Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL).

BACKGROUND: Community-acquired bacterial pneumonia (CABP) is a leading cause of morbidity and mortality, and treatment recommendations, each with specific limitations, vary globally. We aimed to compare the efficacy and safety of solithromycin, a novel macrolide, with moxifloxacin for treatment of CABP. METHODS: We did this global, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial at 114 centres in North America, Latin America, Europe, and South Africa. Patients (aged ≥18 years) with clinically and radiographically confirmed pneumonia of Pneumonia Outcomes Research Team (PORT) risk class II, III, or IV were randomly assigned (1:1), via an internet-based central block randomisation procedure (block size of four), to receive either oral solithromycin (800 mg on day 1, 400 mg on days 2-5, placebo on days 6-7) or oral moxifloxacin (400 mg on days 1-7). Randomisation was stratified by geographical region, PORT risk class (II vs III or IV), and medical history of asthma or chronic obstructive pulmonary disease. The study sponsor, investigators, staff, and patients were masked to group allocation. The primary outcome was early clinical response, defined as an improvement in at least two of four symptoms (cough, chest pain, sputum production, dyspnoea) with no worsening in any symptom at 72 h after the first dose of study drug, with a 10% non-inferiority margin. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT-01756339. FINDINGS: Between Jan 3, 2013, and Sept 24, 2014, we randomly assigned 860 patients to receive solithromycin (n=426) or moxifloxacin (n=434). Patients were followed up to days 28-35 after first dose. Solithromycin was non-inferior to moxifloxacin in achievement of early clinical response: 333 (78·2%) patients had an early clinical response in the solithromycin group versus 338 (77·9%) patients in the moxifloxacin group (difference 0·29, 95% CI -5·5 to 6·1). Both drugs had a similar safety profile. 43 (10%) of 155 treatment-emergent adverse events in the solithromycin group and 54 (13%) of 154 such events in the moxifloxacin group were deemed to be related to study drug. The most common adverse events, mostly of mild severity, were gastrointestinal disorders, including diarrhoea (18 [4%] patients in the solithromycin group vs 28 [6%] patients in the moxifloxacin group), nausea (15 [4%] vs 17 [4%] patients) and vomiting (ten [2%] patients in each group); and nervous system disorders, including headache (19 [4%] vs 11 [3%] patients) and dizziness (nine [2%] vs seven [2%] patients). INTERPRETATION: Oral solithromycin was non-inferior to oral moxifloxacin for treatment of patients with CABP, showing the potential to restore macrolide monotherapy for this indication. FUNDING: Cempra.

Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia.

BACKGROUND: Tigecycline, an expanded broad-spectrum glycylcycline, exhibits in vitro activity against many common pathogens associated with community-acquired pneumonia (CAP), as well as penetration into lung tissues that suggests effectiveness in hospitalized CAP patients. The aim of the present study was to compare the efficacy and safety of intravenous (IV) tigecycline with IV levofloxacin in hospitalized adults with CAP. METHODS: In this prospective, double-blind, non-inferiority phase 3 trial, eligible patients with a clinical diagnosis of CAP supported by radiographic evidence were stratified by Fine Pneumonia Severity Index and randomized to tigecycline or levofloxacin for 7-14 days of therapy. Co-primary efficacy endpoints were clinical response in the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (Day 10-21 post-therapy). RESULTS: Of the 428 patients who received at least one dose of study drug, 79% had CAP of mild-moderate severity according to their Fine score. Clinical cure rates for the CE population were 88.9% for tigecycline and 85.3% for levofloxacin. Corresponding c-mITT population rates were 83.7% and 81.5%, respectively. Eradication rates for Streptococcus pneumoniae were 92% for tigecycline and 89% for levofloxacin. Nausea, vomiting, and diarrhoea were the most frequently reported adverse events. Rates of premature discontinuation of study drug or study withdrawal because of any adverse event were similar for both study drugs. CONCLUSION: These findings suggest that IV tigecycline is non-inferior to IV levofloxacin and is generally well-tolerated in the treatment of hospitalized adults with CAP. TRIAL REGISTRATION: NCT00081575.

PI3K/Akt signaling in peripheral T lymphocytes from systemic lupus erythematosus patients.

PI3K/Akt/mTOR signaling pathway plays an important role in cellular proliferation and growth signaling. It was demonstrated that murine models presenting activated PI3K/Akt/mTOR signaling pathway in lymphocytes develop features of systemic autoimmunity, linking this pathway to autoimmune diseases. Therefore, the goal of our study was to analyze this signaling axis in Systemic Lupus Erythematosus (SLE), the prototype of systemic autoimmune diseases, focusing on Akt and p70S6k, two components of this pathway. Our results demonstrated that both expression and phosphorylation levels of Akt are more increased in SLE than in healthy donors (HDs) CD4+ T cells suggesting an up-regulation of PI3K and mTOR activities. This result was also suggested when p70S6k, one of mTOR substrate, was evaluated. Indeed, in SLE CD4+ T cells an enhancement of p70S6k activity, in direct correlation with its expression level, was found. Since p27kip1, an inhibitor of cell cycle progression, is one of the Akt substrates, we analyzed its expression level in relationship with cell cycle progression and apoptosis. The results demonstrated that p27kip1 expression level was significantly decreased in SLE than in HDs CD4+ T cells. In SLE p27kip1 level was inversely correlated with the percentage of peripheral lymphocytes in apoptosis and in S phase of the cell cycle. Therefore, the increased activity of PI3K/Akt/mTOR signaling pathway and, as a result, the drop of p27kip1 levels observed in CD4+ T cells isolated from SLE patients might explain the accumulation of SLE lymphocytes in S and G2/M cell cycle phases where they undergo apoptosis.

Quantification and molecular characterization of regulatory T cells in connective tissue diseases.

The aim of our study was to investigate and characterize regulatory T cells (Treg) in peripheral blood of patients with connective tissue diseases (Systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, poly- and dermatomyositis) as compared with blood from healthy controls. Treg cells were quantified and phenotypically characterized by flow cytometry while the expression level of Foxp3 mRNA was evaluated by real time PCR. A reduced percentage of peripheral blood Treg cells was found in patients than in controls, irrespective of the type of connective tissue disease. Treg cells, especially those expressing one of the phenotypical markers, seemed to differ not only between patients and healthy controls but also among types of diseases. Additionally, the presence of autoantibodies as well as disease activity appeared to be correlated with particular Treg cell populations, especially those expressing one of the examined phenotypical markers. Correlations with therapy suggested that glucocorticoids plus antimalarial or other immunosuppressor drugs diminished the percentage of Treg cells, especially of those with memory phenotype. These findings indicated dysregulations at the level of Treg cells and suggested an involvement of these cells in the pathology of connective tissue diseases. Moreover, our data are in agreement with the suggestion that Treg cells could be therapeutic targets for some autoimmune diseases.

Low basal levels of circulating adiponectin in patients undergoing coronary stenting predict in-stent restenosis, independently of basal levels of inflammatory markers: lipoprotein associated phospholipase A2, and myeloperoxidase.

OBJECTIVE: The aim of this study was to find a pre-interventional marker with the capacity to predict in-stent restenosis (ISR). Considering the anti-atherosclerotic role of adiponectin (APO), an adipocytokine with anti-inflammatory, anti-proliferative, anti-oxidative and anti-thrombotic properties, low plasma levels of APO might be correlated with the risk of ISR. We investigated the correlations between the plasma levels of APO and two markers of inflammation: lipoprotein associated phospholipase A2 (Lp-PLA2) and myeloperoxidase (MPO). DESIGN AND METHODS: 80 patients with angiographically significant stenosis underwent percutaneous coronary intervention (PCI) with bare metal stent. Plasma APO concentration and plasma Lp-PLA2 and MPO activities were evaluated immediately before and after PCI, then followed-up at 24, 48, 72 h, and at 1, 3, 6 months, respectively. ISR was evaluated at 6 months after stenting by follow-up coronary angiograms, and it was defined as >50% stenosis of the target lesion. RESULTS: ISR was present in 33.75% of patients. Baseline APO plasma concentration, measured before PCI, was lower in ISR patients than those without ISR [3.97 (+/-1.05) vs 6.65 (+/-2.95) microg/mL respectively, p<0.001]. The patients with APO values less than 4.9 microg/mL at discharge were more susceptible to develop ISR (odd ratio, 4.27; 95% CI, 1.56-11.72, p<0.001). ISR rate was independent of inflammation markers Lp-PLA2 and MPO baseline values, measured before PCI. CONCLUSIONS: The persistence of a low APO plasma level at discharge and 6 months afterwards may be used as a clinically useful marker for ISR prediction in patients undergoing PCI.

Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia.

Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.

Plasma markers of endothelial dysfunction in type 2 diabetics.

BACKGROUND: Type 2 diabetes, or non-insulin-dependent diabetes mellitus, represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state. Atherosclerotic lesions occur in diabetic patients at an earlier age with severe clinical manifestations and poor outcome. Our objective was to investigate the correlation between lipoprotein-associated phospholipase A2 (PLA2-LDL), myeloperoxidase (MPO), and paraoxonase (PON), enzymes implicated in the evolution of endothelial dysfunction associated with type 2 diabetes. METHODS: One hundred diabetic patients [50 without documented coronary artery disease (group 1) and 50 with CVD (group 2)] and 46 healthy controls were investigated for PLA2-LDL, MPO, and PON activities. RESULTS: PLA2-LDL activity was significantly higher in group 2 than in group 1 and among controls. PON activity was lower in group 1 than in controls, reaching the lowest level in group 2. MPO activity was higher in type 2 diabetics than among controls, with similar values in groups 1 and 2. CONCLUSIONS: The evaluation of PLA2-LDL, MPO, and PON activities may improve early diagnosis of CVD in asymptomatic patients with type 2 diabetes and can help to evaluate accelerated atherosclerosis and microvascular disease.

The significance of human platelet-activating factor-acetylhydrolase in patients with chronic stable angina.

BACKGROUND: Inflammatory reactions within coronary atherosclerotic plaques are increasingly thought to be crucial determinants of the clinical course in patients with coronary artery disease (CAD). Platelet-activating factor-acetylhydrolase (PAF-AH) is considered to reflect the ongoing inflammatory process in patients with CAD. Our objective was to determine the activity of PAF-AH in patients with stable angina and its correlations to lipoprotein levels and the inflammatory status of the patient. METHODS: Forty-five patients with documented CAD and stable angina and 20 controls were investigated for PAF-AH activity, lipoprotein levels, and peripheral neutrophil (PMN) activity. RESULTS: Patients were divided into two groups according to the values of PAF-AH activity (group 1: 250 IU/l). A correlation was observed between PAF-AH activity and LDL-C and HDL-C in controls and in all patients. The percentage of granulocytes generating intracellular O(2)(-) in unstimulated PMN was higher in group 2 patients than in group 1 patients and controls. The phagocytic activity of PMNs had an inverse correlation with PAF-AH in group 2. High intracellular O(2)(-) generation was coupled with low extracellular release of the anion and phagocytosis impairment in group 2. During the follow-up period, some of the patients in group 2 displayed a worsening of the clinical state and/or resting ECG changes. CONCLUSIONS: PAF-AH activity in patients with stable angina is correlated with hyperlipemia and a high PMN activation state, and it may be considered a potential predictor of vascular risk.

Patients with primary antiphospholipid syndrome and coronary microvascular dysfunction--a distinct clinical subset.

UNLABELLED: Morbidity of patients with cardiac syndrome X (CSX) is high. Impairment of microvascular endothelial function has been suggested to be a mechanism of the disease. The study was undertaken to assess some of the characteristics of patients with primary antiphospholipid syndrome (pAPS) and CSX. METHODS: We studied 36 patients with CSX, 14 patients having pAPS and 10 healthy controls. Patients evaluation included: clinical examination, 12-lead ECG, effort treadmill test (protocol Bruce modified), determination of plasma triglycerides, cholesterol, antiphospholipid antibodies (APLA). There were determined as markers of the inflammatory state: serum phospholipase (PL-A2) and peripheral neutrophils activity. RESULTS: Patients with pAPS presented normal values of serum cholesterol and triglycerides levels, normal PL-A2 activity, moderate superoxide anion generation. Patients without APLA presented hyperlipidemia, increased PL-A2 activity, increased superoxide anion generation. During the follow-up period we found a correlation between P1-A2 activity and ischemic episodes, but only in patients with CSX and pAPS there were registered cardiovascular events. CONCLUSION: Patients with SCX and pAPS represent a distinct clinical subset, being characterized by minimal inflammation, absence of usual risk factors for coronary heart disease, more severe prognosis related to recurrent thromboses and the need for early anticoagulant therapy.

Unstable angina is accompanied by immune cells dysfunction.

Inflammatory process has been found to play an important role in the pathogenesis of coronary heart disease (CHD) and in the prognosis of coronary artery disease (CAD) patients. The purpose of our study was to investigate some cellular immune parameters during the development of angina in the stable and the unstable stage. We have investigated the proliferative capacity of lymphocytes isolated from the peripheral blood of stable and unstable angina patients. The proliferative capacity of peripheral lymphocytes was evaluated with the radioisotopic method of tritiated thymidine incorporation. The peripheral lymphocytes present an enhanced basal proliferation of cells and lectine induced stimulation (P = 0.02/ P = 0.001), especially in the unstable angina patients, correlated with an increased population of CD4+ peripheral T-lymphocytes (P = 0.0006). The cellular immune parameters announce the development of an acute coronary syndrome. The unstable angina presents alteration of some cellular immune parameters that indicate an inflammatory syndrome associated with an increased risk of CHD, having also a prediction value for the plaque instability.

Platelet-activating factor acetylhydrolase activity in patients with chronic stable angina (preliminary results).

Coronary atherosclerotic disease is related to endothelial inflammation and dysfunction, thrombosis and plaque instability. Different inflammatory markers are studied in stable angina and coronary acute syndromes, in order to stratify better the risk and to prevent the cardiovascular events. Platelet-activating factor (PAF) and platelet activating factor acetylhydrolase (PAF-AH) represent a complex with proinflammatory actions, possibly related to progression of atherosclerotic lesions. In our study, we investigated PAF-AH activity in 30 patients with stable angina, trying to demonstrate a relation of PAF-AH activity with the severity of the coronary disease.

Clinical particularities in a Romanian series of Behcet's disease patients.

Behcet's disease (BD) is characterized by a great geographic diversity of clinico-evolutive features. We identify the main clinical characteristics in our series as compared to other data in international literature. We studied 36 patients (16 women and 20 men) with BD fulfilling International Study Group for Behcet's Disease (ISGBD) criteria. We recorded the clinical features and compared the data with other recent statistics. The incidence of clinical manifestations in our group was the following: oral ulcerations -97.4%, genital ulcerations - 55.5%, vascular disease - 50%, antiphospholipid antibodies - 55%, digestive tract lesions - 28.5%, eye disease - 27.7%, pulmonary disease - 8.3%, arthritis - 5.4%, CNS lesions - 2.7%. The clinical course was generally mild. Our patients had a higher incidence of vasculo-thrombotic events, of APLAs and of oral aphthosis, as compared to other statistics. Eye disease, CNS, articular involvement and pathergy were encountered rarer than in other groups. Two cases had atypical onsets: one with a pyoderma gangrenosum-like lesion and the other with severe pulmonary hypertension. BD has protean clinical aspects, with important geographic particularities. Our patients ran a relatively mild course of the disease, more like the Western European than the Asian patients. Vasculothrombotic disease was an important feature, with a subsequent risk for mortality.

Limited Wegener's disease presenting as pharyngolaryngeal tumor.

Wegener's disease (WD) which is mostly a systemic illness rarely presents as isolated, monoorganic, limited disease. Limited pharyngolaryngeal WD is thus a very rare occurrence. We report the case of a 29 years old man who developed a pharyngolaryngeal tumor with clinically benign evolution, histologically showing granulomatous inflammation and small vessel vasculitis, with no signs of: tuberculosis, sarcoidosis, fungal disease, Hodgkin's disease or foreign body aspiration. p-ANCA's were positive. He was considered a limited form of WD and treated with moderate doses of corticoids and cotrimoxazole. One month later, the lesion diminished significantly. The finding of a pharyngolaryngeal tumor with granulomatous inflammation and vasculitis, in the context of p-ANCA positivity and without any evidence for another systemic granulomatous disease, suggested the diagnosis of limited WD. The response to treatment favoured this presumption. Limited pharyngolaryngeal WD is a rare disease, with a potential for life-threatening (even fatal) complications. It should be recognized early and treated promptly. Remissions can be achieved (even without the use of cyclophosphamide).

The antiphospholipid antibodies.

Antiphospholipid antibodies (APLAs) are a group of autoantibodies directed against certain phospholipids, or their protein cofactors. Assay of APLAs is important because their interaction with anionic phospholipid-protein cofactors can generate a syndrome of hypercoagulability associated with a wide variety of thromboembolic events. This article presents the characteristics of some APLAs [anticardiolipin antibodies (aCLAs), lupus anticoagulant (LA) and anti-beta2-glycoprotein I antibodies (anti-beta2-GPIAs)], their action, and their interaction with blood and endothelial cells. The presence of APLAs has been reported in many diseases (autoimmune diseases, atherosclerosis, infections, malignancies), being related to pathogenic mechanisms and/or to a more severe evolution of the disease.

Significance of platelet-activating factor acetylhydrolase in patients with non-insulin-dependent (type 2) diabetes mellitus.

BACKGROUND: Non-insulin dependent diabetes mellitus (NIDDM) represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continuous low-grade inflammation and endothelial activation state. Plasma platelet - activating factor - acetylhydrolases (PAF-AHs) are a subgroup of Ca(2+)-independent phospholipase A(2) family (also known as lipoprotein-associated phospholipases A(2)) that hydrolyze and inactivate the lipid mediator platelet-activating factor (PAF) and/or oxidized phospholipids. This enzyme is considered to play an important role in inflammatory diseases and atherosclerosis. The present study aims to investigate the relations between the levels of PAF-AH activity and LDL-cholesterol / HDL-cholesterol (LDL-ch / HDL-ch) ratio in NIDDM patients as compared to controls. METHODS: serum PAF-AH activity was measured in 50 patients with dyslipidemia, in 50 NIDDM patients and in 50 controls (normal lipid and glucose levels). Total cholesterol, LDL-ch, HDL-ch, triglyceride and blood glucose were determined in all subjects. RESULTS: All NIDDM patients display hiperlipidemia, with increased LDL-ch and triglyceride levels. There is a significant correlation between LDL-ch levels (especially LDL-ch / HDL-ch ratio) and PAF-AH activity in dyslipidemic and NIDDM patients. CONCLUSION: Diabetic and dyslipidemic patients have an increased plasma PAF-AH activity correlated with their LDL-ch levels and mainly with LDL-ch / HDL-ch ratio. Plasma PAF-AH high levels appear to be important as a risk marker for endothelial dysfunction in patients with NIDDM.