Unpredictable polymeric flow dynamics with reaction between HPAM and Al3+ by comparison between pre- and post-reaction fluid properties.

A chemical reaction in the flow field affects the physical property of fluids, resulting in changing flow dynamics. The effect of the reaction on the flow dynamics is normally evaluated by comparison between the physical properties of the fluid between pre- and post-reaction. However, our group found a polymeric reacting flow in which a comparison between pre- and post-reaction fluid properties is insufficient to evaluate the influences of the reaction on the flow dynamics (T. Ueki et al., J. Phys. Chem. B, 2019, 123, 4587-4593). In the study, we examined the stirred flow by an impeller in a beaker with a chemical reaction between partially hydrolyzed polyacrylamide (HPAM) solution and Fe(NO3)3 solution. We found that a so-called Weissenberg effect, where the stirred solution climbs up the stirring shaft because of an increase in the viscoelasticity of the mixed solution, transiently appeared in only the halfway of the reaction, although the reaction slightly decreased the solution's viscosity at the final stage under a certain pH and we proposed the mechanism for the temporal increase in the viscoelasticity. In the present study, we conducted similar experiments as our previous study using HPAM solution at various pH and two concentrations of Al(NO3)3 solutions. The unpredictable flow dynamics by comparison between pre- and post-reaction fluid properties, i.e., the appearance and disappearance of the Weissenberg effect, has been observed under a certain pH and Al(NO3)3 concentration. We investigated the mechanism by means of the simultaneous measurement of pH and the stirring torque and the identification of the dominant species of aluminum aqua complexes by the Henderson-Hasselbalch equation. As a result, we proposed two mechanisms of dissapearance of the Weissenberg effect: one is the same for the Fe(NO3)3 case but the other is unique and novel for the Al(NO3)3 case. This study can contribute to the comprehensive understanding of the conditions for the occurrence of the unpredictable dynamics of polymeric reacting flow by comparison between the pre- and post-reaction fluid properties.

Anomalous patterns of Saffman-Taylor fingering instability during a metastable phase separation.

Phase separation is important in biology, biochemistry, industry, and other areas and is divided into two types: a spinodal decomposition type and a nucleation and growth type. The spinodal decomposition type phase separation occurs under the thermodynamically unstable conditions, and the nucleation and growth type phase separation occurs under thermodynamically metastable conditions. On the other hand, when a less viscous fluid displaces a more viscous one in porous media, the interface of the two fluids becomes hydrodynamically unstable and forms a finger-like pattern. The coupling of the hydrodynamic instability with the thermodynamic instability has been studied. It is reported that the hydrodynamic instability under thermodynamically unstable conditions, where spinodal decomposition type phase separation occurs, creates multiple moving droplets with a radius of 3-4 mm because of the spontaneous convection induced by the Korteweg force, which is driven by a compositional gradient during phase separation. However, the hydrodynamic instability under metastable conditions, where the phase separation of nucleation and growth type occurs, is still unrevealed. In this study, we applied fingering instability (hydrodynamic instability) under the metastable conditions, where the patterns are changed from fingering or droplets to anomalous patterns such as tip-widening or needle-like (top-pointed) fingering patterns when the initial concentration is metastable, which is considered near a binodal curve. These patterns are ubiquitous in nature, similar to dendrite crystals (snowflakes) or our body's cells. Thus, the patterns created can be controlled through hydrodynamic conditions such as the injection flow and thermodynamic conditions such as spinodal decomposition (thermodynamically unstable conditions) and metastable conditions.

Clinically Administered Doses of Pitavastatin and Rosuvastatin.

Clinical studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, can potentially inhibit chronic heart failure. In the Stat-LVDF study, a difference was noted in terms of the effect of lipophilic pitavastatin (PTV) and hydrophilic rosuvastatin (RSV) on plasma BNP, suggesting that statin lipophilicity and pharmacokinetics change the pleiotropic effect on heart failure in humans. Therefore, we assessed the beneficial effects of PTV on hypertrophy in cardiac myocytes compared with RSV at clinically used doses. Cultured cardiomyocytes were stimulated with 30 µM phenylephrine (PE) in the presence of PTV (250 nM) or RSV (50 nM). These doses were calculated based on the maximum blood concentration of statins used in clinical situations in Japan. The results showed that PTV, but not RSV, significantly inhibits the PE-induced increase in cell size and leucine incorporation without causing cell toxicity. In addition, PTV significantly suppressed PE-induced mRNA expression of hypertrophic response genes. PE-induced ERK phosphorylation was inhibited by PTV, but not by RSV. Furthermore, PTV significantly suppressed the angiotensin-II-induced proline incorporation in primary cultured cardiac fibroblasts. In conclusion, a clinical dose of PTV was noted to directly inhibit cardiomyocyte hypertrophy and cardiac fibrosis, suggesting that lipophilic PTV can be a potential drug candidate against chronic heart failure.

Effects of Statins on Left Ventricular Diastolic Function in Patients with Dyslipidemia and Diastolic Dysfunction (Stat-LVDF Study).

Statins, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, are potential drugs for chronic heart failure treatment in clinical studies. However, there may be differences in the effects on heart failure between lipophilic and hydrophilic statins. In this study, we investigated whether hydrophilic rosuvastatin (RSV) and lipophilic pitavastatin (PTV) exert different effects on the left ventricular diastolic function. Subjects were hypercholesterolemia patients with left ventricular diastolic dysfunction. This was an open-label, randomized, parallel, comparative, prospective study. The subjects received treatment with RSV or PTV for 24 weeks, and their low density lipoprotein (LDL)-cholesterol levels were controlled by these statins according to the guideline. The primary endpoint was defined as the change in left ventricle (LV) diastolic function (E/E') estimated by echocardiography, and the secondary endpoint was the plasma B-type natriuretic peptide (BNP) level. No serious adverse effects were observed during the entire study period in any patient, nor were there any significant differences in changes in the body mass index, blood pressure, or heart rate. Statin treatment did not significantly alter the primary endpoint, E/E'. The change ratio of BNP was not significantly different between PTV and RSV groups. However, BNP was significantly increased in the RSV (p=0.030) but not the PTV (p>0.999) group. This study revealed that although neither RSV nor PTV improved LV diastolic dysfunction, BNP, a biomarker of LV wall stress, was increased in the RSV but not the PTV group. Observation for a longer period is necessary to clarify the different effects of these statins on LV diastolic dysfunction. (UMIN-ID: UMIN000003571).

Optimal dose-setting study of curcumin for improvement of left ventricular systolic function after myocardial infarction in rats.

A natural p300-specific histone acetyltransferase inhibitor, curcumin, may have a therapeutic potential for heart failure. However, a study of curcumin to identify an appropriate dose for heart failure has yet to be performed. Rats were subjected to a left coronary artery ligation. One week later, rats with a moderate severity of myocardial infarction (MI) were randomly assigned to 4 groups receiving the following: a solvent as a control, a low dose of curcumin (0.5 mg∙kg(-1)∙day(-1)), a medium dose of curcumin (5 mg∙kg(-1)∙day(-1)), or a high dose of curcumin (50 mg∙kg(-1)∙day(-1)). Daily oral treatment was continued for 6 weeks. After treatment, left ventricular (LV) fractional shortening was dose-dependently improved in the high-dose (25.2% ± 1.6%, P < 0.001 vs. vehicle) and medium-dose (19.6% ± 2.4%) groups, but not in the low-dose group (15.5% ± 1.4%) compared with the vehicle group (15.1% ± 0.8%). The histological cardiomyocyte diameter and perivascular fibrosis as well as echocardiographic LV posterior wall thickness dose-dependently decreased in the groups receiving high and medium doses. The beneficial effects of oral curcumin on the post-MI LV systolic function are lower at 5 compared to 50 mg∙kg(-1)∙day(-1) and disappear at 0.5 mg∙kg(-1)∙day(-1). To clinically apply curcumin therapy for heart failure patients, a precise, optimal dose-setting study is required.

Drinkable preparation of Theracurmin exhibits high absorption efficiency--a single-dose, double-blind, 4-way crossover study.

Curcumin has various biological activities including antioxidant and antiinflammatory actions, and alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to realize its bioactivities. We have generated capsules and tablets containing Theracurmin, a highly absorptive curcumin. In addition, we recently created a drinkable preparation of Theracurmin. To evaluate the absorption efficiency of this type of curcumin, we performed a single-dose, double-blind, 4-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin beverage and 3 other drinkable types of curcumin sold in Japan. Twenty-four healthy subjects (male/female=13/11, age: 23-32) were administered with these 4 drinkable preparations of curcumin. The area under the blood concentration-time curve at 0-8 h was found to be 1.5 to 4.0-fold higher with Theracurmin than with the other 3 kinds of curcumin beverage. Moreover, maximal plasma curcumin concentrations (0-8 h) of Theracurmin were 1.8 to 3.8 times higher than those of the other 3 curcumin beverages. These data indicate that our newly prepared Theracurmin beverage exhibits a much better absorption efficiency than other kinds of curcumin beverage sold in Japan.

Colloidal submicron-particle curcumin exhibits high absorption efficiency-a double-blind, 3-way crossover study.

Curcumin is a major constituent of the spice turmeric and has various biological activities, including anticancer, antioxidant, and anti-inflammatory properties, as well as alcohol detoxification. However, because of its poor absorption efficiency, it is difficult for orally administered curcumin to reach blood levels sufficient to exert its bioactivities. To overcome this problem, several curcumin preparations with a drug-delivery system (DDS) have been developed to increase the bioavailability of curcumin after oral administration, and tested as functional foods and potential medical agents in humans. We have also produced capsules containing Theracurmin, curcumin dispersed with colloidal submicron-particles. To evaluate the absorption efficiency of three types of DDS curcumin, we performed a double-blind, 3-way crossover study. We compared plasma curcumin levels after the administration of Theracurmin and 2 other capsule types of curcumin with DDS, BCM-95 (micronized curcumin with turmeric essential oils) and Meriva (curcumin-phospholipid). Nine healthy subjects (male/female=5/4, age: 24-32 y old) were administered these 3 preparations of DDS curcumin, at commonly used dosages. Six capsules of Theracurmin, 1 capsule of BCM-95, and 2 capsules of Meriva contain 182.4 ± 1.0, 279.3 ± 10.7, and 152.5 ± 20.3 mg of curcumin, respectively. The maximal plasma curcumin concentration (0-24 h) of Theracurmin was 10.7 to 5.6 times higher than those of BCM-95 and Meriva, respectively. Moreover, the area under the blood concentration-time curve at 0-24 h was found to be 11.0- and 4.6-fold higher with Theracurmin than BCM-95 and Meriva, respectively. These data indicate that Theracurmin exhibits a much higher absorption efficiency than other curcumin DDS preparations.