Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Carvedilol can attenuate histamine-induced paw edema and formaldehyde- induced arthritis in rats without risk of gastric irritation Afaf Sayed Osman a,⁎ , Dina Ahmed Labib a , Mahmoud M. Kamel b a Medical Pharmacology Department, Faculty of Medicine, Cairo University, Egypt b Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt ARTICLE INFO Keywords: Carvedilol Lornoxicam Arthritis Gastric ulceration ABSTRACT Background and aim: Rheumatoid arthritis treatment aims to control joint damage and any associated compli- cations such as cardiovascular disease. Most anti-inflammatory drugs have a high tendency to cause gastro- intestinal irritation. The present study is designed to investigate the anti-inflammatory effect of carvedilol and to study its effect on gastric mucosa. Experimental approach: Lornoxicam (1.3 mg/kg) or carvedilol (10 mg/kg) was administrated orally 1 h before histamine injection into animals of a histamine-induced paw edema model and orally daily for 11 days into animals of a formaldehyde-induced arthritis model. Tumor necrosis factor-α and prostaglandin E 2 were mea- sured in animals of the formaldehyde-induced arthritis model. The effect of lornoxicam and carvedilol on gastric mucosa was assessed in normal rats and after induction of cold stress ulcer. Results: Carvedilol succeeded in reducing hind paw edema in both histamine-induced paw edema and for- maldehyde-induced arthritis and in reducing the elevated level of tumor necrosis factor-α and prostaglandin E 2 nearly with near equal efficacy compared with lornoxicam. Carvedilol did not show any ulcerative effect on the gastric mucosa of normal rats, and its use was associated with an improvement of both the gross and histo- pathological pictures of gastric ulcers in animals of the cold stress ulcer model compared with lornoxicam treated rats. Conclusion: The current findings support the use of carvedilol both in the management of inflammation as well as the prevention of cardiovascular complications in rheumatoid arthritis patients. The use of carvedilol was not associated with any gastro-intestinal tract irritation. 1. Introduction Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of synovial joints, proliferation of synovial cells and infiltration of inflammatory cells leading to the destruction of cartilage and bone [20]. Activation of inflammatory cells such as neu- trophils and macrophages results in the generation of reactive oxygen species (ROS) that cause damage of biomembranes [7]. Recruitment of leukocytes leads to the release of multiple cytokines such as TNF-α and IL-6 into the inflamed joints. These cytokines con- tribute to the destruction of articular cartilage and subchondral bone via the activation of matrix metalloproteinases [34]. Another major class of inflammatory mediators is the eicosanoids which are comprised of prostaglandins and leukotrienes. Elevated serum levels of both prostaglandin E 2 (PGE 2 ) and leukotriene B4 (LTB4) have been reported to correlate with the severity of RA [28]. Cardiovascular complications have become the leading cause of morbidity in patients with RA. Ischemic heart disease and heart failure are common causes of death in RA [14]. Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID). It has powerful analgesic and anti-inflammatory effects that can relieve symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spon- dylitis [6]. The anti-inflammatory activity of lornoxicam is mediated through the inhibition of prostaglandin synthesis through the inhibition of cy- clooxygenase (COX) enzymes [42]. Lornoxicam may produce gastro- intestinal irritation and ulceration [21]. Carvedilol is a non-selective β-adrenergic antagonist that is used in the treatment of heart failure, ischemic heart disease and hypertension [37]. Carvedilol has been shown to protect against cisplatin-induced renal toxicities [44], endothelial dysfunction in streptozocin-induced diabetic rats [15] and hepatic injury [19]. These protective properties may contribute to its antioxidant and anti-inflammatory effects [13]. The aim of the present study was to assess the anti-inflammatory http://dx.doi.org/10.1016/j.intimp.2017.07.004 Received 28 January 2017; Received in revised form 2 July 2017; Accepted 6 July 2017 ⁎ Corresponding author. E-mail address: afaf.hassan@kasralainy.edu.eg (A.S. Osman). International Immunopharmacology 50 (2017) 243–250 Available online 12 July 2017 1567-5769/ © 2017 Elsevier B.V. All rights reserved. MARK