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Biomedical subjects

N F Ho

Publications and source records attributed to N F Ho.

At least 55 records · Page 3Linked to original sources
PubMed1984

Physical model approach to gastrointestinal absorption of prostaglandins II: In situ rat intestinal absorption of dinoprost.

In situ absorption studies with dinoprost in the rat jejunum were carried out using a modified Doluisio technique. The absorption rate was first order. There was a sigmoidal decrease in the rate with increasing buffer pH (from 3.5 to 9.5), which strongly indicated the partitioning of weak acid species into the lipoidal membrane. An asymptotic minimum rate was attained from buffer pH 7.5 to 9.5, operationally indicative of transport of anions across aqueous pores. The importance of the aqueous diffusion layer on the mucosal side of the membrane was evident; rates at pH 3.5 and 4.5 were faster at high agitation hydrodynamics in the lumen solution. Preliminary studies showed that there was no metabolism in the lumenal solution and that metabolism occurred within the membrane. The transport mechanism involved simultaneous passive diffusion and bioconversion in the membrane because (a) a 1.5 X 10(4)-fold range in dinoprost concentration (0.014-210 microM) showed no saturable carrier-mediated tendency on the rate, (b) iodoacetic acid and indomethacin did not inhibit the absorption rate, and (c) the shape of the absorption-pH profiles was suggestive of passive diffusion. The prostaglandin did not have apparent adverse membrane and vascular effects under the conditions employed. The quantification and factorization of the physically meaningful transport parameters were accomplished using the physical model previously described. The permeability coefficients of the aqueous diffusion layer for the oscillation and static hydrodynamic situations were 0.8 X 10(-4) and 1.7 X 10(-4) cm/s, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Physical model approach to gastrointestinal absorption of prostaglandins III: In situ rat intestinal absorption of dinoprostone.

In situ absorption studies with dinoprostone in the rat jejunum were carried out to provide a quantitative mechanistic insight of the absorption process. The variables included buffer pH (3.5-9.5), buffer capacity, hydro-dynamics in the lumen, and concentration. The disappearance kinetics from the lumen was first order. The rate decreased with increasing pH in a sigmoidal manner and reached a minimum at about pH 9. These results indicate the effects of the partitioning of nondissociated species in the lipoidal membrane and transport across aqueous pores. The rate was higher with the higher degree of agitation of the lumenal solution. Between two hydrodynamic situations, the differences in the rates were large at pH 4.5 where the transport was largely aqueous diffusion controlled and then tended to become smaller with increasing pH where the transport became effectively membrane controlled. The 15-oxo- and 13,14-dihydro-15-oxo metabolites of dinoprostone were found. The physical model was applied to quantify the permeability coefficients of the aqueous diffusion layer and the aqueous pores of the membrane and the effective membrane transport-bioconversion permeability coefficient at various pH values. The overall absorption dinoprostone was similar to that of the less lipophilic dinoprost reported earlier and also more rapid. Hence, baseline absorption studies were completed with two major reference prostaglandins from which estimations of intestinal absorption can be made for their analogues and derivatives.

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↗
PubMed1982

Theoretical and experimental studies of transport of micelle-solubilized solutes.

A physical model describing the simultaneous diffusion of free solute and micelle-solubilized solute across the aqueous boundary layer, coupled with partitioning and diffusion of free solute through a lipoidal membrane, is derived. In vitro experiments utilizing progesterone and polysorbate 80 showed excellent agreement between theoretical predictions based on independently determined parameters and experimental results. The physical model predicts that micelles can assist the transport of solubilized solute across the aqueous diffusion layer, resulting in a higher solute concentration at the membrane surface than would be predicted if micelle diffusion is neglected. At high surfactant concentrations, the aqueous diffusion layer resistance can be eliminated and the activity of the solute at the membrane can approach the bulk solute activity. This mechanism could explain observed enhanced absorption rates in vivo when both micelle solubilization occurs and the aqueous diffusion layer is an important transport barrier. The importance of determining and defining the thermodynamic activity of the diffusing solute is emphasized.

Biological Transport↗
PubMed1982

Hydration and percutaneous absorption III: Influences of stripping and scalding on hydration alteration of the permeability of hairless mouse skin to water and n-alkanols.

The influence of hydration on the permeability of stripped and scalded skins of hairless mice was investigated in vitro using water and n-alkanols as test permeants. Irrespective of pretreatment, the permeation rates of water, methanol, and ethanol were unaffected by aqueous immersion of skin sections in a diffusion cell, consistent with earlier data on unprocessed skins. The permeation rates of butanol and hexanol also were insensitive to hydration, differing from earlier studies on normal, intact skin in which both solutes' rates doubled after 10 hr of soaking. Following both pretreatments, the permeability of octanol declined over the first 5-10 hr of maceration, but remained invariant thereafter. The decline was most pronounced for the scalded skins. With untreated skin, octanol permeability initially increased and then declined before assuming a constant value. This study indicates that the barrier properties of the epidermis and dermis are not particularly sensitive to extended hydration except in the case of octanol. Scalding at 60 degrees for 60 sec rapidly hydrates the skin, altering tissue permeability to about the same extent as a 10-hr (or longer) immersion in water at 37 degrees. Octanol's unique hydration profile is explained by locating the origin of permeability decline in tissue beneath the horny exterior of the skin.

Abdomen↗
PubMed1982

Permeability of thermally damaged skin v: permeability over the course of maturation of a deep partial-thickness wound.

The permeability of eschar is an important factor governing rational approaches to topical control of burn wound sepsis. Previous work has shown the burn wound to have a highly variable permeability immediately after burning depending on the manner of burning. But the burn is also a dynamic wound and its physical state changes during the process of maturation. The present studies are an early attempt to characterize wound permeability as a function of maturation. Hairless mice were burned dorsally for 15 seconds on a metal surface maintained at 80 degree C. The time and temperature conditions were chosen to effect a deep partial-thickness to full-thickness injury on the animal. Mice were sacrificed daily post burn over a 2-week period and the permeabilities of 3H-methanol and 14C-butanol through the excised eschar were measured. Te eschar permeability coefficients were directly compared to permeability coefficients for the same compounds found with abdominal skin sections taken concurrently from each animal. It was observed that the branding initially caused a 50 per cent increase in the permeability of methanol and a 300-400 per cent increase in the permeability of maturation. Thereafter permeabilities tended to increase, gradually at first, but accelerating to a maximum which was observed at approximately 10 days. At the maximum, methanol's permeability was 20 times and butanol's 12 times their normal values. For both compounds permeability of eschar decreased past the maximum until termination of the studies at 14 days.

Administration, Topical↗
PubMed1981

Factors affecting diazepam infusion: solubility, administration-set composition, and flow rate.

The sorption of diazepam in large-volume i.v. admixtures to administration-set components and in i.v. containers was analyzed quantitatively. Solubility of diazepam in phosphate buffer at various pH levels and in i.v. fluids was measured. Partition coefficients of diazepam into components of i.v. administration sets and i.v. containers were studied by shaking a solution of diazepam in 0.9% sodium chloride, with finely cut components and measuring the change in diazepam in the aqueous phase. Flow studies through an administration set of a 0.04-mg/ml diazepam solution in 5% dextrose injection were done, varying both the flow rate and the length of tubing. The maximum free-base solubility of diazepam in phosphate buffer was 0.048 mg/ml; its solubility was 0.058, 0.050, and 0.064 mg/ml in lactated Ringer's, 0.9% sodium chloride, and 5% dextrose injections, respectively. Equilibrium partition coefficients were highest for polyvinyl chloride tubing and flexible bags. Volume-control sets made of cellulose propionate had lower but sufficiently large partition coefficients to cause diazepam loss. Polyolefin semi-rigid and glass containers had low partition coefficients. In the flow studies, the amount of solution-contact time correlated with the extent of absorption. As flow rate decreased or tubing length increased, the amount of diazepam absorbed increased proportionately. A nomogram and a predictive dosing chart are presented for calculation of actual diazepam doses delivered at various flow rates and tubing lengths. Diazepam can be administered safely and effectively by i.v. infusion. The use of volume-control sets and flexible polyvinyl chloride bags should be avoided with diazepam solutions. Polyolefin semi-rigid containers are acceptable alternatives to glass. The concentration of diazepam infusions should not exceed 0.04 mg/ml.

Absorption↗
PubMed1980

Physical model evaluation of topical prodrug delivery--simultaneous transport and bioconversion of vidarabine-5'-valerate III: Permeability differences of vidarabine and n-pentanol in components of hairless mouse skin.

The permeation behavior of 3H-vidarabine (3H-9-beta-D-ara-binofuranosyladenine) and 14C-n-pentanol through different strata of hairless mouse skin was studied using a diffusion cell at 37 degrees under steady-state conditions. Partition coefficients for the skin components verus 0.9% aqueous NaCl solution also were obtained. Various skin preparations including full-thickness skin, cellophane-stripped skin, and dermis membranes of different thicknesses were employed. The dermis membranes were considered to be diffusionally homogenous, and the product of the permeability coefficient and the thickness was taken as the apparent diffusivity. The apparent diffusivities for both compounds investigated were independent of thickness. Therefore, it was concluded that the molecular diffusivity is constant throughout the dermis. Comparisons of permeability coefficients in various strata of the skin revealed that, while the stratum corneum is the major diffusional barrier, the epidermis appears to be significantly less permeable than the dermis.

Administration, Topical↗
PubMed1980

Physical model evaluation of topical prodrug delivery--simultaneous transport and bioconversion of vidarabine-5'-valerate IV: Distribution of esterase and deaminase enzymes in hairless mouse skin.

A semiquantitative assessment of estrase and deaminase distributions in hairless mouse skin was performed in vitro. The enzyme activities were quantified using 3H-vidarabine and tis 5'-valerate as the substrates. Full-thickness skin of the hairless mouse was cut into two halves, and each half was homogenized in pH 7.4 buffer. BQOTH THE SUPERNATE AND THE RESIDUE OF THE HOMOGENATE were assayed for esterase and deaminase activities. Results show that the outer half-thickness of the skin contained more esterase but slightly less deaminase than the other half. The characteristics of the esterase and the deaminase reactions also were studied employing the crude enzyme extract; these reactions were essentially irreversible. The deaminase reaction was in the linear region of Michaelis-Menten kinetics for substrate concentrations up to 4.5 x 10(-5) M.

Aminohydrolases↗
PubMed1980

Physical model evaluation of topical prodrug delivery--simultaneous transport and bioconversion of vidarabine-5'-valerate V: Mechanistic analysis of influence of nonhomogeneous enzyme distributions in hairless mouse skin.

The mathematical problem of simultaneous transport and metabolism in the case of nonuniform enzyme distributions in the skin was solved, and the solutions were used for analyzing experimental data. Experimental data were obtained from permeation experiments with 3H-vidarabine and its 5'-valerate using cellophane tape-stripped hairless mouse skin. Results of the analyses revealed that the esterase activity was four to nine times higher in the epidermis than in the dermis, whereas the deaminase activity was about the same in the two strata. These results were in good agreement with independent experiments using tissue homogenates. The enzyme distributions and the previously reported diffusivities were employed in generating concentration profiles for the prodrug and the drug in the skin. These results may be used in predicting the possible therapeutic effect of the prodrug when it is topically applied.

Administration, Topical↗
PubMed1980

Permeability of thermally damaged skin: I. Immediate influences of 60 degrees C scalding on hairless mouse skin.

Freshly sacrificed hairless mice were burned dorsally by direct contact with 60 degrees C water for periods ranging from 15 seconds to 8 min. Wounds ranging in degree from superficial epidermis damage to injury penetrating well into subcutaneous musculature were inflicted. Burned skin sections and reference abdominal skin sections were excised, placed in diffusion cells and investigated with regards to their permeabilities to water, methanol, ethanol, n-butanol and n-octanol. The data were couched in terms of ratios of permeability coefficients of burned skin to normal skin (scalding coefficients) for the same animal. Scalding increased permeability of skin to all compounds studied but the effects leveled out by 60 seconds. Protracted scalding was without great effect despite progressively increased depth of damage to the tissue as noted in histological sections. The degree of lost barrier competency attributable to 60 degrees C scalding was not marked for any compound but was definitely different for different alkanols. An approximately 3-fold permeability increase was noted with n-butanol, the most affected compound. The data demonstrate that near instantaneous alterations in permeability of skin accompany scalding, that decreased barrier competency does not correlate with the severity of a burn as measured in depth of the burn, and that thermal alteration of permeabilities is dependent on the physicochemical characteristics of the permeants.

Abdomen↗
PubMed1980

Hydration and percutaneous absorption: I. Influence of hydration on alkanol permeation through hairless mouse skin.

A method to study the influence of hydration on skin permeability where the skin is immersed in saline for up to 30 hr and under circumstances where a steady state rate of permeation can be established in several minutes is indicated. These circumstances allow multiple, sequential runs over a period where the permeability coefficients of some chemicals are gradually changing. It has been found that the permeabilities of water, methanol and ethanol are little affected by such hydration. However, there is a doubling of the permeability coefficients of butanol and hexanol during the first 10 hr of immersion. More hydrophobic alkanols seem to be less sensitive to the protracted aqueous conditioning. In general the results indicate that there are complex molecular structure-permeability relationships operating in skin. More specifically, the hydration effects are insightful with respect to developing barrier models for skin as they are further indications that different parallel diffusional paths are followed by polar and semi- and nonpolar species.

Alcohols↗
PubMed1979

Lyophilization of pharmaceutical injections: theoretical physical model.

A physical model for the lyophilization kinetics of parenteral formulations is presented. Mathematical relationships are derived, which involve the simultaneous change in the receding boundary of the ice-vapor interface with time as well as water vapor diffusion across the dry porous matrix and boundary layer. Heat from an external heat source is transferred across the frozen solution to the receding ice surface. The model predicts that the water lost and the receding boundary distance are linearly related to the square root of time when lyophilization is matrix controlled. The mathematical descriptions are predictive of the physicochemical and transport events and can lead to the design of quantitative experiments to relate theory to formulation design.

Chemical Phenomena↗
PubMed1979

Physical model evaluation of topical prodrug delivery-simultaneous transport and bioconversion of vidarabine-5'-valerate I: Physical model development.

A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method development for factoring and quantifying parameters, and, finally, employment of the deduced parameters to determine the steady-state species fluxes and concentration profiles in the target tissue. The present report describes the physical modeling and theoretical simulation aspects. The physical model for the simultaneous transport and bioconversion of a topically delivered prodrug was formulated assuming homogeneous enzyme distributions and constant diffusivities in the membrane. The mathematical problem was solved, and the solution yielded concentration profiles and fluxes of all species in the biomembrane. These results provided the prevailing levels of the prodrug, the drug, and the metabolite at the target site and the transport rates of all species into the bloodstream. Computations of concentration profiles and fluxes were carried out for a reasonable range of the parameters. The relative activities of the esterase and the deaminase enzymes, as well as the stratum corneum permeabilities, were important in influencing the concentration profiles and fluxes of all species.

Administration, Topical↗
PubMed1979

Physical model evaluation of topical prodrug delivery-simultaneous transport and bioconversion of vidarabine-5'-valerate II: Parameter determinations.

Results of initial studies on methods for determining various model parameters are reported. By employing excised hairless mouse skin in a diffusion cell system, numerous model parameter values were deduced. The stratum corneum permeability was estimated from steadystate fluxes with preparations of heat-separated epidermal membranes. Determinations of dermis diffusivities and enzyme rate constants in situ involved considering the simultaneous transport and the enzyme processes and factoring the diffusivities and enzyme rate constants from the overall kinetics. Dermal diffusivities were on the order of 10-6 cm2/sec for vidarabine and its 5'-valerate ester. The enzyme rate constants were 1.70 x 10-3 sec-1 for the esterase and 8.68 x 10-3 sec-1 for the deaminase.

Animals↗