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Biomedical subjects

W I Higuchi

Publications and source records attributed to W I Higuchi.

At least 109 records · Page 6Linked to original sources
PubMed1985

Examination of the Sephadex G10 beads uptake method for determination of bile salt monomer concentration in taurocholate-lecithin solutions.

Experiments have been undertaken to examine the validity of the method of Ammon and Walter for the determination of bile acid monomer concentrations in taurocholate-lecithin (TC-L) solutions. The procedure involves, basically, the uptake of the bile acid monomer by Sephadex G10 beads (exclusion limits 700 Da) in the presence of a suitable aqueous phase marker (raffinose). Several of the experimental variables involved in the bead-washing technique have been critically studied, and good precision in data (SD in the range of +/- 2-5% of the mean value) has been obtained. Monomer concentrations determined in the absence of lecithin over a wide range (10-70 mM) of TC were found to be in agreement with those obtained by Ammon. Most important, however, is the finding that TC monomer concentrations at constant NMBS were found to be constant in all solutions containing or not containing lecithin [here, the nonmixed micelle bile salt (NMBS) is the total bile salt concentration, but not including species involving lecithin, and is determined by dialysis equilibrium experiments].

Bile Acids and Salts↗
PubMed1985

Influence of 1-dodecylazacycloheptan-2-one (Azone) on the topical therapy of cutaneous herpes simplex virus type 1 infection in hairless mice with 2',3'-di-O-acetyl-9-beta-D-arabinofuranosyladenine and 5'-O-valeryl-9-beta-D-arabinofuranosyladenine.

The predictive value of a recently developed physical model was tested in the topical treatment of cutaneous infections caused by herpes simplex virus type 1 in hairless mice with two ester prodrugs of 9-beta-D-arabinofuranosyladenine (ara-A) (1). The tests were conducted with 2',3'-di-O-acetyl-ara-A (4) and 5'-O-valeryl-ara-A (3) topically applied with and without 15% 1-dodecylazacycloheptan-2-one (2) (Azone), a percutaneous penetration enhancer. In addition to the in vivo studies, in vitro diffusion cell experiments with excised, full-thickness skin from hairless mice were conducted to determine the penetration enhancement effects of 2. As previously observed, 2 was able to induce remarkably large (100- to 1000-fold) flux enhancements in these in vitro experiments. Consistent with predictions based on the physical model studies, formulations of 3 and 4 without 2 had little or no influence on the pathogenesis of the herpes simplex virus type 1 infections; when 2 was present in the formulations, both 3 and 4 had dramatic therapeutic effects consistent with the predictions made with the physical model. Prodrug 4 with 2 was especially efficacious in the prevention of virus-induced lesions and in the survival of all animals. Similar results were obtained with acyclovir plus 2 in this model system.

Acyclovir↗
PubMed1985

Cholesterol monohydrate dissolution rate studies in aqueous micellar solutions of alpha-(nonylphenyl)-omega-hydroxydeca(oxyethylene), n-alkylamines, and fatty acids.

The influences of electrical and nonelectrical factors in the interfacially controlled dissolution of cholesterol monohydrate by mixed micelles of alpha-(nonylphenyl)-omega-hydroxydeca(oxyethylene) (polyoxyethylene [10]-nonylphenol ether; POEPE; 1) in combination with long-chain n-alkylamines or fatty acids were investigated and quantified under pH conditions where the amines and fatty acids exist in their charged and uncharged forms. The experimental findings were generally consistent with a mechanism involving micelle collision with the cholesterol surface. A significant interfacial barrier was found with neutral micelles; however, the magnitude of the barrier was smaller with uncharged mixed micelles than with the simple micelles of 1. With charged micelles, the interfacial mass transfer resistance decreased with the addition of sodium chloride to the extent that the interfacial barrier was essentially abolished and the dissolution kinetics became convective/diffusion controlled. The results are consistent with the phenomena of diffusion of charged micelles toward a charged surface, following the classical collision kinetic theory of colloids. The ease in the transfer of cholesterol monohydrate molecules from the crystal surface and into the micelles during the collision step was examined by considering factors affecting the crystal surface as well as those associated with the hydrophobic-hydrophilic structure of the micelle of 1 and the distribution of charged and uncharged amphipathic additives within the basic micelle structure of 1.

Amines↗
PubMed1985

Cholesterol monohydrate dissolution rate studies in aqueous micellar sodium chenodeoxycholate solutions.

The dissolution rate of cholesterol monohydrate in various concentrations of sodium chenodeoxycholate (1) was significantly influenced by the addition of strong electrolytes. The mass transfer resistances decreased with increasing electrolyte concentrations and attained an asymptotic minimum value predicted and experimentally established for the convective/diffusion-controlled situation. Reduction of the interfacial barrier to dissolution was many times more sensitive to Mg2+ than to Na+ at equimolar concentrations. Cholesterol monohydrate solubilities increased nonlinearly with increasing 1 in 0.01 M phosphate buffer at pH 8.0 and was not influenced by the presence of strong electrolytes. Measured diffusion coefficients gave supporting evidence that the effective micellar size remained the same within the various experimental systems up to 116 mM chenodeoxycholate. The experimental findings indicated that the interfacial barrier is electrostatic in character. They are consistent with the phenomenon of diffusion of negatively charged micelles toward a negatively charged cholesterol monohydrate surface and the subsequent collision complex transfer of cholesterol molecules at the crystal surface. The results and mechanistic interpretations are also in accord with the previous model studies on cholesterol monohydrate dissolution in the presence of mixed micelles composed of nonionic and ionic surfactants.

Benzalkonium Compounds↗
PubMed1985

The development of a rat/human skin flap served by a defined and accessible vasculature on a congenitally athymic (nude) rat.

Experience in microvascular surgery on rats and availability of athymic (nude) rats led us to believe that a long-term functional rat/human skin sandwich flap could be generated on a defined and experimentally accessible vasculature on nude rats. Such a system has been developed and validated. Microvasculature has been assessed. The volume of blood to the flap ranges from 1 to 2 ml/min, collateral circulation to the flap exists, but is negligible, and there is little change in the capillary blood flow as the flap ages. The flap can be utilized to study absorption of compounds from a half-cell diffusion chamber or from direct deposition on the skin, and can be utilized to study various parameters of percutaneous absorption, e.g., the effect of hydration on the stratum corneum. Transdermal flux can be determined. Altering the microcirculation directly affects the percutaneous absorption of compounds that are rapidly absorbed. The absorption of benzoic acid through an experimentally vasoconstricted area (iontophoresis of phenylephrine) significantly alters the time to peak absorption, with values being 14 times that of the control site. The system has been utilized to assess metabolic activity of skin in situ using [3H]adenine arabinoside and studying the appearance of its major metabolite, [3H]Ara-H, in flap blood, as well as the back diffusion of this compound into the donor chamber. Recently the human/rat skin sandwich flap component has been developed. With this system, it has been demonstrated that benzoic acid, when applied to the human skin component of the flap has an absorption profile which is quite different from that when benzoic acid is applied to rat skin, peak flux occurred 2 hr after application. This contrasts with 10 min to peak flux when the same experiment is carried out on the rat/rat skin sandwich flap. To our knowledge, the human/rat skin sandwich flap is the first example of a viable, functional human organ that is chronically maintained by a biologic support system which has the added distinction of being on an independent but accessible vasculature. The validation experiments strongly suggest that this system will be important in gaining insights into the more sophisticated in vivo components of skin, relative to toxicology and pharmacology.

Animals↗
PubMed1985

Effect of the absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin.

The effect of the percutaneous absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin has been investigated by an in-vitro permeation technique using 2-chamber diffusion cells. Azone (3% w/v) emulsions were used. Azone enhanced the permeability of drug 10-100 times across the full-thickness skin although there was a lag time about 10 h. The long lag time, however, disappeared with Azone pretreatment. Azone also affected the transport across stripped skin. These results suggest that Azone mainly affects the stratum corneum. It seems to change the diffusivity of drug in that layer and is not so effective against diffusivities in the epidermis and dermis.

Animals↗
PubMed1984

Powder suspension method for critically re-examining the two-site model for hydroxyapatite dissolution kinetics.

A powder dissolution method has been developed, and experiments with the hydroxyapatite suspensions confirm earlier conclusions based on dissolution from hydroxyapatite disks. Although a quantitative assessment of the properties of site 1 was not possible from the data obtained in the present study, a rather accurate and independent evaluation of the properties and the behavior of site 2 of the two-site model for hydroxyapatite dissolution was possible, and the results clearly validate the original two-site model. The present work together with the earlier disk studies show that dissolution from site 2 is well described by a first-order expression, rate = kc2 (Cs2-C), where kc2 is a first-order rate constant, Cs2 is the apparent solubility for site 2 (defined by an ion activity product, KHAP, of the form a10Ca2+PO43-a2OH-, and the solution conditions), and C is the microenvironmental solution concentration of hydroxyapatite. For four different precipitated hydroxyapatite preparations, a single KHAP value of 1 X 10(-128) +/- 1 was found to be consistent with experiments using solutions covering wide ranges of partial saturation and calcium-phosphate ratios. The hydroxyapatite powder and pellet methods (including the data evaluation procedures) now offer a powerful combination for investigating the complex kinetics associated with dental enamel dissolution in particular and enamel chemistry in general.

Calcium↗
PubMed1984

Quantitative microradiography for studying dental enamel demineralization and remineralization.

A method for quantitative determination of mineral density changes in dental enamel has been developed. It utilizes the quantitative microscopy capabilities of image analysis or photometer systems. Characteristic demineralization of bovine enamel in acetate buffers containing calcium and phosphate has been used to demonstrate the results. The method together with chemical kinetic data obtained from spectrophotometric and ion-selective electrode measurements of the bulk solution for calcium, phosphate, and fluoride permit important basic studies to be conducted on demineralization and remineralization of dental enamel.

Animals↗
PubMed1984

Quantitative microradiographic study of simultaneous demineralization/remineralization of dental enamel in weak acid buffers.

The remineralization behavior of weak acid-treated bovine tooth enamel has been investigated using a recently developed quantitative microradiographic method. Acetate buffer solutions at pH 4.5 containing calcium, phosphate, and 10 ppm fluoride were used in this study. When the solution ion activity product ( KFAP = a10CA a6PO4 a2F ) was 1 X 10(-108), the remineralization of the demineralized region was relatively uniform and complete. On the other hand, when the KFAP was approximately less than or equal to 1 X 10(-112), remineralization of the outer 10-20 micron was incomplete. In addition, for the smaller KFAP solutions there was significant demineralization in the deeper recesses of the originally demineralized region. These results agree with a recent chemical kinetics study in which it was proposed that KFAP = 1 X 10(-112) demarcated the region of solution conditions in which remineralization only occurs from that in which simultaneous demineralization/remineralization takes place. A model consistent with all of the data is proposed.

Acids↗
PubMed1984

Physical model approach in the study of the transport of alkyl amines across a silicone rubber membrane in a two-chamber diffusion cell.

The transport of hexylamine and octylamine through a silicone rubber membrane was studied as a function of buffer (phosphate) concentration and pH. The results were interpreted using a physical model which assumed a steady-state rate of transport and which accounted for the simultaneous diffusion and rapid equilibrium of all the aqueous species, the possible diffusion of both the amine and its protonated form through the membrane, and the effect of a stagnant aqueous diffusion layer on each side of the membrane. The following conclusions were reached: The thickness of the aqueous diffusion layer is approximately 100 micron, which is about the same as that previously measured for benzoic acid in this system. Transport of octylamine at pH greater than or equal to 10 is approximately 90% aqueous diffusion layer controlled, whereas hexylamine is approximately 50% aqueous diffusion layer controlled at high pH. The membrane permeability of octylamine is approximately 15-20 times that of hexylamine. This gives an incremental pi constant for the partition coefficient of approximately 0.61, as compared with the previously reported value of 0.56. At low pH (less than or equal to 5), the transport of the protonated species becomes important. The membrane permeabilities of these ammonium ions are about four or five orders of magnitude less than the membrane permeabilities of the corresponding amines. The membranes were examined at 30,000X with the scanning electron microscope, and no evidence of holes was found.

Amines↗
PubMed1984

Mesophase formation during cholesterol gallstone dissolution in human bile: effect of bile acid composition.

Duodenal bile obtained from patients with gallstones who were acutely infused with chenodeoxycholic acid, ursodeoxycholic acid, or cholic acid were examined for the propensity toward the formation of a liquid crystalline mesomorphic phase when cholesterol gallstones were incubated in these bile acids. Bile taken from patients infused with ursodeoxycholic acid was found to be enriched in ursodeoxycholic acid; mesophase formation was detected in these samples but not in bile from patients infused with chenodeoxycholic acid or cholic acid.

Bile↗
PubMed1984

Synthesis and evaluation of a series of 2'-O-acyl derivatives of 9-beta-D-arabinofuranosyladenine as antiherpes agents.

A series of four 9-(2-O-acyl-beta-D-arabinofuranosyl)adenines (5a-d) was synthesized by acylation of 9-[3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-arabinofuranosyl]adenine (2), followed by removal of the tert-butyldimethylsilyl groups under conditions (HOAc, tetra-n-butylammonium fluoride) that prevented acyl migration. The four 2'-O-acyl derivatives 5a-d showed activity in vitro against herpes type 1 viruses [virus ratings = 1.5-2.6; MIC50 = 26-72 micrograms/mL (8.48-21.3 X 10(-5) M)]. The 2'-O-acetyl (5a) and 2'-O-valeryl (5d) derivatives were evaluated in a guinea pig model for genital herpes (herpes type 2); only 5a showed potent activity when given 6 or 24 h postinfection.

Animals↗
PubMed1983

Permeation of skin and eschar by antiseptics I: baseline studies with phenol.

To assess how the permeability of phenol is altered by thermal injury, it was first necessary to have baselines of comparison on normal skin. Using in vitro diffusion cells and the skin of the hairless mouse, [14C]phenol was applied to skin in an aqueous medium with a reference copermeating species, [3H]methanol, and 37 degrees permeability coefficients of the pair were evaluated as functions of animal age, skin hydration, stripping of the skin, dermis isolation, and phenol concentration. Age proved to be of little consequence to permeability over a wide age range. Prolonged aqueous soaking of the skins was also without much effect. Stripping of the skin and isolating the dermis by soaking techniques allowed assessment of individual skin strata diffusion resistances. When applied to skin in trace radiochemical concentrations, phenol behaved diffusionally as an alkanol with a chain length of six. But at concentrations greater than 2% w/v, phenol facilitated the permeation rates of itself and methanol; the effect was markedly concentration sensitive and only fractionally reversible. Concentration studies using silicone rubber membranes proved that the effects on the skin were the results of destroyed barrier integrity. At 6% phenol concentration there was an essentially instantaneous, 10-fold increase in the phenol permeability coefficient, raising it to two-thirds that observed with fully stripped skin. Overall, the data suggest that the stratum corneum is proportionally impaired as the phenol concentration is increased.

Aging↗
PubMed1983

Permeation of skin and eschar by antiseptics II: influence of controlled burns on the permeation of phenol.

The safe antiseptic use of phenol over the burn-traumatized surface depends on knowledge of how the systemic accumulation of phenol is affected by burn processes. To gain insight into the underlying permeation phenomenon, the diffusion of phenol and a reference cosolute, methanol, through both scalded and branded dorsal skin sections of the hairless mouse was studied as a function of burn temperature using in vitro diffusion cells. Temperatures up to 100 and 150 degrees were used for scalding and branding, respectively, using a 60-sec; exposure time. Permeability coefficients of the traumatized skins were assessed at 37 degrees and compared with control values. Coefficients of both permeating species were not increased significantly by burn temperatures up to 70 degrees applied either by scalding or branding, however, at higher temperatures exaggerated increases in permeation rates were noted. A limiting increase of approximately 7 times the control value was noted for phenol irrespective of the burn method. Permeability of methanol was altered even more dramatically and at 100 degrees by scalding and 150 degrees by branding was over 50 times the control rate. At 80 and 100 degrees for methanol and at 80 degrees for phenol, scalding produced larger increases in the permeability coefficients than branding. Since contact for 1 min at 60 degrees is capable of producing a full-thickness burn injury, it is clear that eschar permeability to phenol immediately postburn is not related to the clinical degree of burning, but is a function of the thermal intensity (hotness) of the burn stimulus. Full-thickness wounds can be expected to have highly variable rates of systemic absorption as a direct consequence of the wide-ranging permeability possible for such burns, with the risks of topical application varying accordingly.

Animals↗
PubMed1983

Topical vaginal drug delivery I: effect of the estrous cycle on vaginal membrane permeability and diffusivity of vidarabine in mice.

Preliminary studies showed that the vaginal membrane permeability coefficients for vidarabine (9-beta-D-arabinofuranosyladenine) varied widely within a group of mice of the same species and age. This finding prompted an investigation of the influence of the female mouse sexual cycle on the vidarabine permeability. By means of a vaginal smear technique, the sexual cycle, which was approximately 5 days in duration, was divided into five phases. The vaginal membrane permeability of vidarabine was determined during each phase. The results revealed that the permeability coefficients for vidarabine during the diestrus phase (3 X 10(-6)-4 X 10(-5) cm/sec) were 10-100 times higher than those obtained at the early estrus or estrus phases (1-3 X 10(-7) cm/sec). Further permeation studies on membranes at early estrus and estrus were performed by separating the cornified layer from the noncornified portion of the membrane. The low permeability coefficient of vidarabine across the cornified layer (4 X 10(-7) cm/sec) suggests that this layer may be the major diffusion barrier for vidarabine when the drug is topically applied. Collectively, the data also suggest that during estrus a three-layer diffusion model is appropriate, that during early diestrus a single-layer diffusion model may apply, and that during proestrus and postestrus the situations are intermediate and more complicated.

Animals↗
PubMed1983

Solution activity product (KFAP) and simultaneous demineralization-remineralization in bovine tooth enamel and hydroxyapatite pellets.

The effects of changing the ion activity product of the remineralization solution at pH 4.5 (pKFAP 108-118) on the remineralization behavior of demineralized bovine tooth enamel and hydroxyapatite pellets have been studied. Solutions containing calcium-4.5, phosphate, and fluoride in acetate buffers were used. The 45Ca/F molar ratios indicated the formation of fluoridated hydroxyapatite in the enamel or the pellet when the pKFAP values for remineralizing solutions were less than 112. When the pKFAP values were greater than 112, the 45Ca/F ratios were found to be much less than 5. Also, when the pKFAP values were large (greater than 112), the remineralization patterns based on the fluoride distribution in the tooth (or pellet) were found to be different than when the pKFAP values were small (less than 112). The hypothesis that a pKFAP value of 112 is the demarcation between remineralization only and simultaneous dissolution-remineralization has been proposed based on these results.

Animals↗
PubMed1983

Evaluation of prodrugs of 9-beta-D-arabinofuranosyladenine for therapeutic efficacy in the topical treatment of genital herpesvirus infections in guinea pigs.

Prodrugs of the antiviral agent 9-beta-D-arabinofuranosyladenine (araA), which were more effective than the parent compound in penetrating vaginal membranes in vitro, were synthesized and examined for efficacy in the topical treatment of genital infections with herpes simplex virus type 2 in female guinea pigs. Treatment with 10% araA-5'-monophosphate or 10% araA-5'-monovalerate twice a day for 7 days, starting 6 h after intravaginal inoculation with virus, completely aborted the primary infection. When initiation of treatment was delayed until 24 h postinfection, araA-5'-monophosphate and araA-5'-monovalerate were no longer effective in reducing the mean lesion scores or mean vaginal virus titers. Treatment with 5% acyclovir, starting at 24 h postinfection, failed to prevent genital lesion development but significantly reduced the peak mean lesion score (approximately 50%). Topical therapy with 10% araA-2',3'-diacetate, initiated at 24 h postinfection, was as effective as, if not more effective than, acyclovir in reducing the severity of herpes genitalis in guinea pigs. Treatment with 10% araA-2',3'-dipropionate or 10% araA-2',3'-dibutyrate was without benefit. Among a series of 5'-monoesters of araA, araA-5'-monobutyrate appeared to be the most effective but was less active than araA-2',3'-diacetate. These data indicate that araA-2',3'-diacetate may be an effective antiviral agent for topical use against genital herpesvirus infections.

Acyclovir↗