Norfloxacin Modulates the Inflammatory Response and Directly Affects Neutrophils in Patients With Decompensated Cirrhosis
Received 15 December 2008; accepted 14 July 2009. published online 06 August 2009.
Background & Aims
Patients with cirrhosis undergoing selective intestinal decontamination with norfloxacin show a reduction in serum cytokine levels, probably because of a combined effect of norfloxacin on bowel flora and neutrophils.
Methods
Thirty-one patients with cirrhosis receiving norfloxacin (400 mg/day) were included. Blood samples were collected at 0.5–4 hours (peak samples group, n = 47) and at 22–24 hours (trough samples group, n = 84) after dose. Fifty-nine ascitic fluid samples were obtained. Single doses of norfloxacin and trimethoprim/sulfamethoxazole were administered to 13 and 5 patients, respectively, (temporal profile group) and samples were collected at 0, 0.5, 1, 1.5, 2, 4, and 24 hours. Norfloxacin, trimethoprim/sulfamethoxazole, cytokines, nitric oxide, expression levels of nuclear factor (NF)-κB and inhibitor of NF-κB (IkB-α), neutrophil oxidative burst, and rate of apoptotic events were determined.
Results
All samples were bacterial DNA negative and had no significant levels of lipopolysaccharide. Serum and ascitic levels of tumor necrosis factor-α, interferon-γ, interleukin-12, and nitric oxide were significantly lower in peak than in trough samples. A correlation was present between serum norfloxacins concentrations and tumor necrosis factor-α (r = −0.68; P < .001), interferon-γ (r = −0.66; P < .001), interleukin-12 (r = −0.66; P < .001), and nitric oxide (r = −0.68; P < .001). Serum norfloxacin’s highest concentrations (1 ± 0.5 μg/mL) were achieved at 1–2 hours and concurred in time with the lower levels of cytokines and nitric oxide. Intracellular norfloxacin’s highest levels (2 ± 1 μg/mL/107 cells) were observed at 2 hours and concurred with a lower NF-κB expression, a reduced anion superoxide generation, and apoptotic rate in response to phorbol myristate acetate. Trimethoprim/sulfamethoxazole did not significantly modulate cytokine expression.
Conclusions
Norfloxacin but not trimethoprim/sulfamethoxazole modulates inflammatory response and directly affects neutrophils in patients with cirrhosis.
⁎Sección de Farmacología Clínica, Hospital General Universitario, Alicante, and Universidad Miguel Hernández, Elche, Spain
‡CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
§Unidad Hepática, Hospital General Universitario, Alicante, and Universidad Miguel Hernández, Elche, Spain
∥Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Campus de Espinardo, Universidad de Murcia, Murcia, Spain
¶Sección de Inmunología, Hospital General Universitario, Alicante, and Universidad Miguel Hernández, Elche, Spain
Reprint requests Address requests for reprints to: Rubén Francés, PhD, Unidad Hepática-CIBERehd, Hospital General Universitario Alicante, Avda. Pintor Baeza 12, 03010 Alicante, Spain. fax: (34) 965 938 355
Conflicts of interest The authors disclose no conflicts.
Funding Supported in part with grants from Instituto de Salud Carlos III, Madrid, Spain (PI06/1453, PI08/1075), Excma. Diputación Provincial de Alicante, and Fundación de Investigación del Hospital General Universitario de Alicante, Alicante, Spain.
ABSTRACT
Norfloxacin Modulates the Inflammatory Response and Directly Affects Neutrophils in Patients With Decompensated Cirrhosis