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Biomedical subjects

T J Franz

Publications and source records attributed to T J Franz.

At least 37 records · Page 2Linked to original sources
PubMed1989

The hamster flank organ model: is it relevant to man?

The critical role that androgens play in the etiology of acne has led to a search for topically active antiandrogens and the frequent use of the flank organ of the golden Syrian hamster as an animal model. 17-alpha-propyltestosterone (17-PT) has been identified as having potent antiandrogenic activity in the hamster model, and this report describes its clinical evaluation. Two double-blind placebo controlled studies comparing 4% 17-PT in 80% alcohol versus vehicle alone were conducted. One study examined 17-PT sebosuppressive activity in 20 subjects. The second study examined its efficacy in 44 subjects having mild to moderate acne. A third study measured in vitro percutaneous absorption of 17-PT through hamster flank and monkey skin, and human face skin in-vivo, using radioactive drug. 17-PT was found to be ineffective in reducing either the sebum excretion rate or the number of inflammatory acne lesions. Failure of 17-PT to show clinical activity was not a result of poor percutaneous absorption. Total absorption in man was 7.7% of the dose and only 1.0% in the hamster. The sebaceous gland of hamster flank organ is apparently more sensitive to antiandrogens than the human sebaceous gland.

Acne Vulgaris↗
PubMed1988

Percutaneous absorption of sulconazole nitrate in humans.

The percutaneous absorption of 1% sulconazole nitrate in a cream formulation containing 3H-labeled drug has been studied in seven human subjects. Two applications of 4.5 g each were made to 450 cm2 of abdominal skin at 0 and 12 h, and the site was washed at 24 h. The application site was subsequently washed at 24-h intervals for 3 consecutive days, and 6.7% of the dose was recovered in the urine and 2.0% in the feces following a 7-d collection period. Radioactivity was detectable in the plasma from 8-96 h, with a peak occurring at 24 h, and could also be recovered in the skin wash up to 96 h after application. Total percutaneous absorption of sulconazole was estimated to be 8.7-11.3% of the applied dose, considerably more than that previously reported for other imidazole drugs.

Adult↗
PubMed1988

Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose.

The percutaneous absorption characteristics of isotretinoin, etretinate, tretinoin, and acitretin were investigated in vitro to assess the feasibility of their topical application for dermatological disorders. The influence of vehicle, photodegradation, and dose was examined. Retinoid absorption through monkey skin was highly vehicle dependent and followed the order: propylene glycol = isopropyl alcohol greater than mineral oil greater than diisopropyl adipate greater than polyethylene glycol 400. Peak flux of etretinate (an ester) was less than 50% that of the acid retinoids in both human and monkey skin. Exposure to light caused a 60% degradation of isotretinoin on the surface of the skin, but did not change the amount of drug which penetrated the epidermis. In accord with this result, the amount of isotretinoin and acitretin which penetrated epidermis did not increase in proportion to dose over a 25-fold range of dose in human skin. Dermal concentration at doses of 10 micrograms/cm2 of isotretinoin and acitretin were greater than that reported for shave biopsies of human skin following treatment for several months with clinically effective doses of isotretinoin and etretinate (the parent ester of the acid acitretin).

Absorption↗
PubMed1986

Minimal spinal hyperostosis with low-dose isotretinoin therapy.

Skeletal abnormalities have been reported on numerous occasions in patients who have received high doses of vitamin A and its derivatives. Recently, a new derivative, isotretinoin (Accutane, Hoffman-LaRoche, Inc.), has become available for the treatment of cystic acne. Ninety-six patients treated for a minimum of four months with low doses of this drug at two University centers have shown overall good to excellent clinical responses. However, ten of these patients have developed small pointed excrescences on the anterior margins of cervical, thoracic, or lumbar vertebral bodies. The findings are of unknown clinical significance but show some similarities to the spinal findings in DISH syndrome. Follow-up studies will be obtained, but, at the present time, the drug still can be recommended for patients who have severe cystic acne because of the excellent clinical response.

Acne Vulgaris↗
PubMed1986

Vehicle effects on percutaneous absorption: in vivo and in vitro comparisons with human skin.

The percutaneous absorption of benzoic acid, caffeine and testosterone through human skin was measured by using in vivo and in vitro techniques. The compounds were applied to the skin in solution in three vehicles: petrolatum, ethylene glycol gel and water gel. Because benzoic acid was ionized at the neutral pH of the gels, these data were difficult to interpret and are not reported. The stratum corneum/vehicle partition coefficients (Km) and percent saturation of the vehicles with substrate were determined to aid in the interpretation of the absorption results. In the in vitro studies, the permeability constants determined for the compounds in each vehicle correlated with either the Km value or the percent saturation of the vehicle. Caffeine penetrated most readily from a petrolatum vehicle, and the greatest testosterone absorption was from a water gel. Permeation was also expressed in terms of the percentage of the applied dose absorbed. Reasonable agreement was obtained between the in vivo and in vitro values. Although no significant differences occurred between most values compared, there was a trend toward lower penetration in the in vitro system.

Adult↗
PubMed1985

Percutaneous absorption of minoxidil in man.

The percutaneous absorption and excretion of 1% and 5% solutions of minoxidil labeled with carbon 14 were measured in 12 adult male subjects. These subjects were randomly assigned to the 1% and 5% minoxidil testing groups, and all received nine topical applications to a bald area on the scalp, with the radioactive solutions applied on days 1 and 9. Urinary excretion of radioactivity was low, with mean values ranging from 1.6% to 3.9% of applied dose. No radioactivity could be detected in fecal samples. Recovery of radioactivity from the skin surface and from scalp and pillowcase washes was in the range of 41% to 45% of applied dose. No adverse reactions or notable abnormalities were noted in the subjects during the study. Although minoxidil is poorly absorbed through the skin, systemic doses in the range of 2.4 to 5.4 mg/day can be anticipated if application is made to entire scalp.

Administration, Topical↗
PubMed1984

Persistence of antifolate activity in skin of rats following systemic administration of methotrexate.

Studies of the time course of methotrexate-derived antifolate activity (methotrexate activity) in plasma and skin of rats have been carried out to evaluate the hypothesis that the formation of therapeutically active poly-gamma-glutamyl conjugates of methotrexate in skin after systemic administration of the drug will result in the prolongation of methotrexate effects in skin. Such a finding may eventually bear on the use of the drug in the treatment of psoriasis. Three groups of 4 rats received a single i.v. dose of methotrexate, 5, 20, or 40 mg/kg, respectively. Serial skin and plasma samples were obtained over 48 h from each rat and analyzed for methotrexate activity by a dihydrofolate reductase enzyme inhibition assay. The values of pharmacokinetic parameters describing the disposition of the drug were calculated from plasma data using standard methods. Skin to plasma ratio of methotrexate activity was also calculated each time a skin sample was obtained. Pharmacokinetic parameter values and skin to plasma ratios were not significantly different between doses. Methotrexate activity declined biexponentially in plasma and skin. The terminal half-life in plasma (mean +/- SD) was 20.3 +/- 9.2 h. At early times, methotrexate activity in skin was less than plasma, but at later times activity in skin was an order of magnitude greater than that in plasma. In a preliminary study to determine whether the persistent activity in skin is associated with the presence of poly-gamma-glutamyl conjugates of methotrexate, a rat was dosed with tritiated methotrexate, 0.18 mg/kg, i.v., and skin was obtained 24 h later. Skin homogenate was treated with papain and applied to an anion-exchange column for cleanup prior to injection on a reversed-phase high-pressure liquid chromatography system. Methotrexate poly-gamma-glutamates were identified by elution with authentic standards and specific hydrolysis with carboxypeptidase G1.

Animals↗
PubMed1984

Pharmacokinetics of the poly-gamma-glutamyl metabolites of methotrexate in skin and other tissues of rats and hairless mice.

The time course of methotrexate (MTX) and its poly-gamma-glutamyl metabolites (PGGs) was examined in the skin, liver and blood of rats and full-thickness skin, epidermis and blood of hairless mice to determine their contribution to the persistence of antifolate activity after a single dose of MTX. [3H]MTX was administered i.v. to rats and i.p. to mice in a dose similar, on a microgram per kilogram basis, to that administered to humans for the treatment of psoriasis. The animals were sacrificed at various times after the dose and skin and other tissues were analyzed for the presence of MTX and the PGGs. The percentage of total antifolates in the skin of rats that was attributable to the PGGs was less than 30% at all times examined (6 to 72 hr). However, more than half of the PGGs present contained three or more glutamic acid residues. The skin from the hairless mice was separated into dermis and epidermis to determine if MTX and its metabolites were present in the ostensible site of action in psoriasis, the epidermis (separation of epidermis from dermis is prohibited by hair in the rat). The PGGs accounted for less than 13% of total antifolates in full-thickness skin of mice at all times studied. The epidermis contained more antifolates, on a picomole per gram basis, at all times (4 to 24 hr) than did the full-thickness skin. In the epidermis, the percentage of total antifolates contributed by the PGGs rose to 35% by 24 hr, more than twice its value at earlier times.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

On the bioavailability of topical formulations of clindamycin hydrochloride.

The role of the vehicle in the percutaneous absorption of clindamycin hydrochloride has been studied. Fourteen vehicles have been examined for their ability (1) to adequately solubilize clindamycin and (2) to effect penetration of the drug into the skin. The solubility of clindamycin was found to be good in ten of the fourteen vehicles studied, with a drug concentration of greater than 1.0% being achieved. A vehicular water content of greater than 20% or the presence of another suitable cosolvent appeared to be necessary for adequate solubilization of drug. Percutaneous absorption varied greatly among the vehicles, ranging from 0.7% to 12.9% of the applied dose in 24 hours. The vehicles effecting the greatest clindamycin absorption contained the penetration enhancers dimethylsulfoxide or N-methyl-2-pyrrolidone. Overall, the vehicles studied varied a hundredfold with respect to clindamycin bioavailability. Correlation of these data with other literature data suggests a possible relationship between clindamycin bioavailability and clinical efficacy in the treatment of acne and, therefore, argues against extemporaneous compounding of this drug in the absence of bioavailability data.

Administration, Topical↗
PubMed1978

The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man.

An in vitro model of percutaneous absorption has been developed which permits close stimulation of conditions commonly associated with topical drug use in living man. Quantitative comparison of the absorption of selected compounds in the model and in living man was made to test the validity of the model. Excellent agreement has been found between the two sets of data, both with respect to the total amount absorbed and the kinetics of absorption.

Aspirin↗
PubMed1975

Percutaneous absorption on the relevance of in vitro data.

The use of in vitro preparations of human skin to study percutaneous absorption is widespread. Yet, up to the present time, little has been done to systematically validate this model and demonstrate the extent to which it mimicks in vivo absorption. In this study, the permeability of 12 organic compounds has been evaluated in excised skin and the results compared to those obtained previously by others in living man. With special emphasis being given here to duplicating in vivo conditions, it was possible to demonstrate an excellent qualitative agreement between the two methods. In all cases, the absorption pattern determined in vitro rather precisely paralleled the pattern which was obtained in vivo. Quantitative agreement between the two sets of data was less than perfect, although the in vitro method adequately distinguished compounds of low permeability from those of high permeability and ranked then in approximately the same order found in vivo. This systematic comparison of in vitro with in vivo data was clearly shown how accurately in vitro absorption studies can reflect the living state.

Aspirin↗
PubMed1968

Further observations on asymmetrical solute movement across membranes.

The permeability of frog skin under the influence of urea hyperosmolarity has been studied. Flux ratio asymmetry has been demonstrated again for tracer mannitol. The inhibitors DNP, CN(-), and ouabain have been used to eliminate active sodium transport and it was found that urea hyperosmolarity produces asymmetrical mannitol fluxes on frog skins having no short-circuit current. These findings suggest that flux ratio asymmetry is due to solute interaction and is unrelated to sodium transport. Studies with a synthetic membrane show clearly that bulk flow of fluid can produce a "solvent drag" effect and change flux ratios. When bulk flow is blocked and solute gradients allowed their full expression, then solute interaction "solute drag" is easily demonstrable in a synthetic system.

Animals↗
PubMed1967

Hyperosmolarity and the net transport of nonelectrolytes in frog skin.

The permeability of frog skin to a series of nonelectrolytes (thiourea, urea, mannitol, and sucrose) under the influence of 2.5 times normal osmolarity in the outer bathing solution has been investigated. Although the flux of the tracer nonelectrolytes across the skin in either direction is greatly increased by hyperosmolarity, the influx is found to be increased to a significantly greater extent than the outflux. Flux ratios as high as 3:1 can be observed. The net inward movement of the nonelectrolyte proceeds in spite of a sizeable bulk flow of water in the opposite direction. Possible driving forces for this phenomenon are discussed.

Animals↗