Prognostic models in end stage liver disease.

Cirrhosis is a major cause of death worldwide, and is associated with significant health care costs. Even if milestones have been recently reached in understanding and managing end-stage liver disease (ESLD), the disease course remains somewhat difficult to prognosticate. These difficulties have already been acknowledged already in the past, when scores instead of single parameters have been proposed as valuable tools for short-term prognosis. These standard scores, like Child Turcotte Pugh (CTP) and model for end-stage liver disease (MELD) score, relying on biochemical and clinical parameters, are still widely used in clinical practice to predict short- and medium-term prognosis. The MELD score, which remains an accurate, easy-to-use, objective predictive score, has received significant modifications over time, in order to improve its performance especially in the liver transplant (LT) setting, where it is widely used as prioritization tool. Although many attempts to improve prognostic accuracy have failed because of lack of replicability or poor benefit with the comparator (often the MELD score or its variants), few scores have been recently proposed and validated especially for subgroups of patients with ESLD, as those with acute-on-chronic liver failure. Artificial intelligence will probably help hepatologists in the near future to fill the current gaps in predicting disease course and long-term prognosis of such patients.

Transjugular intrahepatic portosystemic shunt in non-cirrhotic portal hypertension related to cystic fibrosis in a lung transplant patient.

Liver involvement is not uncommon in patients with cystic fibrosis (CF). Even if serious complications as non-cirrhotic portal hypertension, cirrhosis and liver failure rarely occur, they are associated with impaired survival and reduced quality of life. Herein, we have reported the first case of a patient with CF and non-cirrhotic portal hypertension who underwent transjugular intrahepatic portosystemic shunt placement for recurrent variceal bleeding after bilateral lung transplantation, and we have reviewed the available literature pertaining to this field.

Early versus delayed laparoscopic cholecystectomy for acute cholecystitis.

AIM: Laparoscopic cholecystectomy, currently the gold standard treatment for cholelithiasis, has been extended to treating acute cholecystitis as well. However, operation timing remains controversial. The aim of this retrospective study was to compare our data on the timing of surgery for early and delayed laparoscopic cholecystectomy for acute cholecystitis. METHODS: From January 1, 2006 to December 31, 2010, 508 laparoscopic cholecystectomy procedures were performed, 149 of which for acute cholecystitis: 122 operations were defined as early (performed within 72 hours of symptom onset) and 27 as delayed (72 hours to 9 days from symptom onset). RESULTS: There were no statistically significant differences in operating time, conversion or complications rates between early and delayed procedures. The total length of hospital stay was longer for patients who had undergone a delayed procedure. The success rates were similar irrespective of the surgeon's level of experience. CONCLUSION: Patients operated on for acute cholelithiasis between 72 hours and up to 9 days after symptom onset may benefit similarly as from an earlier operation. Delayed laparoscopic cholecystectomy for acute cholelithiasis is a feasible and safe procedure that compares favorably with early laparoscopic cholecystectomy.

Effect of d-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes.

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic microsomal metabolism of the potential memory-enhancing agent, CL 275,838, to its desbenzyl derivative.

1. The oxidation of the potential memory-enhancer and antidepressant agent CL 275,838 by rat liver microsomes was investigated. CL 275,838 was rapidly and extensively biotransformed in vitro to its desbenzyl derivative (II), the main metabolite observed in vivo. No other known metabolites could be detected in the incubation mixture except for trace amounts of a hydrolysis product (IV). 2. The formation of the desbenzylated derivative II required the presence of an NADPH-generating system and was significantly inhibited by carbon monoxide, SKF 525-A and cimetidine, indicating the participation of P450 in the oxidation of CL 275,838. The reaction was markedly enhanced by phenobarbital and by pregnenolone-16 alpha-carbonitrile [particularly in the female]. beta-Naphthoflavone did not significantly affect desbenzylation. 3. Kinetic studies indicate that there are sex-dependent differences in CL 275,838 metabolism in vitro, as observed in vivo in rat. Maximal velocity for the oxidation of CL 275,838 in microsomes isolated from the male rat was 17 times greater than in the female rat. The apparent Km for metabolism of CL 275,838 was similar in microsomes derived from the male and female rat. 4. CL 275,838 does not appreciably affect its own oxidation and does not cause significant hepatic microsomal enzyme induction in the male or female rat, except for slight enhancement of some components of the P450 system at doses (300 mg/kg once daily for 7 days) well above the effective pharmacological range.

The role of d-norfenfluramine in the indole-depleting effect of d-fenfluramine in the rat.

The importance of d-norfenfluramine in regard to the indole-depleting action of d-fenfluramine has not been well studied in sensitive animal species. The present study therefore examined the intensity and time course of the neurochemical effects of i.p. injected d-fenfluramine (2.5 and 5 mg/kg) and d-norfenfluramine (2.5 mg/kg) in vehicle- and SKF-525A-pretreated rats, relating the effects to the brain concentration-time profiles of the drug and its active metabolite. At the lower dose d-fenfluramine caused only a small, short-lasting decrease in brain serotonin (5-HT) without affecting the 5-hydroxyindoleacetic acid (5-HIAA). Higher doses affected both 5-HT and 5-HIAA (50-60 and 30-40% reductions, respectively), the effect being maximal for at least 8 h. d-Norfenfluramine reduced the brain content of 5-HT and 5-HIAA less (by about 30%) than 5 mg/kg d-fenfluramine did. Brain concentrations of d-norfenfluramine at the time of the maximal depletion of indoles were close to those of the metabolite after 5 mg/kg d-fenfluramine, indicating that the acute indole-depleting effects did not depend solely on the brain concentrations of its nor-metabolite. SKF-525A changed the metabolite-to-parent drug ratios in brain without appreciably influencing the action of d-fenfluramine. However, the maximum decrease in indole content caused by 2.5 mg/kg d-fenfluramine in SKF-525A-pretreated rats was only 12% of the control level, although the brain concentration of unchanged drug was comparable to that after 5 mg/kg d-fenfluramine in vehicle-pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses.

1. High parenteral doses of a twice-daily schedule of d,l-fenfluramine (d,l-F) may cause long-lasting decrease of functional indices of brain serotoninergic neurones in rats. The single- and multiple-dose (b.i.d. x 4 days) kinetics of low (1.25 mg/kg) and high (12.5 mg/kg) subcutaneous (s.c.) doses of d-F, which accounts of the anorectic effects of the racemate, and its deethylated metabolite d-norfenfluramine (d-NF), were therefore examined and compared with those of pharmacologically effective oral doses (0.3-1.25 mg/kg) in rats. 2. There were dose-dependent alterations of kinetic parameters after s.c. and oral dosing, indicating that hepatic clearance of d-F in the rat can be saturated either by increasing the size of the single dose or during repeated dosing. Nonlinearity was also observed for d-NF. Consequently at high doses exposure of rat to the drug, as measured by the sum of area under the plasma concentration-time curve (AUC) of d-F and d-NF considerably exceeded that expected from simple dosage considerations, particularly with repeated administration of d-F. 3. Total exposure at the high doses considerably exceeded that at pharmacological doses, however, indicating an ample margin in favour of anorectic activity. The possibility that the long-term depletion of brain 5-HT by d-F and/or its metabolite d-NF may have relevance at the usual therapeutic dose, is discussed.

[Education for health and the drug problem. The design of a protocol]. / Educazione alla salute e problema dei farmaci. Costruzione di un protocollo.

The article is a report on a training exercise with a group of student health visitors to verify their health education ability. The choice of the subject-matter (drugs) as well as that of the group addressed (the elderly) is subordinate to the main aim of the exercise, which is to test to feasibility and the importance of giving oneself a method of work.

[Usefulness of a study with 99m Tc-labelled erythrocytes for the recognition of hepatic angioma in the staging of cancer patients]. / Utilità dell'indagine con eritrociti marcati con 99mTc per il riconoscimento degli angiomi epatici nella stadiazione dei pazienti neoplastici.

Cavernous hemangiomas are the commonest benign tumors of the liver. Unfortunately, neither US nor CT allows cavernous hemangiomas to be positively discriminated from more dangerous lesions, e.g. metastases. Blood-pool scintigraphy has been reported to be a reliable technique for diagnosing hemangiomas of the liver: in fact, among the liver lesions in which 99m Tc-red blood cells gradually accumulate, only hemangiomas present an increased accumulation of radiotracers as soon as 2 hours afterwards. To determine the present value of blood-pool scintigraphy in oncological patients, we studied 17 patients whose US staging had shown dubious focal liver lesions. This technique allowed one or more hemangiomas to be diagnosed in 15 cases, and metastatic lesions in 2 cases. Scintigraphy with 99m Tc-labelled red blood cells proves thus to be an accurate method for the identification of cavernous hemangiomas of the liver in case of dubious US findings.