Novel hepatitis C virus protease inhibitors: thiazolidine derivatives

This study evaluated the inhibitory effects of thiazolidine derivatives on hepatitis C virus (HCV) protease and other human serine proteases. The inhibition efficacy was tested with a reversed-phase high-performance liquid chromatography (HPLC) assay system using a NS3-NS4A fusion protein as the HCV protease and a synthetic peptide substrate that mimics the NS5A-5B junction. Nine thiazolidine derivatives showed more than 50% inhibition at 50 microg/ml. The most potent derivative was RD4-6250, with 50% inhibition at a concentration of 2.3 microg/ml; this concentration was lower than those of other protease inhibitors reported previously. The most selective derivative was RD4-6205, with 50% inhibition at a concentration of 6.4 microg/ml, a lower concentration than those on other serine proteases (chymotrypsin, trypsin, plasmin, and elastase). These results suggest that the RD4-6205 skeleton is an important structure for inhibitory activity on the HCV protease NS3-NS4A.     

Successful surgical repair for a patient with atrial septal defect and severe pulmonary hypertension--its surgical indication and prostaglandin E1 use for postoperative pulmonary hypertensive crisis

A 45-year-old woman with atrial septal defect and pulmonary hypertension was admitted for surgical repair. Cardiac catheterization data revealed pulmonary to systemic flow ratio (Qp/Qs) of 1.81, pulmonary artery pressure (PAP) of 82/30 mmHg and pulmonary vascular resistance (PVR) of 10.8 unit. Open lung biopsy was added to evaluate pulmonary vascular obstructive disease (PVOD) which was shown Heath-Edwards grade 3 PVOD. Following closure of the defect, PAP (systolic) exceeded momentarily systemic level after cardiopulmonary bypass. Prostaglandin E1 drip was remarkably effective to bring down PAP during early postoperative period. Although PAP has not been shown significant decrease on catheterization of one year after surgery, great symptomatic improvement has been achieved.     

Exchangeability of actin in cardiac myocytes and fibroblasts as determined by fluorescence photobleaching recovery

OBJECTIVE: To assess whether hypertension is a risk factor for hysterectomy performed for benign diseases. METHODS: Self-report questionnaires were collected from 77% of 2301 Danish women aged 30, 40, 50, or 60 years selected at random in 1982 for a prevalence study. Information about cardiovascular diseases, hypertension, use of medicine, weight and dieting history, life-styles, psychologic factors, gynecologic history (including history of hysterectomy), and social background were recorded. Weight, height, and blood pressure were measured. In an incidence study, the cohort was followed during 1982-1990 via central registers to assess the incidence of hysterectomy. Logistic and Cox regressions were used to analyze data. RESULTS: In the prevalence study, history of hypertension partly explained the relation between hysterectomy and cardiovascular diseases. In the incidence study, history of hypertension and use of diuretics were significant risk factors for hysterectomy. After confounder control, use of diuretics was explained by weight-related variables, and hypertension was a risk factor for hysterectomy in educated women (adjusted relative risk [RR] 2.88, 95% confidence interval [CI] 1.07, 7.76) and in women with weight fluctuations (adjusted RR 3.31, 95% CI 1.35, 8.14). Weight cycling and lack of education remained significant risk factors for hysterectomy in women with and without hypertension, respectively. CONCLUSION: History of hypertension, weight cycling, and lack of education are closely related risk factors for premenopausal hysterectomy. These three risk factors contribute to women undergoing hysterectomy having an increased risk for cardiovascular diseases. We proposed that hypertension might be a plausible biological cause of menorrhagia and an indication for hysterectomy.     

The temperature dependence of luminescence from a long-lasting phosphor exposed to ionizing radiation

The temperature dependence of luminescence from a long-lasting phosphor (LLP), SrAl₂O₄ : Eu²⁺,Dy³⁺, exposed to ionizing radiation has been measured to understand the LLP luminescence mechanism. Evaluation of the decay constants of the LLP exposed to -, β- or γ-rays at temperatures from 200 to 390 K showed that the decay constant is divided into four components ranging from 10⁻⁴ to 10⁻¹ s⁻¹ with activation energies of 0.02–0.35 eV.

Total luminous intensity from the LLP with changing irradiation temperature has its maximum value around the room temperature. Irradiation at elevated temperature (390 K) has the total luminescence pattern with monotonous decrease as temperature rises. As a result of evaluating the temperature dependence of luminescence, the luminescence mechanism is considered as follows:

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Extensions of polyacrylic acid ammonium salts in the adsorption layer to fluidize alumina slurries

An average shell volume occupied in the adsorption layer on alumina by a polyacrylic acid ammonium salts molecule (PAA) defined as the average area occupied by an adsorbed PAA on alumina multiplied by the average thickness of the water layer at the limit of thickening, has been calculated from the adsorbed amount of PAA and from the flow points of alumina in the presence of PAA of different molecular weights. A steric effect of the PAA dispersant on the dispersion of alumina resulted in a flow with no yield stress. This was due to the change of the extension of PAA in the adsorption shell from a sphere to an ellipsoid with a long axis which exceeded the effective distance that the van der Waals attraction force reaches at a molecular weight for the PAA of between 10 000–20 000.     

Neutral poly(3,4-ethylenedioxythiophene-2,5-diyl)s: preparation by organometallic polycondensation and their unique p-doping behavior

Neutral and non-doped poly(3,4-ethylenedioxythiophene), PEDOTh(Ni), and its hexyl derivative, PEDOTh-C₆(Ni), have been prepared by organometallic dehalogenation polycondensation of 2,5-dichloro-3,4-ethylenedioxythiophene and its hexyl derivative with a zerovalent nickel complex. PEDOTh-C₆(Ni) was soluble in organic solvents and ¹H NMR data indicated that it had an M_n of 11,000. MALDI-TOF mass analysis of PEDOTh(Ni) gave M_n and M_w of about 1700 and 2400, respectively. PEDOTh-C₆(Ni) showed a UV-Vis absorption peak at 546 nm in CHCl₃. Electrochemical oxidation of PEDOTh-C₆(Ni) started at about −0.40 V vs Ag⁺/Ag and gave a peak at 0.20 V vs Ag⁺/Ag. Chemical and electrochemical oxidation (or p-doping) of PEDOTh-C₆(Ni), both in solutions and in a solid state, led to weakening of the original π-π^∗ peaks and rise of new peak(s) in a region of 800-1500 nm. The p-doping of PEDOTh-C₆(Ni) caused not only a decrease in the intensity of ¹H NMR signals of the bridging ethylene hydrogens but also a decrease in that of the hexyl side chain, suggesting a strong interaction of the p-dopant with the side chain. NMR data of poly(3-methoxythiophene-2,5-diyl) also supported an assumption that p-doping brings about a severe change in electronic state of the substituent attached to the polythiophene main chain. PEDOTh(Ni) had a density of 1.71 g cm⁻³; the molecular packing mode of PEDOTh(Ni) is discussed based on the density of the polymer and its XRD data.     

Antiarrhythmic effect related to the plasma concentration of pentisomide in vivo and the antiarrhythmic-concentration relationship in vitro

Pentisomide, 2-(2-diisopropylaminoethyl)-4-methyl-2-(pyridyl)- pentanamide, is a novel antiarrhythmic agent structurally related to disopyramide. Using a glass bead arrhythmic model, the authors studied the antiarrhythmic effect of pentisomide in dogs by monitoring the plasma concentrations. When pentisomide was infused at 1 mg/kg/min for 20 min, the ventricular tachycardia was significantly reduced at 5 min after starting the infusion; the arrhythmias were reduced to less than 5% at the end of the 20 min infusion. The plasma-free concentration of pentisomide was about 3 micrograms/ml at 5 min; it increased to about 10 micrograms/ml at the end of 20 min infusion. With 0.3 mg/kg/min infusion, the arrhythmias were reduced to about 60% but were not significant at 20 min of infusion. The plasma-free concentration of pentisomide did not reach 3 micrograms/ml until 20 min of infusion. The 3 micrograms/ml plasma-free concentration for pentisomide seems to be a critical concentration in inducing a significant antiarrhythmic effect. Pentisomide dose-dependently inhibited ischaemia-reperfusion arrhythmia at doses of 30 microM and higher concentrations in vitro. In conclusion, pentisomide inhibits arrhythmias dependent with the plasma concentration or with the concentration of the external solution. The critical plasma-free concentration for inhibition of arrhythmias was 3 micrograms/ml (not equal to 10 microM) and the in vitro effect also had a similar concentration. Therefore, the in vivo and in vitro antiarrhythmic concentrations were well correlated.