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TNP-470 Inhibits Oxidative Stress, Nitric Oxide Production and Nuclear Factor Kappa B Activation in a Rat Model of Hepatocellular Carcinoma

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-κB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-κB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-κB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.

An uncommon association of abdominal vascular compression syndromes: Dumbar and Nutcracker.

Abdominal pain associated with nausea and vomiting in a young patient led to a diagnosis of median arcuate ligament syndrome. The presence of mild haematuria was associated with a concomitant Nutcracker syndrome. Diagnosis was achieved by a computed tomography scan, which showed compression of the vessels of the coeliac axis and left renal vein. These syndromes are very rare, and their association in the same patient has not been described before. There is no relationship in the aetiology of these entities. In this report we discuss the diagnosis and therapeutic options, and review the literature.

Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy.

Aim Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography. Methods This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (≥9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12. Results Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4–67.6; P<0.001). Conclusion In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients.

Tratamiento antiangiogénico del cáncer

The process of formation of new vessels from pre-existing capillaries is called angiogenesis. Angiogenesis is a complex process which involves distinct cells, soluble components and factors related to the extra-cellular matrix and which is highly important in a large variety of physiological and pathological processes in the body. Angiogenesis regulation takes place through a perfect equilibrium between the production and release of different stimulatory and inhibitory factors which vary in relation to needs and tissue types. A large number of diseases are characterized by alterations in the angiogenic process, either by an insufficiency or by excessive angiogenesis. The requirement of blood vessel proliferation for tumor growth was observed more than a century ago. Angiogenic treatment would have an indirect antitumoral action, inhibiting tumor vascularization and impairing the supply of essential nutrients for tumoral growth and development.

Interferon-free treatments in patients with hepatitis C genotype 1-4 infections in a real-world setting

AIM To investigated the real-world effectiveness and safety of various regimens of interferon-free treatments in patients infected with hepatitis C virus (HCV). METHODS We performed an observational study to analyze different antiviral treatments administered to 462 HCV-infected patients, of which 56.7% had liver cirrhosis. HCV RNA after 4 wk of treatment and at 12 wk after treatment sustained virologic response (SVR) as well as serious adverse events (SAEs) was analyzed first for the whole cohort and then separately in patients who met or did not meet the inclusion criteria of a clinical trial (CT-met and CT-unmet, respectively). RESULTS The most frequently prescribed treatment was simeprevir/sofosbuvir (36.4%), followed by sofosbuvir/ledipasvir (24.9%) and ombitasvir/paritaprevir/ritonavir (r)/dasabuvir (19.9%). Ribavirin (RBV) was administered in 198 patients (42.9%). SVRs occurred in 437/462 patients (94.6%). The SVRs ranged between 93.3% and 100% for genotypes 1-4. SVRs were achieved in 96.2% patients in the CT-met group vs 91.9% patients in the CT-unmet group (P = 0.049). Undetectable HCV RNA at week 4 occurred in 72.9% of the patients. In the univariate analysis, the factors associated with SVRs were lower liver stiffness, absence of cirrhosis, higher platelet count, higher albumin levels, no RBV dose reduction, undetectable HCV RNA at week 4 and CT-met group. In the multivariate analysis, only albumin was an independent predictor of treatment failure (P = 0.04). Eleven patients (2.4%) developed SAEs; 5.2% and 0.7% of the patients in the CT-unmet and CT-met groups, respectively (P = 0.003). CONCLUSION A high proportion of patients with HCV infection achieved SVRs. For patients who did not meet the CT criteria, treatment regimens must be optimized.

Dilatación de la papila de Vater en el tratamiento de la coledocolitiasis en pacientes seleccionados

Objetivo : Analizar prospectivamente los resultados obtenidos mediante dilatacion neumatica papilar (DNP) en el tratamiento de coledocolitiasis, en pacientes con riesgo de complicaciones si se realizara esfinterotomia endoscopica (EE). Pacientes Y Metodo : Se incluyen 33 pacientes entre enero de 2001 y junio de 2003 (edad media 76,2 anos). Los criterios de DNP fueron: coledocolitiasis ≤ 10 mm en pacientes con diverticulos peripapilares, alteraciones hemostaticas, Billroth II o preservacion del esfinter de Oddi. La sedacion se realizo por anestesista en el 79% de los pacientes. La DNP se efectuo con un cateter balon dilatador de 8 o 10 mm de diametro, durante 2 min. Se valoro la eficacia, la duracion del procedimiento, las complicaciones al dia 30 y el grado de satisfaccion de los pacientes. Resultados : Se consiguio la extraccion de los calculos en todos ellos (100%). La duracion media fue de 26 min. Dos pacientes presentaron pancreatitis leve (6%). Hubo elevacion de la amilasa serica en 16 pacientes (48%): ≥ 3 veces (hiperamilasemia post-DNP) en 11 (33%). La prueba fue nada molesta en 25/26 (96%) pacientes sedados por anestesista frente a 2/5 (40%) sedados por endoscopista. Conclusiones : La DNP es una opcion terapeutica eficaz y sencilla en el tratamiento de coledocolitiasis de pequeno tamano (. 10 mm), en situaciones especiales de riesgo. La duracion de la colangiopancreatografia retrograda endoscopica (CPRE) no supone un tiempo prolongado. Las complicaciones son infrecuentes (6%) y leves. La hiperamilasemia post-DNP es frecuente y generalmente sin trascendencia clinica. La sedacion por un anestesista mejora la satisfaccion del paciente.

Isquemia intestinal en un adulto joven asociada al consumo de cocaína

Sr. Director: Las complicaciones cardiovasculares asociadas al consumo de cocaína son relativamente frecuentes e incluyen infarto de miocardio, arritmias, rotura de aorta y accidentes cerebrovasculares1. Sin embargo, las complicaciones gastrointestinales han sido escasamente comunicadas y engloban las ulceraciones gástricas, infarto visceral, isquemia intestinal, perforación y fibrosis retroperitoneal2,3. Se describe un caso de isquemia mesentérica aguda secundaria a trombosis venosa mesentérica (TVM) en relación al consumo de cocaína.

TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.