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ID PMID Title PublicationDate abstract
23380429 Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix afte 2013 Mar BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug, indicated for osteoarthritis exacerbations, rheumatoid arthritis and ankylosing spondylitis symptomatic treatment. OBJECTIVE: To compare the bioavailability of a 15 mg meloxicam orodispersible tablet (ODT) and a reference 15 mg tablet in healthy volunteers. METHODS: Two randomized, crossover, bioequivalence studies were conducted. In both studies, 28 volunteers were randomly assigned to receive test ODT and reference tablet formulations in single dose under fasting conditions in two study periods, with a 7-day (Study I) or 14-day (Study II) wash-out between administrations. Blood samples were collected at pre-specified times. Pharmacokinetic parameters were obtained by noncompartmental analysis. Bioequivalence was assumed if the 90% confidence interval of the test/reference ratio of the least-squares means for Cmax, AUC0-t and AUC0-∞were within the 80.00 -125.00% range, according to the current guidelines. RESULTS: All 28 subjects in Study I and 26 subjects in study II completed the study and were included in the analysis. The 90% confidence intervals of the geometric means ratios for the logtransformed Cmax, AUC0-t and AUC0-∞were 87 - 96%, 88 - 96% and 87 - 96% in Study I, and 99 - 105%, 98 - 104% and 108 - 120% in Study II. Test product was characterized by a slightly earlier tmax than the reference, i.e., 4.9 ± 1.1 vs. 5.8 ± 2.6 hours in Study I (p = 1.000) and 3.8 ± 2.0 vs. 4.8 ±1.6 hours in Study II (p = 0.0054). The two drugs were well tolerated. CONCLUSIONS: Test and reference formulations met the regulatory criteria for bioequivalence in the fasting healthy volunteers enrolled.
23375848 Cytopenia and autoimmune diseases: a vicious cycle fueled by mTOR dysregulation in hematop 2013 Mar A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T-cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases.
23359495 Interleukin-32 expression is associated with a poorer prognosis in head and neck squamous 2014 Aug Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common malignancy diagnosed worldwide. Patient's survival is low due the high frequency of tumor recurrence. Inflammation promotes carcinogenesis as well as the formation of metastasis. Indeed, proinflammatory mediators are known to stimulate the expression of specific transcription factors such as Snai1 and to increase the ability of tumor cells to migrate into distant organs. The atypical interleukin-32 (IL32) was mainly described to exacerbate inflammatory responses in rheumatoid arthritis and inflammatory bowel diseases. IL32 is expressed in various cancers but its role in HNSCC physiology is still unexplored. Here, we analyzed the expression of IL32 and its implication on HNSCC aggressiveness. We showed that patients with tumor expressing high amounts of IL32 exhibit decreased disease-free periods (20.5 mo vs. 41 mo, P = 0.0041) and overall survival (P = 0.0359) in comparison with individuals with weak IL32 tumor expression. This overexpression was negatively correlated with gender (P = 0.0292) and p53 expression (P = 0.0307). In addition, in vitro data linked IL32 expression to metastasis formation since IL32 inhibition decreased Snai1 expression and tumor cell migration in a Boyden chamber assay. Our data provide new insight into the role of IL32 in HNSCC aggressiveness.
23296204 Lactoferrin activates BMP7 gene expression through the mitogen-activated protein kinase ER 2013 Feb 1 Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to destruction of cartilage in joints. Neutrophil granulocytes are the predominant cell type in the synovial fluid of affected joints. Neutrophils release stimulants that alter the chondrocyte metabolism. Lactoferrin (LF) is a marker of neutrophil granulocyte activation. Local concentrations of LF in synovial fluid are much higher in the joints of RA patients. However, the effect of LF on articular cartilage of joints is not well understood. Effect of LF on gene expression in primary chondrocytes of articular cartilage was investigated in this study. We found that LF preferentially activated BMP7 expression rather than BMP2 or BMP4, and that LF activated BMP7 expression in a dose-dependent and time-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated LF activation of BMP7 gene expression. LF-induced increase in BMP7 protein level was in parallel with the phosphorylation of ERK in primary chondrocytes. Taken together, we provide the first evidence to demonstrate that LF activates BMP7 expression through the mitogen-activated protein kinase ERK pathway in primary chondrocytes of articular cartilage. Since BMP7 is important for the maintenance of homeostasis in articular cartilage, we speculate that there is a protective function of LF at the site of joint inflammation.
23052942 Association between osteoporosis and psoriasis: results from the Longitudinal Health Insur 2013 Jun This population-based analysis explored the association between osteoporosis and a previous diagnosis of psoriasis. We found that the adjusted odds ratio (OR) of having been previously diagnosed with psoriasis for subjects with osteoporosis was 1.65 (95 % confidence interval [CI], 1.42-1.94) when compared to controls. INTRODUCTION: Although previous studies have investigated this association between psoriasis and osteoporosis, significant controversy remains regarding its presence. Therefore, this study set out to explore the association between osteoporosis and a previous diagnosis of psoriasis through a population-based case-control study in Taiwan. METHODS: We identified 17,507 cases with a diagnosis of osteoporosis and randomly extracted 52,521 controls without a history of osteoporosis. We used conditional logistic regression analyses to calculate the OR for having been previously diagnosed with psoriasis. RESULTS: Subjects with osteoporosis had a significantly higher prevalence of previously diagnosed psoriasis (1.50 % vs. 0.87 %, p < 0.001) compared to controls. Conditional logistic regression analysis revealed that the OR of having been previously diagnosed with psoriasis for subjects with osteoporosis was 1.65 (95 % CI, 1.42-1.94) when compared to controls after adjusting for monthly income, hypertension, diabetes, coronary heart disease, hyperlipidemia, rheumatoid arthritis, stroke, renal disease, Parkinson's disease, hyperthyroidism, chronic hepatopathy, Cushing's syndrome, malabsorption, tobacco use disorder, obesity, alcohol abuse/alcohol dependence syndrome, the use of SSRIs, and the use of systemic glucocorticoids. Furthermore, osteoporosis was significantly associated with a previous diagnosis of psoriasis in both sexes; the adjusted OR of prior psoriasis for cases when compared to controls was 1.52 (95 % CI, 1.16-1.99) and 1.73 (95 % CI, 1.44-2.13) for males and females, respectively. We also found that the adjusted OR of prior severe psoriasis for cases was 1.96 (95 % CI, 1.37-2.81) that of controls. CONCLUSIONS: This investigation succeeded in detecting an association between osteoporosis and prior psoriasis among both men and women.
22978559 Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrull 2013 Apr BACKGROUND AND OBJECTIVE: The presence of citrullinated proteins, and peptidylarginine deiminase types -2 (PAD-2) and -4 (PAD-4) in periodontal tissues, determine the presence of anti-cyclic citrullinated protein antibodies (anti-CCP) in gingival crevicular fluid (GCF) and compare the expression of these proteins between inflamed and non-inflamed sites. MATERIAL AND METHODS: Tissue sections were stained using antibodies against citrullinated proteins, PAD-2 and PAD-4. RT-PCR was performed to investigate PAD-2 and PAD-4 mRNA in inflamed and non-inflamed gingival tissues. Anti-CCP antibodies in gingival crevicular fluid were detected by ELISA. RESULTS: Citrullinated proteins, PAD-2 and PAD-4 were detected in gingiva. There was a correlation between inflammation and expression of these proteins. mRNAs for PAD-2 and PAD-4 were detected in both inflamed and non-inflamed gingival tissues. Antibodies to CCP were found mostly in the GCF of individuals with periodontitis. CONCLUSION: PAD-2 and PAD-4 (protein and mRNA) as well as citrullinated proteins are present in inflamed gingiva, and anti-CCP antibodies can be detected in the GCF of some patients. Tissue expression of citrullinated proteins and PAD increased with the severity of inflammation. The presence of anti-CCP antibodies in GCF was almost exclusive to a subset of patients with periodontitis. Increased expression of these proteins in inflamed gingiva lends support to the notion that periodontal inflammation contributes to the inflammatory burden in a similar way to rheumatoid arthritis.
22592810 Association between osteoporosis and urinary calculus: evidence from a population-based st 2013 Feb SUMMARY: This population-based case-control analysis investigated the association between osteoporosis and prior urinary calculus (UC) in Taiwan. We succeeded in detecting an association between osteoporosis and prior UC (adjusted odds ratio = 1.66). This association was consistent and significant regardless of stone location. INTRODUCTION: UC has been demonstrated to be a risk factor for osteoporotic fractures, but no studies to date have directly investigated the association between UC and osteoporosis. This case-control analysis aimed to investigate the association of osteoporosis with prior UC using a population-based dataset in Taiwan. METHODS: We first identified 39,840 cases ≥40 years who received their first-time diagnosis of osteoporosis between 2002 and 2009 and then randomly selected 79,680 controls. We used conditional logistic regression analyses to compute the odds ratio (OR) and the corresponding 95 % confidence interval (CI) for having been previously diagnosed with UC between cases and controls. RESULTS: The OR of having been previously diagnosed with UC for patients with osteoporosis was 1.66 (95 % CI = 1.59-1.73) when compared to controls after adjusting for geographic location, urbanization level, type I diabetes mellitus, coronary heart disease, hyperlipidemia, rheumatoid arthritis, stroke, renal disease, Parkinson's disease, hyperthyroidism, chronic hepatopathy, Cushing's syndrome, malabsorption, gastrectomy, obesity, and alcohol abuse/alcohol dependence syndrome. The results consistently showed that osteoporosis was significantly associated with a previous diagnosis of UC regardless of stone location; the adjusted ORs of prior kidney calculus, ureter calculus, bladder calculus, and unspecified calculus when compared to controls were 1.71 (95 % CI = 1.61-1.81), 1.60 (95 % CI = 1.47-1.74), 1.59 (95 % CI = 1.23-2.04), and 1.69 (95 % CI = 1.59-1.80), respectively. CONCLUSIONS: This study succeeded in detecting an association between osteoporosis and prior UC. In addition, our findings were consistent and significant regardless of stone location.
22033794 Carotid artery intima-media thickness in patients with autoimmune connective tissue diseas 2013 Dec Patients with autoimmune rheumatic disorders have an increased incidence of cardiovascular (CV) events and mortality. Despite this being related to a high prevalence of the traditional CV risk factors, systemic inflammation has been postulated to be an independent CV risk factor, particularly in patients with rheumatoid arthritis (RA). However, data are still controversial. We designed a case-control study, in which patients with autoimmune rheumatic disorders were matched with age-, sex-matched controls. Prevalence of early atherosclerosis was assessed by carotid artery intima-media thickness (IMT) measurement. IMT values were considered normal (IMT ≤ 0.9 mm) or abnormal (IMT > 0.9). Multivariate analysis was performed to identify predictors of pathological IMT. Overall, 152 patients and 140 matched controls were enrolled. Prevalence of >0.9 mm IMT values did not significantly differ between patients with autoimmune rheumatic disorders and controls (61 vs. 69%, p = 0.1). In detail, a similar IMT distribution between the 69 RA patients and controls was observed. Cases with a CV risk factor showed a higher prevalence of pathological IMT as compared to those without any risk factor, both in patients (77.1 vs. 38.6%; p < 0.0001) and controls (84.6 vs. 25%; p < 0.0001). At multivariate analysis, age and presence of CV risk factors were found to be independent predictors of >0.9 mm IMT, while RA as well as any other considered rheumatic disease were not. Our data found a similar prevalence of preclinical arterial wall atherosclerotic damage in patients with autoimmune rheumatic diseases and matched controls. Presence of traditional CV risk factors and patient age remain the main factors involved in preclinical atherosclerosis in patients with autoimmune rheumatic disorders, including RA.
25144619 Antimicrobial activity of Antrodia camphorata extracts against oral bacteria. 2014 Antrodia camphorata (A. camphorata) is a unique, endemic and extremely rare mushroom species native to Taiwan, and both crude extracts of and purified chemical compounds from A. camphorata have been reported to have a variety of significant beneficial effects, such as anti-tumor and anti-inflammatory activity. However, reports on the effects of A. camphorata against dental pathogens have been limited. Oral health is now recognized as important for overall general health, including conditions such as dental caries, periodontal disease and rheumatoid arthritis. Streptococcus mutans (S. mutans) and Porphyromonas gingivalis (P. gingivalis) are the most common bacteria associated with dental plaque and periodontopathic diseases, respectively. Thus, our study examined the ability of five various crude extracts of A. camphorata to inhibit the growth of dental bacteria and anti-adherence in vitro. Among the extracts, the ethanol, ethyl acetate and chloroform extracts exhibited the lowest MICs against P. gingivalis and S. mutans (MIC = 4∼16 µg/mL). The MIC of the aqueous extract was greater than 2048 µg/mL against both P. gingivalis and S. mutans. In vitro adherence of S. mutans was significantly inhibited by the addition of either the ethyl acetate extract or chloroform extract (MIC = 16∼24 µg/mL), while the ethanol extract (MIC = 32∼64 µg/mL) exhibited moderate inhibitory activity. Based on the result of this study, the ethyl acetate and chloroform extracts of A. camphorata may be good candidates for oral hygiene agents to control dental caries and periodontopathic conditions.
25129839 Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and un 2015 Jun The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies.
25005576 Tocilizumab in uveitis refractory to other biologic drugs: a study of 3 cases and a litera 2014 Jul OBJECTIVES: To evaluate the clinical response to Tocilizumab (TCZ) in three patients with non-infectious uveitis refractory to anti-TNF-α drugs. METHODS: Assessment of TCZ-treated patients with immune-mediated uveitis from two Spanish medical referral centers. Uveitis had been refractory to previous standard synthetic immunosuppressive drugs and at least one TNF-α inhibitor. A literature review of patients with immune-mediated uveitis treated with TCZ therapy was also conducted. RESULTS: 3 women (5 eyes) with uveitis refractory to conventional immunosuppressive therapy and at least one anti-TNF-α drug were treated with TCZ. The mean age of the patients was 48.6±16.1 (range 37-67) years. In two cases uveitis was bilateral and in the other unilateral. The underlying diseases were rheumatoid arthritis in one case and Behçet's disease in the other two cases. After a mean follow-up of 7.3±5.7 (range 1-12) months using TCZ therapy, all patients experienced ocular improvement. Also, in 3 eyes inactive intraocular inflammation was achieved. None of the patients had side effects during the period of treatment with this drug. A literature review disclosed that our observations are in keeping with other reports that showed good response to TCZ in 11 of 12 patients with immune-mediated uveitis refractory to other biologic agents. CONCLUSIONS: TCZ appears to be an effective and safe therapy for the management of patients with uveitis refractory to other biologic drugs.
24821433 Chloroquine impairs visual transduction via modulation of acid sensing ion channel 1a. 2014 Aug 4 Acid-sensing ion channels (ASICs) are extracellular pH sensors activated by protons, which influence retinal activity and phototransduction. Among all ASICs, ASIC1a is abundantly expressed in the retina and involved in normal retinal activity. Chloroquine, which has been used in the treatment of malaria, rheumatoid arthritis and systemic lupus erythematosus, has been shown to be toxic to the retina. However, the underlying mechanisms remain unclear. In this study, we investigated the role of chloroquine in phototransduction by measuring the electroretinogram (ERG). The effect of chloroquine on acid-evoked currents in either isolated rat retinal ganglion neurons (RGNs) or Chinese hamster ovary (CHO) cells transfected with ASIC1a were assessed using a whole-cell patch-clamp technique. Chloroquine reduced the b-wave of scotopic 0.01 and photopic 3.0 and amplitudes of oscillatory potentials (OPs), an effect which was almost completely reversed by PcTx1, an ASIC1a-specific channel blocker. Further, patch-clamp experiments demonstrated that chloroquine reduced the peak current amplitude and prolonged the activation and desensitization of ASIC1a currents. These chloroquine-induced effects on the kinetics of ASIC 1a were dose-, pH- and Ca(2+)-dependent. Taken together, these results demonstrate that chloroquine affects vision conduction by directly modifying the kinetics of ASIC1a. Such a mechanism, may, in part, explain the retinal toxicity of chloroquine.
25496242 Angelica sinensis extract inhibits RANKL-mediated osteoclastogenesis by down-regulated the 2014 Dec 12 BACKGROUND: Destructive erosion of bone or osteolysis is a major complication of inflammatory conditions such as rheumatoid arthritis (RA), periodontal disease, and periprosthetic osteolysis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease. METHODS: The effect of Angelica sinensis (AS) extract on RANKL-induced osteoclast differentiation was examined in this study. The osteoclast precursor cell line bone marrow macrophages (BMMs) was cultured and stimulated with RANKL followed by treatment with AS at several doses. Gene expression profiles of c-Fos, c-Jun, NFATc1, TRAP, and OSCAR were sequentially evaluated. RESULTS: AS extract inhibited RANKL-mediated osteoclast differentiation in BMMs in a dose-dependent manner without any evidence of cytotoxicity. AS extract strongly inhibited p38, ERK, JNK, p65 phosphorylation and I-κB degradation in RANKL-stimulated BMMs. AS extract also inhibited the mRNA expression of c-Fos, c-Jun, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs. Moreover, RANKL-induced c-Fos, c-Jun and NFATc1 protein expression was suppressed by AS extract. CONCLUSIONS: These results collectively suggested that AS extract demonstrated inhibitory effects on RANKL-mediated osteoclast differentiation in bone marrow macrophages in vitro, indicating that AS may therefore serve as a useful drug in the prevention of bone loss.
25472926 Occiput/C1-C2 fixations using intra-laminar screw of axis - A long-term follow-up. 2015 Apr BACKGROUND: The surgical management of the craniocervical junction is challenging. Rigid posterior fixation of occiput/C1-C2 can be performed using a variety of surgical techniques including C2 pedicle/pars interarticularis, transarticular and intralaminar screw fixations. METHODS: Forty-one patients were treated with occipital plate/C1 lateral mass and C2 intra-laminar screw fixations for basilar invagination and congenital atlantoaxial subluxation, post-traumatic instability, tuberculous and rheumatoid arthritis-associated atlantoaxial dislocation. Out of forty-one, thirty-six patients had bilateral crossing intra-laminar screws and five had ipsilateral laminar screw fixation bilaterally. RESULTS: Follow-up was done in thirty-nine patients from 6 months to 8 years (mean: 21 months) and solid osseous fusion could be achieved in all (100%). One patient was lost to follow-up and another patient died of a cause unrelated to surgical technique. Pre-operative and post-operative Neurosurgical Cervical Spine Scale showed improvement in all patients having features of myelopathy. There were no neurological or vascular complications. However, nine patients had posterior laminar breach, eight had anterior laminar penetrations and three had wound infections. One patient had transient bulbar palsy and one patient had hardware failure in the form of avulsion of the midline occipital plate. CONCLUSIONS: Intra-laminar screw fixation is a safe alternative to transarticular and transpedicular/pars interarticularis fixation of C2 with advantage of having no risk of injury to vertebral artery and comparable biomechanical and pull-out strength.
25446727 Epidemiology, risk factors and management of cardiovascular diseases in IBD. 2015 Jan IBD is an established risk factor for venous thromboembolism. In the past few years, studies have suggested that patients with IBD might also be at an increased risk of coronary heart disease and stroke. The increased risk is thought to be similar to the level of risk seen in patients with other chronic systemic inflammatory diseases such as rheumatoid arthritis. The risk of developing these conditions is particularly increased in young adults with IBD, and more so in women than in men. Conventional cardiovascular risk factors are not over-represented in patients with IBD, so the increased risk could be attributable to inflammation-mediated atherosclerosis. Patients with IBD often have premature atherosclerosis and have biochemical and genetic markers similar to those seen in patients with atherosclerotic cardiovascular disease. The role of chronic inflammation in IBD-associated cardiovascular disease merits further evaluation. Particular attention should be given to the increased risk observed during periods of increased disease activity and potential modification of the risk by immunosuppressive and biologic therapies for IBD that can modify the disease activity. In addition, preclinical studies suggest that cardiovascular medications such as statins and angiotensin-converting enzyme inhibitors might also favourably modify IBD disease activity, which warrants further evaluation.
25381985 Effects of TNF-alpha inhibitors on circulating Th17 cells in patients affected by severe p 2014 Nov Psoriasis was previously considered to be mostly a Th1 cell-related disorder, but Th17 cell has recently emerged as an important player in the pathogenesis of psoriasis. The Th17 immune pathway is increased in psoriatic patients, both in peripheral circulation and in skin lesions, and positively correlates with the Psoriasis Area and Severity Index. Anti-tumor necrosis factor alpha (TNF-α) agents, in addition to potent inhibition of TNF-α activity, are able to decrease IL-17 levels and Th17 cells in the skin and plasma of patients with moderate-to-severe psoriasis. We found a decrease in the median Th17 cell count in peripheral blood after 4 months' therapy with anti-TNF-α compared with baseline values, but the difference did not reach statistical significance, probably due to the small cohort size. Our data suggest that anti-TNF-α treatment for psoriasis is able to achieve a substantial Th17 cell count reduction in the peripheral blood of patients and that this decrease is significantly associated with an adequate response to biologic therapy, as previous studies in rheumatoid arthritis have shown.
25372368 Fast identification of novel lymphoid tyrosine phosphatase inhibitors using target-ligand 2014 Nov 26 Lymphoid-specific tyrosine phosphatase (Lyp), a critical signaling regulator of immune cells, is associated with various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Recent research suggests that Lyp is a potential drug target for autoimmune diseases. Herein, we applied a target-ligand interaction-based virtual screening method to identify novel Lyp inhibitors. Nine Lyp inhibitors with novel scaffolds were identified with eight reversible inhibitors (Ki values ranged from 2.87 to 28.03 μM) and one covalent inhibitor (Ki = 40.98 ± 13.19 μM). The top four compounds (A2, A15, A19, and A26) displayed selectivity over other phosphatases in preliminary experiments, and kinetic analysis indicated that these compounds are competitive inhibitors of Lyp. Compounds A15 and A19 up-regulated TCR (T cell receptor) mediated signaling and transcriptional activation through inhibition of Lyp activity in T cells. The new chemotypes of Lyp selective inhibitors identified through the target-ligand interaction-based virtual screening may provide new leads for Lyp targeted therapeutic development.
25372212 Hydroxychloroquine retinopathy after short-term therapy. 2014 Winter PURPOSE: To report an unusual case of hydroxychloroquine toxicity after short-term therapy. METHODS: Observational case report. RESULTS: A 56-year-old woman presented to the Ophthalmology Clinic at Walter Reed Army Medical Center (WRAMC) with a 6-month history of gradually decreasing vision in both eyes. The patient had been taking hydroxychloroquine for the preceding 48 months for the treatment of rheumatoid arthritis. Examination of the posterior segment revealed bilateral "bull's eye" macular lesions. Fundus autofluorescence revealed hyperfluorescence of well-defined bull's eye lesions in both eyes. Optical coherence tomography revealed corresponding parafoveal atrophy with a loss of the retinal inner segment/outer segment junction. Humphrey visual field 10-2 white showed significant central and paracentral defects with a generalized depression. The patient was on a standard dose of 400 mg daily, which was above her ideal dose. The patient had no history of kidney or liver dysfunction. There were no known risk factors but there were several possible confounding factors. The patient was started on high-dose nabumetone, a nonsteroidal antiinflammatory drug, at the same time she was started on hydroxychloroquine. She also reported taking occasional ibuprofen. CONCLUSION: Retinal toxicity from chloroquine has been recognized for decades with later reports showing retinopathy from long-term hydroxychloroquine (Plaquenil) use for the treatment of antiinflammatory diseases. Hydroxychloroquine is now widely used and retinal toxicity is relatively uncommon. However, it can cause serious vision loss and is usually irreversible. The risk of hydroxychloroquine toxicity rises to nearly 1% with a total cumulative dose of 1,000 g, which is ∼5 years to 7 years of normal use. Toxicity is rare under this dose. For this reason, the American Academy of Ophthalmology has revised its recommendations such that annual screenings begin 5 years after therapy with hydroxychloroquine has begun unless there are known risk factors. This case report confirms the need for a baseline examination and annual ophthalmologic screening for patients taking hydroxychloroquine at a dose higher than the recommended dosage. It is also reasonable to consider annual examinations in patients taking high-dose nonsteroidal antiinflammatory drugs from the initiation of the medication.
24983446 Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a 2014 Jul OBJECTIVES: Methotrexate (MTX) is recognised as the cornerstone of treatment for rheumatoid arthritis. For some patients, oral MTX demonstrates variable bioavailability, especially at higher doses. Such concerns may be mitigated by subcutaneous (SC) MTX administration. This study investigated the relative bioavailability, safety, and tolerability of MTX administered either by SC injection with a prefilled autoinjector pen (MTX pen) or orally. METHODS: This single-centre, open-label, randomised, 2-period, 2-sequence, single-dose, crossover study enrolled healthy subjects aged 18 to 55 years into 1 of 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single dose of SC MTX and of the oral MTX tablets. Blood samples were collected from subjects predose and at prespecified time points postdose for pharmacokinetic analyses. Adverse events (AEs) were recorded to assess differences in safety and tolerability. RESULTS: Bioavailability, as measured by maximum plasma concentrations (Cmax) and area under the plasma-concentration curves (AUC0-t), was generally higher with the SC MTX pen compared with oral administration for all dose groups. AUC0-t ratios increased with ascending doses; Cmax ratios did not increase. A total of 80 AEs were reported in 35/62 subjects; none were severe. Differences in the safety profiles were related to the route of administration. Single administrations with the MTX pen were well tolerated at the injection site. CONCLUSIONS: Single-dose administration with the SC MTX pen resulted in a higher relative bioavailability compared with oral administration. SC MTX pen administration was associated with fewer gastrointestinal AEs than oral MTX.
24953519 Impact of periodontal therapy on general health: evidence from insurance data for five sys 2014 Aug BACKGROUND: Treatment of periodontal (gum) disease may lessen the adverse consequences of some chronic systemic conditions. PURPOSE: To estimate the effects of periodontal therapy on medical costs and hospitalizations among individuals with diagnosed type 2 diabetes (T2D); coronary artery disease (CAD); cerebral vascular disease (CVD); rheumatoid arthritis (RA); and pregnancy in a retrospective observational cohort study. METHODS: Insurance claims data from 338,891 individuals with both medical and dental insurance coverage were analyzed in 2011-2013. Inclusion criteria were (1) a diagnosis of at least one of the five specified systemic conditions and (2) evidence of periodontal disease. Subjects were categorized according to whether they had completed treatment for periodontal disease in the baseline year, 2005. Outcomes were (1) total allowed medical costs and (2) number of hospitalizations, per subscriber per year, in 2005-2009. Except in the case of pregnancy, outcomes were aggregated without regard to reported cause. Individuals who were treated and untreated for periodontal disease were compared independently for the two outcomes and five systemic conditions using ANCOVA; age, gender, and T2D status were covariates. RESULTS: Statistically significant reductions in both outcomes (p<0.05) were found for T2D, CVD, CAD, and pregnancy, for which costs were lower by 40.2%, 40.9%, 10.7%, and 73.7%, respectively; results for hospital admissions were comparable. No treatment effect was observed in the RA cohorts. CONCLUSIONS: These cost-based results provide new, independent, and potentially valuable evidence that simple, noninvasive periodontal therapy may improve health outcomes in pregnancy and other systemic conditions.