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Biomedical subjects

T J Franz

Publications and source records attributed to T J Franz.

At least 19 recordsLinked to original sources
PubMed2001

Evaluation of creams and ointments as suitable formulations for peldesine.

In-vitro studies were conducted to study the efficacy of mixed and self-emulsifying creams and hydrophobic ointment formulations in delivering peldesine (BCX-34) into and across cryopreserved human cadaver skin (HCS). Oil-in-water cream formulations, containing 1% w/w of radiolabeled C(14) BCX-34 and propylene glycol (PG), glycerin (GLY), isopropyl myristate (IPM), oleic acid (OA) and capric-caprylic esters (CE) were prepared. Petrolatum and lanolin based ointments were also prepared with PG. Sections of the HCS, 250 microm thick, were fitted to vertical Franz diffusion chambers containing a receptor medium of pH 7.4 phosphate buffer solution maintained at 37 degrees C. Using the finite dose technique, 4-6 mg of a formulation sample was applied to the epidermal surface of each section and drug diffusion was permitted for 12 and 24 h periods. The distribution of drug into the HCS epidermis, dermis and into the receptor medium was measured by scintillation spectroscopy. The results show good correlation of the calculated in-vitro values for flux and skin-vehicle partition coefficients against the observed amounts of drug detected in the HCS. The mixed emulsion cream formulation containing PG delivered higher amounts of drug into the skin when compared to the same formulation containing GLY cream. The self-emulsifying cream formulation containing IPM had a higher skin-vehicle partition coefficient and delivered more drug into the dermis when compared to those formulations that contained OA and CE. The petrolatum ointment delivered six times more drug into the epidermis than the lanolin ointment, and had higher skin-vehicle partition values. In conclusion, creams containing PG and petrolatum-base formulations would be suitable for BCX-34 dermal delivery.

Algorithms↗
PubMed1999

Percutaneous absorption of [3H]tretinoin and systemic exposure to mequinol after dermal application of 2% mequinol/0.01% [3H]tretinoin (Solagé) solution in healthy volunteers.

Solagé is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Administration, Topical↗
PubMed1999

Assessment of value and applications of in vitro testing of topical dermatological drug products.

The FDA recently issued a guidance covering practices of scaleup and post approval changes with semisolids (SUPAC-SS). This guidance outlines the steps that must be taken by a company to maintain certification of its semisolid dermatological products after quantitative changes have been made in their compositions and/or after changes have been made in the sourcing of their key ingredients, in their processing, in their batch sizes, and/or after their site of manufacture has been relocated. A key element within the guidance is a release test to be used to determine if the diffusional release of a drug found in a formulation is the same after changes have been made to the formulation as it was prior to implementing the changes. The AAPS-FDA sponsored workshop was set up to explore this qualifying test. The stated aims of the workshop were: a) to illustrate the methodology and techniques of in vitro release testing, b) to show the sensitivity of in vitro release with respect to manufacturing variables and to variations in components and composition (of specific formulations), c) to recognize in vitro release testing as a useful procedure for SUPAC documentation, d) to highlight and evaluate other applications of in vitro release testing, e) to explore the degree to which in vitro release testing and bioavailability may be related, and f) to evaluate the role of in vitro release testing of topical dosage forms as a tool to improve product quality.

Administration, Topical↗
PubMed1999

Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy.

BACKGROUND: A new topical formulation of betamethasone valerate (BMV) with enhanced dermal penetration has been developed. OBJECTIVE: These studies were designed to evaluate: (1) the relative bioavailability of BMV foam, and (2) the safety and efficacy of BMV foam in the treatment of scalp psoriasis as compared to a lotion formulation of BMV and placebo. METHODS: Safety and efficacy were evaluated in a randomized, multicenter, double-blind, active-and placebo-controlled trial in adult patients with moderate to severe scalp psoriasis. A separate study in 18 patients was conducted to evaluate the potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Relative bioavailability was measured using the human cadaver skin model. RESULTS: 72% of patients using BMV foam were clear or almost clear of disease at the end of 28-days of treatment as judged by the investigator's global assessment of response. Only 47% of BMV lotion patients and 21% of placebo showed a similar level of response. There was no evidence of increased toxicity or HPA-axis suppression for BMV foam, but assessment of relative bioavailability showed BMV penetration into the skin to be more than two-fold greater than from BMV lotion. CONCLUSIONS: A novel foam formulation with enhanced BMV bioavailability has been shown to be of increased efficacy in the treatment of scalp psoriasis without an associated increase in toxicity.

Administration, Cutaneous↗
PubMed1998

Retinoic acid-dependent stimulation of 2,2'-azobis(2-amidinopropane)-initiated autoxidation of linoleic acid in sodium dodecyl sulfate micelles: a novel prooxidant effect of retinoic acid.

(E)-Retinoic acid (RA) was shown to stimulate the rate of 2,2'-azobis(2-amidinopropane) (AAPH)-initiated autoxidation of linoleic acid (18:2) in sodium dodecyl sulfate (SDS) micelles. RA-dependent stimulation of 18:2 autoxidation was characterized by enhanced rates of dioxygen uptake which were linear with retinoid concentration. In contrast, 5,6-epoxy-RA, a major oxidation product of RA, failed to affect the rate of dioxygen consumption at all concentrations tested. RA was also shown to stimulate peroxyl radical-dependent oxidation of styrene to the corresponding oxirane when styrene was included in the micellar system as a molecular probe. Furthermore, unequivocal evidence of RA-dependent stimulation of 18:2 autoxidation was obtained by relative quantitation of 13-hydroxy-(9Z, 11E)-octadecadienoic acid (13-HODE) plus 9-hydroxy-(10E,12Z)-octadecadienoic acid (9-HODE) production. In addition, enhanced carbon-centered radical formation was demonstrated in the presence of RA by EPR spectroscopy using alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN) as a spin trap. Analysis and quantitation of RA oxidation products indicated that RA was oxidized to one primary product, 5,6-epoxy-RA, which was identified on the basis of cochromatography with synthetic standard (in a reverse-phase HPLC system), electronic absorption spectroscopy, and positive chemical ionization mass spectrometry of the corresponding methyl ester. Other minor oxidation products were also detected but not characterized. In contrast, reaction mixtures devoid of 18:2 failed to demonstrate significant retinoid oxidation. Mechanisms are proposed to account for the prooxidant effects of RA in this system.

Amidines↗
PubMed1996

A sensitive high-pressure liquid chromatography/particle beam/mass spectrometry assay for the determination of all-trans-retinoic acid and 13-cis-retinoic acid in human plasma.

A highly sensitive assay for the measurement of all-trans-retinoic acid (tretinoin) and 13-cis-retinoic acid (isotretinoin) has been developed. Collected plasma samples were protein precipitated with 2-propanol followed by solid phase extraction. The retinoic acids were subsequently derivatized to their pentafluorobenzyl esters followed by separation and isolation by reverse phase high-pressure liquid chromatography. The HPLC eluate was directed to a mass spectrometer via a particle beam interface. Selected ion monitoring (299 m/z) for the retinoic acid's carboxylate anion produced by negative chemical ionization using methane reagent gas achieved minimum detection limits of 25 pg injected. Endogenous blood levels in 19 male and 9 female subjects were measured. It was found that females have significantly more all-trans-retinoic acid than males and that both sexes demonstrate significantly more all-trans-retinoic acid then 13-cis-retinoic acid.

Adult↗
PubMed1996

Comparative percutaneous absorption of lindane and permethrin.

BACKGROUND AND DESIGN: Because of the concern for potential neurotoxic effects (central nervous system excitation, convulsions) in the treatment of scabies using 1% lindane lotion, 5% permethrin cream has been suggested as an alternative scabicide. Using the finite dose technique, in vitro percutaneous absorption of 5% permethrin cream or 1% lindane lotion was measured in human and guinea pig skin following a single application. In vivo blood and brain levels of the scabicides were measured in guinea pigs following three daily applications of 5% permethrin cream or 1% lindane lotion. Permethrin and lindane levels were quantified by gas chromatography/mass spectroscopy. RESULTS: In vitro percutaneous absorption of the two scabicides was identical in guinea pig skin; however, human skin was 20-fold more permeable to lindane than to permethrin. In vivo guinea pig blood and brain levels of lindane were fourfold greater than permethrin levels. CONCLUSION: The risk for toxic effects, as assessed by systemic exposure during overuse conditions, is projected to be 40 to 400 times lower for 5% permethrin cream than for 1% lindane lotion.

Animals↗
PubMed1993

Percutaneous penetration of N-nitrosodiethanolamine through human skin (in vitro): comparison of finite and infinite dose applications from cosmetic vehicles.

N-Nitroso compounds (nitrosamines) have been detected at the parts per billion level in a wide variety of matrices including industrial chemicals, pharmaceuticals, and food. Although N-nitrosodiethanolamine (NDELA) may be detected as an impurity in some cosmetic products, studies on NDELA absorption through human skin have been limited. A study to determine the extent of NDELA absorption following topical application was therefore undertaken to assist in the proper assessment of risk following unintended exposure. NDELA absorption was measured in vitro through human cadaver skin using isopropyl myristate (IPM) and generic prototype personal-care formulations (sunscreen and shampoo) spiked with [14C]NDELA. When applied as a finite dose at a concentration of 0.06% or lower, NDELA absorption was found to be a linear function of concentration. Total absorption at 48 hr ranged from approximately 35 to 65% of the dose and was formulation dependent (IPM > shampoo > or = sunscreen). Absorption occurred relatively rapidly from all formulations and peak rates of absorption were seen within the first 5 hr from the IPM and shampoo formulations. When applied as an infinite dose, total NDELA absorption followed a different rank order (shampoo > or = IPM > sunscreen) and evidence of barrier damage was seen with the shampoo formulation.

Carcinogens↗
PubMed1993

Quantitative vasoconstrictor assay for topical corticosteroids: the puzzling case of fluocinolone acetonide.

BACKGROUND: The validity of the vasoconstrictor test has been questioned because of the apparent nonequivalence of some generic corticosteroid products. OBJECTIVE: Our purpose was to determine the vasoconstrictor activity of a generic 0.025% fluocinolone acetonide ointment by two different methods, dilution by volume and dilution by area of application. METHODS: Vasoconstrictor activity on a visual 4-point scale was measured in 20 volunteers. Topical fluocinolone acetonide ointment (0.025%) was tested by comparing dilution by volume (1:1, 1:3, and 1:7) in petrolatum and dilution by area of application. Fluocinolone release from the diluted ointments was also measured with an in vitro method. RESULTS: Dilution by area gave the expected results, a decreasing average vasoconstrictor score; but dilution by volume did not. Both the 1:1 and 1:3 dilutions inexplicably showed greater activity than the full-strength product; this finding was similarly reflected in the in vitro studies that showed a greater rate of drug release from the 1:1 and 1:3 dilutions. CONCLUSION: Dilution by area provides a useful quantitative assay for comparative vasoconstrictor activity.

Adult↗
PubMed1993

Effect of age and diet on stratum corneum barrier function in the Fischer 344 female rat.

Stratum corneum barrier function in the female Fischer 344 rat was assessed in animals ranging from 11 to 144 weeks of age, which were either fed ad libitum or a caloric-restricted diet at 60% ad libitum. Caloric restriction has been shown to increase the life span of rodents and delay age-associated degenerative diseases. The penetration of water, lidocaine, and hydrocortisone were measured in vitro using the finite-dose technique in Franz diffusion chambers. Water permeability did not significantly change with either age or diet condition (with the single exception of the ad libitum 144-week animals). However, between 11 and 44 weeks, both lidocaine and hydrocortisone permeability increased with age in both diet groups. By 44 weeks the caloric restriction animals had significantly greater permeability to lidocaine and hydrocortisone then their ad libitum age cohorts. Between 44 and 144 weeks, skin permeability in the ad libitum animals continued to increase with age, whereas permeability in the caloric restriction animals declined. By 144 weeks the caloric restriction skin was less permeable than the age-matched ad libitum animals but still more permeable than the 11-week animals. The data show that the barrier properties of stratum corneum change with age in the female rat and that this change can be modulated by caloric restriction.

Aging↗
PubMed1993

Topical lidocaine for anesthesia in patients undergoing pulsed dye laser treatment for vascular malformations.

Pulsed dye laser treatment of vascular malformations is moderately painful. Twenty-five percent lidocaine in 70% dimethyl sulfoxide-ethanol was used to achieve anesthesia in patients undergoing the procedure. Thirteen of 14 patients had some degree of anesthesia (average of 51%) ranging from 10% to 100%, with 8 of them experiencing good results (> 50% anesthesia). Diminishment of pain was assessed by comparison of laser therapy on lidocaine-treated versus untreated sites within the vascular malformation using verbal and visual analog scales. In vitro permeation demonstrated good absorption of lidocaine, peaking at one hour. Permeation of lidocaine was significantly greater then that observed from acid mantle cream or EMLA. Topical lidocaine at 25% concentration in dimethyl sulfoxide 70% was well tolerated and had no side effects except transient mild erythema.

Administration, Topical↗
PubMed1992

Percutaneous absorption and metabolism of lonapalene in psoriatic skin.

The percutaneous absorption and metabolism of lonapalene (6-chloro-2,3-dimethoxynaphthalene-1,4-diol-diacetate; RS-43179), a topically effective 5-lipoxygenase inhibitor, has been measured in six subjects with stable plaque-type psoriasis of the lower extremities. Lonapalene readily penetrates psoriatic skin, is rapidly and completely metabolized, and is almost entirely excreted in the urine. Unexpectedly we observed a trend for thigh (T) plaque skin to be more permeable than lower leg (LL) plaque skin as measured by total absorption (T, 44.8 +/- 13.4%; LL, 24.9 +/- 12.6% applied dose excreted), peak plasma levels (T, 209 +/- 107; LL, 146 +/- 81 ng Eq/ml), and peak rate of urinary excretion (T, 591.7 +/- 112.2; LL, 318.4 +/- 143.9 micrograms Eq/hr). There were also differences in the metabolic profiles between the two sites as measured by the quantity and proportion of dealkylated and conjugated products excreted in the urine.

Administration, Cutaneous↗
PubMed1992

Absorption of amorolfine through human nail.

The percutaneous absorption of a new antifungal agent, amorolfine, has been measured through both skin and nail using an in vitro technique. Application of a 5% concentration in either an ethanol or methylene chloride lacquer resulted in permeation rates through nail in the range of 20-100 ng/cm2/h and somewhat higher through skin. Absorption was greater from the methylene chloride lacquer than the ethanol lacquer.

Absorption↗
PubMed1991

The negligible systemic availability of retinoids with multiple and excessive topical application of isotretinoin 0.05% gel (Isotrex) in patients with acne vulgaris.

The potential systemic availability of retinoids from topically applied isotretinoin was assessed in 12 men with acne vulgaris. Isotretinoin 0.05% gel was applied to patients at a daily dose of 20 gm (equivalent to 10 mg of isotretinoin) over a 1900 cm2 surface area of skin on the face, back, and chest for 30 days. Blood samples were collected throughout the study and up to 48 hours after the last topical application; they were assayed for isotretinoin, tretinoin, and 4-oxo-isotretinoin by specific high-performance liquid chromatography. Plasma concentrations of isotretinoin, tretinoin, and 4-oxo-isotretinoin were not measurable (less than 20 ng/ml) at any time. Most adverse experiences were cutaneous; a few systemic adverse experiences were judged to be remotely related to topical drug administration. The lack of measurable plasma concentrations of isotretinoin, tretinoin, or 4-oxo-isotretinoin and systemic adverse experiences indicates negligible systemic availability of retinoids even after multiple application of isotretinoin 0.05% gel at doses approximately 12 times greater than normal daily use.

Acne Vulgaris↗
PubMed1990

Transdermal timolol: beta blockade and plasma concentrations after application for 48 hours and 7 days.

An effective and well-tolerated transdermal beta-adrenergic blocker that could be applied once weekly would facilitate compliance. The pharmacokinetics and pharmacodynamics of a once-weekly formulation of transdermal timolol, a beta-blocker, were evaluated in healthy males. One (n = 6), two (n = 5), and three (n = 5) patches (97.5 mg base/12.58 cm2 patch) were applied at weekly intervals to the subjects' inner arm for 48 hours (part A) and two patches were applied for 7 days (part B). In part A, mean exercise (bicycle ergometry) heart rate (beats/min, bpm) was suppressed from baseline at 48 hours after the patch (p less than 0.05) in each case (1 patch 167 vs 131 bpm; 2 patches 165 vs 120 bpm; 3 patches 159 vs 120 bpm). Mean plasma timolol concentrations at 48 hours after the patch for one, two, and three patches were 5, 11, and 14 ng/ml, respectively. For part B, mean exercise heart rate at baseline, 24, and 168 hours was 161, 113, and 130 bpm (p less than 0.05), and mean plasma timolol concentrations at these times were 0, 23, and 4 ng/ml. The relationship between suppression of exercise heart rate and plasma timolol concentrations within subjects was well described by an inhibitory EMAX model, where EMAX ranged from a suppression of 42-65 bpm associated with a 50% inhibitory (IC50) concentration that ranged from 2-4 ng/ml. Transdermal timolol was associated with significant beta blockade for up to 7 days, and caused only minimal skin irritation.

Adult↗