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Biomedical subjects

R H Guy

Publications and source records attributed to R H Guy.

At least 127 records · Page 7Linked to original sources
PubMed1989

Cutaneous responses to topical methyl nicotinate in black, oriental, and caucasian subjects.

The response of human skin to topical methyl nicotinate (MN) has been monitored in black, oriental, and caucasian subjects. The study aimed to address the question: "Do racial differences in percutaneous absorption and microcirculatory sensitivity exist?" MN-induced vasodilatation was assessed visually and by laser Doppler velocimetry (LDV). At three dose levels, in the three subject populations, four parameters were compared: (a) the diameter of the maximum visually perceptible erythematous area (Emx); (b) the area under the erythematous diameter versus time curve (AUE); (c) the maximum LDV response (Lmax); and (d) the area under the LDV response versus time curve (AUL). At p less than 0.05, AUL (black) greater than AUL (caucasian) for all MN concentrations; AUL (oriental) greater than AUL (caucasian) for the higher dose levels. Emx, AUE and Lmx showed no significant differences between races within concentrations. For all subjects, Emx, AUE, and AUL were significantly dependent on MN dose whereas Lmx was not. The results suggest that some racial differences in response to topical MN exist and that perception of these distinctions may depend upon the method of measurement.

Administration, Cutaneous↗
PubMed1989

The effect of aging on percutaneous absorption in man.

Despite much research into the mechanisms of cutaneous aging and the identification of significant age-associated biological and biophysical changes within the skin, the question "How does aging affect percutaneous absorption (PA) in vivo?" remains unanswered. We have made in vivo measurements of PA in young (18-40 years) and old (greater than 65 years) subjects. Standard radiotracer methodology was employed and PA was quantified from the urinary excretion profiles of 14C radiolabel (corrected for incomplete renal elimination). Testosterone (TST), estradiol (EST), hydrocortisone (HC), benzoic acid (BA), acetylsalicylic acid (ASA), and caffeine (CAFF) have been studied. Permeation of HC, BA, ASA, and CAFF was significantly (p less than 0.01, 0.01, 0.01, and 0.05, respectively) lower in aged subjects, whereas the absorption of TST and EST was similar in the two groups. Thus it appears that aging can affect PA in vivo and that relatively hydrophilic compounds are particularly sensitive. The diminished surface lipid content of "old" skin implies a diminished dissolution medium for compounds administered topically. It is reasonable to speculate that this physiologic change will impact most severely upon those permeants whose lipid solubility is lowest (that is, HC, BA, ASA, CAFF). Furthermore, the typically reduced hydration of aged stratum corneum will compound this effect for these chemicals. Conversely, highly lipid-soluble chemicals (TST and EST) may still be able to dissolve readily into the stratum corneum even when the available lipid medium is reduced.

Administration, Topical↗
PubMed1989

Assessment of skin barrier function using transepidermal water loss: effect of age.

To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in "young" (19-42 years) and "old" (69-85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J infinity), which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2-7 g/m2/hr. Initial TEWL rates (mean +/- SD) were found to differ significantly between young (28.6 +/- 7.5 g/m2/hr; n = 26) and old (36.9 +/- 10.5 g/m2/hr; n = 18) subjects (P less than 0.01). Relaxation of TEWL to J infinity was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean +/- SD) 176 +/- 59 min for the young subjects, compared to 360 +/- 76 min for the old (P less than 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.

Adult↗
PubMed1989

In vitro percutaneous penetration: evaluation of the utility of hairless mouse skin.

The permeability barrier of hairless mouse skin has been determined in vitro after exposure of the epidermal surface to volumes of acetone typically used in human in vivo skin penetration studies. It has been shown that the transport of tritiated water (when applied for limited 5-h periods) across hairless mouse skin is not affected by acetone treatments of approximately 15 microliters/cm2. Submersion of the membranes between aqueous donor and receptor phases for periods greater than 24 h, however, leads to significant and catastrophic barrier impairment. The acetone dose in the experiments reported is greater than that employed in vivo when the solvent is used to deposit a penetrant on human skin. We suggest, therefore, that acetone-mediated facilitation of percutaneous absorption in humans is unlikely. A further conclusion of this work is that in vitro solvent-deposition penetration experiments using hairless mouse skin should provide reliable transport information for at least 48 h postadministration. Although hairless mouse skin is more permeable than its human counterpart, in vitro measurements using the murine barrier should, therefore, provide useful and relevant guidelines for risk assessment calculations and bioavailability determinations.

Absorption↗
PubMed1988

The relationship of pKa and acute skin irritation in man.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15-88 micrograms/cm2/hr). Skin irritation and pKa are correlated for pKa less than or equal to 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa less than or equal to 4.

Adult↗
PubMed1988

A new system for in vitro studies of iontophoresis.

This report describes a new iontophoretic diffusion cell that allows both electrodes to be applied to the same side of the same piece of skin. The cell permits a better approximation of the in vivo situation than do conventional side-by-side cells. The unique construction of the cell allows nonliquid material to be applied to the skin surface and makes it possible to investigate horizontal transport paths. Preliminary results utilizing the cell are described. Iontophoretic enhancement of morphine and clonidine delivery across full-thickness hairless mouse skin has been achieved. The importance of pH control in these experiments is apparent. Further experiments with morphine indicate that, for this drug at least, iontophoretically driven lateral transport within the skin is unimportant. Because the cell design allows significant parallels to the use of iontophoresis in vivo, we suggest that it will prove to be a useful tool in the determination of fundamental structure/transport relationships under the influence of an externally applied current.

Animals↗
PubMed1988

Physicochemical aspects of percutaneous penetration and its enhancement.

The classic diffusion model-based interpretation of percutaneous absorption is compared to a simple kinetic analysis. The physicochemical significance and the major deductions of the two approaches are shown to be in general agreement. In particular, the effect of penetrant oil/water partition coefficient on transdermal flux is consistently predicted by the two models. Diffusional and kinetic assessments of skin penetration enhancement are then shown to reveal similar dependencies upon penetrant physical chemistry. It is demonstrated that the requirements for successful promotion of a lipophilic drug's transdermal flux are quite different from those necessary for a hydrophilic penetrant. Finally, in light of published transport data and our increased comprehension of the stratum corneum barrier function, the evidence for (and significance of) different absorption paths across the stratum corneum is considered. In addition, the impact of penetrant "size" on transport is addressed. It is argued that currently held beliefs concerning (i) a putative "polar" route through the stratum corneum and (ii) the dependence of flux on molecular weight warrant considerable further attention before their unequivocal acceptance is appropriate.

Diffusion↗
PubMed1988

Percutaneous absorption of hydroquinone in humans: effect of 1-dodecylazacycloheptan-2-one (azone) and the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (Escalol 507).

Hydroquinone was found to penetrate readily human forehead skin in vivo following a single topical exposure, in an alcoholic vehicle, of 24 h duration. Percutaneous absorption was estimated using radiotracer methodology and 14C-labeled hydroquinone. The effects of a penetration enhancer, 1-dodecylazacycloheptan-2-one, and a sunscreen, the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid, on the percutaneous absorption of hydroquinone were investigated. In vivo penetration of hydroquinone was significantly decreased (a less than 0.05) by the addition of the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (3% w/w) to the vehicle. The penetration enhancer, 1-dodecylazacycloheptan-2-one (0.5% w/w), did not significantly increase (a greater than 0.05) the absorption of hydroquinone. From all hydroquinone preparations, percutaneous absorption was rapid and peak elimination occurred within the first 12 h following application. Elimination was complete within 5 d.

4-Aminobenzoic Acid↗
PubMed1988

Bioavailability of topically administered steroids: a "mass balance" technique.

The percutaneous absorption of four steroids (hydrocortisone, estradiol, testosterone, and progesterone) has been measured in vivo in man under occluded and "protected" (i.e., covered, but non-occlusive) conditions. The experimental approach, involving simple modifications of standard radiochemical methodology, has enabled excellent "mass balance" and dose accountability to be achieved. Consequently, the utility of the procedure for the measurement of in vivo topical bioavailability can be inferred. In addition, because of the precision and accountability of the results, the technique offers a potential means to establish quantitative structure-penetration relationships for skin absorption in man. It was found that steroid absorption increased with increasing lipophilicity up to a point, but that penetration of progesterone (the most hydophobic analog studied) did not continue the trend and was at least partly rate-limited by slow interfacial transport at the stratum corneum-viable epidermis boundary. Comparison of data obtained from the occluded and "protected" experiments permitted the effect of occlusion (defined as the complete impairment of passive transepidermal water loss at the application site) to be assessed. Occlusion significantly increased percutaneous absorption of estradiol, testosterone, and progesterone but did not effect the penetration of hydrocortisone. A mechanism is proposed to explain why the absorption of the more lipophilic steroids is enhanced by occlusion but that of the most water-soluble (i.e., hydrocortisone) is not. It is suggested that the rate-determining role of the sequential steps involved in percutaneous absorption can be revealed by experiments of the type described using related series of homologous or analogous chemicals.

Absorption↗
PubMed1988

Methodology to measure the transient effect of occlusion on skin penetration and stratum corneum hydration in vivo.

The effect of short duration occlusion on skin penetration and stratum corneum water content was studied in vivo in eight human subjects. Percutaneous absorption of hexyl nicotinate was monitored non-invasively by laser Doppler velocimetry (LDV) following each of three randomly assigned pre-treatments: untreated control, 30 min occlusion with a polypropylene chamber and 30 min occlusion followed by exposure to ambient conditions for 1 h. Stratum corneum water content after the same pre-treatments was measured with the dielectric probe technique. The local vasodilatory effect of the nicotinic acid ester was quantified using LDV by the onset of increased blood flow, the time of maximal increase in response, the magnitude of the peak response and the area under the response-time curve. Each of these parameters was significantly different, immediately following occlusion, from the untreated control values. However, if the occluded site was exposed for 1 h prior to hexyl nicotinate application these parameters did not differ significantly from the controls. Stratum corneum water content (expressed as a percentage of a maximal value) showed the same behaviour: the pre-treatment control value was 31.8 +/- 4.8%; after 30 min occlusion, this had risen to 46.9 +/- 6.2%; 1 h later, the reading had returned to 32.1 +/- 6.2%. There was a significant correlation between stratum corneum water content and area under the LDV response-time curve. It appears, therefore, that this method may be useful for quantifying the relationship between increased stratum corneum hydration and enhanced percutaneous absorption in vivo in man.

Adult↗
PubMed1988

Pharmacokinetic considerations in the use of newer transdermal formulations.

This review addresses the pharmacokinetics and pharmacodynamics of transdermally delivered drugs. The systemic input of drugs via the skin has attracted considerable interest over the past 15 years. The early promise of the administration route has, to some extent, been realised with the approval and successful launching of transdermal formulations of hyoscine (scopolamine), glyceryl trinitrate (nitroglycerin), clonidine and oestradiol. The further application of transdermal delivery, however, will require additional effort. While other molecules (e.g. testosterone, fentanyl, nicotine) may ultimately be administered in this way, important questions pertaining to pharmacology (tolerance), toxicity (irritation, sensitisation) and dose sufficiency (penetration enhancement) remain. These problems are illustrated using information which has been published in the literature. Overall, while the enthusiasm for attraction and benefits of transdermal delivery remain evident, it is clear that future successes will demand a heightened level of commitment and skill from the pharmaceutical scientist.

Administration, Cutaneous↗
PubMed1987

Blood flow in psoriatic skin lesions: the effect of treatment.

Laser Doppler velocimetry (LDV) was used to assess the effect of treatment upon cutaneous blood flow in psoriatic skin lesions. The resolution of two separate plaques in each of seven subjects was followed. Six of the subjects received the Goeckerman regimen, the seventh was treated with psoralen-ultraviolet A (PUVA) therapy. Control LDV readings were taken from uninvolved skin sites during the treatment period. Cutaneous blood flow in the psoriatic lesions of the Goeckerman-treated patients decreased to levels comparable to those in uninvolved skin early in the course of treatment and significantly preceeded the observed clinical resolution from 4 to 8 days after initiation of therapy (P less than 0.05). Visible flare-ups sometimes appeared when patients were untreated (over a weekend, for example) and these eruptions were accompanied by a transient elevation of LDV readings. Perfusion of the lesions of the PUVA-treated patient remained consistently higher than perfusion of uninvolved skin despite clinical healing. In a separate series of experiments, blood flow at the extensor surface of the forearm was measured in the skin of normal subjects, the uninvolved skin of psoriatic patients and the untreated lesional skin of psoriatic patients. While the lesional skin had significantly higher perfusion levels than uninvolved psoriatic or normal control skin (P less than 0.01), there was no significant difference between blood flow to the uninvolved psoriatic skin of psoriatics and that to the skin of healthy controls.

Adult↗
PubMed1987

Transdermal drug delivery and cutaneous metabolism.

The delivery of drugs via the skin to achieve systemic therapeutic effect is currently under intense investigation. The skin offers unique advantages and limitations for drug input into the body. For example, while hepatic first pass may be circumvented, the excellent barrier function of the stratum corneum (the thin outermost layer of skin) precludes, at present, all but the most potent drugs from this route of administration. Examples of approved transdermally delivered drugs are scopolamine, nitroglycerin, clonidine and estradiol. The delivery systems which have been formulated for these agents have been designed to provide essentially zero-order input kinetics for between 1 and 7 days. The impact of cutaneous metabolism on transdermal drug delivery has not yet been evaluated rigorously. Limited in vivo data for nitroglycerin suggest a cutaneous first pass effect of between 10 and 20%. More work has been directed towards the use of topical prodrugs and the design of molecules better able to transport across the stratum corneum and then undergo local enzymatic activation. Further research in this area will require a more specific quantitative understanding of the metabolic capabilities of human skin in vivo.

Administration, Topical↗
PubMed1987

Transdermal drug delivery: problems and possibilities.

Transdermal drug delivery has, in recent years, attracted considerable interest. However, despite the obvious advantages of this novel route of drug administration to achieve systemic therapeutic effect, there remain important, and sometimes severe, limitations on the physiochemical and pharmacological properties of the agent to be delivered. This article reviews the present status and accomplishments of transdermal drug delivery. The benefits, disadvantages, and, as yet, unresolved problems inherent to drug input via the skin are addressed. Deficiencies in our knowledge of the percutaneous absorption process in man are identified, and approaches to elucidate these unknowns are discussed. Finally, with respect to the future potential of transdermal drug delivery, experimental and modeling techniques, which can be employed to assess the feasibility and promise of a therapeutic candidate, are described and illustrated with pertinent examples.

Administration, Cutaneous↗
PubMed1986

Pharmacodynamic measurement of percutaneous penetration enhancement in vivo.

Enhanced skin penetration of hexyl nicotinate was measured in human subjects using laser Doppler velocimetry (LDV). The local pharmacodynamic response (vasodilatation) to hexyl nicotinate permitted the kinetics and extent of penetration to be evaluated following topical application of 10 mM drug in a 60:40 v/v propylene glycol: isopropyl alcohol vehicle. Prior to hexyl nicotinate administration, the application site was either untreated (control) or subjected to one of four 30-min pretreatments: (a) occlusion with a polypropylene chamber; (b) occlusion (as in a) in the presence of 0.3 mL of the vehicle; (c) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% 2-pyrrolidone; and (d) occlusion (as in a) in the presence of 0.3 mL of the vehicle containing 25% laurocapram (1-dodecylhexahydro-2H-azepin-2-one). The time-course and magnitude of the LDV response were characterized by the onset of action, time to peak, peak height, and area under the curve (AUC). The onset of action and time to peak were significantly shortened, and the peak height and AUC significantly increased with pretreatments a-d. For example, time to peak values were 35 +/- 4, 29 +/- 3, 22 +/- 5, 19 +/- 4, and 17 +/- 4 min for control and pretreatments a-d, respectively (n = 8). Pretreatments with vehicle, vehicle plus 2-pyrrolidone, and vehicle plus laurocapram did not cause LDV-detectable alterations in skin blood flow. The data support, therefore, a novel, simple, noninvasive, and objective demonstration of enhanced skin penetration of hexyl nicotinate in humans.

Adult↗
PubMed1986

Percutaneous penetration of nicotinates: in vivo and in vitro measurements.

The relationship between chemical structure and percutaneous absorption has been explored with nicotinic acid and its methyl, ethyl, hexyl, and benzyl esters. Skin penetration has been measured in vitro across hairless mouse skin and in vivo in humans. In vitro, methyl and ethyl nicotinates (when applied in acetone) were delivered into skin such that the stratum corneum barrier was effectively bypassed. The lipophilic esters, on the other hand, were not solubilized in this way and penetrated more slowly. Nicotinic acid penetrated poorly, yielding essentially zero-order skin transport kinetics. Tape-stripping experiments, in which penetration was monitored across skin with no stratum corneum, confirmed these observations. In vivo absorption of the esters was determined from the urinary excretion of total radioactivity following topical administration of 14C-labeled penetrant. Kinetic analysis of the data yielded rate constants, the ratio of which correlated acceptably with the penetrant octanol-water partition coefficient (K). The dependence of the rate constants on K was interpreted in terms of the relative affinity of the substrate for the stratum corneum compared with the viable tissue; the relationship agrees well with a previous evaluation involving structurally unrelated molecules.

Animals↗