Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study.

BACKGROUND: GSK2586184 is a selective oral Janus kinase (JAK)1 inhibitor being evaluated as a treatment for moderate-to-severe plaque-type psoriasis. OBJECTIVES: To assess the relationship between dose of GSK2586184 and clinical response, primarily by the Psoriasis Area Severity Index (PASI). METHODS: Sixty patients with moderate-to-severe plaque psoriasis were randomized to cohort A: 100 mg, 200 mg or 400 mg GSK2586184 twice daily or placebo; and eight were randomized to open-label cohort B, a small exploratory cohort treated with 400 mg GSK2586184 twice daily, to explore differential gene expression. RESULTS: At week 12, a 75% reduction in PASI (PASI 75) response rates in the intent-to-treat population were 0% in the placebo group compared with 13%, 25% and 57% in the 100 mg, 200 mg and 400 mg GSK2586184 twice-daily groups, respectively. Increases in the proportion of PASI 75 responses were seen across all dose levels by week 4. Improvement in itch and quality of life were observed at all doses relative to placebo with the greatest improvement seen in the 400-mg dose group. Overall, the incidence of adverse events (AEs) was similar across treatment groups, and no relationship between frequency of AE and GSK2586184 dose was identified. Differential gene expression was observed in involved and uninvolved skin at baseline and in involved skin after 2 weeks of treatment with GSK2586184. CONCLUSIONS: Our study demonstrates that 12 weeks of treatment with GSK2586184 resulted in clinical improvement and was generally well tolerated in patients with moderate-to-severe plaque-type psoriasis.

Neurokinin-1 receptor antagonism in a human model of visceral hypersensitivity.

BACKGROUND: Substance P acting via the neurokinin-1 receptor is involved in the development of hyperalgesia, although studies using neurokinin-1 receptor antagonists (NK-1RA) in human somatic pain have been disappointing. AIM: To evaluate whether Substance P is involved in the development of human visceral pain/hyperalgesia using a selective NK-1RA. METHODS: Using a validated human model of acid-induced oesophageal allodynia, pain thresholds to electrical stimulation (mA) were measured in the proximal oesophagus and the foot (somatic control), pre- and for 4 h postdistal oesophageal acid in 14 healthy subjects, using a double-blind, randomized, two-period, crossover study. Measurements were taken on the third day of dosing with either an oral NK-1RA or matching placebo, with 2 weeks washout between periods. RESULTS: Baseline pain threshold did not differ between treatments (proximal oesophagus 37 +/- 7.4 mA NK-1RA vs. 38 +/- 10.1 placebo P = 0.81, foot 40 +/- 15 mA NK-1RA vs. 38 +/- 14 placebo P = 0.68). NK-1RA did not attenuate the reduction in pain threshold in the proximal oesophagus postacid infusion (AUC-394 +/- 279 NK-1RA vs. -262 +/- 397 placebo P = 0.54). CONCLUSIONS: The lack of effect of NK-1RA on oesophageal pain threshold in our model does not support a role for Substance P in the development of acid-induced oesophageal allodynia.

Focal brain injury induces multiple immediate early genes encoding zinc finger transcription factors.

Focal brain injury is known to markedly induce the fos and jun families of immediate early genes (IEGs). This study employed in situ hybridization to examine the effects of focal brain injury, produced by the intracerebral injection of saline or ibotenic acid on the expression of IEGs encoding zinc finger transcription factors. Thirty minutes after the injections, NGFI-A, NGFI-B, NGFI-C, and egr-3 mRNAs were induced in dentate gyrus, hippocampal pyramidal cells, cerebral cortex, caudate-putamen and piriform cortex of the injured hemisphere. Nurr1 was induced in hippocampal pyramidal cells and dentate granule cells. After three hours the induction of NGFI-A, NGFI-B, NGFI-C and Nurr1 persisted in all brain regions except for the dentate granule cells. By six hours after injection mRNAs for most of the zinc finger genes had returned to control levels. However, the expression of egr-3 3 and 6 h after the injection was identical to that observed at 30 min after the injection and it was the only gene the expression of which persisted 6 h following the injections. Twenty-four hours after the injection, the expression of all five IEGs returned to control levels. In general, no gross differences in the IEG induction were observed between the animals injected with saline and ibotenic acid. Since these zinc finger genes were expressed in the same regions where fos and jun family members are induced by similar types of brain injury, it is suggested that these transcription factors may act in concert with Fos/Jun family members.(ABSTRACT TRUNCATED AT 250 WORDS)

VIP-induced stellation and immediate early gene expression in astrocytes: effects of dexamethasone.

To investigate the actions of glucocorticoids (GCs) on astrocyte functions, interactions of dexamethasone and immediate early genes (IEGs) were studied in cell cultures of rat cerebral cortical astrocytes. Vasoactive intestinal peptide (VIP) induces rapid c-fos mRNA expression and morphological changes (stellation) in cultured astrocytes. Dexamethasone pretreatment decreases this ligand-induced stellation without affecting levels of c-fos mRNA. Moreover VIP does not induce c-jun, jun-B, and NGFI-A mRNA, suggesting that these IEGs may not mediate ligand-induced stellation. The expression of c-fos, c-jun, jun-B, and NGFI-A mRNA are rapidly induced in cultured astrocytes after treatment with phorbol ester, epidermal growth factor, and basic fibroblast growth factor. Dexamethasone pretreatment has no effect on the IEG response induced by any of these agents, suggesting that GCs may not have direct effects on the promoter of these IEGs in cortical astrocytes.

Long-term induction of c-jun mRNA and Jun protein in rabbit retinal ganglion cells following axotomy or colchicine treatment.

The expression of the c-jun, c-fos, and NGFI-A genes was studied in the rabbit retina after optic nerve crush (ONC) or an intravitreal injection of colchicine. By Northern blotting, the basal expression of c-fos and NGFI-A mRNAs were undetectable, whereas c-jun mRNA showed a low basal expression in sham-operated control retinas. Very few or no Jun- or Fos-immunoreactive nuclei were seen in control retinas. From 1 to 95 days after ONC a marked induction of JUN- but not FOS-immunoreactive neurons was seen in the ganglion cell layer peaking at 3 and 7 days. Jun-positive neurons also accumulated immunoreactive phosphorylated neurofilaments, indicating that they were ganglion cells. Northern blots demonstrated that retinal levels of c-jun mRNA, but not of c-fos or NGFI-A mRNAs, were increased 3 and 7 days after ONC. An intravitreal injection of colchicine also induced Jun-immunoreactivity within 24 hr in most of the neurons in the ganglion cell layer, but not in the inner nuclear and outer nuclear layers. The results indicate that axonal damage induces a specific pattern of IEG expression including a long-term induction of the c-jun gene in CNS neurons.

Tetrodotoxin enhances light-induced c-fos gene expression in the rabbit retina.

Action potentials within the rabbit retina were blocked by the intravitreal injection of tetrodotoxin (TTX), and c-fos expression was studied after exposure to flashing light. Light induced Fos proteins in a minority of neurons in the inner nuclear and ganglion cell layers of control retinas. Pretreatment with TTX increased the number of Fos-positive cells and the levels of c-fos mRNA. Wide-field amacrine cells, which presumably generate action potentials, may have an inhibitory role in light-stimulated rabbit retina.

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c-fos proto-oncogene expression in astrocytes associated with differentiation or proliferation but not depolarization.

Expression of the c-fos proto-oncogene in rat neocortical astrocytes in culture was examined using Northern blotting and immunocytochemistry. Marked induction of c-fos mRNA in astrocytes was observed after treatment with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), dibutyryl cyclic AMP (db-cAMP), and phorbol diester (TPA; 12-O-tetra-decanoylphorbol 13-acetate), which are known to induce the proliferation or differentiation of astrocytes. Increase of c-fos protein immunoreactivity (IR) was obtained after treatment with fetal calf serum, EGF, bFGF, db-cAMP and TPA. High concentrations of calcium ionophore A23187, which were lethal to cultured astrocytes, also increased c-fos protein-IR. Treatment with lower concentrations of calcium ionophore (which slightly increase Ca2+ uptake), high K+ and nerve growth factor had no detectable effect on c-fos expression. These results show that depolarization does not induce c-fos in astrocytes and suggest that c-fos may play a role in differentiation and proliferation of astrocytes.