Franz J. Legat

Optimal weekly frequency of 308-nm excimer laser treatment in vitiligo patients.

Background  Recently the beneficial effect of excimer laser treatment has been reported for patients with vitiligo. The influence of treatment frequency on this effect is not clear.

The efficacy of excimer laser (308 nm) for vitiligo at different body sites

Background  The treatment with XeCl‐excimer laser generated 308‐nm UVB radiation has shown promising results in patients with vitiligo.

Treatment with 311-nm ultraviolet B accelerates and improves the clearance of psoriatic lesions in patients treated with etanercept

Background  Some patients with plaque‐type psoriasis respond slowly to treatment with etanercept. In such cases combining etanercept with conventional treatments might be helpful.

Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry.

Background  Few studies have directly compared the clinical efficacy of psoralen plus ultraviolet A (PUVA) vs. biologics in the treatment of psoriasis.

Treatment with 311-nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab-treated patients: a randomized intraindividual trial

Background  Treatment with the interleukin‐12/23 antibody ustekinumab produces a satisfactory response [i.e. 75% reduction in Psoriasis Area and Severity Index (PASI) compared with baseline (PASI 75)] in the majority of patients with moderate to severe chronic plaque‐type psoriasis.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D3 analogue in polymorphic light eruption

Background  Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)‐induced immune suppression. Similar to UV radiation, calcitriol (1,25‐dihydroxyvitamin D3) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties.

311 nm ultraviolet B-accelerated response of psoriatic lesions in adalimumab-treated patients.

Background: Treatment with the tumor necrosis factor‐alpha antibody adalimumab for 12–16 weeks produces a satisfactory response [i.e., 75% reduction in psoriasis area and severity index (PASI)] in a majority (70–80%) of patients with psoriasis. We asked whether 311 nm ultraviolet B (UVB) can improve therapeutic response of psoriatic lesions to adalimumab.

Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling.

BACKGROUND Methodologies for continuous sampling of lipophilic drugs and high-molecular solutes in the dermis are currently lacking. We investigated the feasibility of sampling a lipophilic topical drug and the locally released biomarker in the dermis of non-lesional and lesional skin of psoriatic patients over 25h by means of membrane-free dermal open-flow microperfusion probes (dOFM) and novel wearable multi-channel pumps. METHODS Nine psoriatic patients received a topical p-38 inhibitor (BCT194, 0.5% cream) on a lesional and a non-lesional application site once daily for 8 days. Multiple dOFM sampling was performed for 25 h from each site on day 1 and day 8. Patients were mobile as dOFM probes were operated by a novel light-weight push-pull pump. Ultrasound was used to verify intradermal probe placement, cap-LC-MS/MS for BCT194 and ELISA for TNFα analysis. RESULTS dOFM was well tolerated and demonstrated significant drug concentrations in lesional as well as non-lesional skin after 8 days, but did not show significant differences between tissues. On day 8, TNFα release following probe insertion was significantly reduced compared to day 1. CONCLUSIONS Novel membrane-free probes and wearable multi-channel pumps allowed prolonged intradermal PK/PD profiling of a lipophilic topical drug in psoriatic patients. This initial study shows that dOFM overcomes limitations of microdialysis sampling methodology, and it demonstrates the potential for PK/PD studies of topical products and formulations in a clinical setting.

Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats

The cutaneous neurosensory system is suggested to be involved in the pathophysiology of pruritus and skin diseases such as psoriasis. We investigated if repeated subinflammatory doses of ultraviolet B (UVB) irradiation similar to those used to treat pruritus or psoriasis would affect the cutaneous neurosensory system. Sprague-Dawley rats were irradiated thrice weekly for 2-4 weeks with subinflammatory doses of UVB. Three days after the last UVB exposure: (i), the skin contents of substance P (SP), calcitonin gene-related peptide (CGRP), and nerve growth factor (NGF) were quantified; (ii), the skin nerve fiber density was observed; and (iii), the effect of UVB on mustard oil-induced neurogenic inflammation was determined. UV exposure significantly increased SP and CGRP content and mustard oil-induced neurogenic inflammation in UV-irradiated but not non-irradiated skin; however, it did not affect cutaneous NGF content or overall nerve fiber density. These data suggest that repeated subinflammatory UVB irradiation locally increases the content of cutaneous SP and CGRP by an increase of neuropeptide content of nerve fibers rather than by an increase of overall nerve fiber density.

Effects of the non‐peptide B2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release

The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657. Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 nM) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A pKB value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein. The concentration‐response curves for B2 receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 nM). A pKB of 9.0±0.2 was calculated. FR173657 had no effect on B1 receptor‐mediated relaxations in response to des‐Arg9‐BK. The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 nM) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA2 value of 9.1 was determined. Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 nM). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657. In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 nM FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 nM. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II. The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E2 and I2 into the venous effluent. The BK‐stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 nM) while the basal prostaglandin release was unchanged. In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B2, but not B1, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action in vitro was long‐lasting, but was fully reversible.