Clinical Anti-Inflammatory & Anti-Allergy Drugs (Discontinued) - Volume 1, Issue 2, 2014

Collagen vascular diseases (CVDs), also known as connective tissue disorders (CTDs), include a diverse group of immunologically mediated inflammatory disorders. Systemic inflammatory response may affect many organs. Lung disease—especially interstitial lung disease (ILD)—is frequent in the course of rheumatological diseases and causes mortality and morbidity rates to increase. Since the overall incidence of ILD has been estimated at 15%, physicians are urged to make an early diagnosis and decide the best treatment for ILD in CVDs. There are several tests to improve the accuracy of diagnosis, treatment and prognosis, such as high-resolution computed tomography (HRCT), pulmonary function test, broncho-alveolar lavage (BAL), and surgical lung biopsy. A multi-disciplinary team made up of specialists with extensive expertise in this area must determine when to use each. This document is a review of the diagnosis, treatment and prognosis of ILD in CVDs.

Idiopathic pulmonary fibrosis (IPF) is a diffuse progressive parenchymal disease. Patients with IPF have a poor prognosis and frequently suffer from pulmonary hypertension (PH) complications, which are associated to significantly worse outcomes. In IPF, the pathogenesis of PH varies and has not been completely understood yet, since it may arise from multiple factors. In these patients, PH is associated with reduced exercise capacity and lower survival rate. Due to its prognostic significance, it would be useful to conduct further research into PH in IPF patients. Though right heart catheterization continues to be the gold standard diagnostic test, the first steps to properly diagnose PH are clinical suspicion (based on increased shortness of breath and reduced diffusing capacity) and echocardiography. The options to treat PH in this population are limited. What is more, to date, there are no approved therapies specifically aimed at PH in IPF patients.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive condition of unknown etiology. Both the tomographic patterns and the pathologic anatomy correspond to usual interstitial pneumonia (UIP). Unfortunately, this is an irreversible disease with a variable clinical course that involves different phenotypes. Some patients are stable for a long time, while others present frequent acute exacerbations, or suffer a rapid decline and die. Not long ago, most treatment options for IPF patients focused on inflammation and lung fibrosis, relying on antiinflammatories and immunosuppressants. However, results observed for steroid, azathioprine, and Nacetylcysteine therapies proved ineffective and were associated with increased mortality. During the last 3 years, our understanding of the underlying mechanisms of IPF pathogenesis has evolved remarkably. There is new evidence about the treatment of this disease. New trials have been published and are breaking new ground in the management of IPF patients. There are also numerous ongoing clinical trials studying potential targets related to IPF treatment.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and fatal disease. The average survival time has a range between 2 to 5 years, but the progression rate and the size of damage could result unpredictable. This fibrotic illness is limited to lung with low or absent inflammation. Recently, new therapeutic options have been described. Clinical trials were not powered to detect statistically significant differences in mortality; but these have shown a reduction in the rate of decline in lung function. The results remain variables due to the heterogeneity observed in these patients. The challenge is to discover new predicting outcomes, biological indicators of disease progression, short-term measures of therapeutic response or predictors of survival time useful to take decisions about the treatment or help to determine the need of lung transplantation and contribute to it.

Objectives: Investigation of etoricoxib treatment on markers of inflammation, pain and muscle force after eccentric exercise. Methods: This randomized, placebocontrolled, double blinded, cross over study investigated 50 healthy subjects presenting pain during muscle contraction of ≥5 (range: 0-10) after two runs of eccentric exercise at 45 % of peak torque until volitional fatigue. Subjects were stratified into a young and elderly population (strata1: 18-40 years; strata 2: 50-70 years) and randomized to treatment with etoricoxib (90 mg q.d.) or placebo (1:1) for 7 days. Subjects receiving etoricoxib in period I received placebo in period II. The target leg for exercise in periode I was also determined by randomization. In periode II, the contralateral leg was trained and investigated. Investigations included pain at rest, pain during evaluation of peak torque (11 point numerical analog scale), heat pain threshold at trigger points, peak torque and markers of inflammation (high sensitive C-reactive Protein, sedimentation rate, leucocyte number). Results: Etoricoxib failed to show significant treatment effects on pain during contraction and rest after eccentric exercise as compared to placebo, except a non-significant trend for reduction of pain at rest for the first 24 h. There was evidence of delayed recovery of peak torque and reduced pain with etoricoxib treatment. Etoricoxib induced significant anti-inflammatory effects as shown by reduction in hsCrP as compared to placebo (p=0.0203). Discussion: Despite an anti-inflammatory effect, etoricoxib failed to provide a relevant treatment effect on muscle soreness after eccentric exercise and might even delay recovery. Considering similar reports in the literature, the use of both non-selective and Cox-2 selective NSAIDs cannot be supported in subjects with muscle pain after exercise.

In our previous work, we presented the results of a 12-year study (1998-2010) from which we derived several important conclusions. This was a large cohort, in which were examined 3619 samples of umbilical cord blood. We reached several conclusions from which it was clear that allergy was significantly associated with a positive family history (statistical significance at 1 ‰). The first symptoms of allergic disease occurred in the first years of life. We also observed significant seasonal differences. High levels of umbilical IgE and a positive family history were found to be grounds for preventive intervention by influencing the microbial flora of the gastrointestinal tract (GIT). We used Colinfant Newborn peroral probiotic vaccine - a lyophilized non-pathogenic strain of E. coli. The results in 2005-2008 and 2008-2009 confirmed that in treated patients with primary elevated levels of immunoglobulin E (IgE) in umbilical cord blood, IgE values at one year of age fully normalized in 90 %. The medical history of these children indicated minimal sickness rates. We further investigated IgG values at one year of age and compared this with a control group. After treatment these levels were also normalized. From 2009-2012, we investigated the effect of treatment on the values of immunoglobulins IgE, IgG, but also IgA, and statistically processed the data at 1 year of age and 3 years of age. Statistically, a correlation was observed between IgG and IgA in the 1st year of life and at 3rd years of age with a significance level of 1 ‰. The results show that treatment with Colinfant has a positive effect in the sense that the resulting IgE did not statistically significantly differ from referent values of healthy children. These values changed in time in treated patients between the 1st and 3rd year at a significance level of 1 ‰. IgG and IgA in treated patients were, in median, entirely within the values of normality. In the period after 1 year, we found significant correlations of umbilical IgE with serum IgE, IgG, IgA and correlation of serum IgG with IgA. Very favourable effects of therapy on sickness rate of children compared to control group in a predefined file of the same age period is shown graphically.

Objectives. To clarify in vitro and in vivo effects of tumor necrosis factor-alpha (TNF-alpha) blocker, infliximab, on cytokine production in proliferating CD4+ T cells in patients with rheumatoid arthritis (RA). Methods. Peripheral blood mononuclear cells (PBMCs), separated from patients with RA (n=22) and normal person (n=22), were labeled with CFSE [5 (and 6) carboxyfluorescein diacetate, succinimidyl ester], and cultured with ConA. Cytokine production of IFN-gamma, IL-4 and TNF-alpha in proliferating CD4+ T cells was analyzed by flow cytometry. In vivo effects of infliximab on CD4+ T cells were serially analyzed in active RA patients (n=10). In vitro effects on CD4+ T cells were also examined in culture with infliximab. Results: In the analysis of in vivo, treatment with infliximab augmented IFN-gamma and IL-4 production in proliferating CD4+ T cells and reduced proliferation (p<0.05). In vitro infliximab decreased proliferation, IFN-gamma and TNF-alpha production, and increased IL-4 production in proliferating CD4+ T cells. Conclusions: TNF-alpha blockers altered in vitro and in vivo cytokine production in proliferating CD4+ T cells in patients with RA. Although in vitro and in vivo effects of CD4+ T cells by the drug were not directly linked, clarification of the difference between them is important to understand the mechanism of antiinflammatory drugs in vivo and in vitro in RA patients.

The study aimed to investigate antiallergic potential of methanol extract of aerial parts of Lantana camara L. (Verbenaceae) in animal models of allergy. The test extract (MLC) was screened for mentioned activity using compound 48/80 induced systemic anaphylaxis, mast cell degranulation, milk induced leukocytosis and eosinophilia in mice at different doses (100, 200 and 400 mg/kg, p.o.). Standard used in the study was disodium chromoglycate (10 mg/kg, i. p.). Isolated goat tracheal chain preparation was used to assess antihistaminic activity. Phytochemical studies of MLC revealed presence of saponins (26.32%), flavonoids (7.8%), and alkaloids. Treatment with MLC significantly protected systemic anaphylaxis induced by compound 48/80 as indicated by decreased mortality in MLC treated groups. There is significant protection against mast cell degranulation in MLC treated animals. MLC also showed significant protection milk induced leukocytosis and eosinophilia. Rightward shift of dose-response curve of histamine in presence of MLC showed antihistaminic property. The antiallergic activity of MLC was attributed to the presence of saponins and/or flavonoids.