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Biomedical subjects

G Laffi

Publications and source records attributed to G Laffi.

At least 73 records · Page 4Linked to original sources
PubMed1994

Biosynthesis of platelet-activating factor and its 1O-acyl analogue by liver fat-storing cells.

BACKGROUND/AIMS: Platelet-activating factor (PAF) is an important mediator of proinflammatory cell-to-cell interactions with powerful vasoactive properties. We evaluated the biosynthesis of PAF by cultured human fat-storing cells (FSC), liver-specific pericytes involved in the inflammatory and fibrogenic process of liver tissue. METHODS: PAF synthesis was evaluated by measuring [3H]acetate incorporation under basal conditions and upon stimulation with A23187, thrombin, and lipopolysaccharide. Further analysis of PAF species synthesized by FSC was performed using gas chromatography/mass spectrometry. RESULTS: All stimuli induced a significant increase of basal PAF synthesis by FSC. Further analysis showed that > 50% of the newly synthesized PAF species was secreted whereas the remaining fraction was cell-associated. PAF species produced by FSC were able to induce aggregation of rabbit washed platelets with an effectiveness correspondent to 10(-9) mol/L authentic PAF. Gas chromatography/mass spectrometry analysis revealed that a large percentage (74%) of PAF-like lipids synthesized by FSC consisted of 1O-acyl PAF. Finally, stimulation of FSC with PAF caused an increase in cytosolic free calcium, thus suggesting a possible involvement of this pericyte in the well-known effects of PAF on portal pressure. CONCLUSIONS: These results expand the available knowledge concerning the role of PAF in conditions characterized by extensive activation and damage of the liver sinusoidal endothelium and decreased hepatic scavenger activity.

Acetates↗
PubMed1994

Pathogenesis and treatment of ascites in hepatic cirrhosis.

In cirrhosis of the liver structural distortion of the sinusoidal vessels is the major factor responsible for the increase in portal venous pressure and the development of abdominal ascites. The mechanisms by which advanced cirrhosis of the liver leads to widespread changes in the systemic circulation including vasodilatation, increased cardiac output and expanded plasma volume, together with activation of a range of antinatriuretic and natriuretic factors, are unclear. Several hypotheses have been proposed to explain these pathophysiological consequences, including underfilling of the systemic arterial system, overflow and peripheral vasodilatation, with a decrease in effective arterial blood volume. The evidence for and against these hypotheses is critically examined. In patients with hepatic cirrhosis complicated by ascites, increased intrarenal release of vasodilating prostaglandins may assist in sustaining renal blood flow and glomerular filtration rate by counteracting the vasoconstrictor effects of noradrenaline and angiotensin II. In advanced stages of the syndrome, cirrhotic ascites may become refractory to medical treatment. In this situation renal function becomes progressively impaired and eventually acute renal failure, so-called hepatorenal syndrome, supervenes due to intense renal vasoconstriction and opening of intrarenal arteriovenous shunts. The progressive renal vasoconstriction may also be accentuated by the reduced synthesis of renal vasodilating prostaglandins. The medical treatment of ascites is based on bed-rest, a low-sodium diet and administration of aldosterone antagonists and loop diuretics. Patients who are refractory to such therapy may be further treated by paracentesis or by the LeVeen shunt, though the long-term results of these physical therapies are unsatisfactory.

Ascites↗
PubMed1993

Torasemide in the treatment of patients with cirrhosis and ascites.

The effects of torasemide (20 mg/day) and furosemide (50 mg/day), each given over 4 days, were compared in a randomized and crossover study carried out in seven patients with cirrhosis and tense ascites. Patients also received a low-sodium (40 mmol/day) diet and the aldosterone antagonist, potassium canrenoate (100 mg b.i.d.). Torasemide induced a remarkably higher natriuretic (120 +/- 15 vs. 33 +/- 6 mmol/day, p < 0.02) and diuretic (1450 +/- 63 vs. 900 +/- 58 ml, p < 0.005) effect than furosemide. Body weight loss was also significantly higher (2.5 +/- 1.6 vs. 0.2 +/- 1.3 kg, p < 0.01) during the torasemide period. Kaliuresis was similar during the two treatment periods, despite the striking differences observed in natriuresis. Neither torasemide nor furosemide induced any significant change in serum electrolyte or creatinine concentrations, or in ammonia levels. The results of this study indicate that torasemide is suitable for the treatment of sodium retention in patients with cirrhosis and ascites.

Adult↗
PubMed1993

Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides.

BACKGROUND: Patients with advanced cirrhosis show defective platelet aggregation, which is dependent, at least in part, on intrinsic platelet abnormalities. The aim of this study was to evaluate the activating and inhibitory pathways of platelet signal transduction in cirrhotic patients. METHODS: Twelve cirrhotic patients and 12 control subjects participated in this study. Measurements were performed on washed platelets. RESULTS: Thrombin-stimulated inositol 1,4,5-trisphosphate production was reduced fivefold, and the increase in cytosolic calcium concentration was significantly lower in platelets from cirrhotic patients following stimulation with thrombin, platelet activating factor, or U-46619. In addition, the activity of the platelet Na+/H+ antiporter, evaluated after an acid load, was significantly lower in platelets from cirrhotic patients (0.90 +/- 0.19 vs. 1.37 +/- 0.16 delta pHi/min, P = 0.07). Cirrhotic patients also showed a significantly increased basal intraplatelet content of both 5'-cyclic adenosine monophosphate (cAMP) (2724 +/- 330 vs. 1561 +/- 258 fmol/10(8) platelets, P < 0.05) and 5'-cyclic guanosine monophosphate (cGMP) (217 +/- 18 vs. 159 +/- 29 fmol/10(8) platelets, P < 0.05). CONCLUSIONS: Our results indicate that in platelets from cirrhotic patients, defective early signal transduction is associated with an increase in platelet cAMP and cGMP, thus revealing new mechanisms contributing to the defective platelet function in this disease.

Adult↗
PubMed1993

Impaired superoxide anion, platelet-activating factor, and leukotriene B4 synthesis by neutrophils in cirrhosis.

BACKGROUND: Several alterations of polymorphonuclear leukocyte (PMN) function were found in alcoholic cirrhotics that may contribute to augmented susceptibility to infections. We evaluated function and synthesis of lipid mediators in PMN obtained from nonalcoholic cirrhotics. METHODS: We evaluated the phagocytic and chemotactic response together with superoxide anion (O2-), leukotriene B4, (LTB4) and platelet-activating factor (PAF) production in response to different stimuli in PMN from nonalcoholic cirrhotics as compared with controls. RESULTS: PMN from cirrhotics showed, after stimulation with opsonized zymosan (STZ) and phorbol-12-myristate-13-acetate, a reduced capacity to produce O2- when compared with controls. [3H]acetate incorporation into PAF was significantly higher in PMN obtained from controls in respect to cirrhotics. Gas chromatography/mass spectrometry analysis confirmed a reduced PAF synthesis by PMN obtained from cirrhotics. LTB4 production from PMN, after stimulation with calcium ionophore (A23187) and STZ, was significantly reduced in cirrhotics. [3H]arachidonic acid release from prelabeled PMN, measured upon stimulation with A23187 and STZ, was higher in controls than in cirrhotics. CONCLUSIONS: An altered synthesis of LTB4 and PAF is associated with an impaired O2- production by PMN in nonalcoholic cirrhosis. Reduced synthesis of lipid mediators may be related to an altered phospholipase A, activity.

Adult↗
PubMed1993

Loop diuretic therapy in liver cirrhosis with ascites.

Medical treatment of ascites is aimed at reverting sodium retention, that is, at creating a negative sodium balance to relieve ascites. Bed rest and low-sodium diet induce the disappearance of ascites in about 10% of patients. Loop diuretics and aldosterone antagonists must be administered to the patients not responding to the previous regimen. Available evidence indicates that aldosterone antagonists are the first-choice drugs, as these substances are more effective than furosemide. Nevertheless, loop diuretics potentiate the effects of aldosterone antagonists. The reduced efficacy of furosemide in these patients, when compared with that of spironolactone, may be related to an impairment of both pharmacodynamics and pharmacokinetics. In fact, most sodium not reabsorbed in Henle's loop, due to the action of furosemide, is subsequently taken up in the distal nephron because of hyperaldosteronism. A further mechanism of resistance may be related to an impaired excretion of furosemide into the tubular lumen. The use of diuretics in the treatment of ascites is associated with several side effects, including prerenal azotemia, hepatic encephalopathy, and electrolyte and acid-base disorders. A stepped-care approach, together with careful monitoring of patients, is the best way to reduce the incidence of these complications. Ethacrynic acid has been shown to be highly effective in the treatment of ascites, even in patients refractory to other diuretics, but its use is associated with a high incidence of hypokalemia and hypochloremic alkalosis. Bumetanide and piretanide are comparable to furosemide, in terms of both efficacy and side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗
PubMed1993

Efficacy and safety of the stepped care medical treatment of ascites in liver cirrhosis: a randomized controlled clinical trial comparing two diets with different sodium content.

In order to clarify debated issues of the medical treatment of ascites in cirrhosis--the usefulness of a low sodium diet and washout period preceding diuretic administration, maximal dosage of antimineralocorticoid to be reached before the addition of a loop diuretic, identifications of factors influencing treatment efficacy--115 hospitalized patients with non-azotemic cirrhosis and ascites were recruited and randomized to receive a diet providing either 40 or 120 mmol of sodium daily. After a washout period from the outpatient diuretic regimen for 7 days (Step 1), increasing dosages of K-canrenoate (200 mg/day every 4th day up to 600 mg) were administered to patients not undergoing spontaneous diuresis (Step 2). Upon the failure of Step 2, K-canrenoate (400 mg/day) and furosemide at increasing dosage (25-50-100 mg every other day) were given (Step 3). Nine percent of patients underwent spontaneous diuresis, and 77% developed a negative sodium balance by the end of Step 2 (69% with a dosage of K-canrenoate < or = 400 mg/day) and 93% by the end of Step 3. Two patients were withdrawn from the protocol due to diuretic side-effects. Univariate analysis showed that the type of diet did not influence the response to treatment. The washout period led to a significant increase in endogenous creatinine clearance; natremia significantly rose in hyponatremic patients. Multivariate analysis showed that creatinine clearance and plasma aldosterone were independent predictive factors of the response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗
PubMed1992

Plasma levels of brain natriuretic peptide in patients with cirrhosis.

Plasma levels of brain natriuretic peptide, a recently identified cardiac hormone with natriuretic activity, were measured in 11 healthy subjects, 13 cirrhotic patients without ascites, 18 nonazotemic cirrhotic patients with ascites and 6 patients with cirrhosis, ascites and functional kidney failure. Plasma levels of brain natriuretic peptide were similar in healthy subjects and cirrhotic patients without ascites (5.56 +/- 0.65 and 7.66 +/- 0.68 fmol/ml, respectively). In contrast, cirrhotic patients with ascites, with and without functional kidney failure, had significantly higher plasma concentrations of brain natriuretic peptide (19.56 +/- 1.37 and 16.00 +/- 1.91 fmol/ml, respectively) than did healthy subjects and patients without ascites (p less than 0.01); no significant difference was found between the two groups of cirrhotic patients with ascites with respect to this parameter. In the whole group of cirrhotic patients included in the study, brain natriuretic peptide level was directly correlated with the degree of impairment of liver and kidney function, plasma renin activity and plasma levels of aldosterone and atrial natriuretic peptide. The results of this study indicate that brain natriuretic peptide is increased in cirrhotic patients with ascites and suggest that sodium retention in cirrhosis is not due to deficiency of this novel cardiac hormone.

Alanine Transaminase↗
PubMed1992

Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

Aged↗
PubMed1992

Evidence for a storage pool defect in platelets from cirrhotic patients with defective aggregation.

The mechanisms underlying the defective platelet function in cirrhotic patients were investigated. Eleven cirrhotic patients with mild disease (group 1), 20 patients with severe cirrhosis (group 2), and 31 controls were studied. Platelet aggregation was significantly reduced in cirrhotics compared with controls. Compared with controls, cirrhotic patients in group 2 showed a significant reduction in the total content of adenosine triphosphate (57.8 +/- 7.8 vs. 26.1 +/- 6.3 mumol/10(11) platelets; P less than 0.05), 5-hydroxytryptamine (285 +/- 26 vs. 104 +/- 38 nmol/10(11) platelets; P less than 0.05), beta-thromboglobulin (2129 +/- 120 vs. 1223 +/- 161 ng/10(8) platelets; P less than 0.01), and platelet factor 4 (1389 +/- 108 vs. 805 +/- 176 ng/10(8) platelets; P less than 0.05). In patients with severe disease, an increase in plasma beta-thromboglobulin-platelet factor 4 ratio, an index of in vivo platelet activation, was observed (controls, 3.50 +/- 0.50; group 1, 4.02 +/- 0.80; and group 2, 6.59 +/- 1.15). Our data indicate the existence of a platelet storage pool defect, which may favor the bleeding tendency of cirrhotic patients.

Adenosine Triphosphate↗
PubMed1992

Pathophysiology and treatment of ascites and the hepatorenal syndrome.

Ascites indicates the accumulation of fluid in the peritoneal cavity, due to a wide range of causes. These causes can be classified according to the presence of portal hypertension, severe blood dyscrasia and peritoneal disease. Cirrhosis is the most frequent cause of ascites. The occurrence of ascites in cirrhosis is due to portal hypertension, which is responsible for the increase in hydrostatic pressure at the sinusoidal level and the alterations of splanchnic and systemic haemodynamics. These latter include increased splanchnic inflow, reduced systemic resistance and increased plasma volume and cardiac output. Portal hypertension also plays a major role in determining sodium retention, which occurs in the setting of increased RAA system and SNS activity. The mechanisms by which portal hypertension leads to the activation of antinatriuretic factors and sodium retention are not completely understood; three main hypotheses have been proposed to explain this relationship, namely the underfilling, the overflow and the peripheral arterial vasodilatation theories. In patients with cirrhosis and ascites, there is an overall activation of the renal prostaglandin system, which probably acts to maintain renal haemodynamics and GFR by counteracting the vasoconstricting effects of AII and noradrenaline on renal circulation. In advanced stages, ascites may become refractory to medical treatment and renal function shows a progressive impairment and eventually acute renal failure, the so-called HRS, due to a marked vasoconstriction of the renal arteries and the opening of the intrarenal-arteriovenous (A-V) shunts. In this condition, the reduced renal synthesis of vasodilating prostaglandins is probably of pathogenic importance. Treatment of ascites is usually based on bed rest, low-sodium diet and administration of aldosterone antagonists and loop diuretics. A sequential treatment of ascites based on the progressive addition of more potent drugs is the best way to relieve ascites while avoiding potentially dangerous side-effects. Patients who fail to respond to the above manoeuvres are said to have refractory ascites. Current treatment of this latter condition is mainly based on therapeutic paracentesis and the application of the LeVeen shunt, but long-term results are unsatisfactory.

Ascites↗
PubMed1991

Evidence for alpha 1-adrenoreceptor hyperresponsiveness in hypotensive cirrhotic patients with ascites.

Cirrhosis with ascites is often characterized by arterial hypotension associated with increased plasma norepinephrine levels. Clinical evidence suggests a decreased sensitivity to norepinephrine in this clinical setting, indicating a potential derangement of alpha 1 adrenoreceptors. The aim of the present study was to evaluate the reactivity of the alpha 1-adrenoreceptor, using phenylephrine, a selective alpha 1 receptor agonist. First, we evaluated the pupillar response to the intraconjunctival administration of the agonist. Hypotensive cirrhotic patients showed a trend to a more marked and prolonged response, compared with age-matched healthy controls. Second, we studied the response of alpha 1-adrenoreceptors in the peripheral vasculature by administering iv phenylephrine to a similar group of patients. A significantly greater and longer lasting pressor response was observed in hypotensive cirrhotic patients (p less than 0.0001 vs. healthy controls). Our results indicate that in this group of patients, there is a rather peculiar situation, characterized by alpha 1-adrenoreceptor hyperresponsiveness in the presence of high levels of circulating norepinephrine. This finding could be related to biochemical abnormalities within the peripheral sympathetic nervous system endings.

Adult↗
PubMed1991

Comparison of the effects of torasemide and furosemide in nonazotemic cirrhotic patients with ascites: a randomized, double-blind study.

In a randomized double-blind trial we compared the effects of torasemide, a new loop diuretic, and furosemide in nonazotemic cirrhotic patients with ascites during a 3-day period in association with potassium canrenoate (200 mg/day) administration. Doses of loop diuretics administered in this trial (10 and 25 mg/day of torasemide and furosemide, respectively) had been shown to be equipotent in healthy subjects. Torasemide induced significantly greater natriuresis than furosemide (p less than 0.02), with a twofold greater percentage increase in basal values (day 1: 130% vs. 50%; day 2: 104% vs. 42%; and day 3: 65% vs. 26%, respectively). Body weight loss was significantly higher during torasemide (p less than 0.02) administration, and the overall decrease at the end of the treatment was twice as high for furosemide (2.5 +/- 0.6 kg vs. 1.3 +/- 0.4 kg, respectively). Diuresis was also higher during torasemide administration, but the difference was not significant (p = 0.08). The extent of kaliuresis observed during the two treatments was almost identical despite the striking differences in the natriuretic response. The effects of the two treatments on plasma electrolytes, creatinine clearance, blood urea nitrogen, mean arterial pressure, heart rate and plasma arginine vasopressin concentration were similar. Both drugs caused increases in plasma renin activity at the end of the treatment, whereas plasma aldosterone concentration slightly increased only after torasemide administration. Despite the presence of a trend toward a more pronounced effect on these parameters after torasemide administration, no significant difference between the two treatments was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗
PubMed1989

Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure.

In a randomized double-blind cross-over study the effects of rhein (administered as diacetyl-rhein 50 mg b.d. for 5 days) and placebo on renal arachidonic acid metabolism and renal function have been compared in 12 elderly patients (mean age 75.2 years) with congestive heart failure, whose renal function was known to be dependent on the integrity of the renal prostaglandin system. Rhein like placebo, did not induce any change in the urinary excretion of prostaglandin (PG) E2, 6-keto-PGF1 alpha and thromboxane (TX) B2, nor did it affect creatinine clearance, blood urea, urine output, natriuresis, body weight, plasma renin activity or plasma aldosterone concentration. Separate analysis of the results obtained in the 5 patients receiving diuretic treatment did not show any significant effect of rhein as compared with placebo on the parameters investigated. Serum TXB2 concentration during whole blood clotting, as an index of platelet arachidonic acid metabolism, also showed no significant difference when DAR and placebo were compared. It is concluded that in patients with congestive heart failure rhein does not inhibit renal or platelet eicosanoid metabolism, nor does it modify renal function, sodium excretion or the renal response to diuretics.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion in cirrhosis with ascites.

We investigated the effect of a continuous infusion (50 micrograms as an initial bolus followed by a maintenance infusion at a rate of 0.1 micrograms/min.kg body wt for 45 min) of synthetic human atrial natriuretic factor (hANF) on renal hemodynamics and the renin-angiotensin-aldosterone system in 15 cirrhotic patients with ascites. Basal hANF levels were higher in cirrhotic patients when compared with normal values. Human atrial natriuretic factor infusion induced a significant decrease in mean blood pressure (from 77.8 +/- 1.1 to 68.6 +/- 1.5 mmHg, p less than 0.001) and a significant increase in heart rate (from 76.4 +/- 2.7 to 89.8 +/- 2.4 beats/min, p less than 0.001) in the patients studied. A remarkable increase in natriuresis (i.e., greater than or equal to 200 muEq/min) was observed in 5 patients (responders), whereas the infusion did not modify sodium excretion (i.e., less than or equal to 20 muEq/min) in 6 patients (nonresponders) and induced an intermediate response in 4 patients. Human atrial natriuretic factor-induced natriuresis was related to changes in renal hemodynamics that occurred during hANF infusion. In responders, the extent of the natriuretic response paralleled the increase of effective renal plasma flow and glomerular filtration rate; in non-responders the absent natriuretic response was associated with an evident reduction of these parameters. The reduction of blood pressure was similar in responders and nonresponders, but in the latter group it was followed by a marked increase of plasma renin activity and heart rate. It is likely that in nonresponders the natriuretic effect of hANF was blunted by the hemodynamic and hormonal changes triggered by the concomitant hANF-induced hypotension. This probably occurs in the presence of a greater reduction of effective arterial blood volume, as suggested by the higher baseline levels of plasma renin activity and the inability to increase free water excretion after a water load observed in nonresponders.

Adult↗
PubMed1989

Effects of repeated atrial natriuretic peptide bolus injections in cirrhotic patients with refractory ascites.

The renal and hormonal effects of repeated atrial natriuretic peptide (ANP) boli (1 microgram/kg of body weight) were studied in eight cirrhotic patients with refractory ascites. Under basal conditions the patients showed a striking activation of the renin-angiotensin-aldosterone system (plasma renin activity 19.3 +/- 3.0 ng/ml.h, plasma aldosterone concentration 3.87 +/- 0.58 ng/ml) and a tenfold elevation in plasma ANP levels compared to healthy subjects (131.7, range 47.0-288.6, vs. 9.8, range 5.0-15.0, fmol/ml, p less than 0.001). The first ANP injection was followed by a remarkable increase in plasma ANP levels and by a slight increase in urinary cyclic guanosine-monophosphate excretion (from 1050.8 +/- 454.8 to 1446.6 +/- 822.2 pmol/min). A significant reduction of mean blood pressure (MBP) occurred 5 min after the first injection (from 86.7 +/- 7.2 to 79.9 +/- 5.8 mmHg, p less than 0.05), but values gradually returned to the baseline after 30 min. Heart rate (HR) increased 10 min after the first bolus injection (from 83.75 +/- 4.7 to 88.1 +/- 4.6 beats/min) and reached baseline values after 30 min. Similar behaviour of MBP and HR was observed after the second, third and fourth bolus injections. Urinary sodium excretion, urinary flow, glomerular filtration rate, plasma renin activity, and plasma aldosterone concentration did not show any significant modification during ANP administration, nor did these parameters change in the following 12-h recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗