Pharmacology of psoriasis.

Although psoriasis is a genetically transferred disease, little is known of the factors causing spontaneous eruption of a proliferative lesion in apparently normal epidermis. Cell kinetic studies indicate an increased epidermal turnover in clinically normal and involved skin, but the pharmacological events regulating epidermopoiesis remain elusive. Possible candidates for the defect in psoriasis are the cyclic nucleotides with their associated enzyme systems. The cyclic AMP: cyclic GMP ratio appears to be reduced in lesional skin. Further phosphodiesterase inhibitors are reported to improve psoriasis. Since prostaglandins stimulate epidermal cyclic AMP in vitro they have been investigated, but with conflicting results. However, the prostaglandins' precursor, arachidonic acid, appears to be elevated in the psoriatic lesion. Epidermal levels of cyclic AMP are also elevated by histamine via H2 receptors and the possibility that histamine exerts a regulatory role needs to be investigated. In conclusion, the pharmacology of psoriasis is complex. Not only do we need to know which pharmacological agents are present in abnormal amounts but more importantly we need to know more about their interactions with one another and with their specific epidermal 'receptors'.

The effects of indomethacin on arachidonic acid and prostaglandins e2 and f2alpha levels in human skin 24 h after u.v.B and u.v.C irradiation.

1 Clinically normal human abdominal skin was irradiated with either three times its minimal erythema dose (MED) of ultraviolet B (u.v.B) or six MEDs of ultraviolet C (u.v.C) radiation. In both instances erythema was maximal at 24 h. 2 Exudate was recovered by a suction bulla technique from normal and irradiated skin at 24 h after irradiation. 3 Arachidonic acid, prostaglandins E2 and FSalpha, as measured by GC--MS, were significantly elevated at 24 h. Radioimmunoassay also showed increased PGF2alpha-like concentrations. 4 Oral indomethacin only partially reduced the erythema resulting from both types of radiation but totally suppressed the elevation of PGE 2 and F2alpha concentrations. 5 Topical indomethacin also suppressed u.v.B-induced increases in prostaglandins E2 and F2alpha. Unexpectedly, the vehicle alone produced a similar suppressive effect on prostaglandins although erythema appeared unaltered. 6 Most of the arachidonic acid metabolized by indomethacin-sensitive pathways is not converted to prostaglandins E2 and F2alpha in human skin.

Irradiation of human skin by short wavelength ultraviolet radiation (100--290 nm) (u.v.C): increased concentrations of arachidonic acid and prostaglandines E2 and F2alpha.

1. Human abdominal skin was irradiated with six times the minimal erythema dose of ultraviolet C (100--290 nm) radiation. Erythema appeared at 3 h, was of moderate degree by 6 h and was maximal at 12--24 h. It was reduced at 48 h and by 72 h had disappeared. 2. A suction bulla technique was used for the recovery of exudate from normal and inflamed skin at 6, 18, 24 and 48 h after irradiation. 3. Prostaglandin-like activity, estimated by bioassay, showed maximum increase at 18 h, when erythema was also maximum. PGF 2alpha, measured by both radioimmunoassay and by combined gas-liquid chromatography--gas spectrometry, followed a similar time course then fell to normal, or near normal, levels at 48 h. 4. Prostaglandin E2 and arachidonic acid concentrations, measured by gas chromatography--mass spectrometry, were maximally raised at 18--24 h. At 48 h, when some erythema was still present, though reduced, prostaglandin E2 concentrations were still raised above control values. 5. The results provide direct evidence in support of the view that the erythma following irradiation of human skin by u.v.C involves activation of arachidonic acid metabolism. However, the relationship between the erythema and increased prostaglandin activity is not fully understood.

Inflammatory reactions induced by ultraviolet irradiation.

Exposure of human skin to short wavelength ultraviolet (U.V.) leads to increased concentrations of arachidonic acid and prostaglandins E2 and F2, but their role is uncertain. Although the levels of prostaglandins rise as erythema develops the correlation between intensity of erythema and prostaglandin activity is incomplete. There is mounting evidence that prostaglandins may regulate epidermal cell growth and differentiation through a cyclic-AMP dependent mechanism. The possibility therefore arises that prostaglandins, released in response to U. V. exposure, reduce proliferative activity in the exposed epidermis. This can be expected, in turn, to result in protection of skin from the mutagenic action of U. V. irradiation.

Inflammation in human skin induced by ultraviolet irradiation.

Pharmacologically active mediators of inflammation were obtained from suction bullae raised on normal and ultraviolet B (290-320 nm) inflamed human abdominal skin. The exudates obtained from the bullae were examined by superfusion cascade bioassay, by radioimmunoassay for PGF2alpha and by column, thin-layer and gas-liquid chromatography. Ultraviolet B (u.v.-B) irradiation of human skin produced an erythema which appeared after 2 hr, increased in severity up to 24 hr and persisted for more than 48 hr. Bioassayable and radioimmunoassayable prostaglandin activity was elevated at 6 hr, was maximal at 24 hr and had returned to normal 48 hr. Topical application of indomethacin suppressed both the erythema and the increased concentration of PGF2alpha as measured by radioimmunoassay. Chromatographic studies confirmed increased prostaglandin activity at 6 and 24 hr and in addition demonstrated an increase in arachidonic acid-like activity. The results suggest that prostaglandins may play an important role between 6 and 24 hr of u.v.-B-induced erythema. Whether the reduction of erythema by indomethacin can be partially or wholly attributable to inhibition of prostaglandin biosynthesis is uncertain.

The effect of chlorpromazine on the secretion of immunoreactive beta-MSH and prolactin in man.

The effect of chlorpromazine (50 mg. im) on the plasma concentration of immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) and prolactin was studied in 8 hospitalized subjects with non-endocrine skin disorders. Plasma beta-MSH concentrations remained unchanged over a period of 7 h in 6 subjects. In the remaining 2 subjects there was a slight increase. Plasma prolactin concentrations were greatly increased in all subjects 1 1/2-3 h after the injection and had almost returned to pre-injection levels by 7 h. This suggests that the control of beta-MSH secretion in man, unlike that of prolactin in man and MSH peptides in other mammals, is not predominantly inhibitory. The reason for this discrepancy may be that beta-MSH is not a natural MSH in man and occurs as part of the lipotropic hormone (LPH) or as a breakdown product.

Plasma immunoreactive beta-melanocyte-stimulating hormone and skin pigmentation in chronic renal failure.

Plasma immunoreactive beta-melanocyte stimulating hormone (beta-MSH) concentrations were greatly increased in patients with chronic renal failure. There was no correlation between the severity of the renal failure or the degree of pigmentation and the plasma beta-MSH levels.