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Introduction: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease with heterogeneous phenotypes that may lead to liver transplantation and/or end-stage liver disease. Its multifactorial etiopathogenesis remains uncertain, but gut–liver axis and bile composition and excretion are widely demonstrated to influence the immune-mediated fibrogenic reactive cascade. Areas covered: Different experimental therapeutic options are under investigation, mainly aiming at modulating bile acids excretion, limiting inflammatory-cascade reactions, and changing intestinal microbiota composition; none of them yet demonstrated to prolong transplant-free survival. This review provides a comprehensive description of the experimental drugs recently tested and/or currently under investigation. A bibliographical search was performed in PubMed, MEDLINE, EMBASE, OVID, and clinicaltrial.gov until July 2021. Expert opinion: The heterogeneity and poor prevalence of PSC, its uncertain pathophysiology, and the lack of surrogate endpoints are the major challenges in drug discovery. Strategies that synergistically target microbiota, bile acids, and liver fibrosis are needed. In parallel, we must enhance biomarkers discovery to develop surrogate endpoints, as biochemical markers’ fluctuations over the time hamper their effectiveness. Magnetic resonance cholangiopancreatography tools that accurately measure bile duct changes represent a potential marker for disease monitoring. A collaboration between academia, research consortia, patient’s associations, and industry is required.

Objectives: Amiodarone-induced thyrotoxicosis (AIT) affects up to 3% of tre ated patients. Type 2 AIT (AIT2) is a destructive thyroiditis and is usually treated with medium-high oral doses of prednisone. As AIT may worsen the underlying heart disease, a rapid control of thyroid functi on is desirable. We aimed to determine whether a combined intravenous methylprednisolone (IVMP) pulses therapy associated to prednisone in the interpulse period can represent an efficient and safe alternative to urgent total t hyroidectomy in patients with AIT2 not responsive to prednisone alone. Design and methods: Patients presenting with a severe AIT2 studied in a tertiary r eferral Center from August 2018 to April 2019. We included four patients requiring a rapid improve ment of thyroid function for their underlying cardiac disorders. The baseline doses of oral prednisone (range: 5-12.5 mg/day) and IVMP (range: 250-500 twice a week) were determined according to the severity of the thyrotoxicosis and were titrated based on clinical response. Results: Combined treatment was effective in all patients in the prompt restoration of euthyroidism and no major adverse events were reported during the follow-up. In all cases, FT4 and FT3 levels normalized at 3-5 weeks of treatment. A permanent hypothyroidism was observed in one patient, 3 months after the discontinuation of treatment. Conclusions: We report for the first time that the combined intravenous and oral steroid therapy is effective in patients with AIT2. The treatment is well tolerated and leads to a rapid improvement of thyroid function, avoiding urgent total thyroidectomy and favoring a quick functional recovery and reha bilitation of cardiac patients.

Aim: Recent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA-OXA daily for 15 days. Results: Brain tissues were handled for histological, immunohistochemical, western blot, and immunofluorescence analysis. PEA-OXA treatment evidently reduced the histological alterations and neuronal death induced by VaD and additionally improved behavioral deficits. Further, PEA-OXA decreased GFAP and Iba-1, markers of astrocytes, and microglia activation, as well as increased MAP-2, a marker of neuron development. Moreover, PEA-OXA reduced oxidative stress, modulated Nrf2-mediated antioxidant response, and inhibited the apoptotic process. Innovation: Some drugs may demonstrate their healing potential by regulating neuroinflammation, rather than by their habitually attributed actions only. Palmitoylethanolamide (PEA) is a prototype ALIAmide, well-known for its analgesic, anti-inflammatory, and neuroprotective properties. The inhibition of PEA degradation by targeting NAAA, its catabolic enzyme, is a different approach for treating neuroinflammation. This research offers new insight into the mechanism of PEA-OXA-induced neuroprotection. Conclusion: Thus, the modulation of intracellular NAAA by PEA-OXA could offer a novel means of controlling neuroinflammatory conditions associated with VaD.

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin’s safety profile have been addressed.

The last years have led to advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF), mainly through the discovery of new pathological pathways and drugs and better design of clinical trials. The objective of this review is both to describe the current therapies approved for the treatment of IPF and the emerging therapeutic approaches. Currently, nintedanib and pirfenidone are the basis of IPF therapy, based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease progression. Nonetheless, the ideal IPF therapy is still lacking and trials are underway to test new therapeutic targets. The near future could bring to clinicians and patients a combined therapeutic strategy, hitting the disease from several simultaneous pathways and hopefully leading to clinical stabilization or improvement.

Background Myasthenia gravis (MG) with antibodies to the muscle-specific kinase (MuSK) has a characteristic phenotype. Ocular manifestations have not been systematically evaluated. Objective To investigate the features of extrinsic ocular muscle involvement in patients with MuSK-MG. Methods We retrospectively evaluated the prevalence, time of onset, clinical pattern and outcome of ocular symptoms in 82 patients with a clinical follow-up ≥2 years. Results Ocular manifestations were observed in 79 patients (96.4%) and were the presenting symptoms in 48 (58.5%). Intermittent diplopia with subtle ophthalmoparesis was the most common complaint, ptosis was generally symmetrical and conjugated gaze paresis occurred in 35% of the patients. Ocular manifestations responded well to prednisone and partially to symptomatic treatment. A few patients developed chronic symmetrical ophthalmoparesis, associated with persistent weakness in other muscle groups. All patients with ocular presentation progressed to generalised disease, though weakness spread to other muscle groups was considerably delayed in a few cases. Conclusions In MG with antibodies to MuSK, ocular manifestations were as frequent as in other disease subtypes. Symmetrical ophthalmoparesis with conjugated gaze limitation was rather common and associated with low functional disability. A proportion of these patients developed chronic eye muscle paresis.

Well into the 21st century, we still triage acute myocardial infarction on the basis of the presence or absence of ST-segment elevation, a century-old technology. Meanwhile, we have learned a great deal about the pathophysiology and mechanisms of acute coronary syndromes (ACS) at the clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light on the mechanisms of ACS. This review discusses these advances and their implications for clinical management of the ACS for the future. Plaque rupture has dominated our thinking about ACS pathophysiology for decades. However, current evidence suggests that a sole focus on plaque rupture vastly oversimplifies this complex collection of diseases and obscures other mechanisms that may mandate different management strategies. We propose segmenting coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation. This distinction may have substantial therapeutic implications as direct anti-inflammatory interventions for atherosclerosis emerge. Coronary artery thrombosis caused by plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS resulting from erosion may permit a less invasive approach to management than the current standard of care. We also now recognize ACS that occur without apparent epicardial coronary artery thrombus or stenosis. Such events may arise from spasm, microvascular disease, or other pathways. Emerging management strategies may likewise apply selectively to this category of ACS. We advocate this more mechanistic approach to the categorization of ACS to provide a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner.

Background Fungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect. Methods We treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung. Results We demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatus infection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion. Conclusions We conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity. General significance Myriocin represents a powerful agent for inflammatory diseases and fungal infection.

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Myasthenia gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK +) have predominantly involvement of cranio-bulbar muscles and do not display thymus pathology, as do acetylcholine receptor antibody seropositive (AChR +) MG patients. In search of novel biomarkers for MuSK + MG, we evaluated circulating serum microRNAs. Four analyzed microRNAs were specifically elevated in MuSK + MG patient serum samples: let-7a-5p, let-7f-5p, miR-151a-3p and miR-423-5p. The circulating microRNA profile in MuSK. + MG differs from the profile previously observed in the serum of AChR + MG, thus indicating the etiological difference between these two entities. We propose that the identified microRNAs could serve as potential serum biomarkers for MuSK + MG.

Background: We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening. Methods: By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1-60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up. Results: Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1-57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7-60). Worsening occurred 1-24 months (median 4.5) after IVIg discontinuation and 1-31 months (median 14) after IVMP discontinuation (p=0.0126). Conclusions: A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP.

Several advantages may derive from the use of dietary supplements containing multiple natural antioxidants and/or anti-inflammatory agents. At present, however, there is scarce information on the properties and potential of combined supplements. To fill the gap, the antioxidant and anti-inflammatory activities exerted by a combination of seven natural components (coenzyme Q10, krill oil, lipoic acid, resveratrol, grape seed oil, α-tocopherol, and selenium) contained in a dietary supplement used for the prevention of skin disorders were investigated in vitro. Each component was administered, alone or in combination, to human keratinocytes, and the inhibition of Reactive Oxygen Species production and lipid peroxidation as well as the ability to reduce inflammatory cytokine secretion and to modulate Nuclear Factor-ÎoB pathway was evaluated. The combination exhibited high antioxidant activity and in specific conditions the combination's efficiency was higher than that of the most powerful components administered individually. Moreover, the combination showed remarkable anti-inflammatory properties. It reduced more efficiently than each component the secretion of Monocyte Chemoattractant Protein-1, a crucial cytokine for the development of chronic inflammation in skin, and inhibited Nuclear Factor-ÎoB molecular pathway. Overall, our findings suggest that the combined formulation may have the potential to powerfully inhibit oxidative stress and inflammation at skin level.

Atherothrombosis is a worldwide epidemic accounting for an unacceptable toll of deaths and disabilities. Its pathophysiology is complex and hardly referable to a specific mechanism; however, in the last 20 years, a growing amount of evidence has demonstrated that inflammatory processes play a major role from the very beginning to the ultimate complication of atherothrombosis. These evidences are addressing a growing interest toward anti-inflammatory agents as preventive or curative treatments of atherothrombosis. At present, accumulated data are not conclusive, but strong evidence exists in favor of an anti-inflammatory positive effect for several drugs as statins or renin-angiotensin inhibitors. More conclusive data are expected from ongoing trials directly exploring the role of specific cytokines antagonists. © 2013 Springer Science+Business Media New York.

OBJECTIVE: To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A search of Medline (PubMed) for observational studies published from 1990 to 2011 identified 3829 articles; 31 reported relative risk (RR) of AMI with use of individual NSAIDs versus nonuse of NSAIDs. Information abstracted in a standardized form from 25 publications was used for the meta-analysis on 18 independent study populations. RESULTS: Random-effects RR (95% confidence interval (CI)) was lowest for naproxen 1.06 (0.94–1.20), followed by celecoxib 1.12 (1.00–1.24), ibuprofen 1.14 (0.98–1.31), meloxicam 1.25 (1.04–1.49), rofecoxib 1.34 (1.22–1.48), diclofenac 1.38 (1.26–1.52), indometacin 1.40 (1.21–1.62), etodolac 1.55 (1.16–2.06), and etoricoxib 1.97 (1.35–2.89). Heterogeneity between studies was present. For new users, RRs (95% CIs) were for naproxen, 0.85 (0.73–1.00); ibuprofen, 1.20 (0.97–1.48); celecoxib, 1.23 (1.00–1.52); diclofenac, 1.41 (1.08–1.86); and rofecoxib, 1.43 (1.21–1.66).Except for naproxen, higher risk was generally associated with higher doses, as defined in each study, overall and in patients with prior coronary heart disease. Low and high doses of diclofenac and rofecoxib were associated with high risk of AMI, with dose–response relationship for rofecoxib. In patients with prior coronary heart disease, except for naproxen, duration of use ≤3 months was associated with an increased risk of AMI. CONCLUSIONS: Most frequently NSAIDs used in clinical practice, except naproxen, are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease. For diclofenac and rofecoxib, the risk was increased at low and high doses.

Introduction: In early rheumatoid arthritis (RA), low-dose oral prednisone (PDN) co-medication yields better clinical results than monotherapy with disease-modifying anti-rheumatic drugs (DMARDs). In addition, ultrasonography (US) evaluation reveals rapid and significant effects of glucocorticosteroids on subclinical synovitis. No data currently exist that examine the clinical and US results offered by glucocorticoid co-medication over DMARD monotherapy in early RA patients.Methods: Two hundred and twenty patients with early RA (< 1 year from clinical onset) were treated according to a low disease activity (LDA) targeted step-up protocol including methotrexate (MTX) and, in the active treatment arm, low-dose (6.25 mg/day) oral PDN over 12 months. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of hands was performed at baseline, 6 and 12 months. Grey-scale and power Doppler (PD) synovitis were scored (0 to 3) for each joint. At 12 months, clinical remission according to the disease activity score among 28 joints was defined as the clinical outcome, and a total joint PD score of 0 (PD negativity) as the imaging outcome.Results: Each group included 110 patients with comparable demographic, clinical, laboratory and US characteristics. At 12 months, the LDA rate was similar in the two groups, whilst the clinical remission rate (risk ratio = 1.61 (95% confidence interval = 1.08, 2.04)) and PD negativity rate (risk ratio = 1.31 (95% confidence interval = 1.04, 1.64)) were significantly higher in the MTX+PDN group.Conclusion: In early RA, despite a similar response rate in terms of LDA, low-dose oral PDN co-medication led to a higher proportion of clinical remission and PD negativity compared with MTX monotherapy, thus ensuring a better disease activity control.Trial registration number: Current Controlled Trials ISRCTN2486111.

Introduction: In early rheumatoid arthritis (RA), low-dose oral prednisone (PDN) co-medication yields better clinical results than monotherapy with disease-modifying anti-rheumatic drugs (DMARDs). In addition, ultrasonography (US) evaluation reveals rapid and significant effects of glucocorticosteroids on subclinical synovitis. No data currently exist that examine the clinical and US results offered by glucocorticoid co-medication over DMARD monotherapy in early RA patients.Methods: Two hundred and twenty patients with early RA (< 1 year from clinical onset) were treated according to a low disease activity (LDA) targeted step-up protocol including methotrexate (MTX) and, in the active treatment arm, low-dose (6.25 mg/day) oral PDN over 12 months. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of hands was performed at baseline, 6 and 12 months. Grey-scale and power Doppler (PD) synovitis were scored (0 to 3) for each joint. At 12 months, clinical remission according to the disease activity score among 28 joints was defined as the clinical outcome, and a total joint PD score of 0 (PD negativity) as the imaging outcome.Results: Each group included 110 patients with comparable demographic, clinical, laboratory and US characteristics. At 12 months, the LDA rate was similar in the two groups, whilst the clinical remission rate (risk ratio = 1.61 (95% confidence interval = 1.08, 2.04)) and PD negativity rate (risk ratio = 1.31 (95% confidence interval = 1.04, 1.64)) were significantly higher in the MTX+PDN group.Conclusion: In early RA, despite a similar response rate in terms of LDA, low-dose oral PDN co-medication led to a higher proportion of clinical remission and PD negativity compared with MTX monotherapy, thus ensuring a better disease activity control.Trial registration number: Current Controlled Trials ISRCTN2486111.

Aims: To perform a quantitative systematic review of observational studies on the risk of stroke associated with the use of individual NSAIDs. Methods and results: Searches were conducted using the Medline database within PubMed (1990-2008). Observational cohort or case-control studies were eligible if reported on the risk of cardiovascular events associated with individual NSAIDs versus the nonuse of NSAIDs. We found 3193 articles, in which 75 were eligible for review and abstraction. Of the 75 articles, 6 reported relative risk (RR) of stroke. Data were abstracted into a database using a standardized entry form. Two authors assessed study quality, and discrepancies were resolved by consensus. The pooled RR of all subtypes of incident stroke was increased with the current use of rofecoxib (RR=1.64, 95% CI=1.15-2.33) and diclofenac (RR=1.27, 95% CI=1.08-1.48). The pooled estimates for naproxen, ibuprofen, and celecoxib were close to unity. The risk of ischemic stroke was also increased with rofecoxib (RR=1.82, 95% CI=1.09-3.04) and diclofenac (RR=1.20, 95% CI=0.99-1.45). Data were inadequate to estimate the pooled RR by dose and duration, for other individual NSAIDs or nonischemic stroke subtypes. Conclusion: This meta-analysis supports an increased risk of ischemic stroke with the current use of rofecoxib and diclofenac. Additional studies are required to evaluate most individual NSAIDS, the effect of dose and duration, and the subtypes of stroke. © 2011 John Wiley & Sons, Ltd.

Despite an increasingly understanding of the pathogenetic mechanisms of sepsis, its mortality remains extremely high, caused mainly by hemodynamic impairment-related alterations frequently present in severe sepsis. Currently, treatment of sepsis is based on hemodynamic support, antibiotic therapy, surgical excision of infectious foci and immunomodulatory therapy. In fact, a massive host inflammatory infection response has recently emerged to substantially contribute to the development of septic shock and multiple organ dysfunction. Many clinical trials on various pharmacological agents have been conducted: glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombin III (AT III), anti-endotoxin monoclonal antibodies, nitric oxide inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor (TNF) antibodies. Apart from some likely favourable findings connected to low doses of glucocorticoids, most studies yielded disappointing results. Nevertheless, the use of recombinant human activated protein C (drotrecogin-alpha) has recently proven to have a mortality reduction effect particularly in patients with severe sepsis and dysfunction of at least two organs. Furthermore, the early treatment of hemodynamic instability with volume expanders and vasopressors (early goal-directed therapy), and a strict glycemic control represent important measures in order to significantly reduce mortality from severe sepsis and septic shock, and are fundamental guidelines recommended by most scientific societies (Surviving Sepsis Campaign).

Azithromycin is a macrolide antibiotic that has been structurally modified from erythromycin with an expanded spectrum of activity and improved tissue pharmacokinetic characteristics relative to erythromycin. This allows once-daily administration for 3-5 days of treatment compared with traditional multi dosing 7-10-day treatment regimens. It has been successfully employed in lower respiratory tract infections. Recent data indicate that azithromycin may exert anti-inflammatory/immunomodulatory effects that may be of use in the treatment of both acute and chronic airway diseases. This review examines the role of azithromycin in lower respiratory tract infections analysing published data on exacerbations of chronic bronchitis, community-acquired pneumonia and cystic fibrosis both in adults and children. In addition, pharmacokinetic and pharmacodynamic properties of the drug are also considered

Aspirin was synthesized in 1897 by German chemist Felix Hoffman who knew the basic ingredient, salicin. Salicin is found in ground willow bark, which was used by Hippocrates in fifth century B.C. to relieve pain. Aspirin is now used as an anti-inflammatory agent to relieve arthritic pain, and as an antipyretic compound to reduce fever. Another novel use of aspirin is as an inhibitor of blood clot formation by preventing platelets from releasing thromboxane. More than 40 million pounds of aspirin are sold per year in the U.S., equaling 300 tablets per person. Because aspirin is a COX-1 inhibitor, it has the potential to cause gastrointestinal bleeding, thus it is necessary to take only the suggested dose.

The topical corticosteroids are widely used in the treatment of moderate psoriasis, because of their usefulness for reducing inflammation and controlling itching. The therapeutic effect of corticosteroids in different cutaneous inflammatory diseases may be partially explained by their varying ability to block in vitro the synthesis of different cytokines, which play a pivotal role in epidermal hyperproliferation and leukocyte recruitment into the skin. The purpose of the present investigation was to further elucidate the mode of action of mometasone furoate, a medium-high potency, topical corticosteroid, on adhesion molecules, cytokines and cytokine receptor expression in psoriatic skin. Using an immunohistochemical assessment, we examined lesional skin biopsies from ten psoriatic patients before treatment and after 1 and 3 weeks of therapy. The overexpression of alpha 2, alpha 3, alpha 6, and beta 1 integrins detected in the spinous layer of untreated psoriatic skin was significantly decreased after therapy in 8 out of 10 cases, characterized by only partial clinical remission. In the remaining patients, a disappearance of the above integrin reactivity paralleling the disappearance of psoriatic lesions was induced by the treatment. With the exception of GM-CSF, no or only marginal effects of mometasone furoate on the cytokine and cytokine receptor system were observed. A significant reduction of the positive immunostaining with anti-ICAM-1 and ICAM-2 monoclonal antibodies on dermal vascular endothelial cells was also seen. Thus, our findings indicate that the therapeutic effects of mometasone furoate in psoriasis are mediated principally by decreasing adhesion molecule expression and to a lesser degree by inhibiting cytokine synthesis.

S-(+)-2-(4-Fluorophenyl)-alpha-methyl-5-benzoxazolacetic acid (flunoxaprofen, Priaxim is a new antiinflammatory compound, which in various biological systems interferes with the generation and release of arachidonic acid metabolites of the cyclo-oxygenase pathways without affecting the formation of 5- and 12-lipoxygenase products. Flunoxaprofen reduces the concentration of thromboxane (TX)B2 (ED50 = 35.4 mg/kg p.o.) and prostaglandin (PG)E2-like activity (ED50 = 39.9 mg/kg p.o.) in the inflammatory exudate of rats 8 h after implantation of sponges soaked with carrageenan, whereas the concentration of leukotriene (LT)B4 remains in the range of that of the untreated animals (3.1 ng/ml). Flunoxaprofen inhibits cell infiltration in the exudate and this suggests that LTB4 does not initiate cell recruitment but may represent a mechanism for amplifying the inflammatory response. Using human platelets challenged with collagen, flunoxaprofen only at higher concentration (10(-4) mol/l) reduces TXB2 formation without altering generation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. This suggests a low capacity of flunoxaprofen of affecting platelet aggregation regulated by arachidonic acid metabolites. Flunoxaprofen prevents pulmonary changes due to secondary release of TXA2 in the guinea-pig. In fact this drug prevents changes due to immunological reaction and antagonizes bronchoconstriction due to exogenous administration of histamine and LTC4.(ABSTRACT TRUNCATED AT 250 WORDS)

peer-reviewed, Historically, vitamin K is known for its role in blood clotting; however in recent years additional functions have been identified including a role in sphingolipid metabolism and as an anti-inflammatory agent. Studies have shown correlations between low vitamin K status and poor cognitive function while several biomarkers of inflammation are inversely correlated with cognition. The ELDERMET cohort, a group of well characterised subjects aged ≥ 64 years, were used in this study. The aim of this study was to identify potential associations between vitamin K status and cognition as well as any correlations between biomarkers of inflammation and cognition using a subgroup of the ELDERMET cohort. In addition the study aimed to ascertain significant differences in variables across living stratification i.e. the community dwelling subjects versus those in long term care. Subjects were divided into 4 groups based on their Mini Mental State Exam (MMSE) score. Vitamin K status was determined by measuring dietary and serum phylloquinone (vitamin K) status. Percent undercarboxylated osteocalcin (% ucOC) was also measured in serum as a long-term indicator of functional vitamin K status. Biomarkers of inflammation including high sensitivity C-reactive protein (hsCRP), Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Tumour Necrosis Factor alpha (TNFα) were measured. Analysis of variance (ANOVA) revealed significant differences between markers of vitamin K status and inflammation and MMSE categories. Positive correlations were found between MMSE and serum and dietary phylloquinone. Inverse correlations were found between MMSE and other variables including %ucOC, hsCRP, IL-6, IL-8 and TNFα. Similarly, significant differences were found across living stratification for biomarkers of inflammation. Analysis of covariance (ANCOVA) showed a significant difference in dietary phylloquinone intake between those with severe cognitive impairment and those with normal cognitive function, and be