Segmented poly(urethane urea)s (SPUUs) based on aliphatic diisocyanato (2,6-diisocyanato methyl caproate (lysine-based diisocyanate, LDI)), poly(epsilon-caprolactone diol)s (PCLs) with molecular weights 530, 1250 and 2000, and 1,4-butanediamine were synthesized in absence of catalyst. The resulting SPUUs, with different soft segment length, were characterized by suitable analytical techniques. The synthesized SPUUs had high molecular weights, low glass-transition temperatures (</=-15 degrees C) and high elongation-at-break. The degradation of SPUUs in alkaline solution and in vitro drug release of sulfamethoxazole in pH 7.4 buffer were investigated. In addition, the degradation behavior of PCL1250-based SPUU was investigated by exposing to a buffer solution and biochemical oxygen demand (BOD) tests in an activated sludge. The drug release data was analyzed by an empirical equation ((M(t)/M(infinity))=kt(n)). Finally, NIH3T3 fibroblasts have been used for cell-adhesion studies on these materials to investigate the biocompatibility. The synthesized SPUUs combine physical and bioresponsive and biodegradable properties that might be employed in wound dressing, drug delivery and tissue-engineering applications.

This article demonstrates a water-lubrication system using high-density hydrophilic polymer brushes consisting of 2,3-dehydroxypropyl methacrylate (DHMA), vinyl alcohol, oligo(ethylene glycol)methyl ether methacrylate, 2-(methacryloyloxy)ethyltrimethylammonium chloride (MTAC), 3-sulfopropyl methacrylate potassium salt (SPMK), and 2-methacryloyloxyethyl phosphorylcholine (MPC) prepared by surface-initiated controlled radical polymerization. Macroscopic frictional properties of brush surfaces were characterized by sliding a glass ball probe in water using a ball-on-plate type tribotester under the load of 0.1-0.49 N at the sliding velocity of 10(-5)-10(-1) m s(-1) at 298 K. A poly(DHMA) brush showed a relatively larger friction coefficient in water, whereas the polyelectrolyte brushes, such as poly(SPMK) and poly(MPC), revealed significantly low friction coefficients below 0.02 in water and in humid air conditions. A drastic reduction in the friction coefficient of polyelectrolyte brushes in aqueous solution was observed at around 10(-3)-10(-2) m s(-1) owing to the hydrodynamic lubrication effect, however, an increase in salt concentration in the aqueous solution led to the increase in the friction coefficients of poly(MTAC) and poly(SPMK) brushes. The poly(SPMK) brush showed a stable and low friction coefficient in water even after sliding over 450 friction cycles, indicating a good wear resistance of the brush film. (c) 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.201000001.

Antitumor effects and mechanism of combined therapy with a dendritic cell (DC) vaccine and fluorouracil (5-FU) were investigated. Cytotoxic activity against MC38 cells, untreated or pretreated with 5-FU, was examined in splenocytes from mice inoculated with DCs: DCs pulsed with MC38 lysate or treated with LPS or both and untreated DCs. Inoculation with all types of DCs induced the significant cytotoxic activity of splenocytes, and pretreatment of MC38 cells with 5-FU significantly enhanced the cytotoxic activity of splenocytes. Depletion of natural killer (NK) cells, but not of CD8 or CD4 T cells, in the splenocytes from DC (without MC38 lysate-pulse or LPS treatment thereafter)-inoculated mice decreased the cytotoxic activity. The cytotoxic effect was eliminated by treatment with a monoclonal antibody (mAb) against tumor necrosis factor (TNF)-alpha and was partially inhibited by concanamycin A. Inoculation of mice with DCs upregulated TNFalpha expression on NK cells. MC38 cells pretreated with 5-FU exhibited enhanced expression of procaspase 8 and efficiently underwent apoptosis by TNF-alpha with activation of caspase 8. Although treatment with 5-FU upregulated Rae-1 expression on MC38 cells, the NK-cell-mediated cytotoxic activity was not suppressed by treatment with an anti-Rae-1 mAb or an antinatural killer group 2D mAb or both. These results indicate that combined therapy with a DC vaccine and 5-FU is a promising strategy for cancer treatment mediated by the tumoricidal activity of NK cells through the TNF-alpha pathway.

Poly(1-(2-methacryloyloxy)ethyl-3-butylimidazolium bis(trifluoromethanesulfonyl)imide) (PMIS) and poly(n-hexyl methacrylate) (PHMA) brushes were prepared on initiator-immobilized silicon wafers by surface-initiated atom transfer radical polymerization. The macroscopic frictional properties of the brushes were determined using a ball-on-flat type tribotester under reciprocating motion in a dry nitrogen atmosphere, water, methanol, and 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (EMImTFSI). When the PMIS and PHMA brushes were exposed to EMImTFSI, the friction coefficient of the former was lower than that of the latter. It is thought that the high affinity of the PMIS brush to EMImTFSI led to a reduction in the interaction between the brush and the friction probe, which resulted in a low friction coefficient. The friction force of the PMIS brush in EMImTFSI was proportional to a normal load in the range of 0.2-0.98 N. The friction coefficient gradually decreased to 0.01 with an increase in the sliding velocity from 1 x 10(-4) to 1 x 10(-1) m s(-1). The friction coefficient of the PMIS brush exhibited low magnitude until 800 friction cycles in the dry nitrogen atmosphere, whereas the PHMA brush was abraded away within 150 friction cycles. The XPS spectra of the worn surfaces on the PMIS brush suggested that the brush was gradually abraded by friction.

Chlorophyll (Chl) was immobilized into a 1,4-butanediol-modified MCM-41 (BMCM-41) intercalated by poly(3-hexylthiophene) (P3HT) to form BMCM-41/P3HT/Chl nanocomposites having P3HT contents of 10, 30, 60, and 90 wt % from a solution-casting method. Wide-angle X-ray diffraction and transmission electron microscopy studies indicate that the pore structure of MCM-41 was retained after surface modification and a subsequent P3HT intercalation process. Scanning electron microscopy images showed that the BMCM-41 nanoparticles dispersed into the polymer matrix of BMCM-41/P3HT/Chl, and the sample with 10 wt % P3HT content gives the most homogeneous nanoparticle dispersion. Nitrogen adsorption-desorption results confirmed that the P3HT intercalation and Chl immobilization inside the BMCM-41 mesopore were successfully carried out. The pore volume and surface area of BMCM-41 decreased significantly when the amount of P3HT was increased from 10 to 90 wt %. The UV-vis study showed a blue shift of the pi-pi* transition band of P3HT in the spectra of BMCM-41/P3HT/Chl nanocomposites. The FT-IR study indicates an increase of the thiophene ring stretching and a decrease of the C horizontal lineO stretching when P3HT and Chl were inside the mesopore. The photovoltaic property of Chl-doped P3HT was improved significantly upon the addition of BMCM-41 nanoparticles, and BMCM-41/P3HT-10/Chl exhibits the highest incident photon-to-current conversion efficiency of 7.16%.

Fetal calf serum (FCS)-independent pancreatic cancer cells were established in plasma protein fraction (PPF)-supplemented medium that is an agent of good manufacturing practice (GMP) grade. Dendritic cells (DCs) were activated with the Toll-like receptor agonist, penicillin-inactivated Streptococcus pyogenes (OK-432) that is also a GMP grade agent. Therefore, sufficient amounts of FCS-independent fusions were successfully generated with decreased potential hazards of FCS. The FCS-independent fusions expressed tumor-associated antigens, HLA-DR, costimulatory molecules, IL-12, and IL-10. Stimulation of T cells with fusions from healthy donors resulted in proliferation of T cells with high expression levels of perforin/granzyme B and IFN-gamma and efficient induction of antigen-specific cytotoxic T lymphocytes (CTLs). Selection and expansion of T-cell clones were confirmed by TCR Vbeta analysis. However, fusions from patients with metastatic pancreatic cancer induced increased expression levels of TGF-beta1 in CD4+ CD25high T cells and low levels of CTLs with decreased IFN-gamma production.

We first succeeded in synthesizing ferrite nanoparticles containing Nd and B elements by a chemical route using a polyol process. The lattice constants of the ferrite nanoparticles were equivalent to 8.39A of the lattice constant for Fe(3)O(4) with the spinel structure in a bulk state independently of the size in diameter and composition (Fe:Nd:B). The size in diameter was actually dominated by the amount of ligands (oleic acid and oleylamine) coating the nanoparticles and easily tuned by changing refluxing-time under reaction. The spinel-structured ferrite nanoparticles containing Nd and B elements showed large coercivity as compared to Fe(3)O(4) nanoparticles with the spinel structure, which were prepared by the same chemical method. By doping Nd and B elements into the spinel structure of ferrite, magnetic anisotropy increased in comparison with Fe(3)O(4) nanoparticles. According to the analysis of magnetization curve using the modified Langevin function, the ferrite nanoparticles displayed the coexistence of superparamagnetic and antiferromagnetic phases. The ferrite nanoparticles containing Nd and B elements exhibited magnetic core/shell structure on the basis of various magnetic properties. The interface effect between the superparamagnetic core and antiferromagnetic shell might enhance the effective magnetic anisotropy of the ferrite nanoparticles containing Nd and B elements.

A disulfide-containing polyester indicates a dynamic nature in a bulk state based on a disulfide metathesis reaction driven by photoirradiation.

Calcium channel blockers have been widely recognized as important medicines for the treatment of cardiovascular diseases, including hypertension and angina pectoris. In Japan, more than 15 calcium channel blockers are clinically available, and their pharmacological profiles are known to vary in terms of action on subtypes of voltage-dependent Ca(2 + ) channels, tissue selectivity, and influence on the sympathetic nerve activity. Thus, the classification of calcium channel blockers is useful for understanding the similarity and differences of the drugs' action, leading to optimum prescription.

Effects of NIP-142, a benzopyran compound which terminates experimental atrial arrhythmia, on potassium channel alpha-subunits and mouse atrial repolarization were examined. NIP-142 concentration-dependently blocked the outward current through potassium channel alpha subunits Kv1.5, Kv4.2 and Kv4.3 expressed in Xenopus oocytes. In isolated mouse atrial myocardia, NIP-142 prolonged the action potential duration and effective refractory period, and increased the contractile force. These results suggest that NIP-142 blocks the potassium channels underlying the transient and sustained outward currents, which may contribute to its antiarrhythmic activity.

Azelnidipine is a new dihydropyridine Ca(2+) channel blocker with long plasma half-life. To understand the in vivo cardiovascular profile of azelnidipine, it was assessed in the halothane-anaesthetized, closed-chest canine model and compared with the effect of amlodipine. We administered azelnidipine in doses of 10, 20 and 70 mug/kg, i.v. or amlodipine in doses of 30, 70 and 200 mug/kg, i.v. cumulatively to the animals. The hypotensive effects of azelnidipine and amlodipine were slow in onset and long-lasted, while their extents of dose-related hypotensive effects were similar. Azelnidipine hardly affected the heart rate or plasma noradrenaline concentration at any doses, whereas the high dose of amlodipine increased these parameters. Azelnidipine as well as amlodipine tended to increase the ventricular contraction, which did not achieve statistical significance. During autonomic receptor blockade with atropine and propranolol, neither drug affected the heart rate, ventricular contraction or plasma noradrenaline concentration, although a more significant hypotensive action was observed. These results indicate that azelnidipine and amlodipine do not directly affect cardiac function. Amlodipine may induce sinus tachycardia via reflex-mediated increase in sympathetic tone. Such lack of reflex tachycardia with azelnidipine will provide potential therapeutic strategy for treatment of patients with cardiovascular diseases, being more beneficial than amlodipine.

The direct effects of famotidine, a selective histamine H(2) receptor antagonist, on the cardiac repolarization process were assessed using two in vitro test systems. Neither famotidine (0.1 and 1 microM), nor its solvent, dimethylsulfoxide (0.1%), affected any of the action potential parameters of guinea-pig papillary muscles, whereas the positive control, dl-sotalol (30 microM), significantly prolonged the action potential duration. Moreover, neither famotidine (0.1, 1 and 10 microM) nor dimethylsulfoxide affected the human ether-a-go-go-related gene (hERG) K(+) current expressed in Chinese hamster ovary-K1 cells, whereas the positive control, E-4031 (0.1 microM), significantly decreased the current. These results indicate famotidine does not directly affect the cardiac repolarization process.

BACKGROUND AND PURPOSE: The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death. EXPERIMENTAL APPROACH: The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day(-1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration. KEY RESULTS: Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed. CONCLUSIONS AND IMPLICATIONS: Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.

Clobutinol has been clinically reported to induce long QT syndrome. To clarify its cardiac electrophysiological properties, we compared effects of clobutinol on the isolated myocardium and anesthetized guinea-pig heart with those of a hERG K channel blocker E-4031. In isolated guinea-pig ventricular tissues, clobutinol (3 muM) as well as E-4031 (10-100 nM) prolonged the action potential duration without affecting maximum upstroke velocity, but no further prolongation was observed after application of 30 muM clobutinol. In anesthetized closed-chest guinea pigs, clobutinol (1 and 10 mg/kg, i.v.) and E-4031 (0.01 and 1 mg/kg, i.v.) prolonged the QT interval and duration of the monophasic action potential (MAP) in a dose-dependent manner, and at the same time increased the beat-to-beat variability of the MAP duration, reverse use-dependent prolongation of the MAP duration and triangulation of the MAP configuration. These results suggest that clobutinol delayed the ventricular repolarization and increased the proarrhythmic parameters linked to the hERG K channel inhibitor-induced torsade de pointes arrhythmias.

Pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects were simultaneously assessed using chronic atrioventricular block dogs. After application of the patch (9.8 mg/kg), pilsicainide was continuously absorbed through the skin with a C(max) of 0.49 +/- 0.13 microg/ml, while its plasma concentration was kept above the clinically reported minimum effective plasma concentration for 2 - 8 h. Inter-atrial conduction time was significantly prolonged, whereas statistically significant prolongation was not detected in the atrial effective refractory period. Prolongation of the cycle length of atrial fibrillation and anti-fibrillatory action were confirmed. Thus, pilsicainide can be absorbed transdermally to exert long-lasting electropharmacological effects leading to anti-atrial fibrillatory action.

The voltage-dependent N-type calcium channel (Ca(v)2.2), which is distributed in the nerve endings of the central and peripheral nerves, is known to be strongly associated with the pathological processes of cerebral ischemia and neuropathic pain. Ziconotide, the chemically synthesized version of the 25-residue peptide marine toxin omega-conotoxin MVIIA, has been approved as an analgesic drug for severe chronic pain treatment. A blockade of N-type calcium channels has been suggested for reducing the neuronal injury occurring from ischemia/reperfusion events. Therefore, many efforts have been made to develop systemically available small-molecule N-type calcium channel blockers thus far. This review focuses on the latest updates concerning small-molecule N-type calcium channel blockers as potential candidates for the next generation of therapeutics for neuropathic pain and ischemic stroke. The pharmacological advantages of N-type calcium channel blockers in these pathological states are also described.

Cilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca(2+) channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca(2+) channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca(2+) channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.

We examined the involvement of the Na(+)/Ca(2+) exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca(2+) transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca(2+) transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na(+)/Ca(2+) exchanger underlies the automaticity of the pulmonary vein myocardium.

Specimen contamination induced by electron beam irradiation has long been a serious problem for high-resolution imaging and analysis by a transmission electron microscope (TEM). It creates a deposition of carbonaceous compounds on a region under study, causing the loss of resolution. We developed a method to reduce the beam-induced specimen contamination by cleaning a TEM with activated oxygen radicals. The hydrocarbon contaminants accumulated inside the microscope's chamber can be etched away by gentle chemical oxidation without causing any damage to the microscope. The "contamination-free TEM" can effectively suppress the deposition of carbon-rich products on a specimen and therefore enables us to perform high-resolution carbon elemental mapping by energy-filtering transmission electron microscopy (EFTEM). In this study, we investigated the structure of polymer brushes immobilized on a silica nanoparticle (SiNP), of which molecular weight, length, and density of the brushes had been characterized in detail. The isolated particle showed the stretched formations of the polymer chains growing from the surface, while the densely distributed particles showed the connection of the polymer chains between neighboring particles. Moreover, the polymer brush layer and the surface initiator could be differentiated from each other by the component-specific contrast achieved by electron spectroscopic imaging (ESI). The contamination-free TEM can allow us to perform high-resolution carbon mapping and is expected to provide deep insights of soft materials' nanostructures.

The formation of star-like nanogels with different arm lengths via a radical crossover reaction of alkoxyamine units in diblock copolymers and direct observation of the star-like nanogels by scanning force microscopy were successfully accomplished.