Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.

The retinoids are a class of compounds that includes the natural forms and synthetic analogues of vitamin A. Isotretinoin, often referred to as a first generation retinoid, may be of considerable benefit to patients with severe, recalcitrant acne. Etretinate and acitretin, 2 aromatic compounds representing the second generation, have found their major success in the treatment of psoriasis, particularly in combination with more traditional therapies. Retinoid therapy is associated with a distinctive adverse effect profile typical of hypervitaminosis A; thus, it is especially important that fertile women undergoing retinoid therapy adhere to a contraceptive regimen. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. The terminal elimination half-lives of isotretinoin, etretinate and acitretin after long term treatment are up to 20h, 120 days and 48h, respectively. Because of lack of definite correlation between plasma concentration and desired pharmacological effects, in conjunction with the very pronounced inter- and intraindividual variation in systemic availability (15 to 90%) after oral administration of these drugs, initial dosages in individual patients can only be roughly judged on the basis of the general pharmacokinetics of the agents. Later dosage adjustments should be made on the basis of monitoring of both plasma drug (and possible metabolite) concentrations, and the efficacy and tolerability of the drugs.     

Linoleic acid and dihomogammalinolenic acid inhibit leukotriene B4 formation and stimulate the formation of their 15-lipoxygenase products by human neutrophilsin vitro. Evidence of formation of antiinflammatory compounds

Enzymatic transformation of then-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) by the 5-lipoxygenase (LO) enzyme results in the formation of leukotrienes (LTs) including leukotriene B₄ (LTB₄), which is a potent mediator of inflammation. The purpose of the present study was to determine the effect of othern-6 fatty acids on the formation of LTB₄ by human neutrophils and to determine if thesen-6 fatty acids themselves may be transformed into products with antiinflammatory capacity. Purified neutrophils isolated from heparinized human venous blood were incubated with A23187 (5 M) and different concentrations (0–100 M) of then-6 fatty acids linoleic acid (LA) and dihomo-gammalinolenic acid (DGLA). LO products were determined by use of quantitative reversed-phase high performance liquid chromatography (RP-HPLC) and mass spectrometry. The formation of LTB₄ was dose dependently inhibited by both LA (IC₅₀=45 M) and DGLA (IC₅₀=40M). This inhibition of LTB₄ formation was associated with a dose dependent increase in the formation of the respective 15-LO products of LA (13-hydroxy-octadecadienoic acid; 13-HODE) and DGLA (15-hydroxy-eicosatrienoic acid; 15-HETrE). To determine whether these 15-LO products themselves might inhibit LTB₄ formation, neutrophils were incubated with 13-HODE and 15-HETrE. Both 15-LO products lead to a dose-dependent inhibition of LTB₄ formation (IC₅₀=7.5 M and IC₅₀=0.2 M). For comparison the 15-LO product of AA, 15-hydroxy-eicosatetraenoic acid (15-HETE), also inhibited LTB₄ formation (IC₅₀=0.75 M). The results show that the addition of LA and DGLA to neutrophils results in an inhibition of LTB₄ formation and simultaneously to the formation of 13-HODE and 15-HETrE, that also inhibits LTB₄ formation. Therefore, dietary supplementation or topical application of LA and DGLA or preferentially their respective 15-LO products, may have a therapeutic effect in inflammatroy diseases in which LTs are suspected to play a pathogenic role.     

Increased ATP-ase activity of lymphocytes after rosette formation with sheep red blood cells.

In a number of experiments it was demonstrated that in the E-rosette assay for human T-lymphocytes using sheep red blood cells, the ATP-ase activity of the lymphocytes increased in proportion to the number of rosettes being formed. Also, after increasing the number of rosettes by treatment of the sheep red blood cells (SRBC) with neuraminidase and after diminishing the number of rosettes by treatment of the lymphocytes with antilymphocyte globulin (ALG), change in the ATP-ase activity was proportional to alterations in the number of rosettes being formed. ALG itself stimulated the lymphocyte ATP-ase activity, possibly through activation of the same receptor sites as used by SRBC.     

Topical corticosteroids in psoriasis: strategies for improving safety

Corticosteroids are a mainstay of topical therapy for psoriasis. While efficacious and relatively safe when used carefully, the potential for side effects, notably skin atrophy and adrenal suppression, have been associated with excesses in potency, prolonged or widespread use. The International Psoriasis Council Working Group on Topical Therapy has reviewed the efficacy and safety of topical corticosteroids and recommends strategies for safe, long‐term use of these agents.     

New vitamin D analogs in psoriasis

Psoriasis is a common inflammatory and hyperproleferative skin disease characterized by infiltrated plaques of the skin and may involve nails, scalp and intertreginous areas. Recent years of research has shown that psoriasis can be treated topically with analogs of vitamin-D(3). Impaired differentiation and increased proliferation of epidermal keratinocytes are key features in psoriatic lesions together with a local activation of T lymphocytes. Evidence has accumulated that analogs of vitamin D(3) increase differentiation and inhibit proliferation of keratinocytes. Topical treatment with analogs of vitamin D(3) have in a number of trials shown improvement of psoriasis. Vitamin D analogs show the same efficacy as potent topical corticosteroids and do not produce skin atrophy during long-term therapy. Vitamin D analogs can be used both as monotherapy and in combination with topical corticosteroids, UVB, PUVA, acitretin, methotrexate and cyclosporine. The vitamin D(3) analog calcipotriol has been investigated in most detail and is available as an ointment, a cream and as a scalp solution. From clinical studies involving several thousands of patients, it can be concluded that calcipotriol is efficacious, safe and well-tolerated even on a long term basis.     

Intracutaneous injection of lysophosphatidylcholine induces skin inflammation and accumulation of leukocytes

Various cell stimuli act through activation of phospholipase A2, which hydrolyses fatty acids from membrane phospholipids, resulting in the formation of fatty acids and lysophospholipids. One of the lysophospholipid classes, lysophosphatidylcholine, is a chemoattractant for monocytes and T-lymphocytes and induces the expression of adhesion molecules on cultured endothelial cells. The purpose of the present study was to determine whether lysophosphatidylcholine possesses proinflammatory properties in vivo. This was assessed clinically and histologically by intracutaneous injection of 200-800 nmol lysophosphatidylcholine in healthy volunteers. Lysophosphatidylcholine elicited a dose- and time-dependent local erythema and oedema. The erythema disappeared within 4 h, while the induration lasted for up to 48 h. HE-stained biopsies taken after 24 h showed a leukocytoclastic vasculitis in 2 of the 6 subjects. Microscopic examination of immunohistochemically stained biopsies taken 24 h after the injection showed a significant increase in the number of T-lymphocytes, monocytes and neutrophils, whereas the number of Langerhans' cells was unchanged after lysophosphatidylcholine injection. In addition, the number of intercellular cell adhesion molecule-1 and -3-positive cells was increased approximately 3-fold after injection of lysophosphatidylcholine. In conclusion, the phospholipase A2 hydrolysis product lysophosphatidylcholine can induce erythema, oedema, a mixed cellular infiltrate and the expression of adhesion molecules.     

Inhibition by leukotriene B5 of leukotriene B4-induced activation of human keratinocytes and neutrophils

Leukotriene B5 (LTB5) that is generated enzymatically from eicosapentaenoic acid (EPA), was compared with arachidonic acid-derived LTB4 for its DNA synthetic effect on cultured human epidermal keratinocytes and for its chemokinetic effect on human blood neutrophils. Leukotriene B5 was much less potent than LTB4 in stimulating DNA synthesis and in inducing chemokinesis. Furthermore, the maximum response to LTB5 was only a mean of 38% that of LTB4 for mitogenesis and 70% that of LTB4 for chemokinesis. At an optimally active concentration of LTB4 (10(-10) M) the addition of LTB5 suppressed the enhancement by LTB4 of DNA synthesis in keratinocytes by a mean of 21%, 33%, and 54%, respectively, at 10(-9) M, 10(-8) M, and 10(-7) M LTB5. Leukotriene B5 inhibited to a lesser extent the maximum neutrophil chemokinetic response elicited by 10(-10) M LTB4 with mean inhibition of 10%, 20%, and 18%, respectively, by 10(-9) M, 10(-8) M, 10(-7) M LTB5; LTB5 was without effects on N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-elicited neutrophil chemokinesis and on thrombin-stimulated keratinocyte DNA synthesis. The dietary introduction of n-3 fatty acids, such as EPA, may reduce the epidermopoiesis and neutrophil migration evoked by LTB4 through decreases in generation of LTB4 and the capacity of LTB5 to inhibit the effects of LTB4.