RESUMEN
BACKGROUND: Traumatic spinal cord injury (SCI) triggers a systemic inflammatory response (SIR) that contributes to a high incidence of secondary organ complications, particularly after a cervical or high-level thoracic injury. Because liver plays a key role in initiating and propagating the SIR, the aim of this study was to assess the effects that SCI at differing segmental levels has on the intensity of the inflammatory response in the liver. METHODS: Using male Wistar rats, clip compression SCI was performed at the 4th thoracic (T4 SCI; high-level SCI) or the 12th thoracic (T12 SCI; low-level SCI) spinal cord segment. Sham-injured rats had a partial laminectomy, but no SCI. Leukocyte recruitment to the liver, hepatic blood flow, and hepatocellular injury/death were assessed using intravital microscopy and histology. Chemokine and cytokine concentrations were assessed in the liver. Outcomes were measured at 1.5 hours, 12 hours, and 24 hours after SCI. RESULTS: At 12 hours after injury, T4 SCI caused a threefold increase in hepatic leukocyte recruitment compared with T12 SCI (p < 0.05). T4 SCI induced 50% more hepatocyte injury than T12 SCI at 12 hours (p < 0.05). Hepatic blood flow decreased after SCI, but not after sham injury, and stayed decreased only after T4 SCI at 24 hours after injury. The T4 SCI-induced changes were accompanied by increases in the hepatic concentrations of interleukin-1ß, leptin, interleukin 10, and cytokine-induced neutrophil chemoattractant-1 at 1.5 hours. CONCLUSIONS: Our findings indicate that traumatic SCI triggers an acute SIR that contributes to hepatocellular injury. SCI-induced remote injury/dysfunction to the liver appears to be transient and is more robust after an upper thoracic SCI compared with a lower thoracic SCI.
Asunto(s)
Citocinas/metabolismo , Inflamación/etiología , Hepatopatías/etiología , Hígado/patología , Traumatismos de la Médula Espinal/complicaciones , Animales , Muerte Celular , Modelos Animales de Enfermedad , Estudios de Seguimiento , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , Recuento de Leucocitos , Hígado/metabolismo , Hígado/fisiopatología , Circulación Hepática , Hepatopatías/metabolismo , Hepatopatías/patología , Pruebas de Función Hepática , Masculino , Microscopía por Video , Ratas , Ratas Wistar , Flujo Sanguíneo Regional , Vértebras TorácicasRESUMEN
Twenty-four (24) Caucasian male subjects completed a single-blind, randomised, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 144 mg pipamperone dihydrochloride (CAS 2448-68-2) (equivalent to 120 mg pipamperone; CAS 1893-33-0) as either the reference product (3 x 40 mg tablets), test product A (3 x 40 mg tablets) or test product B (1 x 120 mg tablet). Each consecutive dosing was separated by a washout period of 14 days. Following each dosing, venous blood samples were collected over a period of 120 h for the determination of plasma pipamperone concentrations by high-performance liquid chromatography. The most common drug related adverse events, ranging from mild to moderate in intensity, were bloodshot eyes, nasal congestion, dry mouth, hypotension and dizziness. The geometric mean Cmax of pipamperone for both the reference product and test product A was 266 ng/ml and for test product B 263 ng/ml. The geometric mean AUC0-infinity was 3107 ng.h/ml for the reference product, 3229 ng.h/ml for test product A and 3108 ng.h/ml for test product B. The two test products were shown to be bioequivalent to the reference product with respect to all pharmacokinetic variables investigated.