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Biomedical subjects

W I Higuchi

Publications and source records attributed to W I Higuchi.

At least 91 records · Page 5Linked to original sources
PubMed1990

Equilibrium dialysis studies on aqueous taurocholate-lecithin solutions: further validation of the method.

Since the 1980 publication by Mazer, Benedek and Carey on the concept of the simple micelle-mixed micelle coexistence phenomenon in the bile salt-lecithin systems, it became apparent that a reliable method was needed for measuring the coexisting species concentrations. We recently published a method based on membrane dialysis equilibrium, and the purpose of this report is to review and to validate this previous work. In the present studies, two dialysis membranes with molecular weight cut-off of 8,000 and 12,000 to 14,000 Da, respectively, and two sets of solution volume conditions were investigated with the taurocholate-lecithin system. Coexistence data were obtained over a wide range of lecithin concentrations and the results were found to be in good agreement with those from the previous studies. The bile salt/lecithin molar ratios for the mixed micelles were also deduced from the data. The principal conclusion of this study is that although there is a moderate amount of variability (10% to 15%), the method is both satisfactory and useful in studying bile salt-lecithin equilibria and dynamics.

Bile Acids and Salts↗
PubMed1990

Cholesterol monomer activity and its role in understanding cholesterol saturation and crystallization.

Cholesterol in bile has been linked to the incidence of gallstone disease through the concept of supersaturation as measured by the cholesterol saturation index. The latter is a linear function of cholesterol concentration and is based on the assumption that all cholesterol in bile is solubilized and transported in bile salt-lecithin mixed micelles and in bile salt simple micelles. In light of the discovery of the cholesterol-lecithin vesicles as significant cholesterol carriers, there is a need to reevaluate this old concept. This study examined the feasibility of the silicone polymer uptake method for the direct determination of the cholesterol thermodynamic activity in model bile systems. In cases of unsaturation and near saturation, a linear relationship was observed between the cholesterol concentration in the silicone polymer at equilibrium and the cholesterol saturation index (the cholesterol concentration in the aqueous micellar solution at equilibrium/cholesterol monohydrate solubility in the same medium) for taurocholate and taurochenodeoxycholate systems either containing or not containing lecithin. In taurocholate-lecithin solutions supersaturated with cholesterol, the linear relationship continued to hold up to the point where vesicles started to form. Vesicle formation initiated a negative deviation from linearity. At constant lecithin concentration, the cholesterol thermodynamic activity at which vesicle formation began was a function of the taurocholate/lecithin ratio; the larger the taurocholate/lecithin ratio, the higher the cholesterol thermodynamic activity for the onset of vesicle formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile↗
PubMed1989

Transdermal iontophoretic drug delivery: mechanistic analysis and application to polypeptide delivery.

Three factors are of primary importance in determining the iontophoretic flux of a charged solute: the electrochemical potential gradient across the skin, an increase in skin permeability to passive transport due to iontophoresis (loosely defined as skin damage), and a current-induced water flux. The latter two factors can also affect the transport of uncharged solutes during iontophoresis. A method of correcting for the skin damage effect is introduced. The contributions of the water transport effect relative to that of the applied voltage drop for charged solutes is estimated. It is shown that the water transport contribution is generally lower than the contribution due to the applied voltage drop. The observed iontophonetic flux of the enhancement factors due to the applied voltage drop alone are compared with the theoretical predictions based on the constant field assumption. It is shown that the theoretical predictions are higher than the experimental observations. This work also examines, for the first time, a synergism of iontophoresis and pretreatment with a chemical penetration enhancer as a means for delivering high molecular weight polypeptides. It is shown that a 2-h pretreatment with absolute ethanol followed by iontophoresis dramatically increases the permeability coefficient of insulin through human skin.

Administration, Cutaneous↗
PubMed1989

Effects of long-term hydration leading to the development of polar channels in hairless mouse stratum corneum.

Dramatic increases in in vitro permeability coefficients have been observed following the long-term hydration (days) of hairless mouse skin. The effect is greatest for extremely polar or ionized solutes. Differential scanning calorimetry has been utilize in complementary studies in an attempt to assess if the altered permeability may be due to the irreversible alteration of lipid fluidity or keratin structure. The melting range of the lipid endotherms appears to be unaffected when stratum corneum is subjected to hydration conditions similar to those in the permeability experiments. Endotherms attributed to keratin appear to be altered by long-term hydration. However, no quantitative correlation was found between the keratin endotherm area and the permeabilities. The permeability data fit a model where the total permeability coefficient at a given time is the sum of the permeability coefficients associated with the lipid route and the polar route. Permeation increases with hydration time due primarily to alteration of the polar route. Based on molecular weight, no limitation of diffusion in the polar pathway was detected.

Animals↗
PubMed1989

Dose-dependent enhancement effects of azone on skin permeability.

In vitro permeability experiments have been combined with differential scanning calorimetry (DSC) studies in an attempt to address the dose-dependent influence of Azone on the permeability coefficients of solutes for hairless mouse stratum corneum. A spray technique was developed to deliver uniformly and quantitatively small amounts of Azone to the stratum corneum. Permeability data obtained for several model solutes of varying lipophilicity suggest lipid fluidization and polar route enhancement as the mechanisms of action for Azone. Alkanols and steroids, both of which are enhanced primarily by lipid fluidization, had different degrees of relative enhancement. This provides evidence that the stratum corneum barrier is heterogeneous, rather than a homogeneous slab barrier. Two effects of Azone on the stratum corneum were detected by DSC. A decrease in the area and a shift to lower temperatures were noted for the lipid endotherms with increasing doses of Azone. A lipid fluidizing effect would qualitatively account for the increases in the permeability coefficients noted for more lipophilic solutes. The stratum corneum keratin endotherm also appears to be altered in the presence of Azone. It is possible that alteration of the keratin structure could lead to the development of polar routes in the stratum corneum.

Animals↗
PubMed1989

Electron probe micro-analysis for subsurface demineralization and remineralization of dental enamel.

A quantitative study of fluoride distribution profile changes in dental enamel was conducted by means of electron probe micro-analysis (EPMA). Fluoride-deposited hydroxyapatite powders were chosen as fluoride standards, and analytical conditions were optimized. The lower limit of detection for fluoride was estimated to be 270 ppm, with an accelerating voltage of 5 kV, a specimen current of 40 nA, and a counting time of 40 seconds. Fluoride profiles in fluoride-treated dental enamel, which exhibited intact surface layers and subsurface demineralization, were determined. The results were also compared with those of an acid-abrasion method, and reasonable consistency was found between these two methods, although the acid-abrasion procedure yielded a slightly lower fluoride content in the initial layers, followed by a higher content of fluoride in the deeper layers. The precision of fluoride profile data obtained from EPMA permits further studies to be conducted on the kinetics of subsurface demineralization and intact surface layer formation ("white spot" formation) which is observed during the acid challenge of dental enamel.

Animals↗
PubMed1989

Quantitative study of fluoride transport during subsurface dissolution of dental enamel.

Previous studies using bovine dental enamel as a model have shown that surface and subsurface dissolution of enamel may be governed by micro-environmental solution conditions. We have now investigated the demineralization phenomenon more rigorously with the primary objective of developing a method for deducing solution species concentration profiles as a function of time from appropriate experimental data. More specifically, in this report, a model-independent method is described for determination of the pore solution fluoride gradients in bovine enamel during subsurface demineralization. Microradiography was used to determine the mineral density profiles, and an electron microprobe technique to determine total fluoride (F) profiles associated with the enamel. In each case, matched sections of bovine enamel were exposed to partially saturated acetate buffers at pH = 4.5 containing 0.5 ppm F for various periods of time (from six to 24 hours). The treated enamel was found to have an intact surface layer and subsurface demineralization. The extent of the demineralization and the depths of the lesions increased with time in all cases. The data were first used to calculate (a) the total F gradients in the enamel at various times, and (b) the local uptake rate of F as a function of time and position. Then, by manipulation of the equations describing the uptake and transport of F, we calculated the pore diffusion rate of F and the micro-environmental solution F concentration in the aqueous pores as a function of time and of distance from the enamel surface. It was also possible to calculate an intrinsic F diffusion coefficient in the pores, which was about 1.0 X 10(-5) cm2/sec, in good agreement with reported values. 14C-sucrose uptake and release experiments with identically prepared demineralized enamel sections were also conducted to provide an independent check on the assumed dependence of porosity on mineral density. The results of this investigation, especially the outcomes relative to this new method for determination of pore solution F gradients during acid attack of the dental enamel, should be valuable in future studies of the mechanism(s) of the action of F in inhibiting dental enamel demineralization.

Animals↗
PubMed1988

Silicone polymer uptake method for determination of cholesterol thermodynamic activity in model bile systems.

Cholesterol in bile has been linked to the incidence of gallstone disease through the concept of supersaturation as measured by the cholesterol saturation index (CSI). The latter is a linear function of cholesterol concentration and is based on the assumption that all cholesterol in bile is solubilized and transported in bile salt-lecithin (BS-L) mixed micelles, as well as in bile salt simple micelles. In light of the discovery of the cholesterol-lecithin vesicles as significant cholesterol carriers, there is a need to re-evaluate this old concept. This study examined the feasibility of the silicone polymer uptake method for the direct determination of the cholesterol thermodynamic activity (AT) in model bile systems. In cases of unsaturation and near saturation, a linear relationship was observed between CSP,Eq, the cholesterol concentration in the silicone polymer at equilibrium, and CAq,Eq/Cs,Aq for taurocholate (TC), taurochenodeoxycholate (TCDC), and tauroursodeoxycholate (TUDC) systems either containing or not containing lecithin. Here, CAq,Eq is the cholesterol concentration in the aqueous micellar solution at equilibrium, and Cs,Aq is the cholesterol monohydrate solubility of the same medium. In TC-L solutions supersaturated with cholesterol, the linear relationship continued to hold up to the point where vesicles started to form. Vesicle formation initiated a negative deviation from linearity. At constant lecithin concentration, the CSP,Eq value, or the cholesterol thermodynamic activity at which vesicle formation began, was a function of the TC:L ratio; the larger the TC:L ratio, the higher the cholesterol thermodynamic activity for the onset of vesicle formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile↗
PubMed1988

Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum.

The relationship between the permeability of solutes undergoing transport via the lipid pathway of the stratum corneum and the degree to which the same solutes partition into the stratum corneum has been explored by measuring the permeability coefficients and stratum corneum/water partition coefficients of a series of hydrocortisone esters varying in lipophilicity. Isolated human stratum corneum, used in both the permeability and the uptake experiments, was shown to resemble full-thickness skin in its overall resistance and selectivity to solute structure. As with full-thickness skin, delipidization destroys the barrier properties of isolated stratum corneum. Although a linear relationship is frequently assumed to exist between permeability coefficients and membrane/water partition coefficients, a log-log plot of permeability coefficients versus the intrinsic stratum corneum/water partition coefficients for the series of hydrocortisone esters studied is distinctly nonlinear. This nonlinearity arises from the fact that the transport of these solutes is rate limited by a lipid pathway in the stratum corneum, while uptake reflects both lipid and protein domains. From the relative permeability coefficients of 21-esters of hydrocortisone varying in acyl-chain structure, group contributions to the free energy of transfer of solute into the rate-limiting barrier microenvironment of the stratum corneum lipid pathway are calculate for a variety of functional groups including the -CH2-, -CONH2, -CON(CH3)2, -COOCH3, -COOH, and -OH groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1987

An experimental skin sandwich flap on an independent vascular supply for the study of percutaneous absorption.

Further insights into the composite interactive processes of topically applied agents and percutaneous absorption and metabolism by functional skin in vivo have been hampered by the lack of a model system wherein the blood flow to and from the skin is independent but experimentally accessible. Utilizing microsurgical techniques, split-thickness skin grafting with syngeneic skin grafts, and the congenitally athymic (nude) rat, a skin sandwich flap system has been generated that has an independent but accessible vasculature and thus fills this void. We describe the methodology that has been developed to create the flap and present experiments that: demonstrate a lack of significant collateral circulation; quantify the microcirculation of the skin sandwich flap, host side, and graft side at various times during and after the flap has been generated, and note that blood flow to the flap is basically unchanged from host skin; demonstrate the utility of the system in measuring the amount of [14C]benzoic acid that appears in the flap when deposited on the surface in volatile and nonvolatile vehicles as a function of time; and demonstrate the fact that the flap can be reused, and that the total amount of [14C]benzoic acid absorbed across skin does not change in a substantial way as the flap ages.

Animals↗
PubMed1987

Physicochemical study of percutaneous absorption enhancement by dimethyl sulfoxide: dimethyl sulfoxide mediation of vidarabine (ara-A) permeation of hairless mouse skin.

Dimethyl sulfoxide's (DMSO) concentration-dependent influences on its own permeation rate through hairless mouse skin and on the concurrent permeation rates of water and the antiviral drug vidarabine (ara-A) have been studied at 37 degrees C using in vitro diffusion cells. Solubilities of ara-A in DMSO-water mixtures were also determined in order to assess ara-A's relative thermodynamic activity in the binary solvent media used in the mass transfer studies. Solubilities increased exponentially with increasing percentages of DMSO. Activity coefficients decreased accordingly. When the same DMSO medium was placed in each side of diffusion cell (balanced solvent configuration) permeability coefficients for ara-A decreased exactly as ara-A's solubility increased up to a 50% DMSO concentration, indicating the observed decreases in the mass transfer coefficients have thermodynamic origins. When DMSO media were placed in either the donor or receiver side of the cell up to the same 50% concentration point and opposed by a normal saline medium on the other side (asymmetric solvent configurations), the permeability of ara-A did not decrease and at some DMSO levels was substantially increased, behavior in marked departure from thermodynamic control. The behavior disparity between the 2 configurations of the cell suggests that cross-currents of solvents play a role in permeability enhancement. Regardless of solvent configuration, permeability coefficients for ara-A at 90 and 100% DMSO strengths were exaggeratedly large, consistent with severe impairment of the stratum corneum. Similar overall permeability behavior was observed for the 2 solvents, water and DMSO. Possible underlying mechanisms for these effects and the relative importance of the various mechanisms of DMSO enhancement as a function of DMSO's concentration and configuration are discussed.

Animals↗
PubMed1987

Physical model for non-steady-state dissolution of dental enamel.

The purpose of this study was to provide a rigorous theoretical understanding of the dissolution behavior of dental enamel over the entire time-course of demineralization and to simulate by computer an erosion-type caries lesion according to the physical "hydroxyapatite model". The appropriate diffusion equations which account for simultaneous diffusion and equilibrium of all species in enamel pores, boundary layer, and bulk solution, and which also take into consideration surface reaction kinetics, were employed to allow for calculation of the micro-environmental solution concentration and changes in the mineral density as a function of time and distance within the enamel. This comprehensive physical model for non-steady-state enamel dissolution also explicitly takes into account changes in the diffusivity and the dissolution rate constant as a function of mineral density. Demineralization experiments were conducted in 0.1 mol/L sink acetate buffer (pH = 4.50, mu = 0.50), with ground bovine dental enamel blocks of known surface area mounted (with beeswax) in a rotating disk apparatus. Mineral density profiles were quantified by means of contact x-ray microradiography. The physical model was used to predict mineral density profiles for given demineralization treatments. The experimental profiles agreed quite well with the predicted profiles, when the effective diffusivity of the enamel was assumed to be a function of porosity and when changes in surface area of the crystallites were taken into consideration.

Animals↗
PubMed1987

Effect of acid type on kinetics and mechanism of dental enamel demineralization.

The influence of acid type (pKa effects) of weak organic acid buffers on dissolution kinetics of dental enamel was critically examined for rigorous testing of the behavioral validity of the physical model of Patel et al. (1987). Quantitative evaluation of this model indicated that monitoring initial dissolution rates was a viable approach to critical testing of the model. Initial dissolution rates were determined in 0.1 mol/L acetate (pKa = 4.77), benzoate (pKa = 4.20), and salicylate (pKa = 2.98) buffers (pH = 4.50, mu = 0.50), with ground bovine enamel blocks of known surface area mounted in a rotating disk apparatus. The Levich theory was used to study dependence of dissolution rates on stirring rates in these buffers. The experimental data were analyzed by the physical model which includes pKa effects, complexation of the buffer anion with the other ions, surface kinetics, simultaneous diffusion and equilibrium of all species in enamel pores, diffusion layer thickness, and bulk solution composition. The KIAP (formula: see text) governing the dissolution reaction and the surface resistance factor were deduced from the model. Dissolution kinetics was also followed in these buffers in the presence of calcium or phosphate common ions. In effect, by conducting both the stirring rate studies and common ion experiments, we derived the driving force function independently by these two techniques. The results obtained in this study were consistent with the model, indicating that pKa effects on the dissolution of dental enamel can be accounted for quantitatively by the model, and it was found that weak acids do not influence either the apparent solubility or the surface reaction process of bovine dental enamel.

Acetates↗
PubMed1986

Physicochemical study of percutaneous absorption enhancement by dimethyl sulfoxide: kinetic and thermodynamic determinants of dimethyl sulfoxide mediated mass transfer of alkanols.

By first determining the thermodynamic activities and activity coefficients of methanol, 1-butanol and 1-octanol in binary dimethyl sulfoxide:water media, it has been possible to separate solubilizing (thermodynamic) effects of dimethyl sulfoxide from its kinetic (diffusive) influence as they relate to the skin permeation of these small, nonelectrolyte alkanols. This was done by normalizing the experimental permeability coefficients found with full-thickness hairless mouse skin membranes to unit activity in the vehicle. When the dimethyl sulfoxide media were placed on both sides of the skin sections in a two compartment diffusion cell, activity-adjusted permeability coefficients of the permeants were invariant to dimethyl sulfoxide concentrations of 50% strength. Thus, up to this concentration and in the absence of net solvent crosscurrents, the permeabilities of methanol, 1-butanol, and 1-octanol appear to be strictly determined by partitioning into the stratum corneum. However, when the dimethyl sulfoxide percentage strength was raised to greater than or equal to 75%, activity-adjusted permeability increased systematically and profoundly, indicating severe barrier impairment with increased diffusion across the horny layer (kinetic effect). When neat dimethyl sulfoxide was placed on both sides of the skin, the experimental permeability coefficients of the three alcohols were maximal and equal in magnitude, suggesting total functional impairment of the stratum corneum. When the dimethyl sulfoxide media were placed in contact with the stratum corneum surface of the skin membranes only, accelerating effects were noted at dimethyl sulfoxide concentrations less than 50%, further supporting the idea that solvent cross flows themselves disrupt the horny structure. The degree of impairment was quantified under all experimental circumstances.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
PubMed1985

Direct membrane method for the study of interface-controlled transport of cholesterol in aqueous media.

Studies were designed to demonstrate the use of a silicone rubber membrane diffusion cell in the mechanistic study of cholesterol mass transfer in aqueous media. The method is shown to be simple, precise, and well suited for delineating conditions which facilitate cholesterol transport. Traditional membrane diffusion resistance was determined with cholesterol solubilized in the nonionic surfactant, polyoxyethylene(10)-nonylphenol ether. The use of a charged surfactant additive, either sodium oleate or benzyldimethyltetradecylammonium chloride, reduced cholesterol membrane flux in a manner consistent with a transport barrier residing in the membrane and micelle interfacial regions. Quantitative determination of total transport resistance was good (CV of greater than 95%) for cases more than 99% interface controlled. Interfacial resistance imparted by the charged surfactant additive was essentially abolished by strong electrolyte (sodium chloride). Electrolyte was utilized in either the upstream or the downstream aqueous compartment to enhance cholesterol transport by a mechanism which is consistent with a marked increase in the frequency of micelle collision with the corresponding membrane surface. When the downstream interfacial component of total transport resistance was "short circuited" by electrolyte in sequential transport runs using the same membrane, a "dumping" of cholesterol by the membrane compartment was observed. Limited studies with a second nonionic surfactant, polyoxyethylene(15)-tridecyl ether, suggest that the structure of separate micelle components may also be related to cholesterol mass transfer which occurs via a micelle collision in the interfacial region.

Cholesterol↗
PubMed1985

Quantitative analysis of the interfacial barrier to membrane transport of cholesterol solubilized in a charged micellar system.

The transport of cholesterol solubilized in polyoxyethylene(10)-nonylphenol ether with benzyldimethyltetradecylammonium chloride additive (4:1, w/w) was studied in a diffusion cell separated by a silicone rubber membrane. Overall kinetics revealed the presence of an interfacial barrier. Additions of NaCl or Na2SO4 abolished the barrier to the extent that total cholesterol flux was essentially limited by membrane diffusion considerations. The results are consistent with the concept of micelles diffusing in an electrical field followed by a collision-complex transfer of cholesterol in the aqueous-membrane interfacial region. The electrostatic force of repulsion arises from the overlap of diffuse electrical double layers emanating from the charged mixed micelle and the cationic surfactant adsorbed on the membrane. The influence of surfactant concentration on cholesterol transport kinetics was consistent with electrostatic phenomena. The derived physical model focused on interfacial electrical properties in the donor chamber by maintaining a high concentration (greater than or equal to 0.1 M) of strong electrolyte in the receiver. A linear regression of the logarithm of theoretical transport resistance, total resistance less membrane and receiver boundary layer resistances, versus (ionic strength)1/2 in the donor resulted in a reasonable estimate of the total surface potential of the micelle and membrane surfaces as well as the net dispersion attraction constant.

Chemical Phenomena↗
PubMed1985

Evaluation of lincomycin as a cholesterol gallstone dissolution rate accelerator.

These studies were undertaken to test the hypothesis that interfacial resistance may be an important rate-limiting factor in cholesterol gallstone dissolution. The addition of lincomycin hydrochloride to the gallbladder bile of dogs in an in vitro bath system resulted in an acceleration in the rate of dissolution of a compressed cholesterol monohydrate pellet incubating in the bile. However, the constant infusion of lincomycin for 13 d directly into the gallbladders of conscious, unrestrained dogs, which resulted in biliary lincomycin concentrations comparable to that of the in vitro tests, did not alter the dissolution rate of a compressed cholesterol monohydrate pellet which had been surgically placed into the gallbladder. We therefore conclude that the interfacial resistance between the cholesterol monohydrate pellet and the bile may be reduced by the addition of lincomycin to the gallbladder bile which, in the in vitro environment, results in an acceleration in the rate of dissolution of compressed cholesterol pellets. However, the ineffectiveness of lincomycin in accelerating the dissolution of cholesterol pellets in vivo suggests that interfacial resistance is not the only rate-limiting factor in gallstone dissolution. Other factors, such as mixing, may also be critical.

Animals↗