Biomedical subjects
I Ueda
Publications and source records attributed to I Ueda.
New 2-aryliminoimidazolidines. II. Synthesis and antihypertensive activity of 2-(biphenylimino)-imidazolidines.
For improvement of the duration of action of FR35447 (I), 2-(biphenylimino)imidazolidines (III) were synthesized and their hypotensive activity was tested against conscious normotensive rats. 2-(4'-Fluoro-[1,1'-biphenyl]-2-ylimino)imidazolidine (IIIl) exhibited superior hypotensive potency and was comparable to clonidine (II) in its duration of action. The structure-activity relationships of III are also described.
Effect of a new non-steroidal anti-inflammatory combination of a histamine H2 antagonist and indomethacin on gastroduodenal mucosal membrane in rat.
The new non-steroidal anti-inflammatory drug (NSAID), N-(3-[3-(piperidinyl-methyl) phenoxy] propyl)-carbamoyl-methylthio]ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolyl-acetate (CP 331, CAS 127966-70-5), a compound with a structure of an ester combining indomethacin (IM) and a histamine H2 antagonist, has been reported to have anti-inflammatory, analgesic and antipyretic effects. However, the influence of CP-331 on the gastroduodenal mucosa was not fully investigated. Therefore this study was undertaken to investigate the effect of CP-331 on the gastroduodenal mucosa membrane in rats. After single oral drug administration, the UD50 value (50% ulcerogenic dose) of CP-331 calculated from the incidence rate of gastric ulcer was higher than 1000 mg/kg; that for IM was 5.2 mg/kg. Moreover it was examined whether CP-331 had a preventive effect on NSAID-induced gastric damage. The results showed that the co-administration of CP-331 10-30 mg/kg prevented significantly the acute gastric mucosal injury caused by IM administration (20 mg/kg). CP-331 with anti-inflammatory activity does not cause gastric injury, moreover, because of its preventing and therapeutic effects on the damage to gastric mucous membrane induced by IM, CP-331 might be useful in the treatment of gastropathy caused by NSAID in clinic.
Anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of the new anti-inflammatory drug N-(3-[3-(piperidinylmethyl)phenoxy]propyl)-carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate.
The anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of N-(3-[3-(piperidinylmethyl) phenoxy] propyl)- carbamoylmethylthio] ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate (CP-331, CAS 127966-70-5), a new anti-inflammatory drug, were evaluated using indomethacin as a control. CP-331 exerted anti-inflammatory, analgesic and antipyretic effects on the models of carrageenin-induced paw edema, increased vascular permeability, ultraviolet light-induced erythema, granuloma proliferation, adjuvant arthritis, inflammatory pain, and yeast-induced fever. However, these effects were observed at a molar level similar to or higher than that of indomethacin. In addition, CP-331 influenced more markedly than indomethacin the delayed type hypersensitivity to sheep red blood cells. On the other hand, CP-331 did not damage the gastric mucosa even at a high dose of 1,000 mg/kg and also induced slighter damage to the intestinal mucosa than indomethacin. Thus, CP-331 exerted anti-inflammatory, analgesic, and antipyretic effects but without showing gastric toxicity, which is a common side effect of anti-inflammatory drugs. These results suggest the clinical applicability of this drug in the long-term therapy of inflammatory diseases such as rheumatoid arthritis.
High pressure antagonism of alcohol effects on the main phase-transition temperature of phospholipid membranes: biphasic response.
The combined effects of high pressure (up to 300 bar) and a homologous series of 1-alkanols (ethanol C2 to 1-tridecanol C13) were studied on the main phase-transition temperature of dipalmitoylphosphatidylcholine (DPPC) vesicle membranes. It is known that short-chain alkanols depress and long-chain alkanols elevate the main transition temperature. The crossover from depression to elevation occurs at the carbon-chain length about C10-C12 in DPPC vesicle membranes coinciding with the cutoff chain-length where anesthetic potency suddenly disappears. Alkanols shorter than C8 linearly decreased the transition temperature and high pressure antagonized the temperature depression. Alkanols longer than C10 showed biphasic dose-response curves. High pressure enhanced the biphasic response. In addition, alkanols longer than the cutoff length depressed the transition temperature under high pressure at the low concentration range. These non-anesthetic alkanols may manifest anesthetic potency under high pressure. At higher concentrations, the temperature elevatory effect was accentuated by pressure. This biphasic effect of long-chain alkanols is not related to the 'interdigitation' associated with short-chain alkanols. The increment of the transition temperature by pressure was 0.0242 K bar-1 in the absence of alkanols. The volume change of the transition was estimated to be 27.7 cm3 mol-1. This value stayed constant to the limit of the present study of 300 bar.
A statistical mechanical analysis of the effect of long-chain alcohols and high pressure upon the phase transition temperature of lipid bilayer membranes.
Long-chain n-alcohols decrease the main phase-transition temperature of lipid vesicle membranes at low concentrations but increase it at high concentrations. The nonlinear phenomenon is unrelated to the interdigitation and is analyzed by assuming that alcohols form solid solutions with solid as well as liquid phases. The biphasic response originates from the balance of the free energy difference of alcohols in the liquid and solid membranes (delta gA) and the alcohol-lipid interaction free energy difference (delta u) between the two phases. When delta gA less than 0 and delta u greater than 0, or delta gA less than delta u less than 0, the transition temperature decreases monotonously according to the increase in the alcohol concentration. When delta gA greater than 0 and delta u less than 0, or delta gA greater than delta u greater than 0, it increases monotonously. Biphasic response occurs with a minimum temperature when delta u greater than delta gA greater than 0, and with a maximum temperature when delta u less than delta gA less than 0. When the alcohol carbon-chain length becomes closer to the lipid carbon-chain length, delta u is equalized by delta gA, and the temperature minimum of the main transition is shifted to extremely low alcohol concentrations. Hence, long-chain alcohols predominantly elevate the main transition temperature and lose their anesthetic potency. High pressure decreased both delta gA and delta u. Presumably, high pressure improves the packing efficiency of liquid membranes and decreases the difference between the solid and liquid membrane properties.
Interfacial dehydration by anesthetics: an electrocapillary study of surface charge density of adsorbed monolayer.
We have proposed that anesthetics destruct the hydration shell of macromolecules irrespective of lipid membranes or proteins. These macromolecular structures are supported by the hydrogen-bonded matrix of water molecules. A loss of this support destabilizes the membranes and proteins. The disordered structures are suboptimal for the assigned biological functions, and anesthesia may ensue. We postulated that the dehydration is prompted mainly by the decrease in the interactions of the surface charges with the water dipole. To prove or disprove the above hypothesis, this study measured the effect of volatile anesthetics (chloroform, halothane, and enflurane) on the surface charge density in adsorbed monolayers by an electrocapillary method. The oil phase was methylisobutylketone (MIBK) with cetyltrimethylammonium chloride (CTAC). The aqueous phase was 0.1 M NaCl. The anesthetics decreased the surface charge density, and the effect paralleled the clinical anesthetic potency. At concentrations that induce surgical stage anesthesia in 50% of the population, these anesthetics reduced the surface charge density by 5%.
Anesthetic-protein interaction: effects of volatile anesthetics on the secondary structure of poly(L-lysine).
Effects of volatile anesthetics (chloroform, halothane, and enflurane) on the secondary structure of poly(L-lysine) were analyzed by circular dichroism (CD). The relative proportions among alpha-helix, beta-sheet, and random-coil conformations were calculated by the curve-fitting method on the CD data. Volatile anesthetics partially transformed alpha-helix to beta-sheet but not to random-coil under the present experimental condition. When expressed by the anesthetic partial pressures in the gas phase in equilibrium with the solution, the values that partially transformed alpha to beta conformation by 10% were 1.1 x 10(-2), 4.7 x 10(-2), and 7.9 x 10(-2) atm for chloroform, halothane, and enflurane, respectively. The order of potency is in reasonable agreement with the order of the anesthetic potencies of the agents. The alpha-to-beta transition was completely reversible when anesthetics were purged by nitrogen gas. Volatile anesthetics disrupted the hydrogen bonds of alpha-helix backbones and rearranged them to form the beta-sheet conformation. The beta-sheet conformation is stabilized mainly by the hydrophobic interaction among methylene side groups of poly(L-lysine). Volatile anesthetics promoted the transition by enhancing the hydrophobic interaction among side-chains and by rearranging the hydrogen bonds in the peptide backbone.
Effect of inhalation anesthetics on swimming activity of artemia salina.
The swimming movement of artemia salina in the artificial sea water was measured by using the video camera system in the absence and presence of anesthetics, i.e. enflurane, halothane, and isoflurane. The movement of artemia looked random at a glance but the obtained distribution curve for the swimming speed was skewed toward the high speed side somewhat resembling a Maxwellian distribution curve seen in the statistics of ideal gases. When anesthetic were added, the distribution curve became sharpened and shifted to the low speed side, which is similar to a behavior of ideal gases when they are cooled down. The mean swimming-speed was decreased eventually leading to an irreversible death with increasing the anesthetic dose. The activity was analyzed by using the hydrodynamic equation. The ED(50), which is a dose that causes a 50% reduction in the activity, of all anesthetics used in this study was quite similar to the MAC values for human. It was also suggested that an interaction between anesthetics and artemia was highly cooperative since the larger Hill coefficients were obtained for all three anesthetics used.
Application of a sucrose indicator strip to evaluate salivary sucrose clearance.
This study examined salivary sucrose clearance times of 96 subjects using sucrose indicator strips. Subjects with high caries experience had a longer salivary sucrose clearance time than those with a low caries experience. The flow rate of unstimulated but not of stimulated saliva was significantly related to sucrose clearance. This finding is consistent with that of other studies on salivary clearance. The sucrose indicator strips are simple to use and sucrose clearance tests using these strips do involve instrumental analyses. It is concluded that the strips investigated are simple and effective and merit further investigation.
Two-state model for nerve excitation and local anesthetic action.
Explore the source record for details and available documents.
Antiulcer agents. II. Synthesis and gastric acid antisecretory activity of N-[3-(3-(piperidinomethyl)phenoxy)propyl]-4-(1-methyl-1H- tetrazol-5-ylthio)butanamide and related compounds.
N-[3-(3-(Piperidinomethyl)phenoxy)propyl]butanamides having a 1-methyl-1H-tetrazol-5-ylthio moiety as a pharmacophore and related compounds were prepared and tested for their antisecretory activity against histamine-induced gastric acid secretion in conscious rats with gastric fistulas. Most of the compounds showed antisecretory activity. Among them, N-[3-(3-(piperidinomethyl)phenoxy)propyl]-4-(1-methyl-1 H-tetrazol-5-ylthio)butanamide (5f) was found to posses the most potent activity, and a possibility of isosteric replacement of the methoxycarbonyl group with 1-methyl-1H-tetrazol-5-yl group was indicated. The structure-activity relationships are also discussed.
Design, synthesis and antiinflammatory activity of a new indomethacin ester. 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate.
A novel indomethacin ester prodrug, 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (1) was prepared from a new histamine H2-receptor antagonist, N-[3-(3-(piperidinomethyl)phenoxy)propyl]-2-(2-hydroxyethylthio )acetamide (2) and indomethacin (3). The compound 1 was shown to be essentially similar to 3 in its antiinflammatory action and to almost completely inhibit carrageenin-induced hind-paw edema in the rat at a very high dose of 230 mg/kg (280 mumol/kg), which is comparable to that of 100 mg/kg (280 mumol/kg) of 3, without producing gastric lesions. On a molar basis, the acute gastric lesioning properties of 1 were near one-hundred times less than those of 3, resulting in over a twenty-fold improvement in the ratio of antiedema activity to ulcerogenicity. The effect of the co-administration of histamine H2-receptor antagonists on antiedema activity and ulcerogenicity caused by 3 is also discussed.
A solid-solution theory of anesthetic interaction with lipid membranes: temperature span of the main phase transition.
Anesthetics (or any other small additives) depress the temperature of the main phase transition of phospholipid bilayers. Certain anesthetics widen the temperature span of the transition, whereas others do not. The widening in a first-order phase transition is intriguing. In this report, the effects of additive molecules on the temperature and its span were explained by the solid-solution theory. By assuming coexistence of the liquid-crystal and solid-gel phases of lipid membranes at phase transition, the phase boundary is determined from the distribution of anesthetic molecules between the liquid-crystal membrane versus water and between the solid-gel membrane versus water. The theory shows that when the lipid concentration is large or when the lipid solubility of the drug is large, the width of the transition temperature increases, and vice versa. Highly lipid-soluble molecules, such as long-chain alkanols and volatile anesthetics, increase the width of the transition temperature when the lipid:water ratio is large, whereas highly water-soluble molecules, such as methanol and ethanol, do not. The aqueous phase serves as the reservoir for anesthetics. Depletion of the additive molecules from the aqueous phase is the cause of the widening. When the reservoir capacity is large, the temperature width does not increase. The theory also predicts asymmetry of the specific heat profile at the transition.
Proton flow along lipid bilayer surfaces: effect of halothane on the lateral surface conductance and membrane hydration.
Impedance dispersion in liposomes measures the lateral charge transfer of lipid membrane surfaces. Depending on the choice of frequency between 1 kHz and 100 GHz, relaxation of the counterions at the interface, orientation of the head group, and relaxation of the bound and free water are revealed. This study measured the impedance dispersion in dipalmitoylphosphatidylcholine (DPPC) liposomes at 10 kHz. The surface conductance and capacitance showed breaks at pre- and main transition temperatures. Below the pre-transition temperature, the activation energy of the ion movement was 18.1 kJ.mol-1, which corresponded to that of the spin-lattice relaxation time of water (18.0 kJ.mol-1). At temperatures between pre- and main transition it increased to 51.3 kJ.mol-1, and agreed with 46.2-58.0 kJ.mol-1 of the activation energy of the dielectric relaxation of ice. Because the present system was salt-free, the ions were H3O+ and OH-, hence, their behavior represents that of water. The above results show that below the pre-transition temperature, the conductance is regulated by the mobility of free ions, or the number of free water molecules near the interface. On the other hand when the temperature exceeded pre-transition, melting of the surface-bound water crystals became the rate-limiting step for the proton flow. Halothane did not show any effect on the ion movement when the temperature was below pre-transition. When the temperature exceeded pre-transition, 0.35 mM halothane (equilibrium concentration) decreased the activation energy of the ion movement to 29.3 kJ.mol-1. This decrease indicates that halothane enhanced the release of the surface-bound water molecules at pre-transition. The surface-disordering effect of halothane was also shown by depression of the pre-transition temperature and decrease of the association energy among head groups from 9.7 kJ.mol-1 of the control to 5.2 kJ.mol-1 at 0.35 mM.
Anesthesia cutoff phenomenon: interfacial hydrogen bonding.
Anesthesia "cutoff" refers to the phenomenon of loss of anesthetic potency in a homologous series of alkanes and their derivatives when their sizes become too large. In this study, hydrogen bonding of 1-alkanol series (ethanol to eicosanol) to dipalmitoyl-L-alpha-phosphatidylcholine (DPPC) was studied by Fourier transform infrared spectroscopy (FTIR) in DPPC-D2O-in-CCl4 reversed micelles. The alkanols formed hydrogen bonds with the phosphate moiety of DPPC and released the DPPC-bound deuterated water, evidenced by increases in the bound O-H stretching signal of the alkanol-DPPC complex and also in the free O-D stretching band of unbound D2O. These effects increased according to the elongation of the carbon chain of 1-alkanols from ethanol (C2) to 1-decanol (C10), but suddenly almost disappeared at 1-tetradecanol (C14). Anesthetic potencies of these alkanols, estimated by the activity of brine shrimps, were linearly related to hydrogen bond-breaking activities below C10 and agreed with the FTIR data in the cutoff at C10.
Spontaneous oscillation of artificial membrane: equivalence in effects of temperature and volatile anesthetic.
Oscillatory phenomenon at an oil-water interface in the presence of hexadecyltrimethylammonium bromide (CTAB) has been studied. The oscillation was attributable to successive formation and destruction of surfactant monolayer. According to the temperature elevation, the frequency of the electrical oscillation increased whereas the amplitude decreased. Addition of diethylether increased the frequency and decreased the amplitude. These effects of temperature and anesthetic were analyzed by the theory of the "N"-shaped relationship between surface-pressure and surface-concentration of the surfactant.
Infrared spectra of phospholipid membranes: interfacial dehydration by volatile anesthetics and phase transition.
Fourier-transform infrared attenuated total reflection (ATR) spectroscopy was used to study the effect of volatile anesthetics on fully hydrated dipalmitoylphosphatidylcholine (DPPC) vesicle membranes. The main phase transition was monitored by the change in the C-H2 asymmetric stretching frequencies of the lipid tails. The surface property was analyzed by the changes in the P = O stretching, (CH3)3-N+ stretching of the hydrophilic head, and C = O stretching of the glycerol skeleton. The partial pressures of those agents that decreased the transition temperature 1.0 C degree were halothane 0.75, enflurane 1.90 and CCl4 0.85 kPa. At a 2:1 lipid/anesthetic mole ratio, the polar anesthetics, halothane and enflurane, increased the ratio of (P = O stretching band area)/((CH3)3-N+ stretching band area) by 26.3% and 21.1%, respectively, whereas apolar CCl4 increased it 10.5%. The water molecules bound to the P = O moiety are apparently replaced by the anesthetic molecules. The deconvoluted C = O spectra showed two peaks: free sn-1 that is closer to the lipid core and hydrogen-bonded sn-2 that is closer to the polar head. Addition of halothane and enflurane, but not CCl4, increased the number of peaks to three. The third peak is free sn-2, formed by disrupting hydrogen-bonding to water. Because the temperature-induced spectral change was limited to C-H2 stretching at the main phase transition, the effects of anesthetics on the lipid membrane structure are not identical to temperature elevation. Among anesthetics, the effects of apolar and polar molecules on the interfacial properties are different.