efficacy of simvastatin and pioglitazone in a murine model of chronic asthma

Background: The pathologic mechanisms involved in bronchial asthma have not yet been completely elucidated. Th2 lymphocytes are thought to play a key role in the initiation and perpetuation of this chronic airway inflammation. 0n the other hand, the imbalances between MMP-9 and TIMP-I in addition to increased TGF-beta may contribute to some of the remodeling features seen in asthma. Simvastatin has anti-inflammatory properties unrelated to their serum cholesterol=lowering activity. PPAR-gamma agonist, which is used in treatment of diabetes, plays an important role in the control of inflammatory responses. So we sought to investigate the effects of these drugs on airway inflammation and remodeling in a murine model of chronic asthma

Methods: Actively sensitized mice with OVA were challenged with OVA or saline aerosols for 30 min/day, 3 days/week for 6 weeks. During the OVA-challenge period, mice were divided into 3 groups and treated with either simvastatin [40 mg/kg], pioglitazone [10 mg/kg] or saline orally. The saline challenged mice were treated with placebo [saline] and served as additional controls. At the end of the challenge period, animals were sacrificed and the serum was analyzed for total IgE. Airway inflammation was assessed in BAL fluids on the basis of EPO and Th2 cytokines [IL-4, IL-5]. Airway remodeling markers were evaluated in BAL fluids on the basis of TGF-beta, MMP-9 and TIMP-I concentrations

Results: Th2 cytokines IL-4 and 5 increased significantly in BAL fluid after OVA-challenge of sensitized mice with concomitantly increased migration and activation of leucocytes, namely eosinophils to bronchial tissues. The serum total IgE levels were also increased. OVA-challenge resulted also in increased MMP-9 and TIMP-1 concentrations in BAL fluid with more pronounced increase of TIMP-1. TGF-beta levels in BAL fluids were also elevated after OVA challenge. Both simvastatin and pioglitazone inhibited leucocytic and specifically eosinophilic infiltration and activation in the airways. However, the level of total serum IgE did not significantly change. Both drugs inhibited secretion of IL-4 and lL-5 in BAL fluid. Treatment with simvastatin or pioglitazone resulted in reduction of MMP-9 and TIMP-I levels in BALfluid with more pronounced effect on TIMP. Although pioglitazone significantly inhibited the enhanced levels of TGF-beta in lung lavagefluid, simvastatin failed to exert the same ejfect

Conclusion: We can conclude that although both of the tested drugs can inhibit allergen induced chronic airway inflammation, pioglitazone is relatively more beneficial in ameliorating airway wall remodeling in this murine model of chronic asthma

Rheumatoid arthritis: early induction of disease remission

To evaluate the efficacy of tumor necrosis factor-alpha [TNF-alpha] blockade as bridge-therapy combined with methotrexate [MTX] in induction of early remission in rheumatoid arthritis patients. Patients and Sixty six patients with rheumatoid arthritis with poor prognostic disease features were enrolled in the current study. All had moderate to severe disease activity with unsatisfactory response to disease modifying antirheumatic drugs [DMARDs] mono-therapy. Patients were randomized into 3 groups: Group 1 were the patients who received TNF-alpha blockade therapy in combination with methotrexate [MTX] for 6 weeks than they were maintained on MTX alone for 18 weeks, group 2 included patients who received MTX mono-therapy and patients in group 3 who received prednisolone according to micro-dose regimen with MTX. All patients underwent initial full clinical examination as well as laboratory investigations [baseline evaluation]. The following disease activity parameters were determined at baseline, 6 weeks and 24 weeks after being enrolled in the study: Global patieny's and global physician's assessment scores, patients's pain score, number of tender as well as swollen joints, Health assessment questionnaire, serum C-reactive protein, erythrocyte sedimentation rate as well as morning stiffness duration. Standard plain X-rays were carried out for both hands, wrists, ankles as well as the forefeet. Joint erosions were assessed according to Larsen's score. Induction of disease remission after the 1st 6 weeks of therapy occurred in 45.45%, 27.27%, 36.36% in group1, 2 and 3 respectively, reflecting the higher efficacy of TNF-alpha blockade therapy in induction of early disease remission. After 18 weeks of stopping TNF-alpha blockad and maintaining the patients of group1 on MTX [24 weeks from start of the study], the 3 study groups showed comparable disease control revealing the absence of superiority of TNF-alpha blockade therapy compared with prednisolone-MTX combination as well as MTX monotherapy. On the other hand radiological evaluation of joint damage showed comparable incidence of joint erosions in the 3 groups reflecting equal efficacy of the 3 treatment regimens in controlling joint destruction. In view of results of the current study it can be concluded that TNF-alpha blockade is an effective therapy in RA that can induce early disease remission, however, this induced remission was not associated with superior efficacy in protection of joint damage compared with MTX mono-therapy and combined MTX-steroid therapy

Study of serum zinc, copper, magnesium, postassium and selenium in relation to serum Autoantibodies in siblings of type 1 diabetics

Aim: This work was intended to study the state of some elements namely zinc, copper, magnesium, potassium and selenium in sera of siblings of type 1 diabetic patients and its possible relation to some immunological markers. Subjects and The study included 208 subjects classified into 2 groups: group I included 108 siblings of type 1 diabetic patients and group II included 100 control subjects matched for age and sex. All subjects were subjected to the following: estimation of fasting and 2 hour postprandial plasma glucose and oral glucose tolerance test when needed. Determination of serum level of zinc, copper, magnesium, potassium and selenium was done using atomic absorption spectrophotometry. Measurement of serum insulin autoantibodies [IAA], antibodies to the protein tyrosine phosphatase-like proteins ICA512 [IA-2] and glutamic acid decarboxylase antibodies [GADA] was performed using radioimmunoassay [RIA] technique. The mean serum levels of zinc and copper were significantly higher [P = 0.000 for each], and the mean serum levels of selenium and potassium were significantly lower [P = 0.002 and 0.007, respectively] in type 1 diabetic siblings when compared with control subjects. Zinc and copper were significantly higher [P = 0.000 for each], and magnesium was significantly lower [P = 0.001] in the sera of siblings positive for IAA as compared to the seronegative cases. Selenium was found to be significantly lower in the sera of siblings positive for IAA, IA2 and GADA when compared to the seronegative cases [P = 0.000 for each]. Our results point to a disturbance in the serum levels of zinc, copper, selenium, potassium and magnesium. These nutritional elements may contribute as an environmental factor, that in conjunction with genetic factors, triggers the immunopathogenic sequence responsible, preceding and/or associated with beta cell damage in type 1 diabetes or its complications