Oral Administration of PLGA Nanoparticles to Deliver Antisense Oligonucleotides to Inflammatory Lesions in the Gastrointestinal Tract.

In this study, we prepared antisense oligonucleotide (ASO)-encapsulated nanoparticles (NPs) with a suitable profile for oral administration for the treatment of inflammatory bowel disease (IBD). We chose a water-in-oil-in-water (w/o/w) method to prepare the NPs using poly(lactide-co-glycolide) as a matrix and Pluronic as a stabilizer. The obtained NPs had a suitable diameter (158 nm) for the penetration of the mucus layer, endocytic uptake by enterocytes, and accumulation in inflammatory lesions in the intestine. The amount of ASOs in the NPs was relatively large (6.41% (w/w)). When the NPs were stably dispersed in solutions that mimicked gastrointestinal (GI) juice, minimal leakage of ASOs was demonstrated over the required period. The NPs were administered orally to mice with colitis induced by dextran sodium sulfate, which reduced target gene expression in the colons and rectums of the mice, whereas naked ASO administration caused no reduction in gene expression. Thus, the NPs have the potential of promising oral carriers of ASOs for the treatment of IBD that specifically target inflammatory lesions in the GI tract, thereby reducing the non-specific toxic effects of ASOs.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Differences in mitral valve geometry between atrial and ventricular functional mitral regurgitation in patients with atrial fibrillation: a 3D transoesophageal echocardiography study.

AIMS: This study investigated geometric differences in mitral valve apparatus between atrial functional mitral regurgitation (A-FMR) and functional mitral regurgitation (FMR) with left ventricular (LV) dysfunction in patients with atrial fibrillation (AF) using 3D transoesophageal echocardiography (TOE). METHODS AND RESULTS: In total, 135 moderate or greater FMR patients with persistent AF or atrial flutter underwent 3D TOE. Fifty-six patients had A-FMR, defined as preserved LV ejection fraction (LVEF) of ≥50% and normal LV wall motion. Seventy-nine patients had ventricular FMR (V-FMR), defined as LV dysfunction (LVEF of <50%) or LV wall motion abnormality. To evaluate mitral leaflet coaptation, the coapted area was calculated as follows: total leaflet area (TLA) in end-diastole - closed leaflet area in mid-systole. Although annular area (AA) did not significantly differ between the two groups, TLA was significantly smaller in A-FMR than in V-FMR (P = 0.005). TLA/AA, indicating the degree of the leaflet remodelling, was significantly smaller in A-FMR than in V-FMR (P < 0.001). A-FMR had significantly smaller posterior mitral leaflet tethering height and angle measured at three anteroposterior planes (lateral, central, and medial) than V-FMR (all P < 0.001). However, vena contracta width (VCW) measured on long-axis view on TOE and coapted area, which correlated with VCW (r = -0.464, P < 0.001), were similar between the two groups. CONCLUSION: Mitral leaflet remodelling may be less in A-FMR compared with V-FMR. However, leaflet tethering was smaller in A-FMR than in V-FMR, and this may result in a similar degree of mitral leaflet coaptation and mitral regurgitation severity.

Impact of New Grading System and New Hemodynamic Classification on Long-Term Outcome in Patients With Severe Tricuspid Regurgitation.

BACKGROUND: A new grading of tricuspid regurgitation (TR) beyond severe has been proposed. However, few studies assessing the validity of such a new grading scheme of TR have been conducted. Therefore, we evaluated associations of TR grades beyond severe with patient outcome and hemodynamics. METHODS: We retrospectively studied patients who underwent 2-dimensional echocardiography and were diagnosed with severe TR between January 2014 and December 2015. According to the vena contracta width of TR (VC), the patients were classified into 2 groups: VC under 14 mm (VC<14 mm) and VC 14 mm or greater (VC≥14 mm). Hemodynamic parameters were estimated by echocardiography and were obtained by right heart catheterization. Cardiovascular events were defined as cardiovascular death or admission for heart failure. RESULTS: A total of 679 patients (mean 72±17 years, 56% women) were included. During follow-up (median, 158 days; range, 29-891), 210 patients experienced cardiovascular events. By multivariate analysis, VC≥14 mm and left ventricular ejection fraction were independent predictors of cardiovascular events (hazard ratio, 1.57 [1.06-2.33]; hazard ratio, 0.99 [0.98-0.99], respectively). Patients with VC≥14 mm had significantly lower cardiac index (median, 1.8 versus 2.1 L/min per m2, P=0.001) and a higher prevalence of right atrial pressure 15 mm Hg (74% versus 60%, P<0.001) on echocardiography. Also, right heart catheterization confirmed higher right atrial pressure in patients with VC≥14 mm than those with VC<14 mm (16±8 versus 12±6 mm Hg, P=0.004). The new subset classification developed by cardiac index and right atrial pressure both on echocardiography predicted cardiovascular events (Log-rank P<0.001). CONCLUSIONS: The relationship of VC≥14 mm to adverse outcome and poor hemodynamics showed the clinical relevance and need of a new grading system beyond severe. The new hemodynamic subset classification provides additional prognostic value for cardiovascular events in patients with severe TR.

Characteristics and Prognostic Associations of Echocardiographic Pulmonary Hypertension With Normal Left Ventricular Systolic Function in Patients ≥90 Years of Age.

The high prevalence of pulmonary hypertension (PH) in elderly patients is well known. However, much remains unknown about those population. We sought to find the clinical characteristics of echocardiographic PH and the prognostic factors in patients ≥90 years of age. We retrospectively reviewed 310 patients ≥90 years of age (median age 92 years, 64% women) diagnosed as echocardiographic PH (peak systolic pulmonary arterial pressure ≥40 mm Hg) with normal left ventricular systolic function. We defined left heart disease (LHD) as significant left-sided valve diseases, left ventricular hypertrophy and left ventricular diastolic dysfunction by using echocardiography. The endpoint was all-cause death at 2,000 days after diagnosis. LHD was found in 92% of patients. During the median follow-up of 367 days (interquartile range, 39-1,028 days), 151 all-cause deaths (49%) occurred. Multivariable Cox regression analysis demonstrated that right ventricular fraction area change <35% (adjusted hazard ratio [HR]: 2.31; p <0.001), pericardial effusion (adjusted HR: 2.28; p <0.001), serum albumin <3.5 g/dL (adjusted HR: 1.76; p = 0.001), chronic obstructive pulmonary disease (adjusted HR: 1.93; p = 0.001) and New York Heart Association (NYHA) class ≥II (adjusted HR: 1.73; p = 0.004) were associated with mortality after adjusted for age. In conclusion, LHD was significantly associated with echocardiographic PH in most patients ≥90 years of age. Also, the co-morbid factors at diagnosis (right ventricular systolic dysfunction, pericardial effusion, hypoalbuminemia, chronic obstructive pulmonary disease, and NYHA class ≥II) were independently associated with mortality.

Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors.

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Altered central aortic elastic properties in Kawasaki disease are related to changes in left ventricular geometry and coronary artery aneurysm formation.

BACKGROUND: Recent evidence has suggested that patients display altered arterial elasticity after Kawasaki disease (KD). However, changes in the elastic properties of the central aorta and their relevance to left ventricular geometry have not been studied in patients after KD with and without coronary artery aneurysms (CAAs). METHODS: Clinical and laboratory characteristics of 75 patients with KD were compared with those of 57 controls. The patients with KD included 17 patients with CAAs and 58 patients without CAAs. Values for aortic stiffness index, aortic distensibility, aortic strain, and left ventricular mass index (LVMI) were retrospectively obtained from echocardiographic measurements of the ascending aorta and left ventricle with noninvasive blood pressure evaluation. RESULTS: Systolic blood pressure, pulse pressure, LVMI, and aortic stiffness index were significantly higher and aortic distensibility and aortic strain significantly lower in patients with KD than in the controls. In patients with KD, age at the time of study, interval between the onset of KD and the initiation of this study, CAAs, and LVMI were significantly associated with aortic stiffness index, aortic distensibility, and aortic strain. Multivariate analysis revealed that CAAs and LVMI were independently relevant to aortic stiffness index and aortic distensibility. CONCLUSIONS: The central aortas of patients after KD have altered elastic properties. CAAs and LVMI are independently correlated with central aortic elasticity.

Long-term administration of beraprost sodium for pulmonary arterial hypertension associated with congenital heart disease.

Pulmonary arterial hypertension (PAH) is often associated with congenital heart disease (CHD). Acute administration of beraprost reduces pulmonary vascular resistance in patients with idiopathic PAH and PAH associated with CHD; however, little is known about whether or not long-term treatment with oral beraprost benefits these patients. We report the case of a patient suffering from severe PAH associated with large patent ductus arteriosus (PDA), who was considered to be ineligible for PDA closure using a conventional treatment strategy. Eventually, long-term administration of oral beraprost ameliorated the degree of PAH and the patient subsequently underwent successful closure of the PDA.

Route of penetration of topically instilled nipradilol into the ipsilateral posterior retina.

PURPOSE: To investigate how topically instilled nipradilol penetrates the ipsilateral posterior retina-choroid in normal rabbit eyes. METHODS: Albino rabbits were used. Topical instillation (1%, 100 microL) or intracameral (0.1%, 100 microL) or sub-Tenon injection (0.1%, 10 microL) of [(14)C]nipradilol was performed in one eye. Ocular and periocular distribution and the concentrations of [(14)C]nipradilol were determined by whole-head autoradiography, the results of which were validated by measurements in isolated tissues. In addition, the unchanged form of nonradiolabeled nipradilol in the posterior retina after topical instillation (1%, 100 microL) was quantified by liquid chromatography-tandem mass spectrometry (LC/MS/MS). RESULTS: Autoradiography revealed that the nipradilol concentration after topical instillation was higher in the ipsilateral posterior retina-choroid than on the contralateral side (142.9 ng/g vs. 108.3 ng/g, P = 0.026), and in the periocular tissue around the optic nerve insertion on the ipsilateral side than on the contralateral side (207.1 ng/g vs. 141.1 ng/g, P < 0.001). After intracameral injection, radioactivity was observed only in anterior, but not posterior parts of the eye. Radioactivity was observed only in the ipsilateral posterior retina-choroid and periocular tissues around the optic nerve insertion after sub-Tenon injection. The results in the isolated tissues validated autoradiographic evaluations. CONCLUSIONS: These results suggest that diffusion from posterior periocular tissues across the posterior sclera may be the main route for local penetration of the instilled drug to reach the posterior retina-choroid in albino rabbits.

Noninvasive estimation of left ventricular end-diastolic pressure using tissue Doppler imaging combined with pulsed-wave Doppler echocardiography in patients with ventricular septal defects: a comparison with the plasma levels of the B-type natriuretic Peptide.

BACKGROUND: There are limited data regarding whether the ratio of the peak transmitral flow velocity during early diastole (E) to the peak mitral annular velocity during early diastole (Ea) obtained by tissue Doppler imaging (TDI) and the plasma levels of the B-type natriuretic peptide (BNP) are useful for evaluating the left ventricular end-diastolic pressure (LVEDP) in children with ventricular septal defects (VSD). We investigated the validity of noninvasive estimation of the LVEDP in VSD infants. METHODS: We studied 48 patients (mean age, 9 +/- 6 months). Using pulsed-wave Doppler echocardiography and TDI, E and Ea were measured to calculate the E/Ea ratio. The LVEDP and the ratio of pulmonary to systemic blood flow (Qp/Qs) were determined invasively. RESULTS: There were significant positive correlations between E and both the LVEDP value and the Qp/Qs ratio. In contrast, Ea showed significant negative correlations with the LVEDP value and Qp/Qs ratio. The E/Ea ratio correlated significantly with the LVEDP value and Qp/Qs ratio. The plasma BNP levels correlated significantly with the Qp/Qs ratio, although they did not show a significant correlation with the LVEDP. An E/Ea ratio of >9.8 indicated patients with a LVEDP of >10 mmHg with a sensitivity of 92% and specificity of 80%. CONCLUSION: TDI combined with pulsed-wave Doppler echocardiography predicted the LVEDP of VSD infants, whereas the plasma BNP value did not have a significant association with the LVEDP.

Paradoxical relationship between B-type natriuretic peptide and pulmonary vascular resistance in patients with ventricular septal defect and concomitant severe pulmonary hypertension.

B-type natriuretic peptide (BNP) reflects volume overload on left ventricle and pulmonary hypertension (PH) in patients with ventricular septal defect (VSD). Pulmonary vascular resistance (PVR) has been reported to correlate positively with BNP in VSD patients with various degrees of PH. We aimed to investigate the relationship between PVR and BNP in VSD patients with severe PH. We examined 24 subjects with VSD concomitant severe PH aged from 2 months to 17 years (median: 4 months). The ratio of pulmonary to systemic pressure (Pp/Ps), the ratio of pulmonary to systemic flow (Qp/Qs), the ratio of pulmonary to systemic resistance (Rp/Rs), and PVR were determined by cardiac catheterization. PVR and Rp/Rs ranged from 1.6 to 15.5 (mean: 5.7 +/- 3.9) Wood unit . m(2) and 0.1 to 0.8 (mean: 0.4 +/- 0.2), respectively. BNP ranged from 5.5 to 69 (mean: 31 +/- 19) pg/ml. Negative correlations were observed between BNP and PVR (r = -0.56, p = 0.004) and BNP and Rp/Rs (r = -0.51, p = 0.01). BNP was significantly lower (<10 pg/ml) in VSD patients with Eisenmenger physiology as compared with the others (p = 0.003). We should draw attention to evaluate BNP values in VSD patients with severe PH.

Using transthoracic Doppler echocardiography to diagnose reduced coronary flow velocity reserve in the posterior descending coronary artery in children with elevated right ventricular pressure.

BACKGROUND: Advances in transthoracic Doppler echocardiography enable noninvasive measurements of coronary flow velocity and coronary flow velocity reserve (CFVR) in the posterior descending coronary artery (PD). METHODS AND RESULTS: To evaluate CFVR in the PD of children with elevated right ventricular (RV) pressure, 19 children with RV pressure overload and 13 age-matched controls with normal RV pressure were studied using transthoracic Doppler echocardiography. Average peak flow velocity (APV) was measured at rest and in hyperemic conditions (intravenous administration of adenosine of 0.16 mg.kg(-1).min(-1)). Compared with controls, the PD CFVR was significantly reduced in the patients with elevated RV pressure (1.87+/-0.42 vs 2.49+/-0.55, p<0.01) because their mean baseline APV was significantly greater (27+/-6 vs 19+/-4 cm/s, p<0.01), although hyperemic APV was not significantly different (49+/-10 vs 48+/-14 cm/s, p=NS). CONCLUSIONS: PD CFVR is limited in patients with elevated RV pressure because of elevation of the baseline resting flow velocity.