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Biomedical subjects

R H Guy

Publications and source records attributed to R H Guy.

At least 145 records · Page 8Linked to original sources
PubMed1986

Percutaneous absorption in the aged.

The work described in this article reveals a remarkable lack of consensus as to whether percutaneous absorption changes as humans grow older. The data that have been recorded point to possible significant alterations in the barrier function with age. The importance of these observations with respect to dermatopharmacology and dermatotoxicology is clear. The absence of a clearly defined relationship between aging, percutaneous penetration, and the properties of the molecules crossing the skin barrier represents an unacceptable gap in fundamental dermatologic knowledge. With the changing demographic pattern of Western civilization and the increasing awareness of human subjects for the condition of their skin, and the potential for drug delivery via their skin, it is crucial that we begin to establish precisely how the barrier function alters with increasing age. The answer to this question may permit unique improvements in the quality of both local and systemic health in aging populations.

Adult↗
PubMed1985

Percutaneous absorption in man: a kinetic approach.

A biophysically based kinetic model of chemical absorption via human skin was developed and applied to the penetration kinetics of 12 chemicals: aspirin, benzoic acid, benzyl nicotinate, caffeine, chloramphenicol, colchicine, dinitrochlorobenzene, diethyltoluamide, malathion, methyl nicotinate, nitrobenzene, and salicylic acid. The pharmacokinetic model is linear and includes four first-order rate constants: (1) k1 describes penetrant diffusion through the stratum corneum; (2) k2 relates to further transport across the viable epidermal tissue to the cutaneous blood vessels; (3) k3 is a parameter which delays the partitioning of penetrant at the stratum corneum-viable tissue interface and, in conjunction with k2, reflects the penetrant's relative affinity for the stratum corneum over the viable tissue; and (4) k4 characterizes the elimination rate of chemical from blood to urine. Previously determined diffusion coefficients and molecular weight corrections were used to estimate k1 and k2; k4 values employed were those measured experimentally. Urinary excretion rate data following topical administration were simulated and k3 was estimated for each penetrant by optimizing the fit of the model to the data points. Ratios of k3/k2 should be related to the partition coefficients for the chemicals between stratum corneum and viable tissue and it was shown that these ratios agreed reasonably well with the corresponding octanol-water partition coefficients. This approach may have potential for predicting the general percutaneous absorption kinetics of chemicals based on recognized cutaneous biology and penetrant molecular weight and lipophilicity.

Epidermis↗
PubMed1985

Are there age and racial differences to methyl nicotinate-induced vasodilatation in human skin?

Preliminary experiments have been performed to determine whether there are age and racial differences in the response of human skin to the topically applied vasodilator methyl nicotinate. With the use of a constant stimulus (a 15-second exposure to a 100 mM aqueous solution of drug), the subsequent time-course of the vasodilatation response was followed noninvasively and objectively with the optical technics of laser Doppler velocimetry (LDV) and photoplethysmography (PPG). Three groups of subjects were considered: young white subjects (20 to 30 years of age), elderly white subjects (63 to 80 years old), and young black subjects (20 to 30 years old). Analysis of the results shows that the time to peak response, the area under the response-time curve, and the time for the response to decay to 75% of its maximum value are statistically indistinguishable for all three groups at the p = 0.05 level of significance. Only the magnitude of the peak response revealed some significant differences between the cohorts (young greater than black, determined by PPG; young greater than old, determined by LDV). The data suggest, therefore, a remarkable similarity in response across a wide range of skin types. The origin of this consistency may, however, be complex and is not revealed by these experiments.

Adult↗
PubMed1985

Spatial variability of vasodilatation in human forearm skin.

Vasodilatation elicited by topical application of methyl nicotinate was measured by photoplethysmography at various positions on human ventral forearm skin. The time-to-peak response, the magnitude of the peak response, the area under the response-time curve and the time for the response to decay to 75% of the maximum value, were recorded at six positions on the left and right forearms of eight subjects. There was no significant difference between response on the right and left forearm sites and no difference in response between the lateral and medial sites on the forearms. In a second experiment, the vasodilatation was measured at proximal and distal positions on the forearm. The magnitude of the peak response at the proximal position was significantly higher than that found distally (P less than 0.01) as was the area under the response-time curve (P less than 0.05). These results suggest a possible cause for the variation observed in vasoconstrictor assays of corticosteroids.

Adult↗
PubMed1984

Correction factors for determining body exposure from forearm percutaneous absorption data.

Evaluation of toxic exposure via the skin is invariably based upon forearm percutaneous absorption data and an appropriate area multiplication factor. Published experimental data clearly show, however, substantial site variation in skin penetration such that the use of forearm data may produce an inaccurate prediction of total body exposure. Using literature results for cutaneous absorption as a function of anatomic position and accepted estimations of human body surface areas, correction factors for use with forearm penetration data have been evaluated. Calculations have been performed for an adult, a small child and a neonate. Examples of limited exposure to specific regions of the body have also been assessed relative to predictions based upon percutaneous absorption across forearm skin. It appears that the use of forearm skin penetration data alone underestimates body exposure by at least a factor of two.

Adult↗
PubMed1984

Prediction of drug disposition kinetics in skin and plasma following topical administration.

The development of a physically based pharmacokinetic model for percutaneous absorption is described. The simulation includes four first-order rate constants assigned the following significance: (a) absorption across the stratum corneum; (b) diffusion through the viable tissue; (c) a retardation process which retains penetrant in the stratum corneum (and hence provides a means to mathematically produce a "reservoir" effect, for example); and (d) uptake from the skin into the systemic circulation and subsequent elimination from the body. The kinetic equations of the model are solved and expressions are obtained for the concentration of penetrant within the stratum corneum (and available to subsequently partition into the viable epidermis) and the plasma concentration of the administered substance, as a function of time. Using example values for the four rate parameters, disposition profiles for the penetrant in skin and plasma were derived. The cases considered cover slow and fast stratum corneum penetrants, substances which are excreted rapidly or slowly from the body, and absorbing molecules with a variety of relative stratum corneum-viable tissue affinities. The results suggest a framework for the prediction of pharmaceutically and clinically relevant information following the topical administration of therapeutic agents for local or systemic effect.

Administration, Topical↗
PubMed1984

Minoxidil stimulates cutaneous blood flow in human balding scalps: pharmacodynamics measured by laser Doppler velocimetry and photopulse plethysmography.

In a double-blind study with randomly assigned topical solutions of 0%, 1%, 3%, or 5% minoxidil, the blood flow in balding scalps of 16 human volunteers was measured by the noninvasive techniques of both laser Doppler velocimetry (LDV) and photopulse plethysmography (PPG). On two consecutive days, an 0.25-ml volume of the assigned minoxidil formulation was spread uniformly over a 100-cm2 area of each side of the bald scalp and cutaneous blood flow was recorded for the following 4 h. Both measurement techniques showed that the 5% minoxidil solution stimulated the microcirculation of the bald scalp. Increased blood flow was greater with the 5% minoxidil solution than with the other treatments. Measured by LDV on day 1, the increase (p less than 0.0001) in blood flow occurred within 15 min of application of the 5% solution of minoxidil and was maintained at least through hour 1. On day 2, LDV showed blood flow stimulation with the 5% solution was 3-fold (p less than 0.0001) within 15 min of application and was so maintained for about 1 h. Measured by PPG, the only statistically significant (p less than 0.01) response occurred with the day 2 application of the 5% minoxidil solution. PPG is dependent on local blood volume and is only weakly correlated to cutaneous blood flow, which makes it unsuitable for this kind of study. Analysis of vital signs for days 1 and 2 revealed no systemic effect from treatment with minoxidil, suggesting that the blood flow stimulation was directly related to the topical application of minoxidil.

Administration, Topical↗
PubMed1984

Quantitative assessment of UV-induced changes in microcirculatory flow by laser Doppler velocimetry.

Objective measurements of blood flow changes following UV irradiation in the skin of human volunteers have been made with the noninvasive technique of laser Doppler velocimetry (LDV). This optical procedure allowed perfusion (number of red cells X velocity) alterations in the cutaneous microcirculation to be monitored after exposure of the skin to UVA and UVB + UVC radiation. Response curves were obtained in 6 subjects following irradiation at 4 times the minimal UVB + UVC erythema dose (MED). Measurements were made on control (untreated) skin and on skin pretreated with a sunscreen lotion. It was found that: (1) the lotion vehicle had no protective effect, (2) the active sunscreen constituent (2-ethylhexylcinnamate, 5%) was significantly protective, and (3) the presence of bergapten (5-methoxypsoralen, 30 ppm) did not enhance or diminish the cinnamate protective effect. LDV measurements in 5 subjects were also taken during and subsequent to 5 daily exposures to 1 MED of UVB + UVC radiation. Control and pretreated skin sites were again studied and similar protective effects were observed. However, on subsequent reexposure of these sites to 4 MED of UVB + UVC, 14 days after the first of the 5 single MED doses, no significant change in skin blood perfusion was detected at either control or pretreated sites. In a separate series of experiments, LDV data were collected after UVA radiation exposures up to 15 J/cm2. No changes in microcirculation perfusion were detected in any of the situations considered. All LDV measurements were made with 2 instruments of slightly different design and were compared to subjective assessments of erythema performed by a single observer. The results suggest that LDV has significant potential as a means to quantify (1) UV exposures in excess of the MED and (2) the inhibition of UV-induced changes in microcirculatory flow by chemical protectants.

Adult↗
PubMed1983

Malathion percutaneous absorption after repeated administration to man.

Prediction of exposure and toxic potential of pesticides such as malathion are routinely based upon acute exposure and single-dose percutaneous absorption determination. What has become obvious with pesticide exposure such as the malathion spraying for the medfly is that chronic daily exposure is the more relevant situation. Our objective was to determine the percutaneous absorption of chronically applied malathion in man and to compare chronic absorption to single-dose absorption. The experimental design was to first topically apply [14C]malathion to human male volunteers. This procedure was followed by repeated administration of nonradioactive malathion to the same site of application (ventral forearm). [14C]Malathion was reapplied (Day 8) when urinary excretion of radioactivity from the first application reached minimum detectable levels. The first [14C]malathion absorption was compared to the second [14C]malathion application. The percutaneous absorption from the first [14C]malathion application was 4.48 +/- 1.3% (SD) of the applied dose. The absorption from the second [14C]malathion administration was 3.53 +/- 1.0%, a value not significantly (p greater than 0.05) different from the first application. Therefore, for malathion the single-dose application data are relevant for predicting the toxic potential for longer-term exposure.

Administration, Topical↗
PubMed1983

Kinetics and thermodynamics of interfacial transfer.

The kinetic barrier against the transport of methyl and ethyl nicotinates across the water-isopropyl myristate interface has been studied as a function of temperature using a rotating diffusion cell. The temperature dependence of the interfacial transfer kinetics has enabled calculation of the thermodynamic parameters for the process. It is evident from the results that, for the transferring solutes considered, the activation energy barrier is enthalpic, because there is a large positive entropy for transfer into the interfacial region.

Diffusion↗
PubMed1983

Noninvasive assessments of the percutaneous absorption of methyl nicotinate in humans.

Percutaneous penetration of the vasodilator methyl nicotinate (methyl 3-pyridinecarboxylate) has been monitored in vivo in humans with the noninvasive techniques of laser Doppler velocimetry and photopulse plethysmography. These optical methods use different technologies to generate a voltage output which is related to perfusion of the cutaneous microcirculation. The procedures are therefore sensitive to the pharmacologic stimulus and duration of local vasodilation. Following topical application of methyl nicotinate, excellent correlation was found between the response of both methods and the visual observation of erythema. Lower drug concentrations delayed the onset and magnitude of the response and shortened the time period for which elevated microperfusion was observed. These techniques appear to provide a useful noninvasive assessment of the time course of drug behavior in the region of skin to which topical application is made.

Erythema↗