Infliximab and surgical treatment of complex anal Crohn's disease.

AIM: Perianal fistulae in Crohn's disease are frequently complex, involve the anal sphincter complex and surgical treatment can be associated with poor healing of wounds and damage to the mechanism of continence. The aim of this study was to evaluate the efficacy and duration of response to infliximab in the long-term management of perianal fistulae in Crohn's disease in routine clinical practice. METHOD: A prospectively maintained database was used to identify patients with Crohn's disease and complex anal fistulae who were treated with infliximab (primary treatment, three initial infusions followed by maintenance therapy). Patients who received infliximab for luminal disease or for enterocutaneous, peristomal or rectovaginal fistulae were excluded from this study. RESULTS: Fifty-two patients [25 male, median age 24 (range 15-72) years] were treated with infliximab for perianal Crohn's fistulae for a median of 66 (7-124) months. Twenty-six of the patients underwent pre-infliximab MRI scans and 38 had an examination under anaesthetic (EUA) prior to commencement of treatment, 22 of whom had seton(s) inserted into their fistulae. Maintenance therapy was possible in 42 (81%) of 52 patients. Twenty-two (42.3%) patients had a complete response to treatment, 23 (44.2%) had a partial response and 7 (13.5%) had no response. Less than complete response to infliximab was associated with a greater risk of requiring surgical intervention (Fisher's exact test, d.f. 1, P = 0.005). CONCLUSION: The response rates of Crohn's related complex perianal fistulae to infliximab are good. Complete response is associated with a reduced need for surgical intervention.

Costs of care for Crohn's disease following the introduction of infliximab: a single-centre UK experience.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in patients with Crohn's disease. There are few data, however, examining effect of infliximab therapy on management costs of Crohn's disease. AIM: To assess Crohn's disease-related costs of care and resource use in a single-centre cohort of patients with Crohn's disease 12 months pre- and post-infliximab therapy. METHODS: Data on 100 consecutive patients receiving infliximab were collected. Crohn's disease-related resource use was collected 12 months pre- and post-infliximab. National Health Service reference costs were applied to these data and the total Crohn's disease-related health service costs per patient were calculated (£UK). The cost of infliximab therapy was not included in our analysis. RESULTS: Cost savings were demonstrated in all areas of Crohn's disease-related resource use following infliximab therapy. Mean total Crohn's disease-related cost reduction, 12 months following commencement of infliximab therapy, was £2750 per patient. Mean costs at 12 months post-infliximab in responders were lower than in nonresponders (£1656 vs. £3608, P = 0.02). The number of hospitalizations was reduced. Requirements for examination under anaesthesia were also significantly decreased. CONCLUSION: Infliximab use resulted in Crohn's disease-related cost savings and hospital resource use, although this was not sufficient to cover the cost of therapy.

Anti-tumour necrosis factor-alpha therapies in Crohn's disease.

This article reviews the limitations of existing Crohn's disease therapies and the efficacy and safety of anti-tumour necrosis factor-alpha drugs. Trying to determine which patients may benefit from these therapies while minimizing toxicity is key. Special treatment situations and future developments are also briefly discussed.

Glutamate receptor activation is involved in 5-HT2 agonist-induced Arc gene expression in the rat cortex.

Brain 5-HT regulates the expression of gene transcription factor as well as novel effector immediate early genes (IEGs). The 5-HT regulation of the gene transcription factor IEG, c-fos, involves activation of 5-HT2A and ionotropic glutamate receptors. Here, we investigate whether these receptors are also involved in the regulation of the effector IEG, Arc. In rats, the 5-HT2 agonist DOI induced a marked increase in expression of Arc mRNA in a variety of cortical regions. This effect was blocked by the selective 5-HT2A receptor antagonist, MDL 100,907, but not the 5-HT(2B/2C) receptor antagonist, SB206553. The AMPA receptor antagonist GYKI 52466 also attenuated DOI-induced Arc mRNA expression, as did the NMDA receptor antagonist MK801 in some regions. Immunofluorescence studies showed that DOI increased Arc-immunoreactivity in cortical cells that expressed AMPA and NMDA receptor subunits but not the 5-HT2A receptor. Finally, DOI-induced Arc-immunoreactivity in cortical cells was extensively co-localised with c-fos-immunoreactivity. These results suggest that, as with c-fos expression, ionotropic glutamate receptors (AMPA and NMDA) are involved in 5-HT2A receptor-induced Arc expression. This finding, together with evidence of extensive Arc and c-fos co-localisation, suggests that 5-HT2A receptor activation may induce the expression of both effector and transcription factor IEGs via common molecular and cellular substrates.

Antidepressant drug treatment induces Arc gene expression in the rat brain.

The mechanism underlying the therapeutic effect of antidepressants is not known but neuroadaptive processes akin to long-term potentiation have been postulated. Arc (Activity-regulated, cytoskeletal-associated protein) is an effector immediate early gene implicated in LTP and other forms of neuroplasticity. Recent data show that Arc expression is regulated by brain 5-hydroxytryptamine neurones, a target of many antidepressants. Here in situ hybridisation and immunohistochemistry were used to examine whether Arc expression in rat brain is altered by antidepressant drug treatment. Repeated administration of the monoamine reuptake inhibitors paroxetine, venlafaxine or desipramine induced region-specific increases in Arc mRNA. These increases were greatest in regions of the cortex (frontal and parietal cortex) and hippocampus (CA1 layer) and absent in the caudate putamen. Repeated treatment with the monoamine oxidase inhibitor, tranylcypromine, increased Arc mRNA in a similar fashion to the monoamine reuptake inhibitors. The antidepressant drugs also increased the number of Arc-immunoreactive cells in the parietal cortex. Acute antidepressant injection, and repeated administration of the antipsychotic drug chlorpromazine, produced either limited or no changes in Arc mRNA. The data suggest that chronic treatment with antidepressant drugs induces Arc gene expression in specific regions across the rat forebrain. Up-regulation of Arc expression may be part of the process by which antidepressant drugs achieve long-term changes in synaptic function in the brain.

Effect of different 5-HT1A receptor antagonists in combination with paroxetine on expression of the immediate-early gene Arc in rat brain.

Selective 5-HT(1A) receptor antagonists enhance the effect of selective serotonin reuptake inhibitors (SSRIs) on presynaptic 5-HT function, and have potential as antidepressant augmentation therapies. The present study tested the effect of different selective 5-HT(1A) receptor antagonists (WAY 100635, NAD-299, p-MPPI and LY 426965) in combination with a SSRI (paroxetine), on postsynaptic 5-HT function measured by increased expression of the immediate early gene, Arc. Paroxetine (5 mg/kg s.c.) combined with WAY 100635 (0.3 mg/kg s.c.) increased Arc mRNA in frontal, parietal and piriform cortices, and caudate putamen. Paroxetine (5 mg/kg s.c.) plus NAD-299 (1 or 5 mg/kg s.c.) had a similar effect. None of these drugs increased Arc mRNA when administered alone. Paroxetine (5 mg/kg s.c.) plus p-MPPI (8.5 mg/kg s.c.) also increased Arc mRNA but p-MPPI itself elevated Arc mRNA in many regions. Whilst LY 426965 (3 or 10 mg/kg s.c.) had no effect alone, when combined with paroxetine (5 mg/kg s.c.), the drug increased Arc mRNA in caudate putamen but not cortical regions.In conclusion, this study demonstrates that four 5-HT(1A) receptor antagonists augment the effect of an SSRI on Arc mRNA expression, which is suggestive of increased postsynaptic 5-HT function. However, the data reveal certain differences in the 5-HT(1A) receptor antagonists not recognised in models of presynaptic 5-HT function.

Influence of thyroid hormone on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of hippocampal BDNF mRNA expression.

The aim of the present study was to determine the influence of thyroid hormone, T3, on the regulation of hippocampal BDNF expression by 5-HT receptor agonists. Chronic T3 administration prior to treatment with the 5-HT(1A) agonist, 8-OH-DPAT, significantly decreased BDNF mRNA in the dentate gyrus region of the hippocampus. Administration of 8-OH-DPAT did not alter hippocampal BDNF mRNA expression in naive, euthyroid rats. Pretreatment with the 5-HT(1A) antagonist, WAY 100635, completely blocked the 8-OH-DPAT-induced down-regulation of BDNF mRNA in chronic T3-treated rats. Acute T3 administration prior to 8-OH-DPAT treatment led to a small, but significant, decrease in hippocampal dentate gyrus BDNF mRNA. Acute or chronic administration of T3 did not alter the decrease in hippocampal BDNF mRNA induced by the 5-HT(2A/2C) receptor agonist, DOI. The influence of 8-OH-DPAT and DOI on hippocampal BDNF mRNA was also unaltered in rats rendered hypothyroid by propylthiouracil administration. Chronic T3 treatment or hypothyroidism did not influence the basal expression of hippocampal BDNF mRNA. The affinity and density of 5-HT(1A) receptors, and the hippocampal expression of 5-HT(1A) mRNA were also not influenced by chronic T3 treatment. The results of this study clearly demonstrate a powerful interaction between thyroid hormone and the 5-HT(1A) receptor in the regulation of hippocampal BDNF expression. Crosstalk between signal transduction cascades influenced by T3 and 5-HT(1A) receptors may mediate the synergistic effects of these systems on hippocampal BDNF expression.

Serotonergic regulation of mRNA expression of Arc, an immediate early gene selectively localized at neuronal dendrites.

Arc (activity regulated, cytoskeleton associated protein) is an effector immediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine oxidase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.), and the 5-HT precursor L-tryptophan (L-TP, 100 mg/kg, i.p.), increased Arc mRNA abundance in the cingulate, orbital, frontal and parietal cortices as well as in the striatum but a reduction was observed in the CA1 region of the hippocampus. The 5-HT releasing agent p-chloroamphetamine (PCA, 5 mg/kg, s.c.) also increased Arc mRNA in the cortical and striatal areas. Depleting brain 5-HT with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (pCPA, 300 mg/kg, i.p. for two days), on the other hand, significantly attenuated the increase in Arc mRNA induced by tranylcypromine and L-tryptophan (TCP/L-TP). Pretreatment with the 5-HT2 receptor antagonist ketanserin (2 mg/kg, i.p.) significantly attenuated the effect of TCP/L-TP in the cortex but only partially in striatum and did not affect the reduction in the CA1 region. The 5-HT2 agonist DOI (0.2, 1 and 2 mg/kg, i.p.) dose-dependently increased Arc mRNA abundance in cortical areas with a pattern similar to that of TCP/L-TP and PCA. DOI, however, had much weaker effects on Arc mRNA in the striatum and did not have any significant effect in the CA1, CA3 and the dentate gyms (DG) of the hippocampus. Pretreatment with ketanserin completely blocked the effect of DOI on Arc expression. These data suggest that Arc mRNA expression can be induced in the cortex by increases in extracellular 5-HT and that 5-HT2 receptors play a major part in mediating such effects. Additional 5-HT receptors as well as other neurotransmitters may also be involved, particularly in the striatum and in CA1 subfield of the hippocampus. Overall, our data suggest that expression of Arc mRNA is highly responsive to changes in brain 5-HT functions, and may provide a sensitive marker of postsynaptic 5-HT2(2A and 2C) receptor functions.