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PubMed1993

Induction of peroxisomal beta-oxidation by a microbial catabolite of cholic acid in rat liver and cultured rat hepatocytes.

The capability of (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo-1H-cyclopental[f]quinolin-7 beta-yl)valeric acid (DCQVA), a catabolite of cholic acid produced by enterobacteria, to induce peroxisome proliferation in vivo and in vitro was studied. Rats given 0.3% DCQVA in the diet for 2 weeks showed marked increases in peroxisomal beta-oxidation, mitochondrial 2,4-dienoyl-CoA reductase and microsomal laurate omega-oxidation activities in the liver compared with control rats given the diet without DCQVA. Cultured rat hepatocytes treated with DCQVA for 72 h also exhibited greatly enhanced beta-oxidation activity. The increased activity was concentration-dependent and the effective concentrations were comparable with those of clofibric acid that produced the same degree of induction in the assay. The results demonstrate that DCQVA is a potent peroxisome proliferator that occurs naturally in rat intestine.

Animals↗
PubMed1993

Activation of a peroxisome-proliferating catabolite of cholic acid to its CoA ester.

We have shown that a microbial cholic acid catabolite (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo- 1H-cyclopenta[f]quinolin-7 beta-yl)valeric acid (DCQVA), is a potent peroxisome proliferator. In this paper a possible key stage in DCQVA metabolism, the activation of DCQVA to its CoA ester, has been investigated in rat liver microsomes and particulate fractions. The microsomal reaction was dependent on CoA, ATP, DCQVA (0.2-1 mM) and protein content. The reaction was decreased by storage at 4 degrees C, preincubation of microsomes at 37 degrees C for 5 min, or inclusion of Triton X-100 in the reaction mixture. Such treatments also enhanced generation of long-chain fatty acyl-CoAs, as determined by h.p.l.c. analysis. The same effect was caused by exposing the microsomes to phospholipase A2, suggesting that endogenous fatty acids may compete with DCQVA for esterification with CoA. Subcellular fractionation of rat liver demonstrated that the activity of DCQVA-CoA synthesis was localized predominantly in the microsomal fraction, in contrast to long-chain fatty acyl-CoA synthetase, which was distributed among all particulate fractions. Administration of clofibrate of rats did not affect the distribution of DCQVA-CoA synthesis activity. In contrast to a 2-fold induction of long-chain fatty acyl-CoA synthetase by clofibrate treatment, the activity of DCQVA-CoA synthesis in the microsomal fraction decreased by 80%. These results suggest that DCQVA is activated by an enzyme distinct from long-chain fatty acyl-CoA synthetase. The resulting perturbation of fatty acid metabolism may be involved in the mechanism whereby DCQVA causes peroxisome proliferation.

Acyl Coenzyme A↗
PubMed1998

The molecular basis of glucocorticoid-induced skin atrophy: topical glucocorticoid apparently decreases both collagen synthesis and the corresponding collagen mRNA level in human skin in vivo.

The effects of topical betamethasone-17-valerate on collagen propeptide levels, collagen mRNA level, lysyl oxidase mRNA and matrix metalloproteinase (MMP)-1 and MMP-2 mRNA levels were studied in human skin. Three days' treatment of healthy skin with topical betamethasone caused a 70-80% decrease in type I and III collagen propeptides in suction blister fluid. A similar decrease was found in type I collagen mRNA when assayed by either slot-blot hybridization or a quantitative polymerase chain reaction method, indicating that the decrease in collagen synthesis after topical glucocorticoid treatment is apparently due to a decrease in corresponding mRNA. mRNA of lysyl oxidase, which is an important enzyme catalysing the cross-linking of collagen chains, and collagen-degrading enzyme MMP-1 and MMP-2 mRNAs were not decreased in the same skin samples. This suggests that in vivo, glucocorticoids modulate variably the genes involved in collagen synthesis and degradation. Our study provides a solid molecular basis for glucocorticoid-induced dermal atrophy, which results from the decrease in functional collagen mRNA in the skin.

Administration, Topical↗
PubMed2001

Efficacy and tolerance of topical calcitriol 3 microg g(-1) in psoriasis treatment: a review of our experience in Poland.

Although topical vitamin D3 derivatives have been used in the treatment of patients with psoriasis for the past 15 years, questions remain about the indications and limitations of application. Extensive personal experience gained during the development of calcitriol (1alpha25-dihydroxyvitamin D3) is therefore reviewed. Three double-blind, vehicle-controlled trials have revealed that calcitriol 3 microg g(-1) ointment (Silkis ointment, Galderma Laboratories) has very good clinical efficacy. In a left-right comparison with vehicle ointment, complete clearance of psoriatic lesions was achieved in 48% of sites treated with calcitriol and a further 41% showed considerable or definite improvement. The clinical response to calcitriol in another study was as good as, or even better than, that achieved with betamethasone valerate 0.1% ointment. A preparation containing calcitriol 15 microg g(-1) did not show any clinical superiority to the lower dose but was associated with a higher risk of hypercalciuria, particularly when applied to extensive skin lesions. These results suggest that calcitriol 3 microg g(-1) ointment is an effective and safe treatment for chronic plaque psoriasis.

Administration, Cutaneous↗
PubMed2001

Clinical experience with topical calcitriol (1,25-dihydroxyvitamin D3) in psoriasis.

The use of vitamin D analogues for the treatment of chronic plaque psoriasis is well documented. Of importance now is their comparability and compatibility with other established treatments for psoriasis. This paper reviews five studies with calcitriol 3 microg g(-1) ointment (Silkis ointment, Galderma Laboratories). Calcitriol applied twice daily was found to be as effective as short-contact dithranol in terms of global improvement and PASI scores. However, patients favoured calcitriol over dithranol when both quality of life and treatment acceptability were assessed. Two studies provide evidence of the benefit of combining calcitriol with other antipsoriatic therapies. Combination with ultraviolet (UV) B phototherapy proved as effective as UVB alone over an 8-week period; however, the combination had a radiation dose-sparing effect, thus reducing the risk of adverse events. Likewise, calcitriol combined with betamethasone valerate (each applied separately, once daily) was as efficacious as twice-daily betamethasone, thereby achieving a corticosteroid-sparing effect. Finally, two studies confirm that calcitriol 3 microg g(-1) ointment can be used safely in patients with psoriasis of the head and confirm the high level of clinical efficacy achieved with this compound.

Administration, Topical↗
PubMed2001

Lichen planus-like eruption following autologous bone marrow transplantation for chronic myeloid leukaemia.

A 47-year-old female treated with an autologous bone marrow transplant and cytotoxic chemotherapy developed a lichen planus-like eruption 12 months later. It involved the skin and oral mucosa, with the histological features of a lichenoid graft-versus-host reaction, including satellite cell necrosis. This eruption developed de novo. The eruption resolved with topical betamethasone valerate 0.1% cream despite the ongoing use of the immunomodulatory agent interferon-alpha2b. Such a reaction in an autologous setting has only been described once previously.

Administration, Cutaneous↗
PubMed2000

Double-blind clinical study reveals synergistic action between alpha-hydroxy acid and betamethasone lotions towards topical treatment of scalp psoriasis.

OBJECTIVE: A double-blind, single-site, split-face clinical study was organized and carried out in order to evaluate the efficacy, tolerability, and safety of a glycolic acid containing scalp lotion in conjunction with a betamethasone (as the 17-valerate) scalp application against conditions of psoriasis. BACKGROUND: Alpha-hydroxy acids (AHA) have been proposed as therapeutic modalities against skin exfoliative conditions such as ichthyosis, xeroderma, and psoriasis. AHAs are hereby clinically investigated as therapeutic modalities adjuvant to corticosteroids in order to diminish systemic and topical adverse side-effects most frequently associated with use of the latter. METHODS: Twenty patients suffering from scalp psoriasis and other psoriatic conditions were included in a double-blind, split-face clinical study, using combinations of a 10% (w/w) glycolic acid scalp lotion, placebo lotion (excipients only), and a 0.1% (w/w) betamethasone scalp application, applied twice daily without any bandage for a period of 8 weeks. Clinical assessments were carried out by highly experienced physician evaluations based on a four-grade scale, prior to treatment and after 2, 4, 6 and 8 weeks. RESULTS: Improvement was observed in all cases included in the study following treatment with the 10% glycolic acid lotion. However, when equal parts of the 0.1% betamethasone lotion were combined, most of the treated sites were healed. Moreover, the duration of treatment required for healing was in this case reduced to approximately half of that needed when the glycolic acid or the betamethasone lotions were used separately for treatment. CONCLUSIONS: The present clinical study demonstrates for the first time that the effective and well tolerated therapeutic efficacy of glycolic acid scalp lotions is enhanced when used in conjunction with a 0.1% betamethasone scalp application against scalp psoriasis. This potential offers the practising dermatologist with novel treatment modes against severe skin conditions by combining topical corticosteroid with exfoliative agent therapy.

Administration, Topical↗
PubMed2001

Human epidermal Langerhans' cells are targets for the immunosuppressive macrolide tacrolimus (FK506).

BACKGROUND: The immunosuppressive macrolide tacrolimus (FK506) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings. More recently, successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported. OBJECTIVES: We explored the effects of this compound on epidermal Langerhans' cells (LCs), which are known to play an important pathophysiologic role in inflammatory skin diseases. METHODS: The expression of the intracellular FK506 binding protein (FKBP12) was monitored on freshly isolated and cultured epidermal LCs. Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta-methasone valerate (betaMv) were performed. RESULTS: FKBP12 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells. Tacrolimus inhibited the expression of IL-2R (CD25) and of the costimulatory molecules CD80 (B7.1) and CD40. Expression of MHC class I and II was also affected, whereas CD86 (B7.2) expression was not altered. In contrast, betaMv strongly increased the expression of CD25. Paradoxically, while decreasing CD40 and MHC class I expression, betaMv significantly increased the expression of MHC class II, CD80, and CD86 on cultured LCs but impaired their allostimulatory activity. Tacrolimus was about 100 times more potent than betaMv at inhibiting LC stimulatory function. CONCLUSION: Tacrolimus can exert immunopharmacologic alterations on LCs, which may account, at least in part, for the therapeutic effect of this compound in eczematous skin diseases.

Administration, Topical↗
PubMed1981

Biosynthesis of porphyrins and heme from gamma, delta-dioxovalerate by intact hepatocytes.

The purpose of this study was to assess the ability of hepatocytes to synthesize porphyrins and heme from delta-aminolevulinic acid derived from gamma, delta-dioxovalerate and alanine. An alternate pathway for delta-aminolevulinic acid synthesis, in contrast to the condensation of succinate and glycine by delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] has been suggested. This has been supported by the isolation of gamma, delta-dioxovalerate transaminase from liver mitochondria (Varticovski, L., Kushner, J. P. & Burnham, B. F. (1980) J. Biol. Chem. 255, 3742-3747). Gamma, delta-dioxovalerate transaminase catalyzes the formation of delta-aminolevulinic acid by a transamination reaction involving gamma, delta-dioxovalerate and alanine. To assess the significance of this alternate route, we prepared suspensions of respiring rat hepatocytes, which were incubated with optimal concentrations of various additives and then analyzed spectrophotometrically for synthesized porphyrins. No porphyrin synthesis was detected in cell suspensions incubated with succinate(1 mM) and glycine (20 mM). Cell suspensions incubated with gamma, delta-dioxovalerate (0.5-1.0 mM) and alanine (20 mM) synthesized 0.19 nmol of porphyrin per 10(7) cells per 2 hr (SD, 0.057). Cell suspensions incubated with delta-aminolevulinic acid (0.1 mM) synthesized 1.26 nmol of porphyrin per 10(7) cells per 2 hr (range, 1.18-1.32). Incubations with chemically synthesized gamma, delta-dioxo[5-14C]valerate were followed by extraction and purification of porphyrin esters and heme. Liquid scintillation counting revealed radiolabel incorporation into both porphyrins and heme. These studies demonstrate significant tetrapyrrole synthesis by the gamma, delta-dioxovalerate transaminase reaction. That gamma, delta-dioxovalerate is an important precursor of heme in vivo must be considered.

Alanine↗
PubMed2005

Novel quantitative immunofluorescent technique reveals improvements in epidermal cell populations after mild treatment of psoriasis.

A novel antibody labelling technique, the Zenon technique, was used in fluorescent immunohistochemistry for a better characterization of epidermal cell populations in a quantitative approach. With this technique, differences in proliferation and differentiation characteristics were shown between psoriatic and normal epidermis. The sensitivity of the method was investigated by assessing the effect of a mild topical treatment versus an emollient. Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated once daily with either an emollient or betamethasone-17-valerate for only 2 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently FITC-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner. Treatment of psoriasis with short-term topical steroid resulted towards normalization of Ki-67 antigen, beta-1 integrin, keratin 10 and keratin 6 expression, which are parameters for proliferation and differentiation. Although treatment with an emollient showed hardly any clinical response, changes towards a more normal phenotype could already be detected in several epidermal markers using this method.

Antibodies↗
PubMed2001

Investigation of some commercially available spacer devices for the delivery of glucocorticoid steroids from a pMDI.

Five commercially available spacers were investigated to determine their influence on the percentage of drug retained in the spacer device, percentage fine particle fraction (FPF), percentage deposited in the induction port, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). Betamethasone valerate (BMV) and triamcinolone acetonide (TAA) were used as model drugs in the pressurized metered dose inhaler (pMDI) formulations containing the propellant HFA 134a. The BMV was dissolved in an ethanol/HFA 134a system, and the TAA was suspended in HFA 134a using ethanol as a dispersing agent. The metering chamber volume of the valve was either 50 microl or 150 microl. The spacer devices investigated included the ACE, Aerochamber, Azmacort, Easivent, and Ellipse spacers. Each spacer device was attached to an Andersen Cascade Impactor powered by a vacuum pump. Cascade impaction data were used to derive the percentage drug deposited in the induction port, MMAD, GSD, and FPF. The BMV particles emitted from the spacers were finer than the TAA particles because the dissolved drug precipitated as the cosolvent evaporated. The TAA particles had significantly larger MMADs because many undissolved drug particles were contained within each droplet following actuation. After evaporation of the liquid continuous phase, the suspended drug aggregated to form larger agglomerates than those particles precipitated from the BMV pMDI solution droplets. The addition of a spacer device lowered the MMAD to less than 4.7 microm for particles from both the BMV pMDI solution and the TAA pMDI suspension. The addition of a spacer device also lowered the percentage drug deposited in the induction port. The FPF was significantly increased when a spacer device was used. The MMAD significantly decreased when a spacer device was added for the two model drugs when using the 150-microl metering valves, but the difference was not statistically significant when the 50-microl valves were used (P < .05). The GSD was not influenced by the use of a spacer device. The use of a spacer device will enhance pMDI therapy by reducing the amount of drug deposited in the oropharyngeal region, which will lead to fewer instances of local and systemic side effects. In addition, the spacer devices investigated will allow a higher dose of drug to reach the deep lung, which may permit the use of lower dosage regimens with increased therapeutic efficacy.

Administration, Inhalation↗
PubMed1982

Effect of glucocorticosteroids on epidermal Langerhans cells.

The effects of topical and systemic administration of various glucocorticoids on the density of epidermal Langerhans cells (LC) were studied in guinea pigs. Glucocorticoids, such as betamethasone dipropionate and valerate, caused a marked decrease in LC demonstrable by staining for cell membrane ATPase activity and Ia antigens. By electronmicroscopy, LC also showed morphologic alterations. The observed decrements in LC density correlated with the concentration and known vasoconstrictive potency of the glucocorticoids administered. The anti-inflammatory action of glucocorticoids in skin disorders may, at least in part, be through their ability to alter epidermal LC, thus interfering with the antigen-presenting functions of these cells.

Adenosine Triphosphatases↗
PubMed1973

Anion conductance of frog muscle membranes: one channel, two kinds of pH dependence.

Anion conductance and permeability sequences were obtained for frog skeletal muscle membranes from the changes in characteristic resistance and transmembrane potential after the replacement of one anion by another in the bathing solution. Permeability and conductance sequences are the same. The conductance sequence at pH = 7.4 is Cl(-) Br(-) > NO(3) (-) > I(-) > trichloroacetate >/= benzoate > valerate > butyrate > proprionate > formate > acetate >/= lactate > benzenesulfonate >/= isethionate > methylsulfonate > glutamate >/= cysteate. The anions are divided into two classes: (a) Chloride-like anions (Cl(-) through trichloroacetate) have membrane conductances that decrease as pH decreases. The last six members of the complete sequence are also chloride like. (b) Benzoate-like anions (benzoate through acetate) have conductances that increase as pH decreases. At pH = 6.7 zinc ions block Cl(-) and benzoate conductances with inhibitory dissociation constants of 0.12 and 0.16 mM, respectively. Chloride-like and benzoate-like anions probably use the same channels. The minimum size of the channel aperture is estimated as 5.5 x 6.5 A from the dimensions of the largest permeating anions. A simple model of the channel qualitatively explains chloride-like and benzoate-like conductance sequences and their dependence on pH.

Acetates↗
PubMed2006

Action of topical thyroid hormone analogues on glucocorticoid-induced skin atrophy in mice.

Previously we demonstrated the stimulation of collagen synthesis in triiodothyroacetic acid (TRIAC)-topically treated human and mice. In the present study, we have evaluated the dose response effect of thyroid hormone (TH) analogues and tretinoin on glucocorticoid-induced skin atrophy in a haired mouse model. For this investigation, we treated haired mice twice daily for 7 days with various topically administered doses of TRIAC, triiodothyronine-sodium salt (T(3)-Na), diiodothyroacetic acid (DIAC), 3,5-diiodothyropropionic acid (DITPA), and tretinoin with 0.2 mM betamethasone17-valerate (BM), or with the vehicle as a control group. We also investigated a combination of commercial betamethasone dipropionate (BD) 0.05% cream and various doses of TRIAC on mouse skin. TRIAC was able to reverse the skin atrophy by 25% in a daily dose of 1 nmol/cm(2) in the presence of 0.2 mM BM (p < 0.05). Neither other TH analogues nor TRIAC in lower and higher concentrations had a significant inhibitory effect on dermal atrophy (p > 0.05). A combination of 0.2 mM BM and 10 nmol/cm(2) TRIAC was able to prevent dermal atrophy by 18%. The addition of TRIAC to 0.05% BD cream in a final concentration of 0.1% was able partially to reverse the dermal atrophy by 15% (p < 0.05). TRIAC alone in a concentration of 1,000 nmol/cm(2) stimulated dermal proliferation by 34% (p < 0.05). Other TH analogues alone had no stimulatory effect on dermal proliferation. Tretinoin 0.8 mM was able to inhibit dermal atrophy by 20% (p < 0.05) and had an effect on dermal thickness of 85% (p < 0.05). However, severe side effects with edema, erythema, and scaling were commonly observed in all tretinoin-treated mouse skin, which could partly explain the increase in dermal thickness. In contrast, no skin side effects were observed after treatment with TRIAC. This study indicates that TRIAC may have a therapeutic effect on BM-induced dermal atrophy in mouse skin and a direct stimulatory effect on dermal proliferation when given alone.

Acetates↗
PubMed1982

Immunosuppressive properties of polar organic compounds that induce cellular differentiation in Friend erythroleukemia cells.

We studied the effect of several polar organic compounds, known to induce erythroid differentiation in Friend leukemia (FL) cells, on in vitro human lymphocyte responses and on skin graft survival in mice. The short chain fatty acids, butyric acid (BA), propionic acid (PA), valeric acid, and the polar organic solvents, dimethyl sulfoxide, dimethylformamide, and dimethylacetamide, all mediated significant inhibition of alloantigen-induced proliferation and generation of cytotoxic T lymphocytes (CTLs) in human primary and secondary mixed lymphocyte culture (MLC) reactions. Hexamethylenebisacetemide, another potent inducer of differentiation in FL cells, also mediated significant suppression. Inhibition of MLC with polar organic compounds was accomplished at concentrations known to induce differentiation in FL cells and that are not cytotoxic to peripheral blood mononuclear cells. In distinct contrast, agents that are structurally related to BA, but that do not induce differentiation in FL cells, such as caproic acid, beta-OHBA, gamma-amino BA, and isobutyric acid, did not exhibit immunosuppressive properties. Pokeweed mitogen-driven polyclonal B cell activation was also suppressed by agents that induce erythroid differentiation in FL cells. In addition to potent in vitro immunosuppressive properties, supplementation of drinking water with BA or PA resulted in prolongation of full-thickness skin grafts in DBA/2 (H-2d) to C57BL/6 (H-2b) donor-recipient combinations. Our findings indicate that polar organic compounds that induce differentiation in FL cells are potent immunosuppressive agents.

3-Hydroxybutyric Acid↗
PubMed1976

The influence of corticosteroids and topical indomethacin on sunburn erythema.

The extent to which topical and intradermal corticosteroids and topical indomethacin suppress sunburn erythema was investigated in human volunteers. Both agents retarded the onset and decreased the magnitude of delayed erythema. Suppression by corticosteroids was not demonstrable with ultraviolet doses larger than 2 MEDs (minimal erythema dose). Below 2 MEDs, topical betamethasone valerate produced a dose-related suppression of erythema. Indomethacin was more effective and produced a measurable dose-dependent suppression against 3 and 6 MEDs. Despite significant inhibition of erythema, sunburn damage to epidermal cells was not altered by these drugs.

Administration, Topical↗
PubMed1977

Studies on 133Xe wash-out from human skin: quantitative measurements of blood flow in normal and corticosteroid-treated skin.

Blood flow was measured by the 133Xe technique in normal and corticosteroid-treated skin. Epicutaneous and intracutaneous methods of tracer application were compared in normal skin. The two labeling methods were equally suitable for measuring cutaneous blood flow provided calculations in both cases were based on a biexponential resolution of the wash-out curve in its cutaneous and subcutaneous components and provided the traumatic hyperemia phase was considered, when intracutaneous application of the tracer was used. Results were invalidated if calculations were based on initial slope of the wash-out curves.Topical application of beta-methasone valerate in a reduction in cutaneous blood flow as measured by the intracutaneous technique with curve resolution, whereas no effect could be demonstrated when calculations were based on the initial slopes of the curves. The 133Xe technique is a simple and reliable method for measuring cutaneous blood flow, which might prove useful in estimations of penetration ability and potency of topical corticosteroids.

Administration, Topical↗
PubMed1977

Effects of dermatitis, stripping, and steroids on the morphology of corneocytes. A new bioassay.

This study was designed to investigate the effects of increased or decreased epidermal turnover on the morphology of human corneocytes. The desquamating portion of the stratum corneum was sampled with the detergent scrub technique using Triton X-100. The following parameters were measured: size (surface micron2), shape (regular, irregular), nuclear inclusions, trabeculae, and numerical counts. Specimens were obtained from adult males with allergic contact dermatitis (N=18); with tretinoin-induced dermatitis (N=11); after cellophane stripping (N=11); and after treatment of these conditions with topical steroids (N=40). Data from 250,000 cells were analyzed statistically. The reproducibility of the method is good (r=0.934). Corneocytes from skin of patients with allergic contact dermatitis differed from those of normal skin: they were 15% smaller and of irregular shape with asymmetrical trabeculae; 50% were nucleated and about 3 times as many cells were collected per cm2 skin surface. Tretinoin and stripping produced similar but more pronounced effects. Topical steroids significantly improved all parameters (p less 0.01). Betamethasone-17-dipropionate was more effective than the valerate. This bioassay permits sensitive measurements of corneocyte morphology in conditions with altered epidermal cellular kinetics. It provides a method to evaluate steroid effectiveness.

Adult↗