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Biomedical subjects

W I Higuchi

Publications and source records attributed to W I Higuchi.

At least 37 records · Page 2Linked to original sources

EPR properties of synthetic apatites, deorganified dentine, and enamel.

Electron paramagnetic resonance spectroscopy (EPR) was used to study synthetic hydroxyapatite and approximately 1, 2, and 6% synthetic carbonated apatites, deorganified dentine, and enamel. The carbonated apatites were synthesized by hydrolysis of dicalcium phosphate. Comparisons were made with spectra from enamel and deorganified dentine. Microwave power saturation and dose responses were determined for the synthetic materials. The Marquardt version of the Levenberg decomposition method was used to extract individual signals from the apatite data. Two samples of dentine were irradiated with 25 and 100 Gy, respectively, from a 60Co source. The first sample was then deorganified at 200 degreesC using the Soxhlet extraction technique. A third sample was irradiated with 100 Gy after deorganification. The resulting EPR spectra were then compared. It was determined that the dosimetric signal of 2% synthetic carbonated apatite was approximately the same as that of enamel. It was also verified that the dosimetric signal saturates at about 2% in synthetic carbonated apatites. The study established that the precenters responsible for the dosimetric signal (g perpendicular = 2.0018, g parallel = 1.9985) are preferentially concentrated in the surface-accessible region of the mineral component, as shown by the approximately 80% attenuation of the dosimetric signal in dentine following deorganification. The precenters responsible are not destroyed by the deorganification since the magnitude of the dosimetric signal from the dentine specimen irradiated following deorganification was approximately twice that of the comparable untreated, irradiated sample. Finally, the dose response of 2 and 6% synthetic carbonated apatites was determined.

Apatites↗

Flux enhancement effects of ionic surfactants upon passive and electroosmotic transdermal transport.

This study focused upon the enhancement effects of ionic surfactants upon passive and electroosmotic transdermal flux. The first phase of the study involved validating theories relating surface properties of a membrane to electroosmotic solvent flow under appropriate experimental conditions using a synthetic model membrane (stack of 50 Nuclepore membranes). Numerical solutions to the Poisson-Boltzmann equation and the equations of fluid motion served as the theoretical basis for the experimental studies. Important outcomes of the model membrane studies were that electroosmotic solvent flow velocity was enhanced by the addition of an anionic surfactant, sodium dodecyl sulfate, and reversed by the addition of a cationic surfactant, dodecyltrimethylammonium bromide. The effective membrane pore wall surface charge densities were determined under a variety of experimental conditions. Adsorption of dodecyl sulfate to the pore wall increased the net negative charge on the pore wall. A reversal of the net pore wall surface charge density resulted from the adsorption of dodecyltrimethylammonium. The interrelationship between electroosmosis, surfactant adsorption, and ionic strength was also evaluated. The second phase of the study was an investigation of the effects of sodium dodecyl sulfate upon the transport of neutral polar permeants through human epidermal membrane (HEM). Fluxes of [14C]urea and [3H]sucrose were simultaneously measured across HEM samples under passive and 250 mV conditions; flux measurements were made before, during, and after HEM exposure to sodium dodecyl sulfate. A systematic analysis of the experimental data made it possible to elucidate the specific contributions of sodium dodecyl sulfate and the applied electric potential to the overall flux enhancement. Sodium dodecyl sulfate enhanced the intrinsic passive permeability of the HEM, and it also enhanced the contribution of electroosmosis to the flux during iontophoresis.

Humans↗

Characterization of the transport pathways induced during low to moderate voltage iontophoresis in human epidermal membrane.

This report describes the results of iontophoresis experiments involving the transport of polar nonelectrolytes across human epidermal membrane (HEM) at a moderate applied voltage of 2.0 V and where the data are interpreted via a convective transport model and hindered transport theory. A principal finding is that although HEM iontophoresis at 2.0 V resulted in a large increase in HEM porosity, the pore radii of the newly induced pores in HEM as calculated from the iontophoresis data using the hindered transport theory were found to be in the range of 6-12 A. This supports the view that electroporation at these modest applied voltages results in pores with sizes the same order of magnitude but somewhat smaller than those estimated for the preexisting pores in HEM prior to electroporation. This outcome is also important from a practical standpoint, as flux enhancement for large molecules (such as oligonucleotides and polypeptides) arising from electroporation under these conditions would be expected to be significantly less than if the resulting pore sizes were much greater. Providing a "prepulse" of 4.0, 8.0, and 15 V prior to the 2.0 V iontophoresis generally gave greater increases in HEM conductance (and, therefore, in porosity) but did not significantly change the deduced effective pore radii (around 5-9 A). The alteration during and the recovery of HEM after iontophoresis was also investigated. The recovery behavior was found to be dependent upon both the duration of the applied voltage and the magnitude of its effects: the recovery for a HEM sample that experienced a large increase in electrical conductance during iontophoresis was generally poorer than that for a sample that was more resistant to the electric field. Incomplete recovery was generally observed in experiments with long iontophoresis duration (50 min) and with the higher voltages (4.0, 8.0 V, and 15 V). In these cases, the barrier properties of HEM were more greatly altered as indicated by larger increases in the electrical conductance and passive permeability of HEM after iontophoresis.

Biological Transport↗

Influence of the permeation enhancers 1-alkyl-2-pyrrolidones on permeant partitioning into the stratum corneum.

In a previous study, the enhancing effects of a series of 1-alkyl-2-pyrrolidones (APs; 1-ethyl, 1-butyl, 1-hexyl, and 1-octyl-2-pyrrolidone) on the transport of steroidal permeants across hairless mouse skin were investigated via a parallel pathway skin model. Isoenhancement concentration conditions were deduced under which different APs induce essentially the same transport enhancement for the lipoidal pathway of the stratum corneum (s.c.). As a continuing effort to understand the mechanism of action of permeation enhancers, the influence of the APs on permeant partitioning into hairless mouse s.c. was investigated under the isoenhancement concentration conditions using beta-estradiol (E2 beta) as the model permeant. The amount of E2 beta uptake into s.c. was found to be essentially the same for all the APs under these isoenhancement conditions. This result suggests that inducing a higher partitioning tendency for E2 beta into the lipoidal pathway of hairless mouse s.c. is a principal mechanism of action of the APs in enhancing transdermal transport. The uptake of the APs into s.c. lipoidal domains was also determined, and the results show only a modest (approximately 2-fold) increase in the uptake of the APs in going from 1-ethyl-to 1-octyl-2-pyrrolidone under isoenhancement conditions. This indicates the potency of the APs as permeation enhancers is only very modestly dependent upon the alkyl chain length in this chain length region when compared at concentrations in the microenvironment where the action occurs in the lipid domains.

Animals↗

Assessment of correlation between skin target site free drug concentration and the in vivo topical antiviral efficacy in hairless mice for (E)-5-(2-bromovinyl)-2'-deoxyuridine and acyclovir formulations.

Recently, we reported that the in vivo efficacy of acyclovir (ACV) formulations was a single valued function of skin target site free drug concentration (C) irrespective of the formulation compositions. A long-term objective of this research has been to generalize the C concept using model drugs which are similar to as well as different from ACV in their mechanism of actions. (Bromovinyl)deoxyuridine (BVDU) was selected as a model drug based on the reported similarity in its mechanism of action with ACV. The relationship between the C predictions and the in vivo efficacies for some topical formulations containing different concentrations (0.05-10%) of either ACV or BVDU in 95% DMSO as a vehicle with or without 5% Azone as skin permeation enhancer was examined. Hairless mice infected cutaneously with HSV-1 were used to quantitatively estimate the in vivo topical antiviral efficacy. A finite dose of the test antiviral formulation was applied twice a day for 4 days, starting the day after virus inoculation. On the fifth day, the lesions were scored and the efficacy values were calculated. For each formulation, in vitro flux experiments were performed in an in vivo-in vitro experimental design that closely approximated the in vivo study protocol. As was previously shown, with all ACV formulations, a good correlation was found between the C predictions and the in vivo topical efficacy. With the BVDU formulations, on the other hand, this was found not to be the case. BVDU formulations with 5% Azone were generally much more effective than those without Azone at comparable C values. This finding is believed to be the first of its kind showing that skin "permeation enhancers" may enhance efficacy by more than simply increasing skin permeation rates.

Acyclovir↗

Combined effects of laser irradiation/solution fluoride ion on enamel demineralization.

OBJECTIVE: The effects of CO2 laser irradiation of dental enamel were evaluated in enamel demineralization experiments in partially saturated solutions (i.e., solutions containing both calcium and phosphate ions) with and without fluoride ions. SUMMARY BACKGROUND DATA: Previous studies had shown that a continuous-wave CO2 laser at an energy density of around 130 J/cm2 may induce an increased acid resistance in human dental enamel as assessed by exposure to severe demineralization conditions (0.1 mol/L acetate buffer, pH 4.5 and ionic strength 0.5 mol/L). METHODS: Enamel blocks were irradiated with a continuous-wave CO2 laser at a wavelength of 10.6 microns using energy densities of from 42.5 to 170.0 J/cm2. The blocks were then exposed to a partially saturated demineralizing solution with or without 0.2 ppm fluoride at a temperature of 30 degrees C for 24 hours. The demineralization was examined both qualitatively by light microscopy and quantitatively by microradiography. RESULTS: A comparison between the lased and the unlased portions of enamel showed increased acid-resistance with increasing laser energy density and, at the highest energy density of 170.0 J/cm2, there was little or no lesion development in the fluoride-free dissolution medium. The demineralization of enamel was reduced dramatically in the presence of 0.2 ppm fluoride for both lased and unlased enamel; there was only modest lesion development observed for unlased enamel and, at an energy density as low as 85.0 J/cm2, the surface of enamel was found to be completely protected. CONCLUSIONS: These findings are consistent with the mechanism that laser irradiation of dental enamel results in significant reduction of the effective solubility of enamel mineral and that there is a significant synergism between laser irradiation and solution fluoride with regard to this effect.

Carbon Dioxide↗

Iontophoretic transport across a synthetic membrane and human epidermal membrane: a study of the effects of permeant charge.

The effects of permeant charge (z) on iontophoretic-enhanced transport were investigated with synthetic Nucleopore membranes and with human epidermal membranes using a four-electrode potentiostat with side-by-side diffusion cells. The modified Nernst-Planck model (Nernst-Planck theory with an additional transport term to correct for the effect of the convective solvent flow due to electroosmosis) was first examined in a Nuclepore membrane system with model permeants calcein (z = -4), salicylate (z = -1), and a series of polystyrene sulfonates (from monomer to molecular weight of approximately 8000 with a z range of -1 to approximately -40). The flux enhancement (E) for each permeant was determined at 470 mV. Mannitol (a neutral molecule) was used as a probe to determine a correction for convective solvent flow under the same applied voltage conditions. Good agreement between the experimental results and the predictions from the modified Nernst-Planck model was found for calcein, salicylate, and polystyrene sulfonates up to molecular weight of approximately 1800 (z approximately -8). The flux enhancements for the higher molecular weight polystyrene sulfonates with greater z values were more than a factor of three lower than theoretical predictions; the electrophoretic effect and counterion binding to the permeants are proposed as possible explanations for these discrepancies between experiment and the modified Nernst-Planck theory. In the studies with human epidermal membranes, iontophoretic flux enhancements for calcein, salicylate, and taurocholate were determined at 250 and/or 470 mV. The flux enhancements were generally consistent with the results calculated from the modified Nernst-Planck model.

Diffusion↗

Relationship of skin target site free drug concentration (C*) to the in vivo efficacy: an extensive evaluation of the predictive value of the C* concept using acyclovir as a model drug.

For the past few years, our laboratory has been involved in the development of a novel approach for predicting topical in vivo efficacy based on the estimation of skin target site free drug concentration (C*) from in vitro flux data. We have used acyclovir (ACV) as a model drug in the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice. The goal of this study was to rigorously evaluate the applicability of this approach over the entire range of topical efficacy (i.e., from 0 to 100%). We employed a variety of ACV formulations differing in solvent compositions, enhancers, and excipients (and therefore in their efficacies) to achieve this goal. The C* values were estimated from the in vitro flux data obtained in an in vivo-in vitro experimental design that closely approximated the in vivo treatment protocol. For the in vivo antiviral efficacy studies, a finite dose of ACV formulation was applied twice a day, beginning the day after virus inoculation, for 4 days. The lesions were scored on the fifth day, and the efficacies were calculated as described earlier. Our results indicate that, for a variety of formulations over a wide range of efficacies, the predictions based on C* are in good agreement with the observed in vivo efficacies. These findings strongly demonstrate the predictive value of C* over the entire range of topical efficacy, thereby further strengthening its potential for future studies. The findings also indicate that although the excipients in a formulation may alter the rate and extent of available drug at the target site, in these cases, they do not seem to have any effect on the in vivo potency of the drug.

Acyclovir↗

Effect of sodium bicarbonate amount on in vitro indomethacin release from self-setting carbonated-apatite cement.

PURPOSE: In the present study, to develop a drug delivery system with higher bioactivity in hard tissues by using the self-setting bioactive carbonate apatite cement, we have investigated the effects of sodium bicarbonate content on the in vitro drug release from a self-setting bioactive carbonate apatite cement containing indomethacin (IMC). METHODS: The cement powder systems constituted an equimolar mixture of tetracalcium phosphate (Ca4(PO4)2O) and dicalcium phosphate dihydrate (CaHPO4.2H2O), hydroxyapatite (HAP, Ca10(PO4)6(OH)2) seed crystals and sodium bicarbonate. Two types of 2% IMC loaded-cements were prepared as follows, one containing 0% HAP seed crystal and 0-10% sodium bicarbonate, and the other containing 40% HAP seed crystal and 0-10% sodium bicarbonate. The drug release profiles from 2% IMC loaded-cements were measured in simulated body fluid at pH 7.25 and 37.0 degrees C. RESULTS: The drug release profiles from the cement matrix systems with or without seed crystals were estimated using a moment analysis computer program. The mean drug release time (MDT) and the time required for 50% drug release of the cement containing 0 and 40% seed crystal decreased with an increase of sodium bicarbonate. Furthermore, after the drug release the total pore volume of the cement matrix, as measured by mercury porosimetry, increased with an increase of sodium bicarbonate. CONCLUSIONS: MDT and T50's were a function of adding the amount of sodium bicarbonate. The results of the relationship between the micropore distribution, total volume of pores after drug release and drug release supported the hypothesis that the variation in drug release from the cements resulting from the addition of sodium bicarbonate was mainly due to an increase in the diffusion of the drug in the micropores of the cement by dissolution or erosion of the cement matrix.

Anti-Inflammatory Agents, Non-Steroidal↗

Oestradiol release from self-setting apatitic bone cement responsive to plasma-calcium level in ovariectomized rats, and its physicochemical mechanism.

The effect of plasma calcium levels on the release of oestradiol from a self-setting apatite bone cement containing 0.5% oestradiol was investigated in ovariectomized rats. The profiles of in-vitro release from the cements in simulated body fluid containing 0, 5 or 10 mg calcium per 100 mL indicated that the rate of release of oestradiol decreased with increasing calcium concentration in the dissolution media. After subcutaneous implantation of oestradiol-loaded cement in healthy and vitamin D-deficient rats, oestradiol release in diseased rats with low plasma calcium levels was significantly higher than that in healthy rats. These results suggest that in-vitro release of oestradiol from apatite bone cement was dependent on the calcium concentration in the buffer and that the in-vivo release of oestradiol from apatite bone cement was dependent on plasma calcium levels.

Animals↗

Correlation of in vivo topical efficacies with in vitro predictions using acyclovir formulations in the treatment of cutaneous HSV-1 infections in hairless mice: an evaluation of the predictive value of the C* concept.

The purpose of this study was to carry out an extensive examination of the C* concept for prediction of the topical antiviral efficacies of acyclovir (ACV) formulations in a hairless mouse model for the treatment of cutaneous herpes simplex virus type-1 (HSV-1) infections. This method is based on estimation of the free drug concentration at the target site (C*), which is presumed to be the basal cell layer of the epidermis. Five different formulations (containing 5% ACV) were examined in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. For determination of C*, in vitro ACV fluxes across the hairless mouse skin were measured in an in vivo-in vitro experimental design that approximated the in vivo antiviral treatment protocol. Then, the in vivo antiviral efficacies were measured using a 1-day delayed (after HSV-1 virus inoculation) 4-day treatment protocol. 10 microL/cm2 dose of ACV formulation was applied every 12 h for 4 days after which the lesions were scored and efficacies were calculated. Our results indicate that, over a wide range of efficacies, the predictions based on C* (estimated from the experimental fluxes) are in good agreement with the in vivo antiviral efficacies. These studies, therefore, support the validity of the C* concept for various ACV formulations and suggest that the C* approach has potential for future practical situations.

Acyclovir↗

Calculation of intercrystalline solution composition during in vitro subsurface lesion formation in dental minerals.

Applications of a novel technique to calculate intercrystalline solution composition during enamel demineralization are presented. Bovine tooth enamel blocks and carbonated apatite (CAP) compressed disks were demineralized in an in vitro subsurface lesion system. The demineralization medium was a 0.1 M acetate buffer at pH 4.5, containing calcium, phosphate, and fluoride (0.5 ppm). Mineral samples were demineralized for various times, and fluoride profiles and mineral density profiles of these samples were determined by electron microprobe and X-ray microradiography, respectively. A model independent data analysis (MIDA) technique uses these data along with the differential equations for mass transfer and permits calculation of the local intercrystalline solution composition profiles inside the porous mineral matrix as functions of time and position. The invariance in diffusivity with time as calculated in the analysis was taken as an indicator of the physical reasonableness of the method. Current outcomes suggest that it is the sharp gradient of fluoride concentration in the intercrystalline solution which causes the formation of subsurface lesions. Since the driving force for mineral dissolution is a function of solution composition, a gradient of this driving force is consequently formed. Using a compressed disk of carbonated apatite powder as a model for block enamel excluded the possibility of the existence of a gradient of mineral composition which could also cause a gradient of the driving force for mineral dissolution. An FAP surface complex hypothesis is consistent with the current view that fluoride in the intercrystalline solution has a stronger inhibition effect on the dissolution of mineral than does fluoride in the mineral phase. With the help of the MIDA technique, calculated results indicate that the mechanism of the formation of subsurface lesions is dynamically controlled by the intercrystalline solution composition.

Animals↗

Quantitative description of the effect of molecular size upon electroosmotic flux enhancement during iontophoresis for a synthetic membrane and human epidermal membrane.

This study focused upon quantitatively determining the influence of permeant molecular size upon flux enhancement which results from electroosmosis. The first phase of the study involved validation of a fundamental model describing the molecular size dependence of flux enhancement which results from convective solvent flow. This was accomplished using a model synthetic membrane (stack of 50 Nuclepore membranes) and four model permeants with a molecular weight range of 60-504 (urea, mannitol, sucrose, and raffinose). The steady-state flux of each permeant was determined under passive conditions and applied voltages of 125, 250, 500, and 1000 mV using side-by-side diffusion cells and a four-electrode potentiostat system. On the basis of the permeability enhancement for each permeant at each applied voltage (relative to the passive permeability) it was possible to calculate the effective solvent flow velocity from each permeant at each field strength. An important finding was that the flux enhancement due to electroosmosis was strongly molecular weight dependent (i.e., the flux enhancement ratio was around 4 times greater for raffinose than for urea, with mannitol and sucrose yielding intermediate values), while the calculated effective flow velocity at each voltage was independent of the molecular weight of the permeant. This coupled with a linear correlation between flow velocity and applied voltage served to establish the validity of the method and model. The second phase of the study was an extension of the model to human epidermal membrane (HEM). These experiments involved simultaneously measuring the fluxes of [14C]urea and [3H]sucrose across HEM samples under passive, 250 mV, and 500 mV conditions. Similar to the Nuclepore system, the observed flux enhancement ratios with HEM were approximately 3 times greater for sucrose than for urea. A detailed analysis of the HEM data showed semiquantitative agreement between predictions of the model and experimental results.

Electricity↗

Fluorescent probe studies of the interactions of 1-alkyl-2-pyrrolidones with stratum corneum lipid liposomes.

Previously, the effects of a series of 1-alkyl-2-pyrrolidones (APs; C2-C8) on the lipoidal pathway of hairless mouse skin (HMS) were studied with a parallel pathway skin model. At their isoenhancement concentrations, these 1-alkyl-2-pyrrolidones induce the same transport enhancement (isoenhancement factor, EHMS) on the lipoidal pathway of the stratum comeum for the probe permeants studied. In the present study, the fluidizing effects of APs upon the stratum comeum lipid liposome (SCLL) bilayer were investigated under these isoenhancement conditions using steady state anisotropy and fluorescence lifetime studies with fluorescent probes 2-, 6-, and 9-(9-anthroyloxy)stearic acids, 16-(9-anthroyloxy)palmitic acid, and 1,6-diphenyl-1,3,5-hexatriene to examine a possible correlation between the fluidizing properties of APs and their enhancement effects on transdermal drug transport. Time-resolved fluorescence decay studies were also conducted to further investigate the fluidizing properties of APs and add support to the steady-state fluorescence results. Under an isoenhancement condition of EHMS = 10, these APs fluidized the alkyl chains of the lipids at intermediate depths (C6-C9) in the SCLL bilayer (a 40-50% decrease in the rotational correlation times) but did not significantly change the fluidity in the deep hydrophobic region of the bilayer. Three rotational correlation times were deduced from the global simultaneous analysis in time-resolved fluorescence decay measurements. The slowest of these (greater than 1000 ns) was attributed to the global motion of SCLLs and is probably related to the static component of steady-state anisotropy. The other two rotational correlation times (on the order of nanoseconds) were in the range expected for the local motion of the fluorophores and may correspond to their vibrational and rotational motions. When the concentrations of APs were increased (increasing the EHMS value), the static component (alpha) decreased. This suggests that APs might induce a general fluidizing effect upon the lipid bilayer (i.e., a decrease in the order of the lipid bilayer). The decrease in the longer rotational correlation time (on the order of nanoseconds) with increasing EHMS value, on the other hand, indicates a possible increase in the "cavity volume" for the hindered motions of the fluorophores (i.e., an increase in the free volume at intermediate depths in the bilayer).

Animals↗

Effect of particle size of metastable calcium phosphates on mechanical strength of a novel self-setting bioactive calcium phosphate cement.

Resistance to compressive strength after setting of the calcium phosphate cement consisting of tetracalcium phosphate (TECP), dicalcium phosphate dihydrate (DCPD), and 40 wt/wt% of a synthetic hydroxyapatite (HAP) was tested. An equimolar mixture of the calcium phosphate powder containing DCPD (particle diameter [D] 0.52-3.33 microns) and TECP (D, 1.1-13.1 microns) transformed into HAP at 37 degrees C, 100% RH after being mixed with 25 mM phosphoric acid. X-ray diffraction suggested that the cement containing fine particles of DCPD and TECP completely transformed to HAP, but that mixtures containing larger particles did not. Because particle size of both DCPD and TECP affected the compressive strength of the cement, the crystal growth of HAP during cement formation depended on the specific surface area (Sw) of the raw materials. The crystallite size of transformed HAP was estimated based on X-ray diffraction peaks at 25.8 and 32.8 degrees attributable to the 002 and 300 planes. The crystalline size attributable to the 300 plane decreased with increasing Sw, but that attributable to the 002 plane showed no significant relationship. The compressive strength of the cement after hardening increased with an increase of its Sw. This suggested that the harder calcium phosphate cement was (derived) from the smaller particle size of the raw materials.

Bone Cements↗

Mechanistic studies of the 1-alkyl-2-pyrrolidones as skin permeation enhancers.

The influences of 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octyl-2-pyrrolidone in their saline solutions on the transport of beta-estradiol, corticosterone, and hydrocortisone across hairless mouse skin under in vitro conditions have been investigated by the physical model approach. The experimental data were interpreted with a physical model that treats the stratum corneum as a diffusional barrier with a lipoidal pathway and a pore pathway. Enhancement factors (E values) for the lipoidal pathway were calculated from the permeability coefficients and solubility data as a function of the 1-alkyl-2-pyrrolidone concentration for all three permeants. A pattern of increasing E values with increasing 1-alkyl-2-pyrrolidone chain length was found, and the results were essentially the same for all three steroidal permeants. A nearly semilogarithmic linear relationship was also obtained between the enhancement potency and the carbon number of the alkyl chain; there was about an approximately 3.5-fold increase in the enhancement potency per 1-alkyl-2-pyrrolidone methylene group. An important outcome of this research is that the enhancement potencies of the 1-alkyl-2-pyrrolidones were essentially the same as those for the previously studied n-alkanols when compared at the same carbon numbers of the alkyl groups. This result is somewhat surprising as it suggests that the enhancer action resides (in its entirety) in the alkyl group, and the nature of the polar head group may not be intrinsically important in transdermal enhancement of the lipoidal pathway within a class of permeation enhancers.

Administration, Cutaneous↗

A novel skeletal drug delivery system using self-setting calcium phosphate cement. 9: Effects of the mixing solution volume on anticancer drug release from homogeneous drug-loaded cement.

The effects of mixing solution volume (0.25-0.65 mL/g) on in vitro drug release from a self-setting bioactive calcium phosphate cement containing the anticancer agent 6-mercaptopurine (6-MP) as a model compound were investigated. The drug release profiles from isolated planar surfaces as well as the entire surfaces of cement systems containing 5% 6-MP were measured in simulated body fluid at pH 7.25 and 37.0 degrees C. The drug release rate from both cement system geometries increased with increasing mixing solution volume. Drug release profiles from the planar-release and entire-surface-release cement matrix systems were analyzed by and found to agree with the Higuchi and Cobby equations, and the kinetic parameters were estimated with a nonlinear least-squares computer program. Linear relationships were found between the mixing solution volume and the drug release rate constants or time required for 50% drug release for both cement release geometries. Furthermore, the total pore volume of the cements, as measured by mercury porosimetry, increased with increasing mixing solution volume.

Antineoplastic Agents↗

A mechanistic study of the effects of the 1-alkyl-2-pyrrolidones on bilayer permeability of stratum corneum lipid liposomes: a comparison with hairless mouse skin studies.

The influence of a series of 1-alkyl-2-pyrrolidones (C2-C8) on the transport behavior of lipophilic and polar/ionic permeants across hairless mouse skin was recently investigated by employing a physical model approach that treats the stratum corneum barrier as a diffusional system of parallel lipoidal and pore pathways. In this previous study, the transport enhancement effects (enhancement factor, EHMS) on the lipoidal pathway of the stratum corneum were found to be essentially the same for all steroidal probe permeants investigated at various concentrations of these 1-alkyl-2-pyrrolidones. In the present research, the relationship between solute transport enhancement in the lipoidal pathway of hairless mouse skin and the transport enhancement in the stratum corneum lipid liposome bilayer was studied by comparing the enhancement factor for the lipoidal pathway in the hairless mouse skin, EHMS, with that for the stratum corneum lipid liposome, ESCLL, at equal solution concentrations of the 1-alkyl-2-pyrrolidones. The release rates of D-mannitol, D-glucose, 3-O-methyl-D-glucose, sucrose, and raffinose from stratum corneum lipid liposomes were determined, and the ESCLL values for these permeants were compared with the EHMS values obtained with hairless mouse skin using the steroidal permeants. An important finding in this study was a semiquantitative correlation between the enhancement effects induced by the 1-alkyl-2-pyrrolidones, except 1-ethyl-2-pyrrolidone, with the liposome bilayer using sugar molecules as permeants and those found with the lipoidal pathway in hairless mouse skin using steroid molecules as permeants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗