Comparative Effects of Triflusal, S-Adenosylmethionine, and Dextromethorphan over Intestinal Ischemia/Reperfusion Injury

Ischemia/reperfusion (I/R) is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha), malonaldehyde (MDA), and total antioxidant capacity (TAC) were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC

A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis

Introduction: Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC. Methods: In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline. Results: Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits. Discussion: Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC

Comparative Effects of Triflusal, S-Adenosylmethionine, and Dextromethorphan over Intestinal Ischemia/Reperfusion Injury

Academic Editor: Huaxin Sheng Ischemia/reperfusion (I/R) is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha), malonaldehyde (MDA), and total antioxidant capacity (TAC) were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC

Actividad antiinflamatoria y antioxidante de los α-cetoanálogos de aminoácidos esenciales en un modelo de daño por isquemia-reperfusión en ratas Wistar

Introduction: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion.Objective: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats.Materials and methods: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1β, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity.Results: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups.Conclusions: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión.Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar.Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1β, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total.Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes.Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes

Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion

OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chius classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ¡ standard deviation and compared the baseline and maximum values for each marker using Student’s t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion

Consenso Mexicano para el Tratamiento de la Hepatitis C

El objetivo del Consenso Mexicano para el Tratamiento de la Hepatitis C fue el de desarrollar un documento como guía en la práctica clínica con aplicabilidad en México. Se tomó en cuenta la opinión de expertos en el tema con especialidad en: gastroenterología, infectología y hepatología. Se realizó una revisión de la bibliografía en MEDLINE, EMBASE y CENTRAL mediante palabras claves referentes al tratamiento de la hepatitis C. Posteriormente se evaluó la calidad de la evidencia mediante el sistema GRADE y se redactaron enunciados, los cuales fueron sometidos a voto mediante un sistema modificado Delphi, y posteriormente se realizó revisión y corrección de los enunciados por un panel de 34 votantes. Finalmente se clasificó el nivel de acuerdo para cada oración. Esta guía busca dar recomendaciones con énfasis en los nuevos antivirales de acción directa y de esta manera facilitar su uso en la práctica clínica. Cada caso debe ser individualizado según sus comorbilidades y el manejo de estos pacientes siempre debe ser multidisciplinario. Abstract The aim of the Mexican Consensus on the Treatment of Hepatitis C was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitis C treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary

Nephroprotective Effect of Sonchus oleraceus Extract against Kidney Injury Induced by Ischemia-Reperfusion in Wistar Rats

Introduction. Kidney ischemia-reperfusion (I/R) injury is the main cause of delayed graft function in solid organ transplantation. Sonchus oleraceus is a plant with well-known antioxidant and anti-inflammatory activities; however, its effects on renal I/R are unknown. Objective. To evaluate whether S. oleraceus extract (S.O.e.) has nephroprotective activity in an I/R model in Wistar rats. Materials and Methods. Animal groups (n=6): sham, I/R (45 min/15 h), S.O.e (300 mg/kg p.o.), and S.O.e + I/R (300 mg/kg, p.o.; 45 min/15 h). Renal function, proinflammatory cytokines, alanine aminotransferase, markers of oxidative stress, and histology were evaluated. Results. None of the mediators evaluated differed significantly between the S.O.e and sham groups. Levels of blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and proinflammatory cytokines were higher, and superoxide dismutase (SOD) was lower in the I/R group than in the sham group. Histology showed tubular epithelial necrosis in the medulla and cortex in the I/R group. In the S.O.e + I/R group, S.O.e pretreatment attenuated the I/R-induced increases in BUN, creatinine, MDA, and proinflammatory cytokines induced, SOD was maintained, and histology showed discontinuous necrosis in the medulla but no necrosis in the cortex. Conclusions. S.O.e was neither hepatotoxic nor nephrotoxic. S.O.e. pretreatment showed a nephroprotective effect against I/R

Interferon-based therapy delays but metabolic comorbidity accelerates progression of chronic hepatitis C

Background. We compared mortality and complications of chronic hepatitis C between treated and untreated Mexican patients after long-term follow-up. We used a time-to-event analysis and identified the prognostic factors.Material and methods. Seventy-four patients with chronic hepatitis C were studied. They were ≥ 18 years of age and had a molecular diagnosis of chronic hepatitis C and ≥ 6 months of follow-up. Patients with neoplasia or those infected with human immunodeficiency virus or hepatitis B Virus were excluded. Kaplan-Meier analysis, log-rank test, annualized incidence per 100 person-years, and stepwise discriminant analysis were used to analyse mortality and complications.Results. The end-point of annualized incidence was lowest in sustained virological responders, intermediate in non-responders, and highest in untreated patients. The absence of treatment impacted adversely on cirrhosis development and the occurrence of portal hypertension and hepatic decompensation/hepatocellular carcinoma (log-rank, p < 0.05). Diabetes impacted adversely on liver-related death/liver transplantation among untreated patients. Stepwise discriminant analysis showed that diabetes, high blood pressure, and no retreatment predicted cirrhosis development (eigenvalue ≥ 0.8; p < 0.05). A MELD score ≥ 18 and age ≥ 50 years predicted hepatic decompensation/hepatocellular carcinoma (eigenvalue < 0.8; p < 0.05). APRI ≥ 1.5 predicted mortality/liver transplantation and liver-related death/liver transplantation (eigenvalue < 0.8; p < 0.05).Conclusions. This is the first long-term study of chronic hepatitis C among Mexican patients. Treated patients showed less progression of liver disease. Treated patients showed less progression of liver disease; and older patients, those with metabolic comorbidities, with MELD score ≥ 18 and APRI ≥ 1.5 exhibited adverse effects

Increase of drug use and genotype 3 in HCV-infected patients from Central West and Northeast Mexico

Background. The evolving pattern of HCV genotypes (GTs) and risk factors (RFs) in HCV-infected patients in Mexico is poorly understood. This study aimed to access the temporal trend of HCV GTs and RFs in HCV patients from two care centers.Material and methods. Chronic HCV patients [177 and 153 patients from the Northeast (NE) and Central West (CW) regions, respectively] were selected. Baseline features were demographics, date of birth (DOB), blood transfusion before 1992 (BTb1992), RFs, sexual promiscuity (SP), dental procedure (DP), injection drug use (IDU), viral load (VL), GTs, cirrhosis status and antiviral therapy (AT). Data were analyzed by Chi-square test for trends, unpaired T-test, and logistic regression.Results. HCV GT distribution was: GT1, 67%; GT2, 16%; GT3, 12% and GT4, 1%. RFs were BTb1992, 56%; surgeries, 56%; tattooing, 18% and IDU, 16%. GT1a mostly prevailed in CW than NE patients. GT1b, surgeries, BTb1992 and cirrhosis were more prevalent in older patients (p < 0.05); GT3, male gender IDU, SP, and tattooing showed an upward trend as younger were the patients in both regions (p < 0.05), contrariwise to the prevalence of GT1b. BTb1992 and surgeries were seen in elder women; BTb1992 was an independent RF for GT1. Age ≥ 50 years old, GT1 and exposure to AT (p < 0.05) were associated with cirrhosis. Conclusion. GT1a prevalence in CW Mexico remained stable, whereas GT3 increased and GT1b decreased in younger patients in both regions, along with associated RFs. Further regional molecular epidemiology and RF analyses are required in order to avoid the dissemination of new cases of HCV infection