The effect of FK664, a new cardiovascular drug, on systemic capacitance vessels in anesthetized dogs.

To characterize the cardiovascular effect of FK664, a compound developed for the treatment of heart failure, the mean circulatory pressure (MCP), cardiac output and other parameters were measured in open-chest anesthetized dogs. Milrinone, a cardiotonic agent, and nifedipine, a calcium channel blocker were used as reference substances. Nifedipine (10 micrograms/kg), FK664 (0.1 mg/kg) or milrinone (0.1 mg/kg) given intravenously reduced the total peripheral resistance in a similar extent (35-40%). Whereas nifedipine had no effect on MCP, FK664 produced a significant decrease in MCP. Milrinone caused a minimal decrease in MCP, but not significantly. These results indicate that FK664 dilates the systemic capacitance vessels. This action to reduce the pre-load would be beneficial in the treatment of heart failure.

Improved heart failure protection by FK664, a novel positive inotropic agent, in dog heart-lung preparations.

The effects of FK664, a novel positive inotropic agent, and enoximone on pentobarbital-induced heart failure were compared in dog heart-lung preparations. Both FK664 and enoximone improved the cardiac function curve in a dose-dependent manner and restored it to the control level at drug concentrations of 1 microgram/ml and 10 micrograms/ml, respectively. Therefore, the cardiotonic potency of FK664 appears to be 10 times that of enoximone. These agents were almost equal in force-rate separation of cardiac effect. Neither of the agents produced arrhythmia at any dose tested. These results suggest that FK664 may be a potent cardiotonic agent for the treatment of heart failure.

[The significance of neoadjuvant intra-arterial chemotherapy for locally advanced breast cancer by different methods].

For neoadjuvant intra-arterial (IA) chemotherapy in locally advanced breast cancer patients, Seldinger's methods were found to be convenient and had the same effect and outcome as conventional methods. The prognosis of the patients in whom IA chemotherapy was locally effective and had fewer than n 1 lymph node metastases was comparatively favorable. However, several patients who underwent IA chemotherapy later experienced local recurrence, and the cause of these patient's death was distant metastases in almost all cases. We recommend neoadjuvant IA and systemic chemotherapy, and systemic adjuvant chemotherapy.

[A case report of successful transcatheter arterial embolization therapy for osseous metastasis of hepatocellular carcinoma].

A 74-year-old man was admitted to our hospital with a chief complaint of severe local pain of the hip joint. Radiological findings showed a metastasized lesion on the left side of the pelvic wall originated from hepatocellular carcinoma (HCC) in the anterior segment of the liver. Transcatheter arterial embolization (TAE) therapy using epirubicin, Lipiodol and Spongel was successfully performed twice for primary HCC, and four times for osseous metastasis of HCC. After TAE therapy, the size of the metastasized lesion decreased with relief of pain, and an improvement in performance status of 4 to 2 was achieved. In conclusion, TAE therapy is thought to be very useful in the treatment of osseous metastasis of HCC with severe local pain.

[Intrapericardiac instillation of epirubicin for carcinomatous cardiac tamponade from breast cancer].

Three cases of carcinomatous cardiac tamponade from breast cancer are presented. All patients have had another recurrence and history of treatment. Though the prognoses were considered to be unfavorable, pericardiac drainage and the instillation of epirubicin were effective. Side effects of fever and dyspnea were experienced temporarily by two patients with no serious events. Following the systemic chemotherapy, two patients needed no supplemental drainage. All patients had a sufficient quality of life for about 1 year or longer. We found that positive therapy can be significant for such patients with advanced disease.

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity.

Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infarction via this action mechanism. However, there are individual differences in this action, and aspirin is not effective in some patients, which is referred to as 'aspirin resistance'. In this study, we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine genes involved in platelet aggregation/hemorrhage. Among SNPs involved in platelet aggregation, aspirin was less effective for 924T homozygote of a TXA2 receptor, 924T>C, and 1018C homozygote of a platelet membrane glycoprotein GPIbalpha, 1018C>T, suggesting that 924T and 1018C alleles are involved in aspirin resistance.

Effect of chronic treatment with propranolol on blood pressure and cardiovascular reactivity in spontaneously hypertensive rats.

Young SHR were treated with propranolol (16 or 64 mg/kg per day) from 6 up to 14 weeks of age. Systolic blood pressure was significantly lower in SHR treated with propranolol (64 mg/kg) than in untreated SHR; no effect was seen in SHR treated with 16 mg/kg. The hemodynamic characteristics of the hindquarter vascular beds did not significantly differ between untreated and propranolol-treated SHR. Adult SHR were given propranolol (64 mg/kg per day) from 5 up to 8 months of age. Moderate reduction of systolic blood pressure was observed from 2 to 3 months of propranolol treatment. The cardiovascular pressor response to noradrenaline decreased in propranolol-treated SHR, while the decreased responsiveness was not found after pithing.

Adsorption Characteristics of Poly(acrylic acid) and Poly(vinyl pyrrolidone) on Alumina from Their Mixtures in Aqueous Solution

Adsorption behavior of poly(acrylic acid) (PAA) and poly(vinyl pyrrolidone) (PVP) on alumina from their binary mixtures in aqueous solution at pH 5.2 has been studied by measuring the adsorbed amount of polymers, dispersion stability, and ESR spectra. The adsorption of PAA alone shows a strong affinity with a large adsorbed amount for alumina surface, but that of PVP alone is very weak and small. In fixed initial concentrations of PAA the adsorption of PVP is considerably enhanced, probably due to the interaction of PVP with PAA adsorbed on alumina through hydrogen bonding. From ESR spectra of spin-labeled PAA and adsorbed PVP, it is found that in the co-adsorption of PAA and PVP, adsorbed PAA takes predominantly trains, while PVP is mainly adsorbed in loops or tails. The stability of alumina dispersion has also been discussed from the conformation of polymers adsorbed on alumina.

Simultaneous Adsorption of Poly(ethylene Oxide) and Cationic Surfactant at the Silica/Water Interface.

The simultaneous adsorption of three poly(ethylene oxide) (PEO) with different molecular weights and two cationic surfactants on silica under a constant feed concentration of PEO has been investigated in aqueous solutions. Two cationic surfactants were used; dodecyltrimethylammonium bromide (DTAB) and 1,2-bis(dodecyltrimethyl ammonio) ethane dibromide (2RenQ). The amount of PEO adsorbed decreased with increasing surfactant concentration, while that of the surfactant increased with surfactant concentration but was lower in the presence of PEO than in the absence of PEO, indicating a competitive adsorption. The reduction in PEO adsorption was greater in the presence of 2RenQ than in the presence of DTAB accompanying an increase of the molecular weight of PEO. The dispersion stability of silica suspensions by the competitive adsorption showed a dispersion-flocculation-redispersion sequence with the surfactant concentration, suggesting the importance of electrostatic interactions as well as steric interactions. ESR measurements using spin-labeled PEO show that PEO molecules adsorbed take mainly loops or tails, inducing steric hindrance for the high dispersion stability of silica suspensions. Copyright 1998 Academic Press.

Adsorption and Adsolubilization by Monomeric, Dimeric, or Trimeric Quaternary Ammonium Surfactant at Silica/Water Interface

Adsorption of monomeric, dimeric, or trimeric quaternary ammonium surfactant on silica from its aqueous solution has been investigated by measuring adsorption density, zeta potential, and dispersion stability. The monomeric (dodecyltrimethylammonium bromide, 1RQ), dimeric (1,2-bis(dodecyldimethylammonio)ethane dibromide, 2RenQ), and trimeric (methyldodecylbis[2-dimethyldodecylammonio) ethyl] ammonium tribromide, 3RdienQ) surfactants are used in this study. The amounts adsorbed at saturation decrease with increasing dodecyl chain number of the surfactants from 1RQ to 2RenQ and 3RdienQ. Silica suspensions by adsorption of the surfactants exhibit a process of dispersion-flocculation-redispersion with the surfactant concentration for the three surfactants which can be correlated with the change in zeta potentials. ESR measurements using methyl 12-doxylstearate show that the microviscosities in 2RenQ- and 3RdienQ-adsorbed layers are greater than that in the 1RQ-adsorbed layer. Under a constant feed concentration of 2-naphthol, the adsolubilized amounts of 2-naphthol increase, reach a maximum, and then decrease with the surfactant concentration for the three surfactants. The ratio of maximum amount of 2-naphthol adsolubilized to the adsorbed amount of surfactant on silica increases with an increase in the dodecyl chain number of the surfactants from 1RQ to 2RenQ and 3RdienQ. In addition, from a two-step process of adsorption-adsolubilization, it is suggested that 2RenQ and 3RdienQ adsorb on much stronger than 1RQ, keeping 2-naphthol in their adsorbed layers.

Mixed Micellar Properties of Nonionic Saccharide and Anionic Fluorocarbon Surfactants in Aqueous Solution

Mixed micellar properties of nonionic saccharides (n-decyllactobionamide, C10Glu2; n-dodecyllactobionamide, C12Glu2) and anionic fluorocarbon surfactants (lithium perfluorooctanesulfonate, LiFOS) in aqueous solutions have been studied by means of surface tensiometry, NMR, and light scattering. The interaction parameters estimated from the modified regular solution theory are -5.0 for the C10Glu2/LiFOS system and -0.2 for the C12Glu2/LiFOS system. This difference could be due to the interaction of the surfactant tails. The average aggregation number is almost identical over a wide mole fraction of C12Glu2 for the C12Glu2/LiFOS system, while it shows a minimum at a C10Glu2 mole fraction of 0.4 for the C10Glu2/LiFOS system. It is also found from NMR measurements that the segmental motions of surfactants in the mixed micelles of C12Glu2 and LiFOS are not restricted, whereas they are restricted at a C10Glu2 mole fraction of 0.4 for the C10Glu2/LiFOS system. These motional changes as well as micellar composition reflect the solubilization of decafluorobiphenyl in the mixed micelles. Copyright 1998 Academic Press. Copyright 1998Academic Press

Reexamination of 2-Naphthol Adsolubilization on Alumina with Sodium Dodecyl Sulfate Adsorption.

Adsolubilization behavior of 2-naphthol on alumina with adsorption of sodium dodecyl sulfate (SDS) at pH 3.5 in the presence of 10 mmol dm(-3) NaCl was reexamined. The adsolubilized amount of 2-naphthol increased sharply and reached a maximum, then decreased with SDS concentration. The decrement of the adsolubilized amount began below the critical micelle concentration of SDS. From the dispersion state of the alumina suspension and the SDS adsorption isotherm, it is demonstrated that the decrement of adsolubilization of 2-naphthol is not due to the partition of 2-naphthol between the SDS adsorbed layer and SDS micelles, but is due to the difference of SDS adsorption states such as monolayers and admicelles. Copyright 2000 Academic Press.

Kinetics of Simultaneous Adsorption of Poly(vinylpyrrolidone) and Sodium Dodecyl Sulfate on Alumina Particles.

The adsorption kinetics of poly(vinylpyrrolidone) (PVP) and sodium dodecyl sulfate (SDS) on alumina particles at pH 3.5 has been studied by measuring the amount of PVP and SDS adsorbed and the dispersion stability of solid suspensions with time. Although PVP alone hardly adsorbs on alumina particles, the adsorption of PVP is enhanced by coadsorption of SDS. In the simultaneous adsorption of PVP-SDS at two initial concentrations of SDS which correspond to the formation of a monolayer and a bilayer of SDS, respectively, the adsorption behavior of PVP with time is significantly affected by the initial SDS concentration. In addition, the dispersion stability of alumina suspensions also changes due to the adsorption of SDS-PVP with time. The mechanism of adsorption kinetics of PVP and SDS on alumina particles is discussed. Copyright 2000 Academic Press.

Effect of adenosine and adenosine 5'-monophosphate on cell division of cultured mastocytoma P-815 cells.

The growth of mouse mastocytoma P-815 cells in culture (37 degrees, 42 hr) was inhibited by exogenous adenosine (0.2 to 1.0 mM) and more effectively by AMP (0.01 to 0.1 mM), but not by adenine. The inhibited growth (a 25% inhibition by 0.5 mM adenosine and a 80% inhibition by 0.25 mM AMP) was restored to a near control level by the addition of uridine (0.5 mM) to the medium. The pretreatment (37 degrees, 3 hr) of the cells with adenosine or AMP caused a 60% inhibition of incorporation (37 degrees, 2 hr) of [U-14C]aspartate into uracil nucleotides, accumulating 14C-orotate and orotidine. Both dipyridamole, an inhibitor of adenosine uptake, and exogenous adenosine deaminase suppressed the growth inhibition induced by not only adenosine but also AMP. 2-Chloroadenosine, which is resistant to the action of adenosine deaminase, was a more potent growth inhibitor, while 3'AMP and 2'-AMP, which are not hydrolyzed to adenosine by membrane 5'-nucleotidase, were ineffective. Adenosine 5'-sulfate and other 5'-substituted adenosines were also ineffective. These observations indicate that AMP inhibits the growth of mastocytoma P-815 cells as a result of its continuous conversion to adenosine and a constant exposure of the cells to a low concentration of adenosine which readily permeates the cell membrane. In addition, adenosine, AMP and their agarose-linked forms rapidly (37 degrees, 20 min) elevated cellular levels of cAMP. This effect was not suppressed by dipyridamole. Apparently adenosine and AMP also act extracellularly for growth inhibition by regulating cAMP levels.

Effect of adenosine 3',5'-monophosphate on growth and several functions of cultured mastocytoma P-815 cells.

Growth-inhibited mouse mastocytoma P-815 cells at stationary phase contained more histamine, serotonin and adenosine 3',5'-monophosphate (cAMP), and higher activities of histidine decarboxylase and adenylate cyclase than the cells during exponential growth. The elevation of endogenous cAMP levels induced by several growth-inhibiting agents such as N6, O2'-dibutyryl cAMP (Bt2cAMP), prostaglandin E1, AMP and 2-chloroadenosine stimulated several functions characteristic of mastocytoma P-815 cells in culture, elevating the synthesis of histamine and serotonin, the activity of chymotrypsin-like protease, and the incorporation of [35S]sulfate into acidic glycosaminoglycans. 1-Methyl-3-isobutyl-xanthine (MIX), a potent inhibitor of cAMP phosphodiesterase, potentiated stimulatory effect of these agents. The results indicate that cAMP regulates the growth and functions of mastocytoma P-815 cells. [35S]-Sulfated acidic glycosaminoglycans synthesized in cells at stationary phase or in cells treated with Bt2cAMP plus MIX mainly localized in the 3000-10000 x g sedimentable fraction of cell homogenates, and had a molecular weight of 200000 to 400000 based on gel filtration. This acidic glycosaminoglycan was resistant to chondroitinase ABC and the heparin-degrading enzyme present in the 20000 x g sedimentable fraction of the cells, and was identified as a highly sulfated macromolecular heparin based on behaviors on DEAE-cellulose column and on acidic electrophoresis. Cycloheximide suppressed the stimulatory effect of Bt2cAMP on the synthesis of histamine and [35S]-sulfated acidic glycosaminoglycan.

Effects of vamicamide on urinary bladder functions in conscious dog and rat models of urinary frequency.

PURPOSE: To investigate the usefulness of vamicamide, (+/-)-(2R*, 4R*)-4-dimethylamino-2-phenyl-2-(2-pyridyl)valeramide, as a novel drug for the treatment of urinary frequency and incontinence. MATERIALS AND METHODS: Urinary frequency was evaluated in specially devised conscious dog and rat models by investigating the effects of the drug on urinary bladder function of these animals by cystometrography. RESULTS: In the dog model with transected hypogastric nerves, the bladder volume at micturition (bladder capacity) was less than 50% that of the sham-operated dog, and in the rat model with bilateral lesioning of nuclei basalis, a part of the brain, by ibotenic acid injection, bladder capacity was about 50% that of the sham-operated rat. Other bladder functions in both models were unchanged. In the dog model, orally administered vamicamide at 0.32 and 1.0 mg./kg. significantly increased bladder capacity and did not change residual urine volume or micturition pressure. Oxybutynin 0.10 mg./kg., one of the most popular drugs for the treatment of urinary frequency and incontinence, or atropine 0.10 mg./kg. induced significant increases in bladder capacity similarly to vamicamide at 0.32 mg./kg. In the rat model, oral vamicamide 0.32 mg./kg. also significantly increased bladder capacity and did not change micturition pressure or threshold pressure. Again, oxybutynin 0.10 mg./kg. or atropine 0.32 mg./kg. had almost the same effects as vamicamide 0.32 mg./kg. CONCLUSIONS: These findings suggest that vamicamide should be useful for the treatment of urinary frequency.

NADH measurements in adult rat myocytes during simulated ischemia.

In isolated adult rat myocytes, we tested the hypothesis that metabolic inhibition and simulated ischemia regulate the NADH/NAD+ redox couple with concomitant impairment of energy-dependent process, including contraction and maintenance of high-energy phosphate stores. We developed a method to examine the relationship among the redox couple, ATP content, and contractile performance in single cells under several conditions analogous to myocardial ischemia, with and without reperfusion. Myocytes were paced at 1 Hz while cell contraction and NADH fluorescence were determined simultaneously for single cells at 37 degrees C. Cells were exposed to cyanide and 2-deoxy-D-glucose (metabolic inhibition) or to metabolic inhibition plus 12 mM KCl and 20 mM lactate at pH 6.5 (simulated ischemia). Pyridine nucleotide fluorescence signals from single cells studied in this fashion could be modulated by metabolic inhibitors in a manner similar to that classically described for isolated mitochondria. Metabolic inhibition or simulated ischemia quickly produced maximal reduction of NAD+ to NADH. When cells were exposed to simulated ischemia for 10 min, then superfused with glucose-containing control buffer, 28% of cells exposed to conditions of simulated ischemia developed hypercontracture on reperfusion. Hypercontracture developed despite mitochondrial electron transport being reestablished. When myocyte suspensions in a cuvette were studied spectrofluorimetrically, the pyridine nucleotide fluorescence response to metabolic inhibitors was similar to that for a single cell. This permitted correlation of ATP determinations on cells in suspension with contractile and fluorescence measurements from single myocytes. In the absence of glycolysis there is correspondence among loss of electron transport, decline in high-energy phosphate concentration, and decline in contraction. Irreversible disruption of the electron transport process does not appear to be an early event in ischemic injury.

Comparison of the cardiovascular effect of FR34235, a new dihydropyridine, with other calcium antagonists.

We compared the cardiovascular effect of FR34235, a new dihydropyridine derivative, with the effects of nifedipine, nicardipine, and diltiazem on the dog using in vitro and in vivo preparations. FR34235 reduced the amplitude of coronary arterial contraction induced by K+ more so than that induced by norepinephrine in in vitro preparations. The ID50 values of FR34235 for various arterial strips contracted by K+ were smaller (1/5-1/426) than those of nifedipine and diltiazem, and almost the same as those of nicardipine. There was a greater increase in both the coronary and vertebral blood flow than in the other peripheral arterial flow in anesthetized dogs administered FR34235 (0.32-100 micrograms/kg i.v.), and the duration of effect was about two to three times longer than that of the other drugs. To obtain a vasodilating effect by the intraduodenal route, 10-30 times the intravenous dose of FR34235 was required, far lower than that required of nicardipine. In atrioventricular (AV) and sinoatrial node preparations, FR34235 was weaker in impairing AV conduction than nifedipine, in spite of their similar potencies in increasing coronary flow and decreasing sinus rate. FR34235 was more potent than diltiazem in increasing coronary flow, in spite of their similar potencies on AV conduction. It is concluded that FR34235 has: (a) potent vasodilating activity, probably due to inhibition of Ca2+ influx into the cells; (b) selective and long-lasting effects on the coronary and cerebral arteries in vivo; (c) a wide difference between doses that cause vasodilation and an impairing effect on AV conducting tissues; and (d) therapeutic effects after absorption from the intestinal tract.

Preparation of Hydrophobically Modified Poly(amidoamine) Dendrimer-Encapsulated Gold Nanoparticles in Organic Solvents.

HAuCl(4) in aqueous solution was extracted to toluene or chloroform using a hydrophobically modified poly(amidoamine) dendrimer. Then, by reduction of Au(3+) ions with dimethylamineborane, gold nanoparticles in the size range of 2-4 nm were obtained in toluene or chloroform. It is suggested that gold nanoparticles are encapsulated by the dendrimer. Copyright 2000 Academic Press.