PubMed Health⌕ Search

Biomedical subjects

R H Guy

Publications and source records attributed to R H Guy.

At least 19 recordsLinked to original sources
PubMed1995

Optimization of in vitro flux through hairless mouse skin of cidofovir, a potent nucleotide analog.

The in vitro flux (4-8 h) of cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) was measured across full-thickness hairless mouse skin to evaluate potential formulations for local treatment of herpes virus infections. The effects of propylene glycol, isopropyl alcohol, oleic acid, pH, and cidofovir concentration were examined. In addition, several prototype aqueous gel formulations were studied. Flux values (4-8 h) increased linearly with cidofovir concentration in both solution and gel formulations. Removal of the stratum comeum by tape stripping increased the flux by approximately 400-fold, whereas pH (4.5 versus 7) had little effect on flux. The presence of propylene glycol, isopropyl alcohol, or their combination did not significantly increase mean flux (p > or = 0.05). Pretreatment of the skin with oleic acid resulted in a significant enhancement of cidofovir flux (p < or = 0.01). From the measured flux values, the calculated concentration of cidofovir achievable in the viable epidemis from a 1% cidofovir gel formulation was approximately 14 micrograms/mL, which is comparable to the in vitro 50% inhibitory dose (ID50) values for herpes simplex viruses HSV-1 and HSV-2.

Animals↗
PubMed1994

Characterization of convective solvent flow during iontophoresis.

During iontophoresis under neutral pH conditions, there is a net convective flow of volume (electroosmosis) from anode to cathode leading to the enhanced transport of dissolved polar (but uncharged) solutes in the same direction. The objective of this study was to address the following unresolved questions with respect to electroosmotic transport: [1] Whether the efficiency of electroosmotic transport is solute size-dependent and, if so, how severe is this dependence? [2] Is electroosmosis linearly related to current density in the same way that the iontophoretic flux of charged species appears to be? [3] Are positively charged permeants able to influence their own electrotransport across the skin (by modifying the net charge on the membrane and altering, as a result, the permselectivity) and, if so, why and to what extent? Electroosmosis was assessed from the iontophoreically driven fluxes of mannitol, sucrose and lactose across hairless mouse skin in vitro. It was found that:- (a) The electroosmotic transport rate of mannitol is similar to that of the disaccharides, sucrose and lactose, when examined under identical conditions. The dependence of electroosmotic flux upon molecular size requires study of solutes having a wider range of MW than those considered here. (b) Electroosmotic flow from anode-to-cathode increases with applied current density; similarly, convective flow in the opposite direction diminishes with increasing current density. Apparently, there is correlation between the net movement of solvent and the total flux of ions across the skin. (c) The permselectivity of skin can be 'neutralized' by driving, iontophoretically, a cationic, lipophilic peptide (specifically the leutinizing hormone releasing hormone (LHRH) analog, Nafarelin) into the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro. II: Drug, vehicle, and enhancer penetration kinetics.

The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing putative penetration enhancers (n-nonane, 1-nonanol, and 1-decanol), were measured across hairless mouse skin in vitro. Propranolol transport was augmented significantly by the presence of 4% (v/v) alkane or alkanol in the vehicle; diazepam and indomethacin, on the other hand, were enhanced only by n-nonane. Experiments with saturated solutions of the drugs as the donor phase revealed that the actions of the enhancers were taking place in the skin and were not a result of an alteration of solute thermodynamic activity in the vehicle. In separate runs, the impact of n-nonane and 1-nonanol on the percutaneous penetration of ethanol was determined. Temporal effects identical to those on the flux of propranolol were observed. A further measurement revealed that the penetration of 1-decanol, when administered as a 4% (v/v) solution in ethanol, followed a profile similar to that of the solvent (which, in turn, was comparable with that of the independently assessed propranolol hydrochloride). Thus, considerable linkage exists between the transport of a hydrophilic drug and the major vehicle component in the presence of n-nonane and 1-nonanol. The lipophilic drugs, conversely, were promoted only by n-nonane and only after most of the ethanol had been absorbed. The results show that an apparent synergy of transport between a putative enhancer and a cosolvent may not always lead to augmented drug flux. Study of the transport of all key formulation components is recommended, therefore, to optimize vehicles for transdermal drug delivery.

Alkanes↗
PubMed1992

Sonophoresis. II. Examination of the mechanism(s) of ultrasound-enhanced transdermal drug delivery.

We have shown previously that high-frequency ultrasound (sonophoresis) can significantly enhance the transdermal delivery of a topically applied drug in vivo and that the augmentation of transport was caused by the action of the ultrasound on the skin. However, these earlier experiments did not reveal (i) the mechanism of sonophoresis, (ii) the pathway of drug permeation under the influence of ultrasound, and (iii) any potentially detrimental effects of the enhancement procedure on skin structure and morphology. In the study reported here, these three key issues have been addressed using electron microscopy to follow the penetration of an electron-dense, colloidal tracer (lanthanum hydroxide; LH). Experiments have again been performed using the hairless guinea pig animal model. Colloidal LH suspensions were applied to skin sites, which were then immediately exposed to ultrasound (at 10 or 16 MHz) for 5 or 20 min. Passive transport of LH under identical conditions (but without ultrasound) provided the control measurements. Tissue processing after the treatment periods utilized standard electron microscopy staining procedures. We found the following: (1) LH does not permeate the skin by passive diffusion; under the influence of ultrasound, on the other hand, it penetrates through the stratum corneum (SC) and the underlying viable epidermal cell layers via an apparently intercellular route. (2) LH transports through the epidermis to the upper dermis, even after only 5 min of ultrasound treatment, a remarkable and unexpected finding.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1992

Sonophoresis. I. The use of high-frequency ultrasound to enhance transdermal drug delivery.

Previous attempts to use ultrasound (less than or equal to 1-MHz frequency and 1 to 3-W/cm2 intensity) to enhance transdermal drug delivery (so-called sonophoresis) have produced inconsistent results. Theoretical analysis of ultrasound propagation in tissue predicts that higher-frequency ultrasound (greater than 1 MHz) will increase the concentration of energy deposition in the stratum corneum (SC) (typically, the rate-limiting barrier to percutaneous penetration). This hypothesis was tested by comparing the passive transdermal delivery of salicylic acid with that under the influence of ultrasound at 2-, 10-, and 16-MHz frequency; measurements were performed in vivo in hairless guinea pigs. Total drug absorbed was quantified by determining the amount of salicylic acid (1) present in SC tape strips and (2) eliminated in urine. Sonophoresis for 20 min at 2 MHz caused no significant increase in salicylic acid delivery over passive diffusion; treatment with ultrasound at 10 and 16 MHz, on the other hand, significantly elevated salicylic acid transport, by 4-fold and 2.5-fold, respectively. Kinetic analysis of the sonophoretic data at 10 and 16 MHz also revealed that the diffusion lag time associated with transdermal drug delivery (TDD) was reduced. A shorter period (5 min) of sonophoresis again resulted in enhanced TDD (relative to the corresponding control) at the higher frequencies; the delivered dose, and the level of enhancement, however, were lower than those after the 20-min treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Predicting skin permeability.

Published permeability coefficient (Kp) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (Koct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physiocochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of Kp upon MV (or MW) and Koct. It is found that the existence of an "aqueous-polar (pore) pathway" across the SC is not necessary to explain the Kp values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected Kp. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to greater than 750, and log Koct ranging from -3 to +6), the postulated upper limiting value of Kp for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal Kp values.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1992

Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement.

The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studied in vitro using hairless mouse skin. Storing the skin for 10 days at 4 degrees C did not alter barrier function to total nitrate flux [GTN + 1,2-glyceryl dinitrate (1,2-GDN) + 1,3-glyceryl dinitrate (1,3-GDN)]. However, metabolic function was significantly impaired and suggested at least fivefold loss of enzyme activity. Heating skin to 100 degrees C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still present, however, and remained constant over the 10-hr experimental period, in contrast to the "control," which showed progressively decreasing enzymatic function with time. Pretreatment of hairless mouse skin in vivo (prior to animal sacrifice, tissue excision, and in vitro transport/metabolism studies) with 1-dodecylazacycloheptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3-GDN) was increased from less than unity to slightly above 1 by the Azone treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-strips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1992

Cutaneous metabolism of nitroglycerin in vitro. I. Homogenized versus intact skin.

The metabolism of nitroglycerin (GTN) to 1,2- and 1,3-glyceryl dinitrate (GDN) by hairless mouse skin in vitro has been measured. In the first set of experiments, GTN was incubated with the 9000g supernatant of fresh, homogenized tissue in the presence and absence of glutathione (GSH), a cofactor for glutathione-S-transferase. After 2 hr of incubation with GSH, 30% of the initially present GTN had been converted to 1,2- and 1,3-GDN; without GSH, less than 5% of the GTN was metabolized. The ratio of 1,2-GDN to 1,3-GDN produced by the homogenate was 1.8-2.1. In the second series of studies, GTN was administered topically to freshly excised, intact hairless mouse skin in conventional in vitro diffusion cells. The concurrent transport and metabolism of GTN was then monitored by sequential analysis of the receptor phase perfusing the dermal side of the tissue. Three topical formulations were used: a low concentration (1 mg/ml) aqueous solution, a 2% ointment, and a transdermal delivery system. Delivery of total nitrates (GTN + 1,2-GDN + 1,3-GDN) into the receptor phase was similar for ointment and patch formulations and much greater than that from the solution. The percentage metabolites formed, however, was greatest for the solution (61% and 2 hr, compared to 49% for the patch and 35% for the ointment). As has been noted before, therefore, the relative level of skin metabolism is likely to be greatest when the transepidermal flux is small. Distinct from the homogenate experiments, the 1,2/1,3-GDN ratios in the penetration studies were in the range 0.7-0.9.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1992

Cutaneous blood flow in gestational hypertension and normal pregnancy.

A laser Doppler flowmeter was used to assess skin blood flow changes in three groups of young subjects: women with gestational hypertension, healthy pregnant women, and healthy non-pregnant women. Responses to four vasoactive stimuli were studied: isometric and cognitive activities, cutaneous post ischemic reactive hyperemia, and local heating. The first two stimuli are vasoconstrictive and were performed on the fingertip, whereas the latter two are vasodilative and were performed on the forearm. The most prominent differences were observed in the isometric test, where the expected decrease, which was indeed registered in non-pregnant women, was almost absent in the healthy pregnant group. The gestational hypertension group had a greater decrease in blood flow than normal pregnancy, but lesser than non-pregnant control subjects. We conclude that although normal pregnancy modifies the response of the skin microvasculature to some vasoactive stimuli, gestational hypertension pushes that response back toward the non-pregnancy state.

Adult↗
PubMed1992

An evaluation of structure-penetration relationships in percutaneous absorption.

Prediction of chemical transport across skin is important both to the optimization of topical and transdermal drug delivery and to the assessment of risk following dermal exposure. To facilitate estimation of percutaneous absorption, a number of model in vitro experimental systems have been developed. However, the predictive applicability of the different approaches (with respect to human skin penetration), and the quantitative aspects of the structure-permeation behavior revealed, have not been critically evaluated. The objectives of this paper are to collect, from the literature, the more systematic investigations pertaining to chemical transport across the skin, to quantify the dependence of permeation on the lipophilicity of the penetrants studied, and to assess the relative utility of model systems for the prediction of percutaneous absorption. The categories of chemicals addressed in the survey include n-alkanols, para-substituted phenols, steroids and non-steroidal anti-inflammatory drugs. The experimental systems, used in the studies considered, involve, primarily, steady-state transport measurements across excised skin taken from either human cadavers or hairless mice. Favorable comparisons of these data to solute flux across simple organic liquid membranes are possible. Overall, general patterns of behavior emerge from the analysis such that qualitative predictions can be made. From a quantitative standpoint, though, it is clear that additional "structure-activity" work is necessary to provide appropriate equations that can relate penetration between different test systems and between different chemical classes.

Adult↗
PubMed1992

Epidermal lipids and topical drug delivery.

When a topical formulation is placed on the skin, the active drug is usually required to penetrate through the stratum corneum into the viable tissue. The major control to this process is the slow diffusion through the dead horny layer. The major route of drug penetration through the stratum corneum is via the tortuous intercellular channels. It is therefore important to ascertain the nature of the environment that the drug experiences within the intercellular pathway and how it is affected by the presence of formulation components. The lipids within the intercellular channels are a complex mixture but they are structured into bilayer arrays. Extraction of the lipids by solvents within the formulation will lead to enhanced permeability of the skin. Some penetration enhancers act by creating disorder in the alkyl chains of the lipid bilayers; others modify the solubility characteristics within the stratum corneum. The different interactions that are possible will be discussed in this article.

Administration, Topical↗
PubMed1991

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro: effect of enhancer lipophilicity.

The enhancement of model hydrophilic (propranolol hydrochloride) and lipophilic (diazepam) drug penetration across rat and hairless mouse skin in vitro has been studied. Preliminary experiments established that most n-alkanes having chain lengths of between 7 and 16 promote the flux of both drugs. For propranolol, enhancement varied parabolically with carbon number; for diazepam, heptane was ineffective and all others were essentially equipotent. Enhancement by n-nonane was then compared with that by n-nonanol. Propranolol flux was increased by both enhancers, whereas diazepam penetration was not affected by the less lipophilic alcohol. The enhancement of propranolol by n-nonane and n-nonanol was examined as a function of adjuvant concentration in the applied formulation. Maximum increases in maximum penetration rates of 6.5-fold (n-nonane) and 8.2-fold (n-nonanol) were determined. As expected, the enhancement was saturable, indicative of a maximally perturbed stratum corneum. Finally, the penetration enhancing abilities of six monoterpenes were assessed. The purely hydrocarbon analogues promoted both propranolol and diazepam transport to an extent similar to that of n-nonane. The terpenes with hydrogen-bonding ability, however, only enhanced propranolol flux (at a level comparable to n-nonanol). While the data reported do not directly reveal mechanistic information on percutaneous penetration enhancement, they do provide a starting point for the rational investigation of interrelationships between drug, enhancer, and skin. Such information is clearly essential for the optimization and exploitation of transdermal drug delivery.

Alkanes↗
PubMed1991

The effects of zwitterionic surfactants on skin barrier function.

The action of five zwitterionic surfactants on the barrier function of hairless mouse skin has been studied in vitro. The surfactants considered were dodecylbetaine and hexadecylbetaine (C12BET and C16BET, respectively), hexadecylsulfobetaine (C16SUB), N,N-dimethyl-N-dodecylamine oxide (C12AO), and dodecyltrimethylammonium bromide (C12TAB). Excised skin was pretreated with each surfactant, at various concentrations, for 16 hr, following which the permeation of a model compound, nicotinamide, was measured. The action of the surfactants was assessed by comparing nicotinamide flux through surfactant-pretreated skin with that across control membranes which were exposed to buffer alone for 16 hr. All surfactants decreased skin barrier function to some extent. The degree of nicotinamide penetration enhancement induced was correlated with the ratio of the surfactant pretreatment concentration to the surfactant critical micelle concentration, suggesting that solubilization of stratum corneum lipids may be an important mechanism in explaining the effects observed. More detailed studies with 14C-radiolabeled C12BET and C16BET showed that the dodecyl analog was itself well absorbed, whereas the C16 compound partitioned into the skin favorably but then transferred only very slowly into the receptor phase. These observations were consistent with toxicity studies (albeit at much higher concentrations in a different animal model, the rat) which indicated that the dermal LD50 of C12BET was significantly less than that of C16BET (the value for which was so large that it could not be reliably determined). Overall, this study provides, we believe, useful information pertinent to the potential dermal toxicity of the surfactants considered following occupational or environmental exposure.

Administration, Oral↗
PubMed1991

Percutaneous penetration of para-substituted phenols in vitro.

The percutaneous penetration of 11 para-substituted phenols has been measured across full-thickness hairless mouse skin in vitro. The phenols, which spanned more than a 1000-fold range in octanol/water partition coefficient (P), were applied (14C-radiolabeled) to the skin surface in a small volume of volatile organic solvent. Permeation kinetics were continuously monitored and were characterized by the maximum observed flux (Jmax). The linear correlation of log Jmax with log P was very poor. However, inclusion of molecular volume (MV) in a multiple regression analysis considerably improved the relationship between the measured transport parameter and the physicochemical descriptors. Furthermore, significant parabolic (log Jmax = -0.18 + 1.35.log P - 0.30.[log P]2) and bilinear (log Jmax = -0.17 + 1.08.log P - 1.95.[log(beta.10logP + 1)]) dependencies were obtained, suggesting a change in the rate-limiting transport step (for compounds of high log P) from diffusion across the stratum corneum (SC) to partitioning at the SC-viable epidermis interface. Addition of a term in MV (or molar refractivity) further improved the absolute correlations, but with marginal statistical significance. A wider range of molecular size is necessary to unequivocally define the role of permeant dimensions in percutaneous permeability for this group of compounds. The quadratic log Jmax correlation with log P was compared to the previously reported steady-state permeability coefficients (Kp) of a different set of phenol analogs through human epidermis. Despite the different methodologies, different compounds, and different skin membranes employed, the patterns of behavior in the two data sets were consistent, and suggest that the form of this correlation may be suitable description of phenol permeability under a range of experimental conditions.

Animals↗