Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study.

BACKGROUND: In both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0-∞, AUC0-t, and Cmax. METHODS: In this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child-Pugh A) and eight with moderate liver impairment (Child-Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography-mass spectrometry method was used to determine PFD plasma concentrations. RESULTS: The exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child-Pugh A and Child-Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child-Pugh B and Child-Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. CONCLUSION: The pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

[Epidemiology, physiopathology and diagnosis of pulmonary hypertension in hepatic (PH) cirrhosis]. / Epidemiología, fisiopatología y diagnóstico de la hipertensión arterial pulmonar (HAP) en el cirrótico.

Liver cirrhosis is a complex and progressive disease associated with high mortality. In developing countries, alcoholic liver disease is the most common form of liver cirrhosis, followed by chronic viral disease, especially hepatitis C virus infection. Cirrhosis is associated with systemic and splanchnic hemodynamic abnormalities, including increased vascular volume, decreased systemic vascular resistance, and increased cardiac output. At the splanchnic vascular bed, increases in portal flow and intrahepatic resistance have been described, inducing portal hypertension. Pulmonary arterial hypertension is a progressive disease of pulmonary circulation, without left ventricle and valvular heart disease; it is closely related with structural changes in pulmonary arteries. Idiopathic pulmonary arterial hypertension is related to abnormalities in cellular signals, inducing arterial hypertrophy and increased vascular tone. Porto-pulmonary hypertension includes simultaneous portal and pulmonary arterial hypertension. To confirm disease, it is important to exclude concomitant heart disease. Porto-pulmonary hypertension requires important components: portal hypertension, shear vascular stress, and cellular activation with pulmonary arterial hypertrophy. In this short manuscript, the epidemiology, patho-physiology, and diagnostic criteria of the disease are reviewed to optimize early diagnosis and treatment.

Effect of Prolonged-Release Pirfenidone on Renal Function in Septic Acute Kidney Injury Patients: A Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND: There is no treatment for septic acute kidney injury (sAKI). The anti-inflammatory activity of prolonged-release pirfenidone (PR-PFD) could be beneficial in this clinical setting. METHODS: This study was a double-blind randomized clinical trial in sAKI patients with nephrology consultation at the Civil Hospital of Guadalajara, in addition to the usual treatment of AKI associated with sepsis; patients were randomized to receive either PR-PFD at 1,200 mg/day (group A) or 600 mg/day (group B) or a matched placebo for 7 consecutive days. The primary objective was the decrease in serum creatinine (sCr) and increase in urinary volume (UV); the secondary objectives were changes in serum electrolytes, acid-base status, and mortality. RESULTS: Between August 2016 and August 2017, 88 patients were randomized. The mean age was 54 (17 ± SD) years, and 47% were male. The main site of infection was the lung (39.8%), septic shock was present in 39.1% of the cases, and the mean SOFA score was 8.8 points. 28 patients received PFD 1,200 mg, 30 patients received PFD 600 mg, and 30 patients received placebo. During the study, sCr did not differ among the groups. The reversion rate of sCr, UV, and mortality was not different among the groups (p=0.70, p=0.47, and p=0.38, respectively). Mild adverse events were not different among the groups. CONCLUSION: PR-PFD did not improve the clinical course of sAKI and seemed to be safe in terms of adverse events. This trial is registered with NCT02530359.

Efficacy of triple therapy with thymalfasin, peginterferon alpha-2a, and ribavirin for the treatment of hispanic chronic HCV nonresponders.

BACKGROUND/AIMS: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon alpha-2a (PEG-IFN alpha-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-alpha)/ribavirin. METHODS: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN alpha-2a (180 microg once a week), and ribavirin (800-1,000 mg/day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. RESULTS: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN alpha-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. CONCLUSION: Triple therapy with thymalfasin, PEG IFN alpha-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.

Diagnostic value of the copper/zinc ratio in hepatocellular carcinoma: a case control study.

BACKGROUND: The aim of this study was to assess the accuracy of the copper/zinc ratio in the evaluation of a group of patients with hepatocellular carcinoma (HCC). METHODS: A total of 105 patients were studied and separated into three groups: group I ( n = 40), patients with HCC, group II ( n = 25), patients with liver cirrhosis, and group III ( n = 40), patients with benign digestive disease. Serum levels of copper and zinc were measured by atomic absorption spectrophotometry. RESULTS: The serum levels of copper microg/dl) in patients with HCC (97.4 +/- 27.2; P < 0.05) were significantly higher than those in patients with liver cirrhosis (73.7 +/- 17.5) or benign digestive disease (77.1 +/- 20.8), and the serum levels of zinc microg/dl) were significantly lower (71.6 +/- 30.5; P < 0.05) than those in patients with benign digestive disease (81.7 +/- 17.7 microg/dl) and were similar to those in cirrhotic patients (68.5 +/- 17.1). The Cu/Zn ratio was also significantly higher in patients with HCC (1.52 +/- 0.64; P < 0.05) than in patients with liver cirrhosis (1.06 +/- 0.2) or patients with benign digestive disease (0.95 +/- 0.39). Considering a cutoff value of 1.15, the sensitivity of the Cu/Zn ratio was 87.5%, with a specificity of 86.1%, a positive predictive value of 79.5%, and a negative predictive value of 91.8%. CONCLUSIONS: The Cu/Zn ratio was found to be significantly higher in patients with HCC compared with that in age and sex-matched controls, with a sensitivity of 87.5%; this ratio might be useful in the evaluation of suspected hepatocellular malignancy.

Etiology of liver cirrhosis in Mexico.

BACKGROUND: In the last decades it has been suggested that the main cause of liver cirrhosis in Mexico is alcohol. Currently in Western countries hepatitis C virus stage liver disease and liver transplantation. In Mexico, we have no data relative to the etiology of liver cirrhosis. The aim of this study was to investigate the main causes of liver cirrhosis in Mexico. METHODS: Eight hospitals located in different areas of the country were invited to participate in this study. Those hospitals provide health care to different social classes of the country. The inclusion criteria were the presence of either an histological or a clinical and biochemical diagnosis of liver cirrhosis. RESULTS: A total 1,486 cases were included in this study. The etiology of liver cirrhosis was alcohol in 587 (39.5%), HCV 544 (36.6%), cryptogenic 154 (10.4%), PBC 84 (5.7%), HBV 75 (5.0%) and other 42 (2.8%). There was no statistical difference between alcohol and HCV. CONCLUSIONS: We conclude that the main causes of liver cirrhosis in Mexico are alcohol and HCV.

Diagnostic value of the copper/zinc ratio in digestive cancer: A case control study

The aim of this study was to assess the accuracy of the copper/zinc ratio (Cu/Zn ratio) in the evaluation of a large group of patients with digestive cancer compared to gender and age-matched control subjects. A total of 282 patients was studied and separated into three groups: group I (n=75), patients with digestive cancer, group II (n=112), patients with bening digestive disease, and group II (n=95), healthy subject. Serum levels of copper and zinc were measured by atomic absorption spectrophotometry. The results showed that the serum levels of copper (mg/dL) in patients with digestive cancer (91.6 ñ27.3, p<0.05) were significantly higher than in patients with benign digestive diseasde (75.8 ñ 19.8) or healthy subjects (54.4 ñ 8.9) and the serum levels of zinc (mg/dl) were significantly lower (68.7 ñ 21.9, p<0.05) compared to benign digestive disease patients (80.1 ñ 18.7) or healthy subjects (100 ñ 11.4 mg/dl). The Cu/Zn ratio was also significantly higher in patients with digestive cancer (1.45 ñ .58, p<0.05) than those with benign digestive disease (0.95 ñ 0.28) or healthy subjects (0.55 ñ 0.13). Considering a cutoff value of 0.87, the sensitivity of the copper/zinc ratio was 82.2 percent, with a specificity of 65.7 percent, a positive predictive value of 45.8 percent and a negative predictive value of 91.3 percent. In conclusion, Cu/Zn ratio was found to be considerably higher in patients with digestive cancer compared to age-and gender-matched controls, with a sensitivity of 82.2 percent that might be useful in the evaluation of suspected malignancy