Norfloxacin modulates the inflammatory response and directly affects neutrophils in patients with decompensated cirrhosis.
OBJECTIVE
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)-kappaB and inhibitor of NF-kappaB (IkB-alpha), 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-alpha, interferon-gamma, 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-alpha (r = -0.68; P < .001), interferon-gamma (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 microg/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 microg/mL/10(7) cells) were observed at 2 hours and concurred with a lower NF-kappaB 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.
Zapater
Pedro
P
Sección de Farmacología Clínica, Hospital General Universitario, Alicante, and Universidad Miguel Hernández, Elche, Spain.
Caño
Rocío
R
Llanos
Lucía
L
Ruiz-Alcaraz
Antonio J
AJ
Pascual
Sonia
S
Barquero
Claudia
C
Moreu
Rocío
R
Bellot
Pablo
P
Horga
José F
JF
Muñoz
Carlos
C
Pérez
Jara
J
García-Peñarrubia
Pilar
P
Pérez-Mateo
Miguel
M
Such
José
J
Francés
Rubén
R
D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000209:etiology / Q000517:prevention & control; D015331:Cohort Studies; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D009643:Norfloxacin / Q000494:pharmacology* / Q000627:therapeutic use; D010538:Peritonitis / Q000209:etiology / Q000517:prevention & control; D016897:Respiratory Burst / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D016328:NF-kappa B; D009643:Norfloxacin