Prolonged-release pirfenidone in patients with pulmonary fibrosis as a phenotype of post-acute sequelae of COVID-19 pneumonia. Safety and efficacy.

INTRODUCTION: One of the major concerns with post-acute sequelae of COVID-19 (PASC) is the development of pulmonary fibrosis, for which no approved pharmacological treatment exists. Therefore, the primary aim of this open-label study was to evaluate the safety and the potential clinical efficacy of a prolonged-release pirfenidone formulation (PR-PFD) in patients having PASC-pulmonary fibrosis. METHODS: Patients with PASC-pulmonary fibrosis received PR-PFD 1800 mg/day (1200 mg in the morning after breakfast and 600 mg in the evening after dinner) for three months. Blood samples were taken to confirm the pharmacokinetics of PR-PFD, and adverse events (AEs) were evaluated monthly using a short questionnaire. Symptoms, dyspnea, and pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, plethysmography, and 6-min walk test [6MWT]) were evaluated at baseline, and one and three months after having started the PR-PFD treatment. RESULTS: Seventy subjects with mild to moderate lung restriction were included. The most common AEs were diarrhea (23%), heartburn (23%), and headache (16%), for which no modifications in the drug study were needed. Two patients died within the first 30 days of enrolment, and three opted not to continue the study, events which were not associate with PR-PFD. Pulmonary function testing, 6MWT, dyspnea, symptoms, and CT scan significantly improved after three months of treatment with PR-PFD. CONCLUSION: In patients with PASC pulmonary fibrosis, three months' treatment with PR-PFD was safe and showed therapeutic efficacy. Still, it remains to be seen whether the pulmonary fibrotic process remains stable, becomes progressive or will improve.

Differential effect of CCl4 on renal function in cirrhotic and non-cirrhotic rats.

The pathogenesis of renal function alteration associated with liver disease remains to be elucidated. Although different experimental animal models have been utilized in order to explain such pathophysiological state, none of them have completely explained the mechanisms involved. In this study we performed differential hemodynamic, hepatic and renal function alteration studies after induction of acute liver damage via intragastric administration of a single dose of CCl4 to cirrhotic and non-cirrhotic rats. Cirrhotic rats with acute liver damage exhibited a significant decrease in mean arterial pressure followed by a decreased glomerular filtration rate, urinary sodium concentration and an induction of plasma renin concentration and activity. At the same time, a significant association between oliguria and mortality was observed. The renal histopathological studies revealed glomeruli with mesangial hypercellularity and thickening of capillary wall, but not tubular epithelial injury. All these alterations were not detected in the control group, i.e. by non-cirrhotic rats with acute liver damage. This study suggests that the effect of CCl4 on kidney structure and function depends on the functional state of the liver. Since this experimental model of acute liver damage in cirrhotic rats presents hemodynamics and renal function alterations similar to those observed in the hepatorenal syndrome in man, it could be utilized to study the pathogenesis of renal function alterations associated with liver damage.

Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites.

BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis.

Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.

kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention.

Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects.

BACKGROUND & AIMS: Because controversial roles have been attributed to activation of the hepatic paracrine endothelin (ET) system in cirrhosis, this study assessed whether chronic ET receptor blockade modifies the development of portal hypertension in cirrhotic rats. METHODS: Cirrhotic and control rats received the mixed ET receptor antagonist RO 48-5695 or vehicle daily for 10 weeks. At the end of the treatment period, portal pressure, systemic hemodynamics, standard renal and liver function tests, hepatic concentration of hydroxyproline, and liver messenger RNA (mRNA) expression of procollagen type I were measured. RESULTS: Cirrhotic rats had portal hypertension and hyperdynamic circulation with no differences between animals treated or not treated with the ET-receptor antagonist. However, cirrhotic rats receiving ET-receptor blockade long-term showed a higher hepatic hydroxyproline content and procollagen type I mRNA expression than cirrhotic animals receiving vehicle. CONCLUSIONS: The results indicate that the liver paracrine ET system does not play a major role in the pathogenesis of portal hypertension and support the concept that this system takes part in an autocrine loop that counteracts the development of liver fibrogenesis.

Beneficial effect of carbohydrate maldigestion induced by a disaccharidase inhibitor (AO-128) in the treatment of chronic portal-systemic encephalopathy. A double-blind, randomized, controlled trial.

BACKGROUND: The most widely used treatment of portal-systemic encephalopathy (PSE) is the administration of oral, non-absorbable disaccharides. Theoretically, the inhibition of intestinal disaccharidases should induce malabsorption of disaccharides and increase delivery of undigested carbohydrates to the colon, thus stimulating the effects of lactulose and other non-absorbable disaccharides (that is, lactitol and lactose). AO-128 is an N-substituted derivative of valeolamine, an aminocyclitol that selectively inhibits intestinal disaccharidases. This study was performed to investigate whether AO-128 could be used as adjuvant therapy for the treatment of mild PSE in cirrhotic patients. METHODS: A double-blind, randomized, controlled trial was performed in 35 cirrhotic patients with PSE. Patients were given a 2-week treatment consisting of AO-128 (2 mg three times daily) or an identical placebo. The following features of PSE syndrome were assessed in a semiquantitative fashion before and after I and 2 weeks of therapy: mental state, asterixis, number connection test (NCT), venous blood ammonia concentration, electroencephalogram (EEG), and overall PSE index (PSEI). More patients receiving AO-128 than patients receiving placebo showed >40% improvement in the PSEI (83% versus 35%; P < 0.05). The mean stool pH decreased from 5.8+/-0.3 to 5.5+/-0.3 (P < 0.004) after AO-128 treatment, whereas no changes were observed in the placebo group. The EEG and nitrogen balance did not show significant changes in any of the two groups. A significant improvement was seen in the NCT performance after AO-128 (from grade 2.0+/-1.04 to grade 1.25+/-0.87; P < 0.05). Seven patients treated with AO-128 developed diarrhea, as compared with none in the placebo group (P < 0.05). CONCLUSION: These results suggest that AO-128 may be useful in the treatment of PSE, although further studies are required to establish the benefit of AO-128 and determine adequate individual doses.

Usefulness of cryohemolysis test in the diagnosis of hereditary spherocytosis.

The clinical suspicion of hereditary spherocytosis (HS) must be confirmed at the clinical laboratory. The osmotic fragility test (OFT) and the autohemolysis test (AHT) are the worldwide accepted assays to establish a definite diagnosis of HS; however, they have some disadvantages. We describe herein our experience with the cryohemolysis test (CHT) as a tool to confirm the HS diagnosis. We included four groups of subjects, namely, patients with clinical HS, patients with mechanical heart valve prosthesis, malignant hematological diseases and healthy blood donors. CHT was carried out in all the groups, while OFT and AHT only in the HS patients and healthy individuals. OFT and AHT were performed according to previously described techniques. CHT was performed using red blood cells incubated in a hypertonic solution, preheated for 10 min and then transferred to an ice bath for an additional 10 min. The resulting cryohemolysis was determined measuring the free hemoglobin in the sample. There were no differences among the groups in terms of general characteristics. All HS suspicious patients had a positive OFT and AHT. CHT was positive in all patients from the HS group but in none of the subjects from the control groups (p < 0.001). We found that CHT is a faster and easier-to-perform assay compared with OFT and AHT. Moreover, using CHT, the zone between normal and abnormal results is wider than OFT or AHT. We propose 0.7 to 11% hemolysis as reference values for CHT.

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 benign digestive disease, and group III (n = 95), healthy subjects. 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 +/- 27.3, p < 0.05) were significantly higher than in patients with benign digestive disease (75.8 +/- 19.8) or healthy subjects (54.4 +/- 8.9) and the serum levels of zinc (mg/dl) were significantly lower (68.7 +/- 21.9, p < 0.05) compared to benign digestive disease patients (80.1 +/- 18.7) or healthy subjects (100 +/- 11.4 mg/dl). The Cu/Zn ratio was also significantly higher in patients with digestive cancer (1.45 +/- .58, p < 0.05) than those with benign digestive disease (0.95 +/- 0.28) or healthy subjects (0.55 +/- 0.13). Considering a cutoff value of 0.87, the sensitivity of the copper/zinc ratio was 82.2%, with a specificity of 65.7%, a positive predictive value of 45.8% and a negative predictive value of 91.3%. 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% that might be useful in the evaluation of suspected malignancy.

[Gastropathy caused by nonsteroidal anti-inflammatory agents]. / Gastropatía por anti-inflamatorios no esteroideos.

Nonsteroidal anti-inflammatory drugs (NSAID) are widely used in current clinical practice. Several gastric lesions occur as a side effect. This review paper describes the spectrum of gastric lesions, its pathogenesis, prevalence and incidence as well as clinical data, common risk factors, treatment and the prophylaxis of NSAID gastric toxicity.

[Chronology of portal hypertension, decreased sodium excretion, and activation of the renin-angiotensin system in experimental biliary cirrhosis]. / Cronología de hipertensión portal, disminución de excreción de sodio y activación del sistema renina-angiotensina en cirrosis biliar experimental.

OBJECTIVES: 1) To evaluate the biochemical, renal, histological and splanchnic and systemic hemodynamic abnormalities induced by bile duct obstruction in rats, and 2) to study the temporal relationships between the start of portal hypertension, decrease of urinary sodium excretion and activation of the renin-angiotensin system. METHODS: Bile duct obstruction was induced in 127 male Wistar rats, and renal function, hemodynamic, biochemical and liver histology were evaluated at weeks 1, 2, 3 and 4 after complete bile duct obstruction; the data were compared to that in 30 control rats. RESULTS: Portal pressure significantly increased at week 1 (11.7 +/- 1.5. vs. 7.8 +/- 1.5 mmHg, p < 0.05) while the mean arterial pressure remained stable until week 4 when a slight decrease was observed (91.3 +/- 6.6 vs. 96.1 +/- 8.6 mmHg in control rats). A significant decrease in urinary sodium excretion was observed at week 1 (1.1 +/- 0.5 mEq/24 h) compared to control rats (2.3 +/- 0.6 mEq/24 h). In addition, hyperreninemia was observed at week 1 (5.1 +/- 0.2 vs. 2.4 +/- 1.3 ng Ang l/mL/h, p < 0.05) and hyperaldosteronism at week 2 (103 +/- 46 vs. 25.1 +/- 8.8 ng/24 h, p < 0.05) compared to control rats. CONCLUSION: A temporal relationship between the beginning of portal hypertension and a decrease of renal sodium excretion, hyperreninemia and hyperaldosteronism was observed in bile duct ligated rats. This experimental model could be used to evaluate the effects of new drugs to prevent biliary cirrhosis including the abnormalities in the renal handling of sodium.

In vitro and in vivo lactose and lactulose effects on colonic fermentation and portal-systemic encephalopathy parameters.

Lactose intolerance occurs in the majority of human groups, excluding people from Northern Europe. Because its effect is similar to that of lactulose, lactose seems to be an alternative treatment for patients with portal-systemic encephalopathy (PSE) and lactase deficiency. The mechanism of action of lactose is similar to that of lactulose. In vivo, lactose improves PSE parameters and causes acidic diarrhea. We performed in vitro studies in a fecal incubation system to investigate the biochemical and bacteriological effects induced by different substances customarily used for the treatment of patients with PSE (lactose, lactulose and Neomycin). In vitro experiments showed that lactose and lactulose decreased aerobic flora counts and reduced the pH of fecal incubation. Both disaccharides reduced the ammonia concentration in the incubation system.

[Primary biliary cirrhosis: clinical features and survival of a Mexican population]. / Cirrosis biliar primaria: características clínicas y supervivencia en la población Mexicana.

BACKGROUND: PBC progresses to cirrhosis and results in death due to liver failure or bleeding portal hypertension. Data of the clinical characteristics and survival of PBC patients allows the assessment of therapeutical alternatives as well as the establishment of inclusion criteria for liver transplantation. AIMS: One hundred and twenty patients with histological diagnosis of PBC, admitted from 1972 to 1992, were selected with the purpose of studying the clinical and biochemical characteristics and survival. METHODS: Patients who underwent liver transplant or those who had an incomplete follow-up were excluded. RESULTS: Therefore only 80 patients were included: these were seventy five women and five men, with mean age 46 +/- 11 years (X +/- SD) to whom demographic data, biochemical analysis, liver function (Child-Pugh) and liver damage (Ludwig) were recorded at the time of histological diagnosis, which was considered zero for calculating the survival (Kaplan Meier). The most common symptoms at diagnosis were pruritus in 63 patients, jaundice in 48, asthenia and adynamia in 55 patients. Eight cases were asymptomatic. According to Child-Pugh's classification, patients were grouped as follows: forty in stage A, 29 in B, and three in C; and according to liver damage (Ludwig), 8 in grade I, 28 in grade II, 22 in grade III and 14 in grade IV. The most frequent clinical associations were Sjögren's syndrome, in 30% of patients, although one case was associated to progressive muscular dystrophy and another one to multiple myeloma and hypothyroidism; in 58.7% of the cases, antimitochondrial antibodies were negative. One year survival was 75%, five years 44%, and seven years 13%. CONCLUSIONS: The most important characteristics of the studied patients were elevated percentage of negative antimitochondrial antibodies and short survival. it is important to impel the development of liver transplantation as the only mean to improve survival.

[Utility of the copper/zinc ratio in patients with lymphoma or acute or chronic leukemias]. / Utilidad de la relación cobre/zinc en pacientes con linfoma o leucemias aguda o crónica.

OBJECTIVE: To determine the diagnostic value of serum levels of copper, zinc and the Cu/Zn ratio in patients with hematological malignancies compared to gender- and age-matched control subjects. METHODS: A total of 44 patients with recently diagnosed and non-treated hematological malignancies were included: 17 lymphoma (11 non-Hodgkin), 15 acute leukemia (10 myeloblastic), and 12 with chronic leukemia (8 granulocytic); 95 healthy subjects were included. Copper and zinc serum levels were measured with a Perkin Elmer (model 2380) atomic absorption spectrophotometer. RESULTS: Serum copper levels (microgram/dL) were significantly lower in healthy subjects (54.4 +/- 8.9, p < 0.05) compared to patients with lymphoma (93.7 +/- 37.5), acute leukemia (80.6 +/- 44.6) or chronic leukemia (95.7 +/- 28.9) while serum zinc levels (microgram/dL) were significantly higher in healthy control subjects (100.4 +/- 14, p < 0.05) compared to patients with lymphoma (77.2 +/- 22.6), acute leukemia (66 +/- 15.6), or chronic leukemia (74.8 +/- 14.7). The Cu/Zn ratio was significantly lower in healthy subjects (0.54 +/- 0.13, p < 0.05) than in patients with lymphoma (1.21 +/- 0.5), acute leukemia (1.22 +/- 0.7), or chronic leukemia (1.28 +/- 0.4). Twenty three patients died during a mean follow-up period of 13 months and their serum zinc levels were significantly lower (68 +/- 21) than in the living patients (76 +/- 15, p < 0.05). CONCLUSION: Cu/Zn ratio is significantly higher in patients with lymphoma or acute and chronic leukemias compared to gender- and age-matched control subjects.

[Hepatitis C virus infection and membranoproliferative glomerulonephritis]. / Infección por virus de la hepatitis C y glomérulonefritis membranoproliferativa.

BACKGROUND AND METHODS: A possible association between hepatitis C virus infection (HCV) and membranoproliferative glomerulonephritis (MPGN) or membranous glomerulonephritis has recently been reported. The pathogenesis of this entity appears to be immunologically mediated. The purpose of this report is to describe the clinical, laboratory, and histopathological features of three patients with chronic HCV infection, without hepatitis B virus disease or autoimmune diseases, but with glomerular disease. RESULTS: All three patients had chronic hepatopathy stigmata, ascitis, peripheral edema, and normal blood pressure values. Laboratory results showed mild liver function abnormalities and normal levels of blood nitrogenous waste products. Microscopic hematuria, hypoalbuminemia, and variable proteinuria without hypercholesterolemia were found in all cases. All three had positive rheumatoid factor. Only one patient had positive antinuclear antibodies and antimitochondrial antibodies at low levels, and another displayed low C3 and C4 serum levels. Renal histology in the three cases showed type I membranoproliferative glomerulonephritis and hepatic cirrhosis in the liver biopsy. CONCLUSIONS: This report supports the association between chronic HCV infection and membranoproliferative glomerulonephritis. However, further studies are needed to establish more firmly the association as well as the mechanisms of pathogenesis and causality between them.

Serum zinc concentrations in two cohorts of 153 healthy subjects and 100 cirrhotic patients from Mexico City.

The aim of this study was to assess serum zinc levels in a cohort of healthy subjects and cirrhotic patients from Mexico City. A total of 153 healthy subjects and 100 cirrhotic patients, males and females aged 18-65, were studied. Inclusion criteria for healthy subjects were (1) Mexican-born with first and second generation relatives born in Mexico, and (2) somatometric (body mass index under 30) and clinical evaluation establishing that they had no underlying disease. Entry criteria for cirrhotic patients were (1) clinical and histological proven cirrhosis, (2) compensated liver disease (absence of coma, bleeding hemorrhage or refractory ascitis), and (3) cirrhosis of any cause. Zinc serum levels were measured with atomic absorption spectrophotometry. In healthy subjects, mean serum levels were 77.4 +/- 4.2 micrograms/dl (range 42.9-105.2 micrograms/dl). In cirrhotic patients zinc serum levels (58.9 +/- 16.1 micrograms/dl, range 22-88 micrograms/dl) were significantly lower than in healthy subjects (p < 0.05). A stepwise decline in serum zinc with worsening Child class (A, 73.4 +/- 13; B, 64.4 +/- 12; C, 55.8 +/- 15.6; p < 0.05 by ANOVA test) was found. In conclusion, this study confirms that zinc serum levels are significantly lower in cirrhotic patients and shows that zinc serum levels in a cohort of 153 healthy subjects from Mexico City were unexpectedly lower compared to those found in other countries. This last finding might be explained by different dietetic patterns and deserves further investigation.

Effects of ursodeoxycholic acid on hemodynamic and renal function abnormalities induced by obstructive jaundice in rats.

UNLABELLED: The mechanism of renal function abnormalities in experimental biliary cirrhosis can be partially explained by the absence of gastrointestinal bile flow, which predisposes to translocation of intestinal endotoxin, a potent renal vasoconstrictor. Since bile acids prevent the absorption of intestinal endotoxins, we aimed to evaluate the effects of ursodeoxycholic acid (UDCA) administration on renal function and hemodynamic abnormalities induced by 1 week of obstructive jaundice in rats. METHODS: Fifty-two rats were used; 30 had ligation of the common bile duct, 22 were sham operated. Bile duct ligated rats were randomly and blindly assigned to receive UDCA (25 mg/kg/day, n = 14) or placebo (n = 16) during 1 week. Sham rats received no treatment. Portal pressure (PP) as well as creatinine clearance (CrCl), urinary sodium (US), and plasma renin activity (PRA) were evaluated. Results are mean +/- SEM, with a significant value of p < 0.05. RESULTS: Portal pressure (10.4 +/- 1.1 vs. 12.1 +/- 0.8 mm Hg) was significantly lower in UDCA than in placebo-treated rats. ALT serum levels were also significantly lower in bile duct ligated rats receiving UDCA (77.3 +/- 28 IU/L) than in placebo-treated rats (162 +/- 65 IU/L). US (1.1 +/- 0.5 vs. 2.1 +/- 0.3 mEq/24 h) was significantly lower and PRA (6.0 +/- 2.6 vs. 1.9 +/- 1.0 ng Ang 1/mL/h) higher in bile duct ligated than in sham-operated rats. No differences were found between UDCA or placebo-treated bile duct ligated rats. CrCl was similar between sham (0.39 +/- 0.12 mL/min/100 g BW) and UDCA (0.32 +/- 0.16) but significantly lower in placebo-treated (0.28 +/- 0.07) than sham-operated rats (p < 0.05). CONCLUSION: UDCA administration had very mild effects on renal function abnormalities induced by experimental obstructive jaundice in rats. However, portal hypertension and biochemical abnormalities were partially improved.

Portal-systemic encephalopathy and gastrointestinal bleeding after cardioselective beta-blocker (metoprolol) administration to patients with portal hypertension.

The use of the non-selective beta-blocker propranolol has been widely recommended to prevent gastrointestinal bleeding in patients with portal hypertension. We conducted a prospective, randomized controlled trial of metoprolol, a selective beta-blocker for prevention of gastrointestinal bleeding from portal hypertension in 29 non-selected patients with liver disease and previous gastrointestinal bleeding. Fifteen patients received placebo treatment for 40 +/- 18 months and 14 patients received metoprolol for 31 +/- 17 months. A sustained reduction in resting pulse was observed in those patients treated with metoprolol. There was no significant difference in acute re-bleeding episodes between the two groups. Of the 14 patients treated with metoprolol, three (21%) re-bled, all three requiring blood transfusion. Four (26.5%) of the 15 patients treated with the placebo re-bled, two cases with acute bleeding and the remaining two cases presented a positive stool guaiac test. All cases who bled during the metoprolol therapy required exclusion from the trial, and surgical procedures or sclerotherapy as well. After both metoprolol or placebo treatments, similar deterioration of standard liver function tests was observed. Further, at the end of the trial, 11 patients on metoprolol (78%) and four of the patients treated with the placebo (27%) required treatment for clinical portal-systemic encephalopathy (p < 0.01). The risk of poor sympathomimetic response after cardioselective beta 1-blocker during acute bleeding episodes and the appearance of hepatic encephalopathy deserve further investigation. The selective beta-blocker metoprolol seems to be an inadequate choice to prevent gastrointestinal re-bleeding in patients with portal hypertension.

Early colchicine administration reduces hepatic fibrosis and portal hypertension in rats with bile duct ligation.

Chronic administration of colchicine has been suggested as a potential treatment for hepatic fibrosis. The purpose of this study was to examine the effects of chronic oral administration of colchicine on the histological and hemodynamic abnormalities of bile duct ligation in the rat. Forty-eight rats with ligation-section of the common bile duct were randomly and blindly assigned to receive either colchicine (50 mu/kg day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that hepatocyte and sinusoidal volume fractions were significantly higher in rats treated with colchicine than in rats receiving placebo (42.4 +/- 1.3 vs. 32.1 +/- 2.6% (mean +/- S.E.) and 8.3 +/- 0.6 vs 4.7 +/- 0.4%, respectively), while bile duct volume fractions (reflecting bile ductular proliferation) and connective tissue fractions were significantly lower in rats treated with colchicine than in rats receiving placebo (12.1 +/- 0.9 vs. 17.0 +/- 0.1% and 37.2 +/- 0.9 vs. 46.1 +/- 2.0%, respectively). Portal pressure (13.4 +/- 0.7 vs. 17.8 +/- 0.5 mmHg), portal tributary blood flow (5.8 +/- 0.4 vs. 8.7 +/- 0.5 ml.min-1.100 g-1) and cardiac index (40.8 +/- 2.3 vs. 50.6 +/- 1.5 ml.min-1.100 g-1) were significantly lower in colchicine-treated rats than in placebo treated animals. In conclusion, in rats with bile duct ligation, colchicine limits the severity of liver lesions and, consequently, of portal hypertension and hyperkinetic syndrome.