Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand.

BACKGROUND: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. METHODS: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. RESULTS: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). CONCLUSIONS: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).

Nasal glucagon as a viable alternative for treating insulin-induced hypoglycaemia in Japanese patients with type 1 or type 2 diabetes: A phase 3 randomized crossover study.

AIM: To compare nasal glucagon (NG) with intramuscular glucagon (IMG) for the treatment of insulin-induced hypoglycaemia in Japanese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This phase 3, randomized, open-label, two-treatment, two-period crossover non-inferiority study enrolled Japanese adults with T1DM or T2DM on insulin therapy, with glycated haemoglobin levels ≤86 mmol/mol (≤10%). After ≥8 hours of fasting, hypoglycaemia was induced with human regular insulin (intravenous infusion). Patients received NG 3 mg or IMG 1 mg approximately 5 minutes after insulin termination. The primary endpoint was the proportion of patients achieving treatment success [plasma glucose (PG) increase to ≥3.9 mmol/L (≥70 mg/dL) or ≥1.1 mmol/L (≥20 mg/dL) increase from the PG nadir within 30 minutes of receiving glucagon]. Non-inferiority was declared if the upper limit of the two-sided 95% confidence interval (CI) of the mean difference in the percentage of patients achieving treatment success (IMG minus NG) was <10%. RESULTS: Seventy-five patients with T1DM (n = 34) or T2DM (n = 41) were enrolled; 72 patients (50 men, 22 women) received ≥1 study drug dose (T1DM, n = 33; T2DM, n = 39). Sixty-eight patients completed the study and were evaluable. All NG- and IMG-treated patients achieved treatment success (treatment arm difference: 0%; upper limit of two-sided 95% CI 1.47%); NG met prespecified conditions defining non-inferiority versus IMG. Glucagon was rapidly absorbed after both nasal and intramuscular administration; PG profiles were similar between administration routes during the first 60 minutes post dose. Study drug-related treatment-emergent adverse events affecting >2 patients were rhinalgia, increased blood pressure, nausea, ear pain and vomiting in the NG group, and nausea and vomiting in the IMG group. CONCLUSION: Nasal glucagon was non-inferior to IMG for successful treatment of insulin-induced hypoglycaemia in Japanese patients with T1DM/T2DM, supporting use of NG as a rescue treatment for severe hypoglycaemia.

Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects.

OBJECTIVES: Assess the safety, tolerability, and pharmacokinetic (PK) profiles of daclatasvir (DCV) and asunaprevir (ASV) in healthy male Japanese subjects. METHODS: AI444-007 and AI447-005 were phase I, double-blind, placebo-controlled, sequential, single-ascending dose (SAD), and multiple-ascending dose (MAD) studies assessing DCV or ASV, respectively. Eight subjects per panel were randomized to study drug or placebo (3 : 1). In the SAD part of each study, subjects received single oral dose DCV 1/10/50/100/200 mg or ASV 200/400/600/900/1,200 mg. In MAD, subjects received 14-day oral multiple dose DCV 1/10/100 mg once-daily or ASV 200/400/600 mg every 12 hours. Serial PK blood sampling occurred from predose to 72-hours postdose or post-last-dose. Safety and tolerability was assessed throughout. RESULTS: 64 (SAD, n = 40; MAD, n = 24) and 65 (SAD, n = 40; MAD, n = 25) subjects were enrolled in AI444-007 and AI447-005, respectively. DCV and ASV were generally well tolerated, with no serious adverse events or clinicallyrelevant changes in vital signs or ECG parameters. Baseline demographic characteristics were comparable across treatment groups in both studies. DCV was readily absorbed, with median tmax of ~ 1 - 2 hours postdose and concentrations declining in a multi-phasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state was achieved between days 4 and 5 of multiple dosing. ASV was readily absorbed, with median tmax of ~ 2 - 4 hours postdose and concentrations declining in a biphasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state appeared to be achieved between days 3 - 5 of multiple dosing. CONCLUSIONS: Results suggest no clinically significant short-term safety signals with DCV and ASV at single or multiple doses in this population.

Home blood pressure-lowering effect of a non-steroidal mineralocorticoid receptor blocker, esaxerenone, versus trichlormethiazide for uncontrolled hypertension: the EXCITE-HT randomized controlled study.

The EXCITE-HT study aimed to evaluate the efficacy and safety of esaxerenone versus thiazide diuretics (trichlormethiazide) as second-line treatment for Japanese patients with uncontrolled essential hypertension. This was a 12-week, multicenter, randomized, open-label, parallel-group study. The non-inferiority of esaxerenone to trichlormethiazide was confirmed if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic blood pressure (SBP)/diastolic blood pressure (DBP) change between groups was below 3.9/2.1 mmHg. A total of 295 and 290 patients were included in the esaxerenone and trichlormethiazide groups, respectively. The non-inferiority of esaxerenone to trichlormethiazide was demonstrated: least squares mean change differences in morning home SBP/DBP at end of treatment (EOT) were -2.2 (95% CI, -3.6, -0.8) mmHg for SBP/-0.6 (-1.4, 0.2) mmHg for DBP. Morning home, bedtime home, and office BP significantly decreased (all p < 0.001) from baseline to EOT in both groups. The urinary albumin-to-creatinine ratio and N-terminal pro-brain natriuretic peptide level decreased from baseline to Week 12 in both groups, with no notable intergroup difference. Serum potassium elevations occurred more frequently with esaxerenone, while serum potassium reductions occurred more with trichlormethiazide. Uric acid elevations were observed in both groups, but more frequently with trichlormethiazide than esaxerenone. No cases of gout occurred in this study. Reductions in estimated glomerular filtration rate were similarly observed in both groups. EXCITE-HT is the first randomized controlled study to demonstrate evidence that esaxerenone is non-inferior to trichlormethiazide as second-line treatment for Japanese patients with uncontrolled essential hypertension, with no new safety concerns. The EXCITE-HT study demonstrated the non-inferiority of esaxerenone to trichlormethiazide in its morning home blood pressure lowering effect and safety profile in Japanese patients with uncontrolled essential hypertension who were previously treated with an angiotensin II receptor blocker or calcium channel blocker.

Home blood pressure-lowering effect of esaxerenone versus trichlormethiazide for uncontrolled hypertension: a predefined subanalysis of the EXCITE-HT randomized controlled trial by basal calcium channel blocker versus angiotensin receptor blocker.

This prespecified subanalysis of the multicenter, randomized, open-label, parallel-group EXCITE-HT study aimed to examine the non-inferiority of esaxerenone to trichlormethiazide as a second-line antihypertensive agent according to the basal antihypertensive agent used (angiotensin receptor blocker [ARB] or calcium channel blocker [CCB]). The primary endpoint, change in morning home systolic/diastolic blood pressure (SBP/DBP) from baseline to end of treatment was similar between the two groups (intergroup difference in least squares mean change [95% confidence interval]: -1.3 [-3.8, 1.3]/-0.2 [-1.6, 1.3] mmHg for ARB; -2.7 [-4.2, -1.2]/-0.8 [-1.7, 0.1] mmHg for CCB). The respective incidences of serum potassium levels <3.5 mEq/L and ≥5.5 mEq/L in the ARB subgroup were 3.4% and 4.2% for esaxerenone and 7.9% and 0% for trichlormethiazide; in the CCB subgroup, they were 2.8% and 0.6% for esaxerenone and 13.9% and 1.2% for trichlormethiazide, respectively. The incidence of uric acid level ≥7.0 mg/dL was numerically higher in the trichlormethiazide group than the esaxerenone group in both the ARB and CCB subgroups. The non-inferiority of esaxerenone to trichlormethiazide in lowering morning home BP was demonstrated regardless of whether the basal antihypertensive agent was an ARB or CCB. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering SBP, without any new safety concerns. Serum potassium levels tended to be higher when esaxerenone was combined with an ARB than with a CCB, but this can be mitigated if administered according to the package insert. A subgroup analysis of the EXCITE-HT study according to basal antihypertensive agent demonstrated the non-inferiority of esaxerenone to trichlormethiazide in lowering morning home BP regardless irrespective of the basal antihypertensive agent. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering SBP, without any new safety concerns.

Effect of Sucrose on Amino Acid Absorption of Whey: A Randomized Crossover Trial.

Protein intake has been reported to secrete insulin and lower glucose levels, but the effect of carbohydrate and protein co-ingestion on amino acid absorption has not been well documented. A randomized, placebo-controlled, single-blinded, crossover trial was conducted to evaluate the effect of sucrose on blood amino acid levels. Eleven volunteers (both sexes aged 20-60 years with body mass index 21.4 ± 2.4 kg/m2) randomly received one of four test solutions: water (P-group), 10 g sucrose (S-group), 10 g whey protein (W-group), or 10 g whey protein + 10 g sucrose (W-S-group), and blood amino acid concentration, glucose levels, and insulin levels were monitored over 180 min. Following the wash-out period, randomized treatment and blood parameter monitoring were repeated. Consequently, amino acid concentration was significantly lower in the S-group than in the P-group, showing that single ingestion of sucrose decreased blood amino acid levels in a fasted state. However, there was no significant difference between blood amino acid levels of the W- and W-S-groups, suggesting that co-ingestion of sucrose does not affect blood amino acid concentration. Insulin levels were significantly higher in the W-S than in the S-group, and glucose levels were significantly lower in the W-S- than in the S-group, suggesting positive impact on glycotoxicity by reducing blood glucose levels. Therefore, whey protein co-ingestion with sucrose suppresses glucose levels and increases insulin levels as opposed to the sucrose ingestion, but does not affect amino acid absorption of whey protein, indicating that this co-ingestion may not be a problem for protein supplementation.

Blood Glucose Response of a Low-Carbohydrate Oral Nutritional Supplement with Isomaltulose and Soluble Dietary Fiber in Individuals with Prediabetes: A Randomized, Single-Blind Crossover Trial.

A high-energy-type oral dietary supplement (ONS), with a low proportion of available carbohydrate (LC-ONS), which contains a slowly digestible carbohydrate, isomaltulose, and is fortified with soluble dietary fiber, was newly developed for individuals with diabetes or prediabetes. This study aimed to evaluate the impact of LC-ONS on blood glucose levels after ingestion in individuals with prediabetes. A single-blind, randomized crossover clinical trial was performed on 20 individuals with prediabetes. After overnight fasting, all subjects ingested one serving (200 kcal/125 mL) of either LC-ONS (40% energy proportion of available carbohydrates) or standard ONS (ST-ONS, 54% energy proportion of available carbohydrates) on two separate days. The incremental area under the curve of blood glucose levels for 120 min was significantly lower after LC-ONS ingestion compared to ST-ONS (2207 ± 391 mg/dL·min (least mean square value ± standard error) and 3735 ± 391 mg/dL·min, respectively; p < 0.001). The LC-ONS showed significantly lower blood glucose levels than the ST-ONS at all time points, except at baseline. Similarly, the incremental area under the curve of plasma insulin was significantly lower after LC-ONS ingestion. These results suggest that LC-ONS is useful as an ONS for energy supply in individuals with postprandial hyperglycemia.

Pitavastatin prevents postprandial endothelial dysfunction via reduction of the serum triglyceride level in obese male subjects.

Obesity is a well-established risk factor for the development and progression of coronary heart disease. Moreover, endothelial dysfunction is an early event in atherosclerosis and is known to be associated with postprandial hypertriglyceridemia. The purpose of this study was to determine whether a statin might have an effect on postprandial hypertriglyceridemia, and thereby on endothelial function in obese subjects. Twenty-four obese male subjects were recruited for this study. They were randomly assigned to receive pitavastatin (2 mg/day) or placebo for 2 weeks. The oral fat loading test using OFTT cream was performed pre- and post-treatment, in which the lipid profile and flow-mediated dilation (FMD) were assessed before and 4 h after an oral fat load. In the oral fat loading test conducted pretreatment, the oral fat load induced a marked increase of the serum triglyceride (TG) level and decrease in FMD in the pitavastatin and placebo group. In the test conducted post-treatment, the increase in postprandial TG was attenuated (+183 vs. +81 mg/dL, P < 0.001) and decrease in postprandial FMD was completely abolished (-1.1 vs. +0.1%, P < 0.01) by pitavastatin treatment. Moreover, there was a good correlation between the change in postprandial TG and the change in postprandial FMD after the 2 weeks of treatment (r = -0.737, P < 0.001). Pitavastatin might prevent endothelial dysfunction caused by postprandial hypertriglyceridemia within 2 weeks of therapy in obese subjects.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652, a Reversible Fatty Acid Amide Hydrolase Inhibitor, in Healthy, Nonelderly, Japanese Men and Elderly, Japanese Men and Women: A Randomized, Double-blind, Placebo-controlled, Single and Multiple Oral Dose, Phase I Study.

PURPOSE: This study aimed to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of ASP3652, a peripherally acting inhibitor of peripheral fatty acid amide hydrolase (FAAH) after 30-, 100-, 300-, 600-, and 900-mg single and 100- and 300-mg BID multiple oral dose in Japanese patients. METHODS: This was a randomized, double-blind, placebo-controlled, single and multiple oral dose Phase I study in healthy, nonelderly men and elderly men and women. The study consisted of 2 parts: in the single oral dose part, 40 healthy, nonelderly men were randomized to receive placebo or ASP3652; in the multiple oral dose part, 48 enrolled nonelderly men and elderly men and women were randomized to receive placebo or ASP3652. In both parts, the investigator judged whether the individuals were healthy based on the results of physical examinations and screening. The safety profile was assessed by examining adverse events, defined as any untoward medical occurrence in an individual administered the study drug and that did not necessarily have a causal relationship with the study treatment; clinical laboratory evaluations; vital signs; the Profile of Mood States scale; and standard 12-lead ECGs and 12-lead ECGs for QT assessment. Pharmacokinetic parameters were estimated using unchanged ASP3652 concentrations in plasma and urine. Pharmacodynamic parameters were estimated using FAAH activity and plasma anandamide, oleoylethanolamide, and palmitoylethanolamide concentrations. Safety and tolerability profiles were compared with the placebo group. FINDINGS: ASP3652 was rapidly absorbed to reach Cmax in a single dose and near steady-state at approximately 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 were slightly higher than dose proportional after a single dose of ASP3652 at 30-900 mg. There was no apparent accumulation based on Cmax and AUC0-12 after multiple doses. Although no differences were found in Cmax or AUC0-12 by age in men, Cmax and AUC0-12 were slightly higher in elderly women than elderly men. FAAH activity was inhibited in a dose-dependent manner, and plasma levels of anandamide, oleoylethanolamide, and palmitoylethanolamide increased in all dose groups after single and multiple doses of ASP3652. The incidence of adverse events after multiple doses, which ranged from 44.4% to 66.7%, was similar across all treatment groups, including the placebo group. IMPLICATIONS: Single and multiple doses of ASP3652 were well tolerated and increased endogenous cannabinoids.

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. METHODS: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). RESULTS: After single oral doses, maximum plasma concentrations (C max) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. CONCLUSION: Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

Expression of peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells is upregulated in cystic medial degeneration of annuloaortic ectasia in Marfan syndrome.

BACKGROUND: Cystic medial degeneration (CMD) is a histological abnormality that is common in annuloaortic ectasia (AAE) and aortic dissection with Marfan syndrome. Apoptosis and loss of vascular smooth muscle cells (VSMCs) is one of the features of CMD, but little is known about its pathogenesis. Peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor of the nuclear receptor superfamily, has been reported to show antiproliferative effects on VSMCs as well as anti-inflammatory effects on macrophages. PPARgamma agonist has been recently reported to induce apoptosis of cultured VSMCs. METHODS: We examined the histopathology of ascending aortas in AAE of Marfan patients (n=21) and control patients (n=6) at surgery. RT-PCR was performed to demonstrate expression of PPARgamma in CMD. Localization of PPARgamma was determined by double immunostaining using antibodies against PPARgamma and cell-specific markers (ie, SMCs, macrophages, and T lymphocytes). RESULTS: PPARgamma expression was upregulated in AAE samples but minimal in control samples by RT-PCR (P=0.07). Immunoreactivity against PPARgamma in numerous nuclei of VSMCs was observed in CMD lesions. Severity of CMD correlated with positive immunoreactivity of PPARgamma in medial VSMCs (P=0.03). No inflammatory cells (ie, macrophages or T lymphocytes) were detected in CMD lesions. CONCLUSION: PPARgamma expression is upregulated in SMCs of CMD without any inflammatory response. Activated PPARgamma in VSMCs might be involved in the pathogenesis of CMD in Marfan's aortas. Regulation of PPARgamma might lead to clinical implication in protection against progression of AAE.

The status of lipid management in 1,836 patients with coronary artery disease: a multicenter survey to evaluate the percentage of Japanese coronary artery disease patients achieving the target low-density lipoprotein cholesterol level specified by the Japan Atherosclerosis Society.

To determine the status of lipid management in patients with coronary artery disease (CAD) in Japan, we assessed CAD patients who had been receiving lipid-lowering therapy for six months in a cross-sectional survey conducted between June 2001 and December 2002. We defined the achievement rate as the percentage of patients who achieved the target LDL-C level (< 100 mg/dl) specified by the Japan Atherosclerosis Society (JAS). A total of 1,836 Japanese CAD patients were enrolled. In total, 549 (29.9%) achieved the target level. The achievement rate among those receiving statin therapy was 41.3%, which was significantly higher than that (23.4%) among the patients not receiving statin (P < 0.0001). The rate differed with the type of statin; being 54.7% for atorvastatin, 24.8% for pravastatin, 37.1% for simvastatin, and 27.8% for fluvastatin. A multiple regression analysis revealed that atorvastatin use (P < 0.001), and simvastatin use (P = 0.004) significantly contributed to the achievement of the target LDL-C level. In conclusion, large proportions of CAD patients are not achieving the JAS target and the success rates are not similar among different statin therapies, suggesting that cardiologists should consider a more aggressive lipid-lowering therapy with the appropriate choice of statins in Japanese CAD patients.

Therapeutic value of statins for vascular remodeling.

HMG-CoA reductase inhibitors (statins) are effective lipid-lowering drugs widely used in patients with dyslipidemia at risk of cardiovascular diseases. Primary and secondary prevention studies have revealed a significant reduction of risk for cardiovascular diseases. However, recent studies have demonstrated that statins have direct vascular effects (pleiotropic effects) independent of lipid-lowering action. Vascular remodeling, defined as changes in size and/or structure of adult vasculature, not only allows physiological adaptation and healing but also underlines the pathogenesis of major cardiovascular diseases. Vascular remodeling can be inward, occlusive, and outward. Various cardiovascular diseases probably represent a terminal phenotype of such vascular remodeling. In this review, we will focus on the basic actions and clinical implications of statin therapy to each type of vascular remodeling in response to various stimuli.

Accessory mitral valve tissue causing severe left ventricular outflow tract obstruction in an adult.

Accessory mitral valve (AMV) is a rare cause of left ventricular outflow tract (LVOT) obstruction and is extremely rare in adults. We report a case of an older adult with an AMV that caused severe LVOT obstruction. A parachute-like piece of tissue (the AMV) protruding into the LVOT during systole was first detected in a 45-year-old woman by echocardiography. Because the pressure gradient and dyspnea gradually progressed, she finally underwent a successful operation for removal when she was 48 years old.

First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers.

PURPOSE: TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. This was a first-in-human, phase 1 study that investigated the pharmacokinetics (PK) and safety of single-agent TAS-114 when it was given at single and multiple doses. METHODS: For the single-dose cohort (n = 25), healthy male volunteers received a single dose of TAS-114 at 6, 18, 60, 150, and 300 mg. The magnitude of dihydropyrimidine dehydrogenase (DPD) inhibition and the food effect on TAS-114 PK were also investigated. For the multiple-dose cohort (n = 10), subjects received TAS-114 for 14 days consecutively. RESULTS: In the dose-escalating single-dose cohort, the disposition of TAS-114 followed linear kinetics. The elimination half-life was approximately 2 h. The urine excretion rate and food effect were minimal. A significant increase in uracil Cmax was observed at administered doses of 150 mg or higher of TAS-114, suggesting that significant inhibition of DPD occurred at these doses. No apparent CYP3A4 auto-induction was observed in the multiple-dose cohort. No significant safety concerns at these dose levels were noted after single and multiple dosing. CONCLUSIONS: TAS-114 has shown both a favorable safety and pharmacokinetic profile after single and repeated doses. TAS-114 was considered to possess a moderate DPD inhibitory effect. These findings will facilitate clinical studies of the combination chemotherapies in cancer patients and may reduce the safety risk in the frail cancer patients.

Aldosterone blockade by Spironolactone improves the hypertensive vascular hypertrophy and remodeling in angiotensin II overproducing transgenic mice.

OBJECTIVES AND BACKGROUND: Recent evidence has revealed that aldosterone (ALDO) is produced in the vasculature, and acts directly in the cardiovascular system. This study was designed to examine the role of ALDO in the process of long-term renin-angiotensin system (RAS) induced vascular remodeling. MATERIAL AND METHOD: Hypertensive transgenic mice that overproduce angiotensin II (AngII), i.e., Tsukuba-Hypertensive-Mice (THM), were given tap water or 1% salt water and treated with or without Spironolactone (SPRL: 20mg/kg/day) for 4 weeks. We also employed A7r5 cells and investigated the effect of SPRL on the AngII mediated signal transduction in the vascular smooth muscle cells. RESULTS: Intimal hyperplasia, medial hypertrophy and degradation of medial elastic laminae were observed in the abdominal aorta, independent of blood pressure. Taking 1% salt water markedly enhanced these changes. In contrast, SPRL-treated THM showed almost complete disappearance of these intimal hyperplasia and medial hypertrophy. Osteopontin (OPN) was markedly up-regulated in the intima and media. However, it was inhibited by SPRL treatment in spite of high level of AngII. In A7r5 cells, AngII (10(-7)muM) induced OPN expression and pretreatment with MEK, PI3K, and EGFR inhibitor suppressed it. SPRL pretreatment also inhibited AngII-induced ERK and AKT phosphorylation, and resulted in the suppression of AngII-induced OPN expression. CONCLUSIONS: ALDO blockade by SPRL restores the vascular remodeling caused by the long-term RAS enhancement even in the high level of AngII, independent of blood pressure. Blocking AngII alone may not be sufficient, and direct ALDO blockade is also important to prevent vascular disease.

Improvement of cardiac function and neurological remodeling in a patient with tachycardia-induced cardiomyopathy after catheter ablation.

Incessant ventricular tachycardia and long-standing ectopic beats lead to tachycardia-induced cardiomyopathy. Catheter ablation eliminates ventricular tachycardia and reverses left ventricular (LV) dysfunction. 201-Thallium ((201)Tl) scintigraphy demonstrates perfusion defects with ischemic cardiomyopathy. Reversible perfusion defects are observed even in non-ischemic cardiomyopathy, related to regional flow or metabolism derangements. 123-I-metaiodobezylguanidine ((123)I-MIBG) scintigraphy delineates regional cardiac sympathetic denervation and heterogeneity. We demonstrated the progression of tachycardia-induced cardiomyopathy in a patient with idiopathic LV outflow tract tachycardia using (201)Tl and (123)I-MIBG scintigraphic findings. Regional defects were reversed predominantly in the basal interventricular septal wall in (201)Tl scintigraphy and (123)I-MIBG scintigraphic findings. This report suggests that incessant ventricular tachycardia or long-standing ventricular ectopic beats may develop adverse myocardial remodeling and sympathetic neurological remodeling. Treatment with catheter ablation for tachycardia-induced cardiomyopathy can reverse sympathetic neurological remodeling as well as myocardial structural remodeling.

Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects.

AIMS: HMG-CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol-lowering effect. METHODS: We investigated the effect of a single dose of cerivastatin on vascular endothelial function by measuring flow-mediated dilatation of the brachial artery on ultrasound in 30 healthy volunteers with normal serum cholesterol concentrations. They were randomized to either placebo group (n = 15) or cerivastatin group (n = 15), and flow-mediated dilatation and endothelium-dependent dilatation were evaluated at before and 1 h, 3 h, 6 h, and 12 h after administration of placebo or cerivastatin. RESULTS: There were no differences in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, malondialdehyde-LDL, and high-sensitivity C-reactive protein before and after administration of placebo or cerivastatin. Cerivastatin significantly increased flow-mediated dilatation at 3 h (P < 0.001), and this increase rapidly returned to the baseline level 6 h after administration. Endothelium--independent dilatation of brachial artery was not altered. CONCLUSIONS: A single dose of cerivastatin increased vascular endothelial responsiveness. Our data suggest that cerivastatin has a direct effect on the blood vessels that is independent of its lipid-lowering effect, and thus can be considered as a vascular statin.

An angiotensin-converting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats.

OBJECTIVE: Cystic medial degeneration (CMD) is a histologic abnormality that is common in aortic diseases such as aortic dilation, aneurysm, or dissection. Although little is known about the mechanism underlying CMD, we have previously demonstrated that angiotensin II signaling via angiotensin II type 2 receptor (AT2R) plays a central role in apoptosis of vascular smooth muscle cells (VSMCs) occurring in CMD associated with Marfan syndrome. The aim of this study is to elucidate the role of angiotensin II signaling in THE pathogenesis of aortic diseases associated with CMD. METHOD: We investigated the effects of angiotensin-converting enzyme inhibitor (ACEI), temocapril (n = 15), angiotensin II receptor type-1 (AT1R) blocker, CS-866 (n = 15), and vehicle control (n = 17) on 0.25% beta-aminopropionitrile monofumarate (BAPN)-induced aortic dissection and histopathologic findings in a rat model. RESULTS: Temocapril significantly prevented aortic dissection (P <.05), CMD (P <.01), and VSMC apoptosis (P <.01) compared with vehicle control in BAPN-fed rats. However, CS-866 did not show any preventive effect. Reversed transcriptase-polymerase chain reaction demonstrated that expression of both AT1R and AT2R was detected in control rat aortas, and that AT2R expression was significantly upregulated in the aortas of BAPN-fed rats (P <.01). Blood pressure was significantly and equally lowered in both temocapril and CS-866 groups compared with control. CONCLUSIONS: Differential expression of angiotensin II receptors and AT2R signaling are involved in the pathogenesis of CMD and aortic dissection in BAPN-fed rats. ACEIs might be of clinical value for the prevention and treatment of aortic diseases related to CMD.

A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall.

AIM: Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs. METHODS: We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture. RESULTS: Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 micromol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner (P <.001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling. CONCLUSION: These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA.