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Anthralin for psoriasis: short-contact anthralin therapy compared with topical steroid and conventional anthralin.

Anthralin is an effective topical drug for psoriasis therapy. Recent studies have suggested that anthralin may be effective in high concentrations for short periods of skin contact. The purpose of these studies was to compare psoriasis improvement rates in patients treated with 0.3% anthralin ointment for 10 minutes' skin contact daily with patients treated with a topical steroid, difluorosone diacetate. A further study conducted was a bilateral paired comparison between conventional strength (0.1%-0.5%) anthralin ointment overnight with high concentration anthralin (0.5%-3%) for short contact periods of 10 minutes daily. The results showed good responses in all treatment groups. Short-contact anthralin is confirmed as a practical means of outpatient therapy for psoriasis.

Administration, Topical

Multifunctional analysis of the interaction of anthralin and its metabolites anthraquinone and anthralin dimer with the inner mitochondrial membrane.

We studied the interaction of the antipsoriatic compound anthralin (1.8-dihydroxy-9-anthrone), and its metabolites anthraquinone (1.8-dihydroxy-9.10-anthraquinone) and anthralin dimer (1.8.1'.8'.-tetrahydroxy-10.10'-bis-9[10]-dianthrone) with the inner mitochondrial membrane. Mitochondrial membrane functions such as ubiquinone redox equilibria, redox status of iron sulfur clusters, cyanide-sensitive and cyanide-insensitive oxygen consumption, adenosine triphosphate (ATP) synthesis, ATP hydrolysis, and adenine nucleotide content of mitochondria were analyzed. Anthralin is an inhibitor of mitochondrial oxygen uptake in the presence of ADP and substrate (cyanide-sensitive respiration), inhibits ATP synthesis without affecting ATP hydrolysis, and depletes mitochondria of ATP. Anthralin dimer is a much weaker inhibitor of mitochondrial functions and anthraquinone is almost inactive. Anthralin, but not anthraquinone and anthralin dimer, reverses uncoupler stimulated oxygen consumption, stimulates cyanide-insensitive respiration, reduces mitochondrial ubiquinone-9 and -10 to the corresponding ubiquinols and reduces mitochondrial iron sulfur clusters. Anthralin may induce formation of reactive oxygen species by enhancing autoxidation of mitochondrial components and/or by catalyzed oxidation of anthralin. Taken together, anthralin acts as an electron donor to inner mitochondrial membrane associated redox components, inhibits the electron transport chain, and has an oligomycin-like effect. Anthralin dimer and anthraquinone do not function as electron donors and act by a different reaction mechanism. Respiratory measurements in human keratinocytes revealed similar results as obtained with isolated mitochondria. We suggest that modulation of membrane redox status may be a common concept of anthralin action in target cells such as keratinocytes and neutrophils.

Adenine Nucleotides

Combined tar-anthralin versus anthralin treatment lowers irritancy with unchanged antipsoriatic efficacy. Modifications of short-contact therapy and Ingram therapy.

In 44 patients with chronic plaque psoriasis anthralin therapy was used as high-strength short-contact therapy in a bilateral comparison of anthralin versus 5% crude coal tar-anthralin combination. These two trials were undertaken with and without ultraviolet (UV) irradiation immediately after anthralin therapy. The combined tar-anthralin therapy was significantly less of an irritant during the first 3 weeks of treatment than anthralin alone, and it did not decrease the antipsoriatic efficacy. The use of UV irradiation, either with anthralin or tar-anthralin combination, did not produce an additional therapeutic effect. These findings lead us to prefer combined tar-anthralin therapy because of its lower irritancy in comparison with anthralin alone and they show the ineffectiveness of additional UV irradiation under the conditions of this study.

Administration, Topical

Mechanism of anthralin inflammation. 2. Effect of pretreatment with glucocorticoids, anthralin and removal of stratum corneum.

The inflammatory dose-response to anthralin was measured in human skin 24 h after pretreatment with topical corticosteroids and anthralin, and 48 h after removal of the stratum corneum with adhesive tape. Anthralin inflammation was increased after 1% hydrocortisone application and decreased by 0.1% betamethasone valerate and 0.05% clobetasol propionate; although the difference between these effects was not significant, the difference between the effect of hydrocortisone and clobetasol propionate was. Anthralin inflammation was not significantly affected by pretreatment with anthralin and was reduced, although not significantly by removal of the stratum corneum. The finding that anthralin inflammation is not altered in skin in which aryl hydrocarbon hydroxylase (AHH) activity is increased and that anthralin inflammation may be altered in situations in which AHH activity is unchanged, excludes a direct relationship between anthralin inflammation and AHH activity.

Administration, Topical

Inhibition by retinoids of anthralin-induced mouse epidermal ornithine decarboxylase activity and anthralin-promoted skin tumor formation.

The retinoids all-trans-retinoic acid, 13-cis-retinoic acid, 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1E- propen-1-yl]benzoic acid, 6-[1-(4-carboxyphenyl)-1E-propen-2-yl]-3,4-dihydro-4,4-dimethyl-2H -1-benzothiopyran, and 6-(5,6,7,8,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)- 2-naphthalenecarboxylic acid inhibited the induction of ornithine decarboxylase in CD-1 mouse epidermis treated with the weak tumor promoter anthralin (444 nmol). Enzyme activity reached maximal levels 48 h after the application of the promoter. This activity was most effectively inhibited when retinoids were applied to the epidermis 24 h after the promoter. These retinoids also inhibited the appearance of papillomas in mouse epidermis in the two-stage tumorigenesis model using 7,12-dimethylbenz(a)anthracene (200 nmol) as the initiator and anthralin (444 nmol) as the promoter during the 32-week period of promotion. Comparison of the doses of retinoids required to inhibit anthralin-induced ornithine decarboxylase by 50% and those required to inhibit anthralin-induced tumor promotion by 50% demonstrated that these values correlated.

Administration, Topical

Anthralin decreases keratinocyte TGF-alpha expression and EGF-receptor binding in vitro.

Anthralin is an effective topical treatment for active psoriasis; however, its mechanism of action is unknown. Both TGF-alpha and its receptor, the EGF receptor, are overexpressed in active psoriatic plaques and might, therefore, play a role in psoriatic epidermal hyperplasia. In order to assess whether anthralin might act via alteration of this growth factor pathway, we examined the in vitro effects of pharmacologic concentrations of anthralin on cultured normal human keratinocytes. Keratinocyte proliferation was inhibited by 98% at an anthralin concentration of 10 ng/ml. In contrast, lymphocyte proliferation was inhibited by only 50% at an anthralin concentration of 10 micrograms/ml. Anthralin treatment did not induce cell-cycle-specific growth arrest as assessed by flow-cytometric analysis of acridine-orange-stained keratinocytes. Northern analysis of anthralin-treated keratinocytes demonstrated a marked decrease in TGF-alpha mRNA expression. Anthralin-treated keratinocytes showed decreased binding of 125I-EGF and 125I-IGF-I to their respective receptors, but EGF receptor binding was inhibited to a greater extent. Anthralin decreased ligand-binding affinity and cell-surface numbers of EGF receptors as assessed by Scatchard analysis of 125I-EGF binding to anthralin-treated keratinocytes. These results indicate that anthralin alters components of the EGF receptor pathway in cultured keratinocytes and that these effects might contribute to the clinical efficacy of anthralin in the treatment of active psoriasis.

Anthralin

The release and percutaneous permeation of anthralin products, using clinically involved and uninvolved psoriatic skin.

The release and permeation of 1% Westragel and 1% Westrastick and three commercial 1% anthralin products were investigated in vitro with the use of a Franz diffusion cell unit. An inert Teflon membrane with a mesh opening of 74 mu was used for measuring the rate of release. Involved psoriatic and uninvolved human skin collected from the same subjects were used for the permeation study. The permeation of danthron and dianthrone, the major degradation products of anthralin, was also studied with the use of microemulsion gels of 1% danthron and 1% dianthrone, which were prepared in the same way as 1% Westragel. The penetrating anthralin, danthron, and dianthrone were stabilized by a modified receptor fluid, and sample solutions were analyzed by a high-power liquid chromatography method. Involved psoriatic skin was found to be much more permeable to anthralin than was uninvolved psoriatic skin. The slow permeation rate of anthralin, danthron, and dianthrone through normal skin and uninvolved skin indicates that the stratum corneum is the rate-limiting barrier. In involved psoriatic skin, the release rate of anthralin from the topical product becomes the rate-determining step. Large individual variations were found in the permeation of anthralin through involved psoriatic skin, suggesting that the permeation rate of anthralin also may depend on the disease state of psoriatic patients. The anthralin molecule, possessing both hydrophilic and lipophilic centers, diffused significantly faster than did danthron and dianthrone. Westragel, 1%, showed the highest diffusion rate as well as the highest driving force when compared to other commercial 1% anthralin products. This suggests that 1% Westragel may be an optimal design, especially for short-contact anthralin therapy.

Anthracenes

Anthralin, a non-TPA type tumor promoter, synergistically enhances phorbol ester-caused prostaglandin E2 release from primary cultured mouse epidermal cells.

Primary cultures of mouse epidermal cells (i.e., target cells of skin tumor promotion) stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) release prostaglandin E2 within 30 min. Anthralin, a non-TPA type tumor promoter, also stimulated PGE2 release; however, no release was detectable at least up to 4 hr after the addition of anthralin. When the cells were incubated with TPA plus anthralin, both PGE2 and arachidonic acid release were synergistically enhanced. Other non-TPA type tumor promoters, i.e., chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, did not potentiate the TPA-caused PGE2 release. In protein kinase C-down regulated cells, the synergistic stimulation of PGE2 and arachidonic acid release by TPA plus anthralin were not detected. Anthralin plus TPA did not alter the incorporation of arachidonic acid into cellular phospholipids. Cellular cyclooxygenase activity was increased 2 hr after TPA stimulation. Anthralin-caused increase in cyclooxygenase activity was detected at 6 hr after the addition of anthralin. Cyclooxygenase activity was synergistically increased by treating the cells with TPA plus anthralin. Cycloheximide and actinomycin D inhibited the increase in cyclooxygenase activity caused by anthralin or TPA plus anthralin. These results indicate that anthralin synergistically stimulates TPA-caused PGE2 release by synergistically increasing arachidonic acid release and cellular cyclooxygenase activity.

Animals

A comparative study of calcipotriol and anthralin for chronic plaque psoriasis in a day care treatment center.

Eighteen patients with symmetric plaque-type psoriasis were recruited for an open, controlled, bilateral half-body comparison study to evaluate the efficacy of calcipotriol/tar/UVB vs. anthralin/tar/UVB in a day care treatment setting. No patient had been on systemic antipsoriatic agents for at least 3 months prior to enrolment. One half-body was arbitrarily assigned to treatment with gradually increasing concentrations of anthralin as tolerated. The other half-body received calcipotriol ointment twice daily. Both sides received UVB and additional coal tar distillate in accordance with our standard day care regimen. Patients who were admitted to the day care program attended the clinic for UVB, anthralin, and calcipotriol on weekdays for two consecutive weeks. Anthralin was applied to psoriatic plaques on one side in the following fashion: anthralin 0.1% with salicylic acid 3% in zinc oxide paste on days 1 and 2; anthralin 0.2% with salicylic acid 3% in zinc oxide paste on days 3-5; anthralin 1% with salicylic acid 3% in hydrophilic petrolatum for 60 min on days 8-10 to thicker lesions; and anthralin 2% with salicylic acid 3% in hydrophilic petrolatum for 60 min on day 11 to thicker lesions. On the contralateral side, calcipotriol ointment 0.05 microgram/mL (Leo Pharmaceuticals, Ajax, Ontario) was applied to lesions twice daily. No anthralin or calcipotriol was applied on weekends. All patients applied coal tar oil 50% (Doak Oil Forte, Trans CanaDerm, St-Laurent, Québec, equivalent to 5% coal tar distillate) with salicylic acid 5% in hydrophilic petrolatum to their lesions at home in the evenings and on weekends. UVB (FSX72T12 lamps, National Biologic Corporation, Twinsburg, Ohio) was administered twice daily on weekdays in increasing doses as tolerated (to erythema) prior to the application of the topical medications. No trial medications were applied to the face, scalp, or genital regions. For clinical evaluation, the standard Psoriasis Activity and Severity Index (PASI) score was modified by splitting the score for area under 10%; the modified score (mPASI) for an area of coverage of 1%-4% was 0.5 and for an area of 5%-9% was 1. The head and neck area was excluded from the analysis since neither anthralin nor calcipotriol was used at these sites. Each half-body was considered to represent 100% in the area score determination. The maximum modified score for each side was 64.8 (vs. 72 in the standard PASI scoring system). Clinical evaluations were completed at days 0 (baseline), 3, 7, 10, and 42. The primary end-point was day 10. On day 10, patients were asked to compare the calcipotriol ointment to the anthralin on a five-point scale in terms of efficacy and irritancy and to state their future preferred treatment modality. Following discharge from day care, patients were continued on outpatient UVB and tar treatments three times weekly and asked to return for a repeat clinical assessment after 4 weeks (day 42). Blood samples taken prior to treatment and at day 10 were analyzed for serum calcium. Comparisons of treatment efficacy were based on changes in the mPASI scores from onset of treatment to day 10, as well as on the corresponding percentage changes. Analyses were carried out using the Wilcoxon test. Subjective patient comparisons of effectiveness and irritancy, as well as patient preference, were tested for equiprobability using the chi-square goodness-of-fit test with an examination of the adjusted residuals.

Administration, Topical

Multifunctional inhibition by anthralin in nonstimulated and chemotactic factor stimulated human neutrophils.

Treatment of human polymorphonuclear leukocytes (PMN) with anthralin (0.2-50 micrograms/ml) results in dose-dependent inhibition of nondirected as well as directed migration (chemotaxis) against the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a and leukotriene B4. Polymorphonuclear leukocytes (PMN) pretreated with anthralin at concentrations which inhibit cell motility also show a dose-dependent inhibition of superoxide anion generation. In contrast to anthralin two derivatives (danthrone and anthralin dimer) were ineffective. Specific binding of [3H]FMLP to neutrophil membrane receptors was impaired by anthralin at concentrations 5-10 fold higher than those which were inhibitory for cell function. Release of beta-glucuronidase from azurophilic (lysosomal) granules provoked by various chemotaxins in the presence of cytochalasin B was not affected by anthralin over a wide range of concentrations. Also there were no signs of cytotoxicity e.g., leakage of cytoplasmatic lactate dehydrogenase (LDH) caused by anthralin, These data indicate that neutrophil functions may become substantially altered by anthralin. The effective dosages correspond to concentrations obtained in vivo after local application. Danthrone as well as anthralin dimer, known to be clinically ineffective, showed no effects upon PMN function. It is suggested that anthralin via a free radical mechanism alters sensitive sites at or in the cellular membrane including receptors.

Anthracenes

Anthralin: how does it act and are there more favourable derivatives?

Anthralin is still the most effective and safest therapeutic agent for treatment of psoriasis. Our data may assist toward an understanding of its mode of action and introduce new derivatives, more antiproliferative and less toxic than anthralin in vitro. Anthralin exerts a direct effect on keratinocytes and leukocytes. In time-lapse studies it significantly prolonged the prophase of mitotic keratinocytes in subtoxic doses and suppressed the expression of keratin 6 mRNA in the immediately suprabasal layer of psoriatic epidermis in vivo. Anthralin inhibits the transformation of lymphocytes and the release of reactive oxygen species from activated leukocytes, in vitro. We provide evidence that these effects of anthralin are mediated by protein kinase C. Twelve new hydrophilic derivatives of anthralin, including a 1,8-dimethoxy compound, as well as C-2 and C-10 substituted anthrones were tested on human keratinocytes. The antiproliferative effect of those derivatives bearing lacton rings at a C-10, consisting of 4, 5, or 6 C atoms, exceeded that of anthralin and were equally or less cytotoxic than the parent drug. These compounds had no pro-drug character in vitro, since they did not metabolize via anthralin, as shown by HPLC. These data indicate that there may be anthralin derivatives with more favourable properties for topical therapy than anthralin itself.

Anthralin

Anthralin. Different concentration effects on epidermal cell DNA synthesis rates in mice and clinical responses in human psoriasis.

There had been recent interest in psoriasis treatment regimens with low anthralin concentrations of 0.01% and 0.05%. These regimens used salicylic acid, coal emollient baths, and ultraviolet energy. We were interested in evaluating the effects of different concentrations of anthralin without adjunctive therapy. We studied the effects of anthralin on epidermal cell DNA synthesis in hairless mice and found that, in concentrations between 0.1% and 0.4%, anthralin produced significant suppression. However, 0.05%, 0.025%,and 0.01% anthralin failed to inhibit DNA synthesis. Clinical studies of 0.05% and 0.1% anthralin in a water-in-soil emulsion (Eucerin) were performed on 14 patients with psoriasis. Psoriasis severity was scored before and during the period of anthralin use and showed a significant improvement in 0.1% anthralin-treated sites. No significant differences were noted between 0.05% anthralin-treated areas and those areas treated with the vehicle alone.

Adolescent

The antipsoriatic drug, anthralin, inhibits protein kinase C--implications for its mechanism of action.

In psoriatic patients, anthralin is known to attenuate lesional inflammation, but often generates perilesional dermatitis. This phenomenon is well reflected by the contrasting action of anthralin on human leukocytes. The release of reactive oxygen species (ROS) is inhibited by anthralin in phorbol ester-activated leukocytes, whereas anthralin directly induces this cellular response in unstimulated cells. In order to elaborate further the underlying mechanisms, we compared the kinetics of anthralin and different well-characterized stimuli, including the phorbol ester, phorbol-12-myristate-13-acetate, in this test system. Compared with standard stimuli, anthralin only marginally induced the release of ROS from human leukocytes and displayed different kinetics. Protein kinase C (PKC), the major cellular phorbol ester receptor, is considered to be involved in the regulation of this cellular response. Furthermore, its involvement in the pathophysiology of psoriasis has been suggested. Therefore, we also investigated the effects of anthralin on purified PKC. Anthralin was found to inhibit the enzyme activity in a dose-dependent manner but not to display any stimulatory effects. The present results provide first evidence that the therapeutic activity of anthralin, at least in part, might be mediated by inhibition of PKC.

Animals

Inactivation of mouse epidermal 12-lipoxygenase by anthralin--implications for the role of oxygen radicals.

In activation of 12-lipoxygenase (12-LO) in mouse epidermal homogenate by the antipsoriatic drug anthralin has been studied in detail. In view of the chemical instability of anthralin in a physiological buffer, the biological effects ascribed to the molecule itself may be related to some of its breakdown products. However, the inhibitory activity could not be attributed to the known stable oxidation product of anthralin, danthron, which did not decrease (12-LO activity. Addition of the antioxidants 2,6-di-tert-butyl-4-methylphenol (BHT) or beta-carotene, or the hydroxyl radical scavenger sodium benzoate, protected against anthralin-mediated 12-LO inactivation, suggesting that pro-oxidant species derived from anthralin play a key role in the inhibitory action. Even though inhibitory effects of anthralin against catalase and superoxide dismutase (SOD) have been observed under the conditions applied in this study, these antioxidant enzymes also partially prevented the inhibition of 12-LO by anthralin when added to the incubation mixtures. Control experiments without anthralin revealed that the oxygen radical scavengers and antioxidant enzymes, themselves, did not appreciably influence epidermal 12-LO activity. A mechanism underlying the inactivation of epidermal 12-LO by anthralin is proposed, which involves active oxygen species formed during the auto-oxidation of the drug.

Animals

Antirespiratory and antiproliferative activity of anthralin in cultured human keratinocytes.

The effect of anthralin and its oxidation products, anthralin-dimer and anthralin-quinone, on protein content and thymidine incorporation as well as CO2 production from glucose and glutamine has been studied in transformed human keratinocytes in vitro. Anthralin exhibited the strongest inhibition, the dimer was generally less active and the quinone inactive. Respiration and thymidine incorporation were the most sensitive cellular functions showing 50% inhibition at about 1 and 3 microM anthralin, respectively. Comparison of the inhibition kinetics of anthralin with those of antimycin A and mitomycin C showed that anthralin behaved as an inhibitor of mitochondrial function rather than of DNA replication. The biologic effects were triggered in the first minutes of exposure to the cells when anthralin became rapidly associated with the cell membranes. Labeling experiments with [14C]anthralin revealed that the manifestation of the biologic response occurring after a latency phase of some hours coincided with the accumulation of radioactivity in the intracellular particulate fraction. The cytosol remained essentially unlabeled.

Anthracenes

The antipsoriatic compound anthralin influences bioenergetic parameters and redox properties of energy transducing membranes.

Bioenergetic parameters and redox properties of energy transducing membranes in rat liver mitochondria and cyanobacteria were investigated in the presence of the antipsoriatic compound anthralin (1,8-dihydroxy-9-anthrone). Transmembrane pH and electrical gradients were determined using electron paramagnetic resonance spectroscopy. In mitochondria, ubiquinones 9,10 and other redox components of the electron transport chain are reduced by anthralin; the proton motive force is increased. In the absence of ADP, anthralin slightly stimulates mitochondrial cyanide-insensitive oxygen consumption. It is suggested that increased cyanide-insensitive respiration is due to enhanced autoxidation of mitochondrial components and/or catalyzed oxidation of anthralin. In the presence of ADP mitochondrial respiration is decreased, and ATP synthesis is inhibited. Uncoupler-induced mitochondrial respiration is also decreased by anthralin, indicating inhibition of the electron transport chain. In the cyanobacterium Synechococcus PCC 6311 anthralin increases the pH gradient and decreases ATP levels. Thus, anthralin acts as an electron donor to membrane associated redox components and inhibits ATP synthesis in two different biologic systems. In human keratinocytes oxygen metabolism is influenced by anthralin in a similar pattern as in isolated mitochondria, and ATP content is decreased. Because anthralin reacts with redox components in different biologic membranes, alterations of subcellular/cellular redox status and energy metabolism might contribute significantly to its antiproliferative activity.

Animals

Anthralin: chemical instability and glucose-6-phosphate dehydrogenase inhibition.

The chemical stability of the antipsoriatic drug, anthralin (1,8-dihydroxy-9-anthrone), in solution has been studied using high-performance liquid chromatographic analysis. The time course for decomposition in solution has been correlated with that of the inhibition of glucose-6-phosphate dehydrogenase, one of the most widely documented biochemical properties associated with anthralin. Solutions of anthralin in aqueous buffer (37 degrees, pH 7.5, under light protection) completely within 4 hr giving the 10,10'-dimer (40%), no detectable 1,8-dihydroxy-9,10-anthraquinone, and a greatly increased potency of inhibition of glucose-6-phosphate dehydrogenase. This increased inhibitory potency could not be explained by formation of the dimer which, like anthralin and its quinone, were shown to be only weak inhibitors of the enzyme. In acetone solution exposed to light and air, anthralin decomposed completely within 4 days, in part via the dimer as intermediate. The final solution had the characteristic color of anthralin-brown, contained the quinone (20%), and like decomposed aqueous solutions of anthralin, completely inhibited glucose-6-phosphate dehydrogenase. The results show that neither anthralin, nor either of its two identified decomposition products, is the potent toxic species against glucose-6-phosphate dehydrogenase.

Acetone