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C Surber

Publications and source records attributed to C Surber.

36 records · Page 2Linked to original sources
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↗
PubMed1989

Tests for local toxicity of intramuscular drug preparations. Comparison of in vivo and in vitro findings.

The local tissue tolerance after intramuscular injection caused by two multivitamin preparations, two excipient preparations without vitamins and a reference preparation (glycine 2.5%) was determined in albino rats and volunteers by measuring the creatine phosphokinase activity in the blood. The creatine phosphokinase activity was determined 2 h after the injection in the rats and before, 6, 12, 24, and 48 h after the injection in the volunteers. These measurements were compared to findings from an in vitro test using the haemolytic effect of the preparations in human erythrocytes. The haemolytic potential of the drug and excipient preparations was closely correlated to the creatine phosphokinase elevation in rats. The elevation of creatine phosphokinase in the volunteers was not indicative of any differences between the test preparations. Thus it could be shown that the elevation of the creatine phosphokinase activity is useful in demonstrating muscle damage and that the haemolytic potential of the drug and excipient preparations are closely related to the elevation of the creatine phosphokinase activity in rats. However, the results of the elevation of the creatine phosphokinase activity in humans are inconclusive for determining local muscle damage.

Adult↗
PubMed1988

[Changes in creatine kinase activity in serum following intramuscular injection].

The effect of intramuscular injections of two multivitamin preparations, two excipient preparations without vitamins, and a placebo preparation (glycine 2.5%) on serum creatine kinase activity (S-CK) in ten healthy volunteers (three female, seven male) aged between 23 and 25 years was investigated. One of the multivitamin preparations contained no lidocaine, the other 1% lidocaine. The one excipient formulation was isoosmotic, while the other contained added saline to bring it to the same degree of hyperosomolarity as the multivitamin formulation without lidocaine. The formulations were administered by deep ventrogluteal injection by means of a standardized injection technique. Blood samples were taken before and 6, 12, 24 and 48 h after injection. Following the administration of all the formulations except that of the glycine 2.5%, a marked increase in S-CK activity (1260 I.U./l) was observed 12 h after injection (normal range: male: 47-243 I.U./l, female: 39-226 I.U./l). The relative standard deviation for the 12 h S-CK value was 66.4-97.3%. On applying a threeway analysis of variance to the parameter S-CKmax, no significant differences (alpha = 5%) were found between the effects of the multivitamin and excipient formulations. There was a difference between these and glycine 2.5%, however. There were significant differences between individual volunteers but no significant differences based on the sequence in which the injections were given. With regard to the parameter S-CK AUC (area under the curve, trapezoidal rule), a significant difference (alpha = 5%) was observed only between glycine 2.5% and the multivitamin formulation containing 1% lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Tissue tolerance of intramuscular injectables and plasma enzyme activities in rats.

The local tissue damage after intramuscular injection caused by various commercially available injection solutions was determined in the albino rat, by measuring plasma activities of creatine phosphokinase, aspartate aminotransferase, and lactic dehydrogenase, the tissue activity of creatine phosphokinase, and macroscopic changes in the muscle at the injection site (gastrocnemius muscle). The plasma enzyme activities were determined 2, 6, 18, and 28 hr after the injection. After 28 hr the animals were sacrificed for macroscopic inspection of the injection site and for the determination of tissue enzyme activity. The tissue injury caused by the test substances correlated well with the elevated creatine phosphokinase activity (2 hr). The elevations of aspartate aminotransferase (18 hr) and lactate dehydrogenase (2 hr) activity as well as the loss of tissue creatine phosphokinase activity were less indicative of differences between test preparations. The i.p. administration of some of the test preparations caused increased enzyme activity without muscle damage, which could interfere with the test results. The creatine phosphokinase determination indicates the damage occurring immediately after the administration of the test solution, and the macroscopic inspection offers the possibility to obtain some information on the evolution of the muscular lesion.

Animals↗