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C Surber

Publications and source records attributed to C Surber.

At least 37 records · Page 2Linked to original sources
PubMed1994

Determination of acitretin in the skin, in the suction blister, and in plasma of human volunteers after multiple oral dosing.

Several HPLC methods for quantification of acitretin and its 13-cis isomer in biological fluids have been described. Only limited data are available on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin. With a new optimized mobile phase [methanol: acetonitrile (7:3, v/v), purified water with 1.5% (v/v) acetic acid, mixed in a 85:15 ratio (v/v)] and a new internal standard (arotinoid ethyl sulfone), a limit of quantification of 1 ng/g tissue was reached. Nine male volunteers were given an oral daily dose of 50 mg acitretin for up to 28 days. Blood and skin samples (punch and shave biopsies, suction blister skin, and fluid) were taken at various time points during and after treatment. Drug concentration and metabolism in plasma and skin samples appeared to be linked in that the trans-isomer concentration was always higher than the cis-isomer concentration during dosing and 3 h after the last dose. However, 7 and 14 days after the last dose in plasma and in all tissue samples (except the shave biopsy), the all-trans-acitretin concentration rapidly decreased and approached the detection limit. In the shave biopsy, the all-trans-acitretin concentration remained higher than the 13-cis-acitretin concentration. Furthermore, the elimination of two isomers from the shave biopsy was delayed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗
PubMed1994

Pastes: what do they contain? How do they work?

BACKGROUND: Pastes are semisolid stiff preparations containing a high proportion of finely powdered material. Powders such as zinc oxide, titanium dioxide, starch, kaolin or talc are incorporated in high concentrations into a preferably lipophilic, greasy vehicle. A clinically distinctive feature which is generally attributed to pastes is the quality to absorb exudates by nature of the powder or other absorptive components. Reviewing the various pharmacopoeias serious doubts arise from the various formulas of pastes and their absorptive features. The zinc oxide pastes of the USP XXII, the DAB 10 and BP 88 (US, German and British pharmacopoeias). are composed of petrolatum, zinc oxide and starch. Petrolatum, a highly lipophilic, water-immiscible vehicle surrounds the powder particles preventing any absorption of water or exudates. OBJECTIVE: The goal of our investigation was to test a simple experimental setting to characterize the clinically important absorptive feature of powders and pastes. METHODS: The absorptive features of the powders were determined by the method of Enslin. The absorptive features of the paste preparations were calculated from the weight difference between the paste preparation before and after incubation with water using a simple standardized procedure. RESULTS: The absorptive features of titanium dioxide, zinc oxide, kaolin, corn starch and methylcellulose powder in pharmacopoeia quality were determined. Zinc oxide and kaolin powder showed the highest absorption of 1,000 mg water/g powder (100%). The water absorption of corn starch and titanium dioxide was 700 and 450 mg/g powder, respectively. The absorptive features of a series of paste preparations were studied in a simple experimental setting. The data show that two-phase pastes consisting of two immiscible components, one (the dispersed or inner phase; powder) being suspended in the other (the continuous or outer phase; lipophilic vehicle), have no absorptive features. In contrast, three-phase pastes consisting of a hydrophilic two-phase emulsion with high concentrations of incorporated powder (cream pastes) show considerable water uptake. CONCLUSIONS: We conclude that the classical two-phase pastes such as the zinc oxide pastes have no absorptive features. On the contrary, these formulations are highly occlusive. Therefore lipophilic pastes are only indicated when protection of intact skin against aggressive body exudates and humidity is required. The hydrophilic three-phase pastes or cream pastes show considerable water uptake and fulfil common expectations of pastes to dry the skin.

Absorption↗
PubMed1994

Acitretin biotransformation into etretinate: role of ethanol on in vitro hepatic metabolism.

The aim of this study was to investigate the possible esterification of acitretin into etretinate by using hepatocytes in primary culture from the rat, monkey, dog and man. With rat and human hepatocytes, etretinate was detectable only when ethanol was co-administered with acitretin. With monkey and dog cells, traces of etretinate were found without ethanol addition, but the esterification of acitretin was highly enhanced by ethanol. The metabolic profile was not changed when cells were pre-incubated with ethanol. Therefore acitretin seems to act rather as a substrate than an enzymatic inducer.

Acitretin↗
PubMed1994

Pain assessment after intramuscular injection.

Several parameters (pH, osmotic pressure) influencing the local tolerance of injectable drugs have been well-documented; however, little attention has been paid to pain following an injection--a common problem in clinical practice. A pain questionnaire was used to record pain up to 24 h after a deep ventrogluteal injection. Two groups of healthy volunteers were recruited: the first group (n = 6) received 3 different cotrimoxazole preparations and placebo and the second group (n = 10) received 4 different multivitamin preparations and placebo (double-blind, cross-over). Parameters monitored during and after injection included pain localization (line drawing), pain intensity (visual-analog scale: VAS) and verbal description of pain (pain rating index: PRI). In both groups, the equality of pain (VAS, PRI) induced by the preparations was rejected in all cases (Friedman's test, p < or = 1%). The pairwise comparisons of the groups showed significant differences (p < or = 5%) between various preparations. The correlation (Spearman's rank correlation) between pain parameters VAS and PRI was high. The present investigations have shown that the pain questionnaire is a valuable tool to investigate the subjective pain symptoms during and after the injection of different preparations.

Adult↗
PubMed1993

In vivo skin penetration of acitretin in volunteers using three sampling techniques.

Etretinate and acitretin are given orally to treat psoriasis and various keratinization disorders. Acitretin, the main active metabolite of etretinate, has the pharmacokinetic advantage of being rapidly eliminated, but it shares etretinate's toxicologic profile. Thus a topical delivery of acitretin with no or reduced systemic adverse effects is desirable. To characterize the therapeutic potential of topically delivered acitretin, we quantitatively assessed its percutaneous penetration in healthy human volunteers. Additionally, three skin sampling techniques, the punch biopsy, the shave biopsy, and the suction blister technique, were validated to quantitate acitretin in the skin. The results suggest that topical delivery of acitretin renders skin concentrations which exceed those reported after oral administration of etretinate or acitretin. However, because of possible interlaminate drug contamination, drug localization within a particular skin compartment cannot be determined.

Acitretin↗
PubMed1993

In vivo percutaneous absorption of [14C]acitretin in the hairless guinea pig and in the rhesus monkey.

The oral administration of retinoids such as etretinate and acitretin (Ro 10-1670, CAS 55079-83-9), provides a successful therapeutic approach in various cutaneous diseases characterized by disturbed keratinization, e.g. psoriasis. Nevertheless oral therapy is often associated with systemic adverse effects. This makes a topical form with no or reduced systemic side effects desirable. Direct application of a topical acitretin formulation to the skin might result in therapeutic skin concentrations while minimizing systemic exposure. In the hairless guinea pig and in the rhesus monkey the percutaneous absorption of [14C]acitretin from an isopropylmyristate formulation (160 micrograms acitretin/2.5 cm2/animal) were investigated in vivo. After a 24 h exposure drug concentration in the skin was higher in the hairless guinea pig (620 ng-eq/g wet tissue) than in the rhesus monkey (380 ng-eq/g wet tissue). A similar observation was made comparing the 24 h absorption data determined as amount of drug excreted. The results are compared with in vitro absorption data using skin from the same species.

Acitretin↗
PubMed1993

[Distribution of acitretin in human skin].

Acitretin has recently been introduced for the systemic treatment of dermatologic diseases such as psoriasis and congenital disorders of keratinization. At present, only an oral form of this drug is available. However results from recent studies have shown that considerable drug concentrations can be delivered to the skin by topical administration of acitretin. Based on this data we addressed the question whether the topical administration of acitretin can produce in humans a drug concentration in the skin which exceeds the drug concentration that is found in the skin after multiple oral acitretin dosing and is reported to be clinical effective. Drug concentrations in the skin were investigated under conditions in which the maximum dose that can be administered in a therapeutic situation was applied. Additionally, three different skin sampling techniques, the punch biopsy, the shave biopsy and the suction blister technique were validated to quantitate acitretin in the skin. The drug concentrations in skin after systemic application in a steady state situation were comparable with the drug concentration reached after a single 24 hours topical application of a saturated acitretin/isopropylmyristate formulation. However, no unequivocal effects in psoriasis and disorders of keratinization were observed up to now by the topical administration of acitretin. The inverse drug concentration gradients which are present in the skin, depending on the route of administration, may explain differences in activity. The skin samples in our and other studies were homogenized or dissolved and thus much of the anatomical information is lost. The latter may be most important for the understanding of the local events.

Acitretin↗
PubMed1992

Effect of a new topical cyclosporin formulation on human allergic contact dermatitis.

We studied the effect of a new topical cyclosporin (CS) formulation on the suppression of allergic contact dermatitis. 4 test sites were outlined on the back of healthy male volunteers. For 7 consecutive days, the test sites were treated as follows: #1: CS formulation (10%), #2: placebo formulation, #3: flumethasone pivalate (FP) formulation (0.02%; #4: no treatment. On day 8, we challenged all test sites in the diphenylcyclopropenone (DCP) sensitized individuals. Photographic and clinical documentation was performed daily. 24 h after the DCP skin challenge, a marked redness accompanied by severe itching and slight pain occurred in the test sites pretreated with CS (#1) and placebo (#2). A considerably milder reaction was noted in the untreated test site (#4) and only a faint redness was noted in the test site pretreated with FP (#3). After 36 h, a further increase in the cutaneous reaction was documented in CS and placebo pretreated test sites (#1, 2). In agreement with other workers, topical CS did not suppress experimentally-induced allergic contact dermatitis in man. On the contrary, in CS and placebo pretreated areas (#1, 2), an increased cutaneous reaction was observed. This observation may be explained by the extensive pretreatment with the topical formulation of CS and placebo, which possibly caused a profound perturbation of the stratum corneum, enabling excessive allergen penetration compared to the untreated area with intact stratum corneum.

Administration, Cutaneous↗
PubMed1992

Clinical controversy on the effect of topical ciclosporin: what is the target site?

In recent years attempts have been made to treat T-cell-mediated skin diseases with topical therapeutics. Based on clinical data on the local treatment of recalcitrant erosive lichen planus (LP) with ciclosporin (CS) we discuss in vitro and in vivo studies on percutaneous absorption of CS, drug localization and drug metabolism in the skin as well as clinical data. Clinically relevant immunosuppressive activity depends not only on drug distribution in the target organ skin. The inhibition of T cell response is also dependent upon T cell subsets involved and the activation stage of the T cell. There are different proportions in T cell subpopulations during different evolutional stages of LP. Thus responsiveness to therapy with this drug may depend on the disease activity. Furthermore lymphocyte migration throughout various organs in the body including skin depend on a variety of molecular and cellular interactions. Whether local CS is sufficient to inhibit these interactions or to inactivate already activated T cells remains unclear. Assuming that the T lymphocyte is the target site for CS, local therapy reaches only a small fraction of the T cell population. This may be insufficient, and a systemic inhibition of helper/inducer T lymphocyte function is needed for successful therapy. With CS and with other drugs it seems that percutaneous absorption is not the only key to variable clinical responses to topical therapy.

Administration, Cutaneous↗
PubMed1992

Lack of effect after local treatment with a new ciclosporin formulation in recalcitrant erosive oral lichen planus.

We treated 7 patients with recalcitrant enoral lichen planus (Lp) with a new hydrophilic ciclosporin (CS) formulation during 8 weeks. The preparation with proven in vivo percutaneous absorption was designed for topical use and contained 100 mg CS/g formulation. The patients applied a cumulative daily dose of about 126 mg CS. We did not see the previously reported clinically impressive response with our CS formulation. No CS was detected in the blood of our patients. We conclude that percutaneous absorption of CS is not the key event to the clinical responses. Clinical benefit after CS in enoral Lp seems rather to the clinical responses. Clinical benefit after CS in enoral Lp seems rather to be related to a systemic effect of the drug.

Administration, Topical↗
PubMed1991

Effect of sodium lauryl sulfate-induced skin irritation on in vitro percutaneous absorption of four drugs.

The influence of irritant contact dermatitis on percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC), indomethacin (IM), ibuprofen (IB), and acitretin (AC). Hairless guinea pigs were pretreated in vivo for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment animals were sacrificed. Percutaneous penetration was then measured using in vitro diffusion cells and the removed (pretreated) skin. The following parameters were determined: cumulative amount of compound penetrated, steady state flux, lag time, and permeability coefficient, skin concentration per unit area, and the relative amount of drug remaining in the skin (as a percentage of the cumulative amount of compound penetrated through the skin). SLS pretreatment resulted in moderate irritant dermatitis in all animals and increased in vivo transepidermal water loss 4.5 times. Flux was increased in SLS-pretreated skin as compared with controls for all four compounds, with the greatest enhancement for hydrocortisone (HC) (5.9 times), followed by indomethacin (IM) (4.6 times), ibuprofen (IB) (3.9 times), and acitretin (AC) (3.4 times). Skin concentrations increased to a smaller degree from 1.6 times (IB) and 2.6 times (HC) to 3.4 times (IM). However, AC skin concentrations were not different between the two groups. Thus, percutaneous penetration parameters were equivocally influenced by SLS-induced irritation. Increased skin concentrations were paralleled by even higher increases in flux.

Acitretin↗
PubMed1991

Effect of sodium lauryl sulfate-induced skin irritation on in vivo percutaneous penetration of four drugs.

The influence of sodium lauryl sulfate-induced irritant contact dermatitis on in vivo percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC), indomethacin (IM), ibuprofen (IB), and acitretin (AC). Hairless guinea pigs were pretreated for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment, 450 microliters saturated solutions of HC, IM, IB, or AC in isopropylmyristate were applied to the pretreated skin for 24 h. Systemic absorption was determined by urinary and fecal excretion of compounds. Drug concentrations in stratum corneum (obtained by tape cellophane stripping after decontamination of the application site) and in epidermis/dermis (punch biopsy) were also investigated. Systemic absorption of topically applied drugs (as evaluated by urinary and fecal excretion) in SLS-irritated skin was significantly increased for HC (factor 2.6) followed by IB (1.9 times) and IM (1.6 times) but not increased for AC. However, drug concentrations in the viable epidermis and dermis were 70% lower in SLS-irritated than normal skin for HC, but not different for IB, IM, and AC. Thus, the influence of the state of the skin (irritant dermatitis versus healthy) on percutaneous penetration was different for diverse drugs. The general assumption that percutaneous penetration and drug tissue concentrations were higher in diseased versus healthy skin was not found to be true in our irritated-skin model.

Acitretin↗
PubMed1991

In-vitro skin pharmacokinetics of acitretin: percutaneous absorption studies in intact and modified skin from three different species using different receptor solutions.

The aromatic synthetic retinoid acid derivative, acitretin, is efficacious in several cutaneous diseases. Its toxicological profile makes a topical form with no or reduced systemic adverse effects desirable. Direct application of a topical acitretin formulation might result in therapeutic skin concentrations at the site of the disease while minimizing systemic exposure. The present studies define the percutaneous absorption characteristics of acitretin from an isopropylmyristate formulation. We investigated, in-vitro, (1) the role of receptor solution variations, (2) the role of skin modifications, (3) the influence of skin from three different species on the absorption of topically applied acitretin and (4) the drug distribution within the skin. Addition of solubilizers (Polyethylenglycol-20 and albumin) to the receptor solutions improved the flux of acitretin through monkey skin, whereas the acitretin concentration in the skin was not affected by the various receptor solutions used. Acitretin flux through tape-stripped monkey skin and dermis was only slightly higher than through intact skin. Acitretin concentration in human skin was significantly higher than in rhesus monkey or guinea-pig skin. Topical application of acitretin can produce dermal concentrations in excess of those achieved by therapeutic oral doses.

Acitretin↗
PubMed1990

Partitioning of chemicals into human stratum corneum: implications for risk assessment following dermal exposure.

Assessment of the health hazard associated with chemical contamination of the skin is a complex problem of occupational and environmental relevance. A particularly important question is to what extent can the skin permeability of a given compound be predicted from simple experiments. The literature on percutaneous absorption identifies two key observations: (i) the stratum corneum (SC), the skin's outermost layer, is the major barrier to chemical transport, and (ii) there are qualitative correlations between penetrant permeability and various oil/water partition coefficients (PCs). To obtain more quantitative predictions of permeation, we have evaluated SC/water and SC/isopropyl myristate (IPM, a model lipophilic vehicle) PCs of (a) para-substituted phenols of diverse physicochemical properties (4-acetamido-, 4-cyano-, 4-iodo-, and 4-pentyloxyphenol), (b) polychlorinated biphenyls (54%), and (c) 1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane. Partition coefficients were determined as a function of the following variables: length of equilibration, initial drug concentration in the vehicle, SC delipidization, and SC source and preparation technique. The data demonstrate that reproducible partitioning can be obtained using the biological tissue of greatest relevance, and that the pattern of behavior observed, for the two different vehicles studied, is compatible with physicochemical expectations. We suggest that the PC values measured may be useful predictors of in vitro and in vivo skin transport and valuable assets, therefore, in the evaluation of risk following dermal exposure.

Animals↗
PubMed1990

Sulfur revisited.

Explore the source record for details and available documents.

Administration, Cutaneous↗
PubMed1990

Optimization of topical therapy: partitioning of drugs into stratum corneum.

To optimize a topical formulation for therapeutic effect generally implies that the flux of drug into the skin be maximized. This requirement means that the product of drug concentration in the vehicle (Cv) and drug partition coefficient (PC) between stratum corneum (SC) and vehicle be as large as possible. While Cv is a formulation variable which can be easily manipulated up to the drug's saturation solubility, PC is a parameter that is difficult to predict a priori. However, there is no question that an ability to evaluate PC would greatly facilitate the efficient screening of drugs and formulations. We have measured the SC/water and SC/isopropylmyristate (a model lipophilic vehicle) PCs of seven drugs; acitretin, progesterone, testosterone, diazepam, estradiol, hydrocortisone, and caffeine, SC/water PCs were determined as a function of the following variables: (i) initial drug concentration in the vehicle, (ii) length of equilibrium, (iii) SC source and preparation technique, and (iv) SC delipidization. The data obtained were reproducible and physicochemically consistent, and they show that useful partitioning information from both aqueous and nonaqueous vehicles can be obtained with the biological tissue of greatest relevance. The SC/water PCs of the steroids were in reasonable agreement with previous measurements. A facile approach to an integral determinant of formulation optimization is suggested, therefore, by these observations.

Administration, Cutaneous↗
PubMed1990

Sodium hydroxide-induced subclinical irritation. A test for evaluating stratum corneum barrier function.

This report concerns the development of a short, simple, non-invasive test for assessing sensitivity to irritant dermatitis. Application of NaOH (0.005-2.0 mol/l) to human skin resulted in significantly greater skin surface water loss directly after exposure (1-15 min) than of control (water). The increase in skin surface water loss after NaOH application was dose-dependent (0.005-0.1 mol/l) and application time-dependent (1-10 min). Application times exceeding 10 min did not further increase skin surface water loss and doses higher than 0.1 mol/l reversed the effect on skin surface water loss. 15 min after removal of the alkali, skin surface water loss baseline values were almost regained. This procedure did not cause visible reactions or discomfort for the volunteers. In a subsequent experiment, volunteers were exposed to 0.2 mol/l NaOH for 5 min on one forearm and to 1% sodium lauryl sulfate for 24 h contralaterally. Skin surface water loss after 5 min of NaOH application was significantly correlated with transepidermal water loss measurements after 24 h of sodium lauryl sulfate patch application. This is, to our knowledge, the first description of a procedure for quantifying interindividual differences in stratum corneum barrier function without inducing visible changes or causing volunteers discomfort. Use of this model should help to further investigate skin barrier function as well as to test protective devices and barrier creams.

Adult↗