zithromax and Arthritis

A middle-aged woman presented with fever of 1-month duration along with bilateral knee joint pain, swelling and difficulty in walking for 2 weeks. The patient's Typhidot test was positive for IgM antibodies. Her Widal test was negative, and blood culture and synovial fluid culture were sterile. She was started on ceftriaxone, to which her fever initially responded. However, after 4 days of treatment her disease course was complicated by relapse of fever and acute respiratory distress syndrome (ARDS). This settled with respiratory support and addition of azithromycin. Following recovery from ARDS and fever, her persistent knee arthritis responded to intra-articular methyl prednisolone instillation.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Azithromycin; Female; Humans; Knee Joint; Middle Aged; Prednisolone; Respiratory Distress Syndrome; Typhoid Fever

Inflammation-driven immune dysfunction supports the development of several chronic human disorders including inflammatory bowel diseases and rheumatoid arthritis. Macrolides are effective antibiotics endowed with immunomodulatory effects. In this study we report the chemical synthesis and the pharmacological characterization of CSY0073, a non-antibiotic derivative of azithromycin. CSY0073 was tested for efficacy in two experimental models of colitis induced by administering mice with dextran sulfate (DSS) and trinitrobenzene sulphonic acid (TNBS) and in collagen induced arthritis. Like azithromycin, CSY0073 improved clinical, macroscopic and histopathological scores in mice administered DSS (12.5μmol/kg/day p.o.) and TNBS (45μmol/kg/day p.o.). When administered to TNBS-treated mice, CSY0073 effectively attenuated influx of neutrophils and macrophages into the colonic mucosa and reduced the intestinal expression pro-inflammatory cytokines TNFα, IL-2 and IFNγ. CSY0073 (0.1 to 10μM) counter-regulated TNFα, IFNγ, IL-12 and IL-23 release caused by exposure of mouse spleen monocytes and CD11b+ cells isolated from the colonic lamina propria to endotoxin. CSY0073 (25μmol/kg/day) reduced clinical scores in the collagen induced murine model of rheumatoid arthritis. In myeloid cells, CSY0073 (10μM) prevented the nuclear translocation of the p65 subunit of NF-κB and its binding to canonical NF-κB responsive elements. In summary, we report a novel class of non-antibiotic 14-member macrocycles with anti-inflammatory and immune-modulatory effects. CSY0073, the prototype of this new class of macrolides exerts counter-regulatory activity on NF-κB signaling. This study suggests the exploitation of non-antibiotic macrolides in the treatment of inflammatory disorders characterized by immune dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Azithromycin; CD11b Antigen; Colitis; Collagen; Dextran Sulfate; Disease Models, Animal; Drug Discovery; Female; Humans; Immunologic Factors; Inflammation; Inflammatory Bowel Diseases; Male; Mice; Mucous Membrane; NF-kappa B; Signal Transduction; Trinitrobenzenesulfonic Acid