A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Association between dry eye and periodontal disease in community-dwelling Japanese adults: data from the Uonoma cohort study.

BACKGROUND: While research has explored the risk of periodontal disease in various eye conditions, the link between dry eye and periodontal disease remains underexplored, especially in Japanese adults. This study aims to investigate the association between dry eye and periodontal disease in community-dwelling Japanese adults. METHODS: This study is a subset of the Uonuma cohort study, which includes Japanese adults aged 40 years and older residing in the Uonuma area of Niigata Prefecture, Japan. Participants completed a self-administered, paper-based questionnaire. Statistical analyses, including the chi-square test, independent t test, ANOVA test, and logistic regressions, were employed to assess the association of periodontal disease with independent variables. RESULTS: Among 36,488 participants (average age 63.3 years, 47.4% men), 39.3% had a history of periodontal disease, and gender differences were statistically significant (p < 0.001). Significant associations were found between periodontal disease and dry eye diagnosis or symptoms. Univariable logistic regression revealed links between periodontal disease and age, gender, living status, alcohol consumption, remaining teeth, bite molar availability, and history of dry eye disease or symptoms. Multiple-adjusted regression found that doctor-diagnosed dry eye was associated with a higher likelihood of periodontal disease (odds ratio, 1.12; 95% confidence interval, 1.03-1.22). Participants who never experienced dryness or foreign body sensation had lower ORs of periodontal disease than those who always experienced such symptoms across all models. CONCLUSION: A significant correlation was found between dry eye and periodontal disease in Japanese adults. Regular check-ups, early detection, and effective management of both conditions are strongly recommended.

Associations between Plasma Antibody Levels against Porphyromonas gingivalis and Atrial Fibrillation among Community-Dwelling Older Individuals in Japan: A Cross-Sectional Study.

PURPOSE: To investigate the association between plasma antibody levels against Porphyromonas gingivalis (PG) and atrial fibrillation (AF) history in community-dwelling older individuals in Japan. MATERIALS AND METHODS: This study was a subset of the Uonuma cohort study, including 3091 participants aged 60-79 years. Data were collected, including AF history as a dependent variable, plasma immunoglobulin G antibody levels against PG as an independent variable, and previously reported AF risk factors and demographic information as covariates. RESULTS: The median age of the participants was 69 years. Of the 3091 participants, 1411 (45.6%) were men, and 56 (1.8%) had an AF history. AF prevalence was significantly higher in participants with higher antibody levels against PG than in those with lower antibody levels (3.0% vs 1.4%; p = 0.005). Multivariable logistic regression analysis showed that participants with higher antibody levels against PG had twofold higher odds of having AF (odds ratio = 2.13; 95% confidence interval = 1.23-3.69). Restricted cubic spline analysis indicated a nonlinear relationship between antibody levels against PG and AF history. CONCLUSION: Plasma antibody levels against PG were associated with AF history in community-dwelling older individuals in Japan.

Characteristics of medication-induced xerostomia and effect of treatment.

OBJECTIVE: Side-effects of medications cause xerostomia. There have been cases where a medication has been discontinued owing to its severe side-effects. Therefore, the xerostomia must be treated to ensure that the primary disease is managed effectively. This study analyzed the actual status of patients with medication-induced xerostomia and investigates factors associated with its improvement. METHODS: This study assessed 490 patients diagnosed with medication-induced xerostomia who had an unstimulated salivary flow of ≤0.1 mL/min and received treatment for xerostomia at a xerostomia clinic. Patient age, sex, medical history, medications used, disease duration of xerostomia, and psychological disorders were recorded. The anticholinergic burden was assessed using the Anticholinergic Cognitive Burden scale. The unstimulated salivary flow was measured by the spitting method. According to their symptoms and diagnoses, the patients were introduced to oral lubricants, instructed on how to perform massage, and prescribed Japanese herbal medicines, and sialogogues. Factors associated with the subjective improvement of xerostomia and objective changes in the salivary flow rate were recorded at six months. RESULTS: Xerostomia improved in 338 patients (75.3%). The improvement rate was significantly lower in patients with psychiatric disorders (63.6%) (P = 0.009). The improvement rate decreased as more anticholinergics were used (P = 0.018). However, xerostomia improved in approximately 60% of patients receiving three or more anticholinergics. The unstimulated salivary flow increased significantly more in patients who reported an improvement of xerostomia (0.033±0.053 mL/min) than in those who reported no improvement (0.013±0.02 mL/min) (P = 0.025). CONCLUSION: Xerostomia treatment improved oral dryness in 75.3% of patients receiving xerogenic medications in this study. If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the quality of life of patients with xerogenic medications and may reduce the number of patients who discontinue medications.

Clinical and Microbial Evaluation of Dental Caries Status and Associated Factors Among Primary Schoolchildren in Myanmar: A Cross-Sectional Study.

The study aimed to investigate the prevalence and associated factors of dental caries on primary teeth and to evaluate the cariogenic bacteria in dental plaque and saliva among Myanmar schoolchildren. A cross-sectional study was undertaken among 264 schoolchildren from three primary schools in the urban area of Yangon city in 2019. Clinical oral examinations, caries risk tests, and questionnaire surveys were conducted. Overall caries prevalence was 84.1% with a mean decayed, missing, filled primary teeth (dmft) count of 5.84 ± 4.57. Children's caries experience and debris scores were significantly associated with their bacteria score level. Father's occupation was significantly associated with caries prevalence (P = .024) and dmft (P = .021). Father's occupation, snack types, habit of eating sweet food combinations, drink types, and debris score were five significant predictors of dental caries in our study. Dental caries is currently a public health problem among Myanmar children. Caries experience and oral hygiene status were strongly influenced by cariogenic bacteria.

Effects of Interval Walking Training on Oral Health Status in Middle-Aged and Older Adults: A Case-Control Study.

The purpose of this study was to determine the effect of walking training "Interval Walking Training (IWT)" on oral health status. Participants were divided into two groups: an exercise intervention group and a non-intervention group (control). The intervention group consisted of 59 subjects (20 males, 39 females) aged 50 years or older who participated in the IWT program in Matsumoto from 2019 to April 2022. The control group consisted of 33 subjects (14 males and 19 females) aged 50 years or older who have visited Niigata University Medical and Dental Hospital and agreed to participate in the study. The intervention group underwent walking training (interval walking training) for at least 5-6 months. The walking training consisted of five sets of fast walking above 70% peak aerobic capacity for walking (VO2peak) for 3 min, followed by 3 min of slow walking at ~40% VO2 peak per day for more than four days/week. The oral health status was evaluated for the number of teeth, occlusal force, salivary occult blood, masticatory performance, and tongue pressure. A total of 57 participants were analyzed in the intervention group (18 males and 39 females, age: 66.7 ± 0.8 (mean ± S.E.) years) and 33 participants in the control group (14 males and 19 females, age: 74.5 ± 1.1 (mean ± S.E.) years). There were no significant differences in gender, salivary occult blood, tongue pressure, masticatory performance, or occlusal force between the two groups at the start of the intervention (p = 0.36, p = 0.48, p = 0.42, p = 0.58, and p = 0.08, respectively by unpaired t-test or χ2 test). On the other hand, there were significant differences in age and BMI, with a trend toward lower age and higher BMI in the intervention group (p < 0.001 and p < 0.001, respectively, by unpaired t-test). In terms of rate of change, the intervention group showed a significant increase in occlusal force (F = 4.5, p = 0.04, ANCOVA) and a significant decrease in BMI (F = 7.3, p = 0.009, ANCOVA). No significant differences were observed in the other measured items. It was found that walking training in both middle-aged and older people does not only affect the physical aspect of weight loss but may help maintain and improve the occlusal force.

Anti-caries and Anti-microbial Effects of School-based Fluoride Programs in Myanmar Schoolchildren.

PURPOSE: To investigate the anti-caries effects of the school-based fluoride varnish (FV) application at 3-month intervals and ?weekly fluoride mouthrins?ing? (FMR) ?on primary teeth and to evaluate the anti-microbial effects of FV or FMR on cariogenic bacteria among Myanmar children. MATERIALS AND METHODS: A 6-month interventional study was conducted on 234 schoolchildren who were divided into three groups: group A received FV application at 3-month intervals, group B received weekly FMR,? and group C received no fluoride application. A clinical oral examination and caries risk tests were performed at baseline and the 6-month follow-up. RESULTS: Caries prevalence and ?the debris score did not change statistically significantly from baseline to the 6-month follow-up in all groups, whereas the dmfs score statistically significantly increased in group C (p = 0.001). The plaque and saliva scores of Dentocult SM statistically significantly decreased in group A (p = 0.049 and p = 0.006), but those scores statistically significantly increased in group C (p = 0.001 and p = 0.014) after six months. On the other hand, no statistically significant changes were observed in group B. Although the Cariostat scores decreased from baseline to the 6-month follow-up in group A and group B, but increased in group C, no statistically significant differences were observed in any of the groups. CONCLUSION: Better anti-microbial effects were obtained for children who received FV application than for those who received FMR, but no statistically significant difference existed between the anti-caries effects of these two approaches.

Interaction between and impact of IL-6 genotype and alpha-tocopherol levels on periodontal condition in aging individuals.

BACKGROUND AND OBJECTIVES: Few studies have assessed the possible interaction between and impact of IL-6 variants and serum α-tocopherol levels on periodontal condition in older individuals. Here, we assessed the relationship between IL-6 variants and serum α-tocopherol levels on periodontal condition by considering effect modification. MATERIAL AND METHODS: Among the study participants, 359 who were 71 years of age underwent a dental examination, biochemical analysis, and interview. After dividing the participants into tertiles based on serum α-tocopherol levels, we conducted Poisson regression analysis to compare the prevalence rate ratio (PRR) for periodontal disease markers with the IL-6 genotype (rs1800796) based on each tertile adjusted by the number of teeth present (offset). RESULTS: The PRRs of the IL-6 genotype for periodontal condition (probing pocket depth [PPD], clinical attachment level [CAL], and bleeding on probing [BOP]) which were adjusted by the number of teeth present (offset) were 1.17 (P < .001), 1.37 (P < .001), and 1.08 (P = .048), respectively. In addition, a significant association was found between the reciprocal number of PRRs of the IL-6 genotype and three serum α-tocopherol levels. The adjusted PRRs (± standard error) of the IL-6 genotypes for PPD were 0.48 (0.12) for the first group (P < .001), 1.54 (0.04) for the second group (P < .001), and 2.11 (0.03) for the third group (P < .001); similar tendencies were seen for CAL and BOP. CONCLUSION: The results of this study suggest a potential association between the IL-6 genotype and periodontal condition in relation to serum antioxidant concentrations.

Radiological imaging features of the salivary glands in xerostomia induced by an immune checkpoint inhibitor.

The clinical features of xerostomia induced by immune checkpoint inhibitors (ICI) are similar to those of Sjögren's syndrome (SS), whereas the immunohistological and serological features are known to differ from those of SS. However, the radiologic imaging features of salivary glands are not yet well known. We report a case of a 56-year-old male patient diagnosed with ICI-induced xerostomia. The patient underwent various imaging examinations to investigate the condition of the salivary glands, which indicated the following: (1) less specific findings on contrast-enhanced computed tomography, (2) mixed with intermediate and low signal intensity on both T1-weighted and fat-suppressed T2-weighted magnetic resonance imaging and poor "salt and pepper" appearance on magnetic resonance sialography, and (3) multiple ovoid hypoechoic areas with hyperechoic bands without acute sialadenitis on ultrasound. These radiologic imaging findings suggested remarkable lymphocyte infiltration, which could be a characteristic of ICI-induced xerostomia.

Interaction between beta-3 adrenergic receptor genotype and environmental factors on periodontal progression.

OBJECTIVES: The purpose of this longitudinal study was to evaluate the relationship between beta-3 adrenergic receptor polymorphism and environmental factors such as smoking on periodontal disease by considering effect modification. MATERIALS AND METHODS: A total of 294 subjects who participated in all follow-up surveys over the 6-year study period were analysed. After dividing subjects into tertiles according to the number of years exposed to smoking, we conducted Poisson regression analysis to compare the incidence rate ratio (IRR) for periodontal disease events during the 6-year study period with beta-3 adrenergic receptor genotype (1: Arg allele carriers, 2: Arg allele non-carriers) for each tertile adjusted for other four variables. RESULTS: The number of years exposed to smoking (mean ± standard deviation) for the 1st, 2nd and 3rd tertiles was 0 ± 0, 20.1 ± 9.1 and 45.3 ± 7.7 years, respectively. The IRRs ± SE were 0.89 ± 0.08 (p = 0.218) for the 1st tertile, 1.93 ± 0.36 (p < 0.001) for the 2nd tertile and 2.56 ± 0.23 (p < 0.001) for the 3rd tertile. CONCLUSION: There was a clear dose-response relationship between beta-3 adrenergic receptor genotype and periodontal disease progression based on the number of years exposed to smoking.

Relationship between vitamin D receptor gene polymorphism and susceptibility to chronic kidney disease and periodontal disease in community-dwelling elderly.

OBJECTIVES: The aim of this study was to investigate the possible correlation between vitamin D receptor (VDR) gene polymorphism and susceptibility to chronic kidney disease (CKD) and periodontal disease. MATERIAL AND METHODS: This study analysed 345 participants, who were all 79 years of age. Kidney function levels were determined based on the estimated glomerular filtration rate (eGFR; non-reduced function: ≥60 and reduced function: <60 ml min-1  1.73 m-2 ). VDR TaqI genotyping was also studied. We calculated the periodontal inflamed surface area (PISA). After classifying participants into quartile groups according to eGFR or PISA values, the subjects were then split into two groups (highest quartile versus the other three groups combined). Multiple logistic regression analysis was performed to evaluate the odds ratios between the eGFR and VDR TaqI genotype with the different PISA groups. The eGFR was set as the dependent variable while the VDR TaqI genotype, HbA1C, gender, smoking habits and body mass index were defined as independent variables. RESULTS: A significant association was observed between the VDR TaqI genotype and eGFR in the PISA high group (odds ratio = 3.97, p = .027). CONCLUSION: Study results suggest that VDR TaqI genotype might be associated with CKD during inflammatory conditions caused by periodontal disease.

Factors associated with mucosal dryness in multiple regions and skin: A web-based study in women.

AIM: We hypothesized that feeling mucosal dryness in one body region and the skin may be associated with dryness in other regions and that there are common background factors for dryness. In an earlier web-based survey, we reported prevalence figures of dry eyes, nose, mouth, skin, and vagina. In the present study, additional analyses were made to investigate the factors associated with dryness in each region, and simultaneous dryness in multiple regions. METHODS: A web-based questionnaire was completed by 310 Japanese women. The questions included dryness of the eyes, nose, mouth, vagina, and skin. Menopausal and other symptoms were also addressed. Multiple logistic regression modeling was performed to identify factors associated with dryness in each region and in multiple dry regions. RESULTS: Dry eyes were associated with dryness in the nose and with headache; dry nose was associated with dryness in the vagina and eyes; dry mouth was associated with sticky mouth symptom and dryness of the nose; dry skin was associated with use of xerogenic medications and vaginal discharge; and dryness of the vagina was associated with vaginal itchiness and dry nose. Vaginal discharge (odds ratio, 9.64; 95% confidence interval, 3.15-29.51) and sticky mouth (odds ratio, 6.35; 95% confidence interval, 1.29-31.29) were further associated with dryness in multiple regions. CONCLUSION: The present results confirmed our study hypothesis by showing that dryness in one region was clearly associated with that in another or in multiple regions. The result implies the need for holistic diagnosis and counseling for patients with dryness complaints.

Serum antibody to Porphyromonas gingivalis in metabolic syndrome among an older Japanese population.

BACKGROUND AND OBJECTIVE: Potentially significant associations between metabolic syndrome (MetS) and periodontal disease have been reported in recent studies; however, there is a dearth of literature regarding the relationship of MetS with serum antibody levels to periodontal pathogens. The aim of this cross-sectional study was to investigate the association between MetS and serum antibody to the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) in 216 Japanese individuals aged 79 years. MATERIALS AND METHODS: Serum antibody levels to P. gingivalis were measured by enzyme-linked immunosorbent assay. An elevated serum antibody response was defined as the upper quartile and was considered as the outcome variable. A multivariable logistic regression model was used to evaluate the association of MetS defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria with an elevated antibody status. Adjustments for gender, income, education, smoking status, dental-care utilisation patterns and brushing frequency were considered. RESULTS: The prevalence of MetS was 22.2% (n = 48). Study participants with MetS were 2.9 times more likely to have an elevated serum antibody to P. gingivalis (adjusted odds ratio = 2.91, 95% confidence interval = 1.24-6.85) after simultaneous adjustment for other covariates. CONCLUSION: Our findings suggest an independent relationship between MetS and serum antibody levels to P. gingivalis in the Japanese elderly. Additional longitudinal epidemiologic studies with larger, more diversified samples and more complete information are needed to substantiate our findings.

Protective effect of K201 on isoproterenol-induced and ischemic-reperfusion-induced ventricular arrhythmias in the rat: comparison with diltiazem.

AIM: Ventricular arrhythmia (VA) is a risk for sudden death. Polymorphic ventricular tachycardia (VT) degenerating to ventricular fibrillation occurs subsequent to the prolongation of the QT interval following administration of catecholamines under Ca(2+) loading. Fatal VA also occurs in ischemia and ischemic-reperfusion. We compared the suppressive effect of K201 (JTV519), a multiple-channel blocker and cardiac ryanodine receptor-calcium release channel (RyR2) stabilizer, with that of diltiazem, a Ca(2+ )channel blocker, in 2 studies of isoproterenol-induced (n = 30) and ischemic-reperfusion-induced VAs (n = 38) in rats. METHODS: Adult male Wistar rats were administered 12 mg/kg/min calcium chloride (CaCl(2)) for 20 minutes and then 6 µg/kg/min isoproterenol was infused with CaCl(2) for a further 20 minutes. In other rats, the left coronary artery was ligated for 5 minutes followed by reperfusion for 20 minutes. K201 or diltiazem (both 1 mg/kg) was administered before infusion of the isoproterenol or induction of ischemia. RESULTS: After administration of isoproterenol under Ca(2+) loading, fatal VA frequently occurred in the vehicle (9 of 10 animals, 90%) and diltiazem (8 of 10, 80%) groups, and K201 significantly suppressed the incidences of arrhythmia and mortality (2 of 10, 20%). In the reperfusion study, the incidence and the time until occurrence of reperfusion-induced VA and mortality were significantly suppressed in the K201 (2 of 15 animals, 13%) and diltiazem (1 of 9 animals, 11%) groups compared to the vehicle group (8 of 14 animals, 57%). SIGNIFICANCE: Induction of VA in an experimental model was achieved with a low dose of isoproterenol under Ca(2+) loading. K201 markedly suppressed both the isoproterenol-induced and the reperfusion-induced VAs, whereas diltiazem did not suppress the isoproterenol-induced VA. The results suggest that both VAs are related to early after depolarization (EAD) and indicate that K201 has the potential to suppress EAD by stabilizing RyR2 to mediate Ca(2+) release from the sarcoplasmic reticulum and acting as a multiple-channel blocker.

Association between glucan synthesis by streptococcus mutans and caries incidence in schoolchildren receiving a fluoride mouth rinse.

PURPOSE: To determine whether variation in glucan synthesis by Streptococcus mutans isolates is associated with caries development in children receiving a fluoride mouth rinse (FMR). MATERIALS AND METHODS: Of 122 children (aged 9 to 10 years), 64 had received FMR (FMR(+) group) and the remaining 58 children had not (FMR(-) group). The number of decayed and filled teeth (DFT) and increases in the number of DFT in 1 year (dDFT) were recorded. Saliva samples were collected to isolate the clinical S. mutans strains. The isolates were incubated in heart infusion broth supplemented with 1% sucrose, then the amount of water-insoluble glucan (WIG) formed on a glass tube surface was evaluated. RESULTS: In the FMR(-) group, children carrying S. mutans had a higher DFT (P = 0.039) and tended to have a higher dDFT (P = 0.080) than the others. In the FMR(+) group, although the differences between children with and without S. mutans were not significant, children carrying S. mutans that produced a high amount of WIG had higher dDFT than the other S. mutans-positive children (P = 0.034). CONCLUSIONS: This study revealed that the variation in glucan synthesis by S. mutans is associated with caries development in children receiving a FMR.

Three-dimensional reconstruction of the human capillary network and the intramyocardial micronecrosis.

Three-dimensional reconstruction of the human heart was performed to define the structure of the intramyocardial microvasculature. A total of 200 consecutive serial sections of 6 µm each were prepared from the left ventricular tissue of an autopsied human heart with normal coronary arteries. The corresponding arteriole, venule, and all capillaries were reconstructed using three-dimensional software. The capillary network extended right and left along the cardiomyocyte with major and minor axes of about 130 and 120 µm, respectively. The capillary length from an arteriole to an adjacent venule was about 350 µm. Two types of sack-like structures, the precapillary sinus and the capillary sinus, were present in the capillary network, and many capillaries diverged from these sinuses. The cardiomyocytes were covered with reticular capillaries. In contrast, the precapillary and capillary sinuses were surrounded by many cardiomyocytes. The arterial and venous capillaries were positioned alternately, forming a lattice pattern. Intramyocardial microcirculatory units forming a capillary network from an arteriole to adjacent venules on both sides were present. The sizes of myocardial micronecroses corresponded to that of the intramyocardial microcirculatory unit. These results show that the capillary network is an ordered and anatomically regulated structure and that the microcirculatory unit and the precapillary and capillary sinuses may play an important role in maintaining the intramyocardial microcirculation during contraction and relaxation.

K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum.

In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 microM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 microM; developed tension -9.8 +/- 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 microM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 microM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 +/- 0.06, K201 1.01 +/- 0.03, P < 0.01). In addition at high [Ca2+]e) K201 (0.3 microM) treatment significantly improved systolic function [developed tension +27 +/- 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201.

Early effect of lipid-lowering therapy with pitavastatin on regression of coronary atherosclerotic plaque. Comparison with atorvastatin.

BACKGROUND: Virtual histology intravascular ultrasound (VH-IVUS) is used to diagnose coronary plaques and evaluate statin therapy. However, in most cases, quantitative changes in plaques have been evaluated in the chronic stage. We evaluated the quantitative and qualitative early effects of 2 statins on coronary lesions using VH-IVUS. METHODS AND RESULTS: Patients with acute coronary syndrome who underwent emergency percutaneous coronary intervention (PCI) were randomly assigned to receive pitavastatin (n=80; 2 mg/day) or atorvastatin (n=80; 10 mg/day) immediately after PCI. All patients underwent a blood lipid test and VH-IVUS evaluation of non-PCI lesions at admission and after 2-3 weeks of statin administration. After treatment, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) showed significant decreases to similar levels in each group (P<0.001). In the pitavastatin group, the plaque volume index and fibrofatty volume index (FFVI) also decreased significantly. In patients from the pitavastatin group with a dense calcium ratio of < or =10% (n=61), the percentage changes in FFVI and LDL-C were correlated positively (r=0.305, P=0.017), whereas no significant changes were found after treatment in the atorvastatin group. CONCLUSIONS: Fibrofatty composition and plaque volume decreased significantly following treatment with pitavastatin, which suggests that pitavastatin might have a higher affinity for fibrofat compared with atorvastatin.

Pharmacological characteristics and clinical applications of K201.

K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a non-specific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca(2+) release from the sarcoplasmic reticulum, suppression of spontaneous Ca(2+) sparks and Ca(2+) waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.