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Objectives: To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics., Methods: This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6-8 mg every week versus MTX 6-8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26., Results: A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed., Conclusions: Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.

Background: Pain and depression are frequent co-morbid disorders. The prevalence rate of depression is several times higher in patients with chronic pain than in the general population but the mechanism underlying this association is unknown. A combination of interactions between neurotransmitters, neuropeptides, oxidative and nitrosative stress and cytokines are thought to take part in pathogenesis of pain as well as depression. Thus, the aim of the present study was two-fold, first to investigate the interplay between nociception and associated depression and second to investigate the protective potential of berberine against the reserpine-induced nociceptive and depressive behaviour and further to explore the role of oxidative-nitrosative stress mediated inflammatory cascade and apoptotic signalling pathway in this dyad., Methods and Results: Nociception and associated depression were induced by administration of reserpine (1mg/kg subcutaneous daily) for three consecutive days. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, oxidative-nitrosative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats., Limitation: More studies are still warranted in similar rodent models of pain and depression, so, that the present findings can be further substantiated to establish the clinical effectiveness of berberine in a subset of patients suffering from pain as well as depression., Conclusion: The findings from the current study suggested that reserpine-induced neurochemical alterations and dysregulation of oxidative-nitrosative stress induced inflammatory cascade underlies the co-morbidity of nociceptive behaviour and associated depression in rats., (© 2013 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA)., Methods: Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index., Results: Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases., Conclusions: In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

Ethanol-induced damage in the developing brain may result in cognitive impairment including deficits on neuropsychological tests of learning, memory and executive function, yet the underlying mechanisms remain elusive. In the present study we investigated the protective effect of tocotrienol against cognitive deficit, neuroinflammation and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8 and 9. Ethanol-exposed pups showed significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. Time spent in target quadrant, % total distance traversed in target quadrant and frequency of appearance in target quadrant was also significantly decreased in ethanol exposed pups in probe trial. Poor memory retention was exhibited by ethanol-exposed pups in elevated plus maze test also. Impaired cognition was associated with significantly enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-α, IL-1β and TGF-β1) and neuronal apoptosis (NF-κβ and Caspase-3) in different brain regions of ethanol-exposed pups. Co-administration with tocotrienol significantly ameliorated all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol exposed pups. The current study thus demonstrates the possible involvement of NF-κβ mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure in rats and points to the potential of tocotrienol in the prevention of cognitive deficits in children with fetal alcohol spectrum disorders (FASDs)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Chronic unpredictable stressors can produce a situation similar to clinical depression and such animal models can be used for the preclinical evaluation of antidepressants. Nitric oxide, a secondary messenger molecule, has been implicated in neurotransmission, synaptic plasticity, learning, aggression and depression. Vaccinium myrtillus (bilberry) extract is a potent inhibitor of reactive oxygen/nitrogen species and cytokine production. The present study investigated the role of nitric oxide in the antidepressant action of Vaccinium myrtillus in unpredictable chronic mild stress-induced depression in mice. Animals were subjected to different stress paradigms daily for a period of 21 days to induce depressive-like behavior. Pretreatment with L-arginine significantly reversed the protective effect of bilberry (500 mg/kg) on chronic stress-induced behavioral (immobility period, sucrose preference) and biochemical (lipid peroxidation and nitrite levels; endogenous antioxidant activities) in stressed mice. Furthermore, L-NAME (10 mg/kg) pretreatment with a sub-effective dose of bilberry (250 mg/kg) significantly potentiated the protective effect of bilberry extract. The study revealed that modulation of the nitric oxide pathway might be involved in antidepressant-like effects of Vaccinium myrtillus in stressed mice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Invasive aspergillosis usually affects immune-compromised patients and is common in diabetics. Proptosis, visual loss and ophthalmoplegia due to intra-orbital extension are common presentations. Three out of five patients in our series were immune-compromised. All the patients had visual loss and three patients presented with unilateral blindness. Three patients were treated by surgical debridement followed by Amphotericin B therapy. Two patients who had intra-cranial extension of the disease died during the treatment. Only one patient had improvement in vision following the treatment. High index of suspicion in immune-compromised patients, early diagnosis and prompt aggressive treatment is required to achieve clinical cure.

Unlabelled: Development of tolerance, inadequate relief, and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve diabetic neuropathic pain. The aim of the present study was to explore the effect of sesamol on thermal and mechanical hyperalgesia, allodynia, oxidative-nitrosative stress, inflammation, and apoptosis in STZ-induced experimental diabetes. Diabetic rats developed neuropathy, which was evident from a marked hyperalgesia and allodynia associated with enhanced nitrosative stress, release of inflammatory mediators (TNF-α, IL-1β, TGF-1β), and caspase 3. Chronic treatment with sesamol (2, 4, and 8 mg/kg body weight; po) for 4 weeks starting from the 4th week of STZ injection significantly attenuated behavioral, biochemical, and molecular changes associated with diabetic neuropathy. Moreover, diabetic rats treated with insulin-sesamol combination produced more pronounced beneficial effect as compared to their per se groups. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, the combination with sesamol not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release, and caspase-3 in diabetic rats, and thus it may find clinical application to treat neuropathic pain in the diabetic patient., Perspective: This study shows the beneficial effect of sesamol on neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release, and caspase-3 in diabetic rats, and thus it may find clinical application to treat neuropathic pain in the diabetic patient., (Copyright © 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes., Methods: This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX (8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters., Results: Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects (P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of -0.84 seconds (P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT (P = 0.03). Similar results were observed with RBF., Conclusions: RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor.