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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]

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.

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.

The article reports about spreading pigmented actinic keratoses. The common type of actinic keratosis is yellow-brown in colour, possesses an adherent scale and is less than 1 cm in diameter, with little tendency to continuing centrifugal spread. The authors have recently seen ten lesions arising on the face, which were large, flat and pigmented and in six cases had led the clinician to diagnose Hutchinson's malignant lentigo. Histology showed all to be pigmented actinic keratoses. The spreading pigmented type of actinic keratosis should be considered in the differential diagnosis of pigmented lesions of the face. Clinically, it may be difficult to distinguish from a Hutchinson's malignant lentigo.

The rhino mouse has been used as an experimental model to screen topically active comedolytic agents. Adult rhino mice were treated on the back once daily for 5 consecutive days per week during 3 weeks. Skin histological preparations were analyzed by image analysis techniques to quantify the number of epidermal comedones, comedo profile and epidermal thickness. Using both a negative (treated with acetone) and a positive (treated with Aberel gel 0.025%) control group of animals in all experiments conducted over a period of about 3 years, we defined the upper and lower limit of acceptability of the results. Topical treatment with an acetone solution of all-trans retinoic acid (0.01, 0.03, 0.1%) and 13-cis-retinoic acid (0.1%) induced comedolysis and a marked increase in epidermal thickness. Commercial preparations of all-trans retinoic acid (Aberel lotion, gel and cream, Retin A cream, Retacnyl cream) presented a similar comedolytic activity. However, the epidermal thickening was higher with Retin A and weaker with Retacnyl. CD271, a new modulator of cell differentiation, applied either in acetone solution (0.01, 0.1%) or in lotion, gel or cream formulations (0.1%) also demonstrated a marked activity (i.e. comedolysis and epidermal thickening). These data confirm that the rhino mouse model can be used to assay drugs applied either in solvent or in topical formulations. Activity in this model compares favorably with published clinical observations in the treatment of acne.

We have examined the effects of a standardized, moderately erythemogenic dose of long-wave ultraviolet (UVA) radiation on normal human skin, with the use of an appropriately filtered solar simulator and sequential biopsy specimens processed as 1-micron Epon-embedded sections. Histologic changes were present immediately after irradiation and evolved slowly during the 48-hour study. The epidermis manifested slight intracellular and intercellular edema and progressive loss of Langerhans cells to approximately one-fifth control values. A dermal infiltrate of neutrophilic polymorphonuclear leukocytes was present in all postirradiation specimens and peaked at 3 hours. A perivascular lymphocytic infiltrate, moderate endothelial cell enlargement, mast cell hypogranulation, occasional massive venular dilation, and sparse red blood cell extravasation were also noted. Overall, our findings expand and quantify earlier impressions that, compared to UVB, UVA has a relatively greater histologic effect on the dermis than on the epidermis, depletes epidermal Langerhans cells, and recruits neutrophils into irradiated human skin.

1 Prostacyclin activates adenylate cyclase of the NCB-20 neuronal hybrid cell line. 2 There is a guanosine 5'-triphosphate requirement for the activation of adenylate cyclase by 5,6 beta-dihydroprostacyclin (a stable analogue of prostacyclin). 3 Steady-state kinetic analysis of the activation of adenylate cyclase by 5,6 beta-dihydroprostacyclin suggests a simple non-cooperative bimolecular interaction between the ligand and single receptor population. 4 Structure-activity relationships of selected prostanoids elucidated certain functional requirements for activation of adenylate cyclase.

A within-patient randomized, double-blind, crossover study was performed to investigate mechanisms of action of bendroflumethiazide in mild essential hypertension. Significant reductions in lying, standing, and postexercise blood pressure were seen after both 3 days and 10 wk treatment with bendroflumethiazide 10 mg daily. Plasma levels of 6-oxo-PGF1 alpha, the chemical hydrolysis product of prostacyclin, were increased by both 3 days and 10 wk therapy with bendroflumethiazide. This raises the possibility that thiazides may reduce peripheral resistance by increasing prostacyclin biosynthesis.

1 Clinically normal human abdominal skin in 11 subjects, was irradiated with three times the minimal-erythema dose of ultraviolet B (u.v. B) irradiation. 2 Erythema was assessed visually, and exudate was recovered by a suction bulla technique from normal skin, and from skin at 6, 24 and 48 h after irradiation. 3 Erythema was moderate at 6 h, but increased to a maximum at 24 h, which was maintained at 48 h. 4 6-oxo-PGF1 alpha was markedly raised at 6 h, moderately raised at 24 h, but had returned to control levels at 48 h, when the erythema was still maximal. 5 Prostaglandin I2, the precursor of 6-oxo-PGF1 alpha and 6-oxo-PGF1 alpha may, therefore, play a part in the early inflammatory process after u.v. B irradiation, but is unlikely to be responsible for the erythema still present at 48 h.

1. Gas chromatography-mass spectrometry demonstrated the presence of arachidonic acid (AA), 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2 alpha were usually found more often in the mucosal extracts. The 12-hydroxy-derivative of AA (12-HETE) was detected in all extracts of the colon but in only some of the other tissues. 2. Most prostanoids tested contracted the longitudinal muscle, the order of potency being U-46619 (an epoxymethano analogue of PGH2) greater than PGE2 greater than PGF2 alpha greater than PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects. 3. U-46619 or, less potently, PGF2 alpha contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha or TxB2 usually had little or no effect. 4. PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine. 5. For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach greater than distal ileum greater than sigmoid colon. 6. The results are discussed in relation to gastrointestinal physiology and pathophysiology.

Two sensitive and selective quantitative methods for 6-oxo-PGF1 alpha, the stable hydrolysis product of prostacyclin are described and compared. Prostaglandins were extracted from biological fluids with organic solvents. Samples for gas chromatographic mass spectrometric analysis required additional thin-layer chromatographic separation prior to conversion to the O-methyloxime, methyl ester, tri-trimethylsilyl ether. Ion fragments at m/z 418 and 508 (protium) and m/z 422 and 512 (deuterium) were monitored to prepare 6-oxo-PGF1 alpha standard curves. The gas chromatographic mass spectrometric detection limit was 500 pg injected on column with a method coefficient of variation of 11.6% at this level. At 590 pg ml-1 the coefficient of variation for reproducibility of measurement was 1.77%. Antisera raised against a 6-oxo-PGF1 alpha-bovine serum albumin conjugate in sheep had a higher titre and greater selectivity than those raised in rabbits. Cross-reaction of sheep antisera with all prostaglandins and fatty acids tested was less than 0.5%. The radioimmunoassay limit of detection was 60 pg ml-1 (6 pg per tube) with a coefficient of variation of 10.4% (intra-assay) and 10.75% (inter-assay). The double blind comparison of gas chromatographic mass spectrometric and radioimmunoassay quantitation of the same samples gave a correlation coefficient of 0.97. Both methods offer sensitivity, selectivity and reproducibility. Gas chromatography mass spectrometry is necessary to validate the radioimmunoassay method which offers advantages of time, sample capacity and volume, expenditure and sensitivity.

1 In order to test the proposal that the anti-inflammatory effect of corticosteroids is attributable to inhibition of release of the prostaglandin precursor, arachidonic acid, the effect of systemic prednisolone on arachidonic acid and prostaglandin levels in abdominal skin of six patients receiving this treatment for alopecia totalis, was studied. 2 Inflammation was produced in an area of abdominal skin by topical application of 5% w/w tetrahydrofurfuryl nicotinate (THFN) cream. 3 The erythema produced was assessed visually, and exudate recovered from normal and inflamed skin, by a suction bulla technique. 4 Arachidonic acid and PGE2 and PGF2 alpha levels, as measured by gas chromatograph-mass spectrometry (GC-MS) were significantly elevated in the reddened (THFN) treated skin, compared with control areas. 5 After prednisolone treatment both arachidonic acid and prostaglandin levels in THFN-treated areas were suppressed near to values obtained from untreated skin, before prednisolone therapy. There was partial reduction of THFN induced erythema in three out of six subjects. Levels of arachidonic acid on control skin were not affected by the steroid. 6 These results provide direct evidence that steroids inhibit prostaglandin formation by blocking evoked rise in the concentration of free arachidonic acid. The relationship of this effect, in human skin, to the anti-inflammatory action of systemic steroids is uncertain.