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.

Prognostic value of (13)C-phenylalanine breath test on predicting survival in patients with chronic liver failure.

AIM: To evaluate the prognostic value of percentage of (13)C-phenylalanine oxidation ((13)C-PheOx) obtained by (13)C-phenylalanine breath test ((13)C-PheBT) on the survival of patients with chronic liver failure. METHODS: The hepatic function was determined by standard liver blood tests and the percentage of (13)C-PheOx in 118 chronic liver failure patients. The follow-up period was of 64 mo. Survival analysis was performed by the Kaplan-Meier method and variables that were significant (P < 0.10) in univariate analysis and subsequently introduced in a multivariate analysis according to the hazard model proposed by Cox. RESULTS: Forty-one patients died due to progressive liver failure during the follow-up period. The probability of survival at 12, 24, 36, 48 and 64 mo was 0.88, 0.78, 0.66, 0.57 and 0.19, respectively. Multivariate analysis demonstrated that Child-Pugh classes, age, creatinine and the percentage of (13)C-PheOx (HR 0.338, 95% CI: 0.150-0.762, P = 0.009) were independent predictors of survival. When Child-Pugh classes were replaced by all the parameters of the score, only albumin, bilirubin, creatinine, age and the percentage of (13)C-PheOx (HR 0.449, 95% CI: 0.206-0.979, P = 0.034) were found to be independent predictors of survival. CONCLUSION: Percentage of (13)C-PheOx obtained by (13)C-PheBT is a strong predictor of survival in patients with chronic liver disease.

Endocrine and biochemical studies in a 46,XY phenotypically male infant with 17-ketosteroid reductase deficiency.

A 46,XY phenotypically male patient with 17-ketosteroid reductase deficiency is described. The patient was a 6-month-old infant who presented with micropenis and bilateral cryptorchidism. Baseline plasma levels of testosterone (T), delta 4-androstenedione (delta 4A), and 5 alpha-dihydrotestosterone (5 alpha-DHT) were within the normal range [patient: 0.17 (T), 0.12 (delta 4A), and 0.032 (5 alpha-DHT) ng/ml; normal infants: 0.03-0.55 (T), 0.14-0.45 (delta 4A), and 0.01-0.23 (5 alpha-DHT) ng/ml]. hCG administration induced a significant rise in plasma delta 4A levels (up to 8.39 ng/ml) and a slight increase in T and 5 alpha-DHT levels. The delta 4A/T ratios before and during the hCG challenge were 0.86 and 55.61, respectively (controls: 0.83 and 0.13). Incubation of genital skin-derived fibroblasts from the patient with either [3H]T or [3H] delta 4A revealed normal formation of delta 4A from T and diminished conversion of delta 4A to T. The development of a male phenotype despite both a testicular and peripheral 17-ketosteroid reductase deficiency is difficult to explain. It is possible that the fetal testes were the source of sufficient amounts of T during the early periods of embryonic life, and that late onset of the enzyme deficiency prevented the development of completely normal male genitalia. The in vitro finding of normal T to delta 4A conversion by the mutant fibroblasts suggests that in this particular tissue 17 beta-reduction and dehydrogenation of androgens are mediated by two isoenzymes with distinct substrate and/or cofactor specificities.

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.

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.

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.

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.

[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.

[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.

[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.

[Rationale for the use of sodium benzoate in clinical hepatology]. / Benzoato de sodio. Fundamentos para su uso clínico en hepatología.

Sodium benzoate is widely used in the Alimentary Industry at low doses for its antimicrobial action. It has also been used as a liver function test. The principle is to evaluate the liver capacity for conjugation of glycine to benzoic acid and to form hippuric acid which is excreted in the urine. In hyperammonemic syndromes, secondary to enzymatic deficiency of the urea cicle, sodium benzoate has the property to act as an alternative way of nitrogen excretion to urinary hippurate instead of urea. Recently, it has been proposed as a therapeutic alternative in cirrhotic patients with portal systemic encephalopathy. Historical, biochemical and clinical data which constitute the principles to validate its clinical application in Hepatology are reviewed in this manuscript.

[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.

[Sodium benzoate in portal-systemic-encephalopathy-induced blood ammonia normalization and clinical improvement. Interim report of a double-blind multicenter trial]. / Derivación metabólica del amonio plasmático con benzoato de sodio, como método de tratamiento en pacientes con cirrosis y encefalopatía portosistémica. Informe interino de un estudio multicéntrico, doble ciego.

To investigate the therapeutic efficacy of sodium benzoate (SB) in a cirrotic population with chronic portal systemic encepalopathy (PSE), we performed a double blind, randomised, multicentric, clinical trial, comparing SB versus a standard therapy of lactitol (LA). To perform the study blind, syrups containing the two drugs were prepared. To date 27 patients have been studied. Of these, 12 received SB (5.6 g/day) and 15 received LA (29 g/day). Standard PSE parameters were assessed and hippurate urinary excretion was measured before and after the trial. For the SB group, basal and final PSE index were 0.39 +/- 0.16 and 0.17 +/- 0.1 respectively (p < 0.001). The Group on LA had a PSE index of 0.40 + 0.1 and 0.23 +/- 0.18 (basal and final respectively) (p < 0.001). The final hippurate excretion for SB group was 2498.9 mg/24 h. The hippurate excretion for the LA group suffer no changes (traces). No serious side effects were observed with either therapy. We suggested that SB is a safe, efficacious and comfortable alternate treatment for PSE.

[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.

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.