Carlos Piera

COMPARISON OF RIFAMPICIN WITH PHENOBARBITONE FOR TREATMENT OF PRURITUS IN BILIARY CIRRHOSIS

The anti-pruritic effects of rifampicin (10 mg/kg) and phenobarbitone (3 mg/kg) were assessed in 22 patients with primary biliary cirrhosis in a crossover randomised clinical trial. Each agent was given for 14 days, with a 30-day washout period between treatments. 21 patients completed the course of rifampicin and 18 that of phenobarbitone; rifampicin was withdrawn from 1 patient when anaemia and renal failure developed, whereas 3 patients stopped taking phenobarbitone because of a rash and the 4th merely refused the drug. Rifampicin had a greater anti-pruritic effect than phenobarbitone. The symptom improved in 19 patients taking rifampicin and in 8 taking phenobarbitone, the degree of improvement being greater with rifampicin than with phenobarbitone. Pruritus disappeared in 9 patients receiving rifampicin, and three of them were free of itch when switching over to phenobarbitone. Both drugs were equally effective in inducing hepatic microsomal function but rifampicin has the additional effect of reducing cholestasis. Its anti-pruritic effect should be tested in long-term clinical trials.

Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats.

BACKGROUND/AIMS Excessive nitric oxide biosynthesis caused by expression of inducible NO synthase has been implicated in the hyperdynamic circulation of portal hypertension. The aim of the study was to investigate whether inducible NO synthase is expressed in portal hypertension an accounts for the hyperdynamic circulation. METHODS In study 1, NO synthase activities were measured by the conversion of L-arginine to citrulline in tissues from portal-hypertensive, cirrhotic, and sham-operated rats and from normal rats pretreated with endotoxin and after long-term administration of dexamethasone, which inhibits the expression of inducible NO synthase. In study 2, systemic and splanchnic hemodynamics (radiolabeled microspheres) and gastric blood flow (hydrogen gas clearance and reflectance spectrophotometry) were measured in portal-hypertensive rats after long-term administration of dexamethasone (0.25 mg.kg-1.day-1) or vehicle. RESULTS In study 1, constitutive and inducible NO synthase activities in portal-hypertensive or cirrhotic rats were similar to those observed in sham-operated rats. The significant increase in the inducible activity observed after endotoxin injection was prevented when rats received long-term treatment with dexamethasone. In study 2, cardiac index, portal-pressure, portal venous inflow, and gastric blood flow were similar in dexamethasone-or vehicle-treated portal-hypertensive rats. CONCLUSIONS These results to not support a role for an increased expression of the inducible NO synthase in the hyperdynamic circulation of portal hypertension.

Effects of contrast media on renal function in patients with cirrhosis: A prospective study

Patients with cirrhosis are frequently submitted to radiological procedures that require the administration of contrast media. Contrast media is a well‐known cause of renal failure, particularly in the presence of some predisposing conditions. However, it is not known whether cirrhosis constitutes a risk factor for contrast media–induced renal failure. The aim of this study was to assess the possible nephrotoxicity of contrast media in patients with cirrhosis. In a first protocol, renal function was evaluated with sensitive methods (glomerular filtration rate using iothalamate I 125 clearance and renal plasma flow using iodohippurate I 131 clearance) before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal failure). Solute‐free water clearance, urine sodium, prostaglandins, and markers of tubular damage were also measured. The administration of contrast media was not associated with significant changes in renal function tests, neither in the whole group of patients nor in patients with ascites or renal failure. Urinary prostaglandin E2 and N‐acetyl‐β‐D‐glucosaminidase increased significantly, but sodium and solute‐free water excretion remained unchanged. In a second protocol, a different series of 60 patients with cirrhosis and renal failure were examined prospectively. No patient had renal failure due to contrast media. Only in 1 patient with septic shock was contrast media a possible contributing factor. In conclusion, the administration of contrast media is not associated with adverse effects on renal function in patients with cirrhosis. Cirrhosis does not appear to be a risk factor for the development of contrast media–induced nephrotoxicity. (HEPATOLOGY 2004;40:646–651.)

Effects of somatostatin on renal function in cirrhosis

To investigate the renal effects of somatostatin in cirrhosis, renal function and plasma and urinary levels of endogenous neurohumoral vasoactive substances were measured in conditions of intravenous water overload (20 mL/kg body wt with 5% glucose) before and during the intravenous infusion of somatostatin (250-500 micrograms/h) in 6 cirrhotic patients without ascites and 17 nonazotemic cirrhotic patients with ascites. Somatostatin induced a significant reduction of renal plasma flow, glomerular filtration rate, and free water clearance in both groups of patients. In patients with ascites, somatostatin also reduced urinary sodium excretion. Changes in renal function were significantly more marked in patients with ascites than in those without ascites and occurred in the absence of changes in mean arterial pressure and plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide. Somatostatin induced a significant reduction in the plasma concentration of glucagon and urinary excretion of prostaglandin E2 that was not related to changes in renal function. These findings indicate that somatostatin administration induces renal vasoconstriction and impairs glomerular filtration rate, free water clearance, and sodium excretion in cirrhosis by a mechanism unrelated to systemic hemodynamics and endogenous neurohumoral vasoactive systems.

Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd‐Chiari syndrome

Budd‐Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 ± 0.7 vs. 4.9 ± 1.2 L · min−1 · m−2; P < .001; systemic vascular resistance [SVR] index, 2,189 ± 736 vs. 1,377 ± 422 dyne · s · cm−5 · m−2, P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 ± 21.5 ng/mL · h, 76.7 ± 106.8 ng/dL, 586 ± 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis. (HEPATOLOGY 2006;43:27–33.)

Usefulness of 99mTc-ciprofloxacin scintigraphy in the diagnosis of prosthetic joint infections.

ObjectiveTo evaluate the usefulness of 99mTc-ciprofloxacin scintigraphy (CFS) in patients with hip or knee arthroplasty and suspected infection. MethodsForty patients (26 women, 14 men) with a mean age of 66±10 years and local pain in the hip (21), knee (16), or shoulder (three) prosthesis were recruited. CFS was performed at 1, 4, and 24 h after intravenous injection of 370 MBq. Anterior and posterior views centered on the affected joint were performed in all patients. A routine bone scan, 99mTc-hexamethylpropyleneamine oxime leukocyte scan, and 99mTc-colloid scan [leukocyte scintigraphy–bone marrow scintigraphy (LS–MS)] were performed. Final diagnosis of infection was confirmed by positive microbiological analysis or macroscopic evidence of purulent material. ResultsDiagnosis of arthroplasty infection was established in 16 out 40 cases: coagulase-negative staphylococci (nine), Staphylococcus aureus (three), Enterococcus (one), and macroscopic infection in the remaining three cases. CFS imaging showed the 24-h image to be the best acquisition time-point. The sensitivity, specificity, negative predictive value, and positive predictive value for LS–MS were 75, 92, 86, and 85%, whereas for CFS at 24 h these figures were 88, 71, 67, and 89%. The sensitivity and specificity for LS–MS and for CFS at 24 h for hip were (74, 90, and 88, 85%) and for knee (83, 90 and 100, 50%). ConclusionCFS can be useful in the diagnosis of arthroplasty infection of the hip as a substitute for LS–MS. It is recommended that CFS images be obtained 24 h after injection. The lack of specificity of CFS makes this technique inadequate for knee prostheses in this series.

Intracellular and exchangeable potassium in cirrhosis: Evidence against the occurrence of potassium depletion in cirrhosis with ascites

The intracellular potassium content of leukocytes, the extracellular fluid volume (82Br space), and exchangeable potassium were determined in 28 patients with cirrhosis of the liver (18 with ascites) and in 15 hospitalized controls. No intracellular potassium depletion could be identified in these patients. Leukocyte potassium was similar in cirrhotic patients with and without ascites (355.9±25.3 and 348.1±31.9 mEq/kg of dry solids, respectively) and in hospitalized controls (359.7±27.4) (mean±sd). The extracellular fluid volume was similar in controls and cirrhotics without ascites, but markedly increased in cirrhotics with ascites. The exchangeable potassium (mEq/kg of body weight) was similar in nonascitic cirrhotics and in hospitalized controls, but significantly lower in patients with cirrhosis and ascites. However, when the estimated weight of the extracellular fluid volume was substrated from the total body weight, thus obviating the influence of the increased extracellular fluid volume of ascitic patients in the body weight, the exchangeable potassium (mEq/kg of “corrected” body weight) was similar in cirrhosis with ascites (52.9±6.7 mEq/kg), nonascitic cirrhotics (55.8±6.1 mEq/kg) and hospitalized controls (55.0±8.3 mEq/kg), and a significant correlation was obtained between the exchangeable potassium and the leukocyte potassium content. In five patients, the measurements were repeated after relieving ascites with diuretics. No change was observed in the leukocyte potassium, but exchangeable potassium (mEq/kg of body weight) increased, reaching values not significantly different from controls or nonascitic cirrhotics. The exchangeable potassium (mEq/kg of “corrected” body weight) did not change. Our results strongly suggest that potassium depletion was not present in the series of cirrhotic patients studied.

123Iodine-labelled anti-VCAM-1 antibody scintigraphy in the assessment of experimental colitis.

Objectives To evaluate the usefulness of 123I-labelled anti-vascular cell adhesion molecule-1 (VCAM-1) monoclonal antibody (MAb) scintigraphy in the assessment of colonic inflammatory damage. Design Colitis was induced by intracolonic administration of 30 mg trinitrobenzenesulphonic acid in 0.5 ml of 50% (v/v) ethanol. Rats injected with vehicle served as controls. Animals were studied at day 7 after induction of colitis. Methods Scintigraphy was performed in control and trinitrobenzenesulphonic acid-induced colitic rats 2, 4 and 24 h after intravenous administration of 123I-anti-VCAM-1 MAb. Scintigraphic uptake was quantified in selected areas on scintigraphs. Animals were killed, tissue 123I radioactivity accumulation was measured, and accumulation of anti-VCAM-1 MAb in each organ was calculated. 99mTc-hexamethyl propylene amine oxime-labelled leucocyte scintigraphy was performed in additional groups of animals for comparison. Results Colonic tracer uptake was visible in scans of colitic, but not control animals. Quantification of scintigraphic uptake in the colon was significantly higher in colitic rats than in control animals (P < 0.0001). The specificity of the increase was demonstrated by lack of 123I-labelled non-binding MAb uptake in the colon, and by displacement of 123I-anti-VCAM-1 MAb colonic uptake by pre-treatment with unlabelled MAb. Accumulation of anti-VCAM-1 MAb in the colon of colitic rats was eightfold higher than in control animals. Strong correlations were found between quantification of scintigraphic uptake, anti-VCAM-1 MAb accumulation, histological damage and myeloperoxidase activity in the colon. Conclusion 123I-labelled anti-VCAM-1 MAb scintigraphy allows an accurate evaluation of colonic inflammatory damage in trinitrobenzenesulphonic acid-induced colitis, suggesting a potential role for this imaging technique in the assessment of human IBD.

Age-dependent enzymuria, proteinuria and changes in renal blood flow and glomerular filtration rate in rats

The time course of urinary excretion of two enzymatic indicators of renal damage, N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP) was measured in female Wistar rats at different ages. NAG and AAP are localized at different sites of the nephron and are released into the urine when kidney damage occurs. Total protein flow, urinary volume and creatinine flow were also determined. In a parallel experiment, the effect of aging on renal blood flow (RBF) and glomerular filtration rate (GFR) was examined in young (1.5-month) adult (3-month) and elderly (20-month) female rats. Clearance following a single injection of [131I]o-iodohippurate (hippuran, OIH) was used for the measurement of effective RBF and as an index of tubular cell function. [125I]Iothalamate (IOT) clearance was used to measure GFR. With advancing age, an increase in NAG and AAP urinary flow appeared. The increases in protein excretion were greater than and previous to those of enzyme excretion. It is shown that absolute RBF and GFR (ml/min) in old rats are greater than in young or adult animals. When absolute RBF or GFR was divided by kidney weight (ml/min/g) no clearance changes appeared in any age group studied; only when clearance was expressed in relation to body weight (ml/min/100 g), a decrease in RBF and GFR was evidenced. This indicates that the rate of increase of both RBF and GFR with age is similar to that of kidney weight and lower than that of body weight. The present findings indicate that urinary markers of renal injury increase with age, whereas GFR and RBF only decrease when expressed as clearance related to body weight.

Acute Effects of the Anti-Inflammatory Cyclooxygenase-2 Selective Inhibitor, Flosulide, on Renal Plasma Flow and Glomerular Filtration Rate in Rats

Nephrotoxicity of nonsteroidal anti-inflammatory drugs is associated with other risk factors (volume-depletion) and may be secondary to functional changes mediated by the inhibition of renal cyclooxygenases. Acute anti-inflammatory doses of flosulide and indomethacin were determined on carrageenan paw edema and its effects on renal plasma flow (RPF) and glomerular filtration rate (GFR) were studied in normovolemic and hypovolemic rats. In normovolemic rats, flosulide increased RPF and GFR (25 mg/kg) and indomethacin (5–10 mg/kg) was without effect. Volume-depleted rats were obtained by oral furosemide (32 mg/kg), urinary eicosanoids were determined. After furosemide, plasma volume, RPF and GFR and PGE2 decreased. Treatment of hypovolemic rats with flosulide (5–25 mg/kg) or indomethacin 10 mg/kg reduced RPF and GFR. Flosulide at 5 mg/kg reduced 6-keto-PGF1α whereas at 25 mg/kg and after indomethacin at 10 mg/kg a fall in 6-keto-PGF1α and TXB2 appeared. Our data suggest that acute COX-2 selective inhibition may alter renal function.