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A variety of chemical stimuli, including tetrahydrofurfuryl nicotinate (Plummer et al, 19771 and anthralin (Barrel a!., 1982) are known to increase the levels of arachidonic acid and various prostanoids recovered from the fluid of suction blisters raised on human and animal skin. Recently we have demonstrated that the skin of mini-pigs behaves qualitatively and quantitatively, in a pharmacological manner similar to human skin with respect to the above two stimuli (Chatelus et al., 1982) However, the present studies with these two drugs suggest that the selection of the vehicle in which the drug is applied to the skin is of paramount importance since, as will be presented below, significant pharmacological effects of the vehicles can he detected on the levels of various prostanoids measured. [ABSTRACT FROM AUTHOR]

The 15-lipoxygenase from soya bean has been claimed to represent a rapid assay procedure for drugs and chemical agents that inhibit other lipoxygenase products (Kingston, 1981). Although the exact role of products derived from skin lipoxygenase enzymes is not well established, many of these products, e.g. leukotriene B4, have inflammatory characteristics that warrant further examination (Camp, 1982). We have therefore started to evaluate anti-inflammatory drugs in vitro for their ability to inhibit soya bean 15-lipoxygenase, before appraising their effects in vivo in animal and human skin. [ABSTRACT FROM AUTHOR]

Investigates the role for prostanoids in various human skin diseases. Details on the pharmacology of many prostanoids; Quantitative analysis of prostaglandins; Levels of the various prostanoids in both vitiligo and tuberculin.

- Prostaglandins have been implicated in the development and spread of malignant tumours. Gas chromatography and mass spectrometry (GC-MS) analysis of prostaglandins in benign and malignant prostatic tissue showed that prostacyclin (PGI2), a prostanoid known to induce bone resorption, was the major component. PGI2 is hydrolysed to 6-oxo-PGF1a. Plasma levels of 6-oxo-PFG1a were measured as an index of PGI2 formation in patients with benign and malignant prostatic disease. The mean plasma 6-oxo- level in an age-matched control group was comparable to that of patients with benign prostatic hypertrophy. A significant elevation was found in patients with a TO carcinoma (P<0.05). Plasma 6-oxo- levels rise with advancing disease and the concentration varied with the degree of tumour differentiation. Plasma 6-oxo- levels were a more accurate monitor of disease progression than tartrate labile acid phosphatase in patients with M1 carcinoma. Persistently elevated levels were associated with a bad prognosis. [ABSTRACT FROM AUTHOR]

This is the first report of human gastrointestinal arachidonate and prostanoids measured quantitatively by gas chromatography-mass spectrometry (GC-MS) in extracts of human cancers and macroscopically normal tissues from the stomach and colon. There were microgram/g amounts of arachidonate, and the particularly high yield from the tumours may explain why they usually produce more prostaglandins than the normal tissues in which they arise. There was only a small conversion of the arachidonate into prostanoids. 6-Keto-PGF1 alpha was the most abundant metabolite measured, particularly in the tumour extracts, with smaller amounts of prostaglandins E2, F2 alpha and D2. [ABSTRACT FROM PUBLISHER]

1 Indomethacin treatment of postural hypotension in four patients with chronic autonomic failure increased their pressor supersensitivity to intravenous noradrenaline without causing fluid retention. 2 All patients were supersensitive to angiotensin II in spite of normal levels of plasma renin activity in the supine position and therefore (by inference) of angiotensin II. This suggests that in autonomic failure, the degree of angiotensin receptor occupancy by endogenous angiotensin II is not important in determining pressor sensitivity to exogenous angiotensin II. Indomethacin increased the pressor supersensitivity to angiotensin II in all patients. 3 Indomethacin treatment decreased supine plasma renin activity to 50% of the level present before indomethacin treatment. 4 Indomethacin increased the lying but not the standing blood pressure. The failure to raise the standing pressure may be the result of the additional postural stress overcoming any vasoconstriction resulting from the increased sensitivity of vascular receptors to noradrenaline. The decrease in plasma renin activity could also contribute to the failure of indomethacin to prevent a fall in blood pressure on standing. 5 In our patients the excretion of the main urinary metabolite (PGFM) of prostaglandin F2 alpha was higher than recorded previously in normal controls. During treatment with indomethacin, plasma indomethacin levels were in the range at which inhibition of prostaglandin synthesis occurs and the excretion of PGFM was decreased. 6 Indomethacin was not effective in the treatment of postural hypotension in these patients with autonomic failure. [ABSTRACT FROM AUTHOR]

This article discusses the mode of action for non-steroidal, anti-inflammatory agents (NSAI) and their ability to inhibit the biosynthesis of prostaglandins. It says that for this mechanism of action to be valid it must be dearly demonstrated: (a) that one or more prostaglandin has potent inflammatory properties; (b) that they are released by inflammatory processes; and finally (c) that non-steroidal, anti-inflammatory agents directly inhibit the biosynthesis of prostaglandins and related compounds. The presence of increased concentrations of prostaglandins and other products of arachidonic acid metabolism in inflamed skin has now been firmly established for a wide variety of different forms of skin injury.

The photosensitizing psoralens are increasingly used for treatment of a variety of skin disorders but little information has been available until recently on the pharmacokinetic and biochemical properties of these compounds in man, as of December 1978. Lack of suitably sensitive and specific analytical procedures for the psoralens has been the major difficulty. Gas-liquid chromatography with flame ionization detection, high pressure liquid chromatography with ultraviolet detection and thin layer chromatography with photodensitometric detection have all recently been applied to the analysis of 8-methoxypsoral in human plasma and serum.

CD 271 possesses a potent anti- inflammatory activity in a large number of models particularly when compared with known reference anti-inflammatory agents. Retinoids (all-trans retinoic acid, 13 cis retinoic acid and Etretinate) show very weak or no activity. In view of these properties of CD 271, an enhanced therapeutic value can be anticipated in the treatment of skin diseases such as acne and psoriasis. [ABSTRACT FROM AUTHOR]

In model systems where anthralin and butanthrone have a high anti-proliferative activity, e.g., inhibition of keratinocyte metabolism in culture or inhibition of ornithine decarboxylase induction in vivo, CD 003 is inactive. However, in the skin disease psoriasis there is both an inflammatory as well as a differentiation/proliferation component, and consequently we have evaluated anthralin and butanthrone for their potential in vivo antiinflammatory activities. In addition, we have compared a new analogue, substituted at C, with these two compound. Our results support the belief that modification of the anthralin structure can result in the formation of less toxic, less irritant and less staining analogues, which maintain or significantly improve upon the topical antiinflammatory properties of anthralin. The possibility that such analogues will be of use in the treatment of skin diseases with a major inflammatory component is at present being investigated. [ABSTRACT FROM AUTHOR]

Arachidonic acid and prostaglandins E&sub2; and F&sub23; are known to be elevated in exudate from healthy human skin during the first 24 hours after exposure to three times the minimal erythema dose of ultraviolet light. Indomethacin reduces the erythema and prostaglandin concentrations with both types of ultraviolet radiation but does not influence photochemotherapy (PUVA) erythema. Furthermore the pharmacological events occurring in PUVA treated skin are unknown. PUVA, in contrast to ultraviolet radiation induced erythema is not associated with increased concentrations of arachidonic acid and a role for these agents in the photochemotherapy of psoriasis seems unlikely.

The article focuses on prostaglandin synthesis in human skin inflammation after UV-C irradiation, and the effects of indomethacin. The authors irradiated skin with 6xMED of UV-C in 30 volunteer subjects. In four subjects the procedure was repeated on skin to which 25% indomethacin was applied immediately after irradiation. Exudates was obtained from irradiated and control skin using a suction blister method. The exudates were analyzed for: Smooth muscle contracting activity by cascade superfusion bioassay; PGF by radioimmunoassay; and PGE, PGF and arachidonic acid (AA) by combined gas-liquid chromatography mass- spectrometry. UV-C causes inflammation and activates the AA cascade in human skin. Reduction of prostaglandin activity and increase in AA by indomethacin is consistent with inhibition of prostaglandin biosynthesis.