed in the EHE-treated mice. It was suggested that this atrial fibrillation was induced by stimulation of adrenaline ß1 receptors, but not by hypokalemia. However, EFE did not affect cardiac electrophysiology. These results suggest that the abovementioned side effects are caused by ephedrine alkaloids in EHE, and that EFE is free from these adverse effects, such as excitation, insomnia, and arrhythmias. Thus, EFE is a promising new botanical drug with few adverse effects.

Anti-steatosis compounds from leaves of Mallotus furetianus.

There is no drug administration-approved therapy for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In this study, eight compounds, gallic acid (1), methyl gallate (2), corilagin (3), 3,4,8,9,10-pentahydroxydibenzo[b,d]pyran-6-one (4), repandinin B (5), (Z)-3-hexenyl-ß-D-glucopyranoside (6), (+)-lyoniresinol-3α-O-α-L-rhamnopyranoside (7) and mallophenol A (8) were isolated from the active fractions of Mallotus furetianus. Three compounds, (6, 7 and 8) revealed potent anti-steatosis activity in the oleic acid (OA)-induced steatosis cell model, with the minimum effective concentration of 0.05 (6), 0.0005 (7) and 0.0005 (8) µg/mL, which were much lower than the control compound, fibrate (72.4 µg/mL).

Inhibition of UDP-glucuronosyltransferase (UGT)-mediated glycyrrhetinic acid 3-O-glucuronidation by polyphenols and triterpenoids.

Glycyrrhetinic acid (GA) is an active metabolite of glycyrrhizin, which is a main constituent in licorice (Glycyrrhiza glabra). While GA exhibits a wide variety of pharmacological activities in the body, it is converted to a toxic metabolite GA 3-O-glucuronide by hepatic UDP-glucuronosyltransferases (UGTs). To avoid the development of the toxic metabolite-induced pseudohyperaldosteronism (pseudoaldosteronism), there is a limitation in maximum daily dosage of licorice and in combined usage of other glycyrrhizin-containing natural medicine. In this study, we investigated the inhibitory effects of various polyphenols and triterpenoids on the UGT-mediated GA 3-O-glucuronidation. In human liver microsomes, UGT-mediated GA glucuronidation was significantly inhibited by protopanaxadiol with an IC50 value of 59.2 µM. Isoliquiritigenin, rosmarinic acid, alisol B, alisol acetate, and catechin moderately inhibited the GA glucuronidation with IC50 values of 96.4 µM, 125 µM, 160 µM, 163 µM, and 164 µM. Other tested 19 polyphenols and triterpenoids, including liquiritigenin, did not inhibit UGT-mediated GA glucuronidation in human liver microsomes. Our data indicate that relatively higher dosage of licorice can be used without a risk of developing pseudohyperaldosteronism in combination of natural medicine containing protopanaxadiol such as Panax ginseng. Furthermore, supplemental protopanaxadiol and isoliquiritigenin might be useful in preventing licorice-inducing pseudoaldosteronism.

Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus.

We encountered a 45-year-old Japanese man who suffered from pulmonary thromboembolism and huge right ventricular thrombus after inferior vena cava (IVC) filter implantation without apparent thrombus in either the deep veins or inside the IVC filter. The biochemical data showed a discrepancy in the level of fibrinogen between the immunological and thrombin time methods, suggesting hypodysfibrinogenemia. The sequencing of the fibrinogen γ-chain gene (FGG) revealed a novel heterozygous missense mutation in exon 8 - a TGT to TCT transversion in codon 326 - resulting in an amino acid substitution of serine for cysteine (γCys326Ser). The characterization of the protein did not show known mechanisms for thrombosis in dysfibrinogenemia, such as dimer or albumin-binding complex formation. In summary, the current case with a life-threatening thrombotic event was found to have a novel heterozygous missense mutation resulting in γCys326Ser, which was suggested as a predisposing factor of the thrombosis. Known mechanisms responsible for thrombosis in the current case were not demonstrated, suggesting other mechanisms including superimposing inherited and/or acquired risk factors. When a patient presents with unusual thrombosis such as breakthrough pulmonary embolism and huge thrombus in the right ventricle, as in the current case, the laboratory process for heritable thrombophilia should be considered.

Safety and Efficacy of Cryoballoon Ablation for Paroxysmal Atrial Fibrillation in Japan　- Results From the Japanese Prospective Post-Market Surveillance Study.

BACKGROUND: Outcomes of cryoballoon ablation for paroxysmal atrial fibrillation (PAF) have been reported in the Western countries but not in Japan. The CRYO-Japan PMS study was a single-arm, observational, multicenter, prospective study of the 2nd-generation cryoballoon Arctic Front Advance(TM). We evaluated device- and procedure-related complications and clinical outcomes at 6 months. METHODS AND RESULTS: The 616 patients (male, 72%; mean age, 63±11 years) were enrolled from 33 Japanese hospitals. Of all patients, 610 had PAF, and procedural data were analyzed in 607. A subset of 328 patients was followed for 6 months for the primary efficacy analysis. AF recurrence outside the 3-month blanking period or repeat ablation was considered treatment failure. Pulmonary vein isolation was achieved in 606/607 patients (99.8%); 1 patient (0.3%) had a repeat ablation during the blanking period. Freedom from AF at 6 months was 88.4% (95% CI: 84.1-91.6%). Device- and/or procedure-related adverse events included phrenic nerve injury unresolved at hospital discharge in 9/616 patients (1.5%), which resolved within 6 months in 7, pericardial effusion in 5/616 (0.8%), and tamponade in 4/616 (0.6%). One non-device-related death from pneumonia was reported 6 days post-procedure. CONCLUSIONS: Cryoballoon ablation is safe and effective for Japanese PAF patients, with 88.4% AF freedom at 6 months post-ablation. (Circ J 2016; 80: 1744-1749).

[Kampo Medicine in the New Model Core Curriculum of Pharmaceutical Education].

What should we educate for Kampo medicine in the model core curriculum of pharmaceutical education? The curricular core should be discussed considering the points mentioned below. (1) Positioning of Kampo medicine in the Japanese medical care system. Kampo medicine is an authorized medical care category in the National Health Insurance (NHI) program in Japan. The NHI drug price list carries 148 Kampo formulations. According to the report of the Japan Kampo Medicines Manufacturers Association in 2011, approximately 90% of Japanese physicians prescribe Kampo medicines. (2) Differences between Kampo medicine and western medicine: In Kampo medicine, the most suitable formula among various Kampo formulas to normalize the psychophysical state of individual patients is selected. In other words, if there is a complaint, there are always some treatments. (3) A strong point of Kampo medicine: Kampo medicine enables physicians to deal with difficult-to-treat conditions by western medicine alone. Also, by using the scale of Kampo medicine, each patient can grasp his or her own systemic state and improve their lifestyle. To extend healthy life expectancy, a basic knowledge of Kampo medicine may play a significant role in integrated health care. "The guide book of the approval standards for OTC Kampo products", "the pharmaceutical advanced educational guideline", and "the manual of the exam questions preparation for registered sales clerks" should also be consulted before selecting the area and contents that should be covered.

Iminimycin A, the new iminium metabolite produced by Streptomyces griseus OS-3601.

A new natural product, designated iminimycin A, was isolated from the cultured broth of a streptomycin-producing microbial strain, Streptomyces griseus OS-3601, via a physicochemical screening method using HP-20, silica gel and ODS column chromatographies and subsequent preparative HPLC. Iminimycin A is an indolizidine alkaloid, containing of an unusual iminium group and a cyclopropane ring with a triene side chain. The absolute configuration of iminimycin A was elucidated by NMR studies and electronic circular dichroism analysis. Iminimycin A shows anti-bacterial activity against Bacillus subtilis, Kocuria rhizophila and Xanthomonas campestris pv. orizae, and cytotoxic activity against HeLa S3 and Jurkat cells with IC50 values of 43 and 36 µM, respectively.

Enhancement of Pentobarbital-induced Sleep by the Vaporized Essential Oil of Citrus keraji var. kabuchii and its Characteristic Component, y-Terpinene.

Kabuchii (Citrus keraji var. kabuchii hort. ex Tanaka, Rutaceae) is a peculiar Okinawan citrus fruit. Local farmers cultivating various Citrus fruits say that the fragrance of Kabuchii is the most relaxing, but, there are few reports on the biological effects of the essential oil of Kabuchii and its chemical components [1]. In this study, the sedative effects of inhalation of the vaporized Kabuchii essential oil in open field, Rotarod, and pentobarbital sleep tests are compared with diazepam, as a positive control. In the open field test, both Kabuchii essential oil and diazepam decreased the spontaneous motor activity dose-dependently. The reduction in spontaneous motor activity in the 0.3 mg/cage (ca. 0.0278 mg/L) Kabuchii essential oil group was greater than that in the 1 mg/kg diazepam group. In the Rotarod test, Kabuchii did not affect the motor performance, even at the highest dosage tested (3 mg/cage), whereas diazepam decreased it dose- dependently. The effects of the major or characteristic components of Kabuchii, d-limonene, y-terpinene, thymol, and p-cymene, were also evaluated in the- open field and Rotarod tests. y-Terpinene and thymol significantly decreased spontaneous motor activity at a dosage of 0.3 mg/cage, without affecting motor performance. Thus, y-terpinene was estimated to be the main active component. Reduction in spontaneous motor activity by y-terpinene in the open field test was not observed in intranasal zinc sulfate irrigation-induced anosmic mice. In the pentobarbital sleep test, both Kabuchii essential oil and diazepam potentiated pentobarbital-induced loss of the righting reflex (LRR). The LRR duration prolonging effects of both treatments were inhibited by pretreatment with flumazenil, a benzodiazepine receptor antagonist. The LRR latency reducing effect of Kabuchii was not affected by flumazenil, while that of diazepam was suppressed by it. y-Terpinene showed similar potentiating effects on pentobarbital-induced sleep. Thus, vaporized Kabuchii essential oil and its active component, y-terpinene, have sedative effects comparable with diazepam without inducing motor incoordination, which is a well-known side effect of. diazepam.

Cytotoxic activity of two natural sesquiterpene lactones, isobutyroylplenolin and arnicolide D, on human colon cancer cell line HT-29.

In this study, we found that two sesquiterpene lactones, isobutyroylplenolin and arnicolide D, from Centipeda minima L. (Compositae) exerted stronger cytotoxic activity than cisplatin on the human colon carcinoma HT-29 cell line. Furthermore, the cytotoxicity of these two compounds on normal cells was weaker than that of cisplatin. Treatment with isobutyroylplenolin and arnicolide D increased the levels of intracellular reactive oxygen species and decreased the levels of nuclear factor-κB protein, resulting in cell cycle arrest in G1 phase and apoptosis. We also discuss the difference in structure and activity between these two compounds.

Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice.

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.

A new approach for the comparison of conduction abnormality between arrhythmogenic right ventricular cardiomyopathy/dysplasia and Brugada syndrome.

BACKGROUND: Right ventricular outflow tract ventricular tachycardia (RVOT-VT), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD), and Brugada syndrome (BrS) were characterized by arrhythmias originating in the right ventricle, and the pathophysiologic mechanism underlying these arrhythmias has not been fully understood. METHODS: This study consisted of 40 subjects, including 20 patients with RVOT-VT, 10 patients with BrS, and 10 ARVD patients. The parameters on the signal-averaged electrocardiography (ECG) and the frequency components recorded from the wavelet-transformed ECG were compared between the three groups. Late potentials were positive in none of the patients with RVOT-VT, seven of the patients with BrS, and all of ARVD patients. RESULTS: In Brugada and ARVD patients, the power of high-frequency components (80-150 Hz) was developed to a greater extent than in RVOT-VT patients. In the power analysis of the high-frequency components between BrS and ARVD, the frequency showing the greatest power was significantly higher in ARVD patients than that in BrS patients (145.4 ± 27.9 Hz vs 81.7 ± 19.9 Hz, P < 0.01). CONCLUSIONS: High-frequency components were developed in ARVD and BrS, but not in RVOT-VT. The frequency levels showing high power by wavelet analysis obviously differ between ARVD and BrS. Wavelet analysis may provide new insight into unsolved mechanisms in arrhythmogenic right heart disease.