Liver damage and plasma concentrations of paracetamol and its metabolites after paracetamol overdosage in mice.

The effects of single oral and intraperitoneal (i.p.) overdoses of paracetamol (500 mg/kg) were studied in mice. The correlation between hepatocellular damage and plasma levels of paracetamol metabolites derived from the oxidative pathway were also investigated. Animals were killed at different intervals (1, 2.5 and 6 h) after drug administration. Plasma concentrations of paracetamol and its sulphate, glucuronide, cysteine and mercapturate conjugates were determined by HPLC. Paracetamol plasma levels were significantly higher at 1 and 2.5 h after i.p. administration as compared to oral administration (p = 0.01 and p = 0.02, respectively). Plasma levels of mercapturic acid conjugate were significantly higher at 6 h after i.p. administration (p = 0.04). After 6 h, animals given oral paracetamol showed significantly less necrosis than animals given i.p. paracetamol (p = 0.03). Plasma levels of mercapturate conjugate at 6 h showed a significant correlation with the severity of liver necrosis (r = 0.64; p = 0.02). The results suggest that i.p. paracetamol seems to be more adequate for hepatotoxicity studies in mice.

Protective effect of diltiazem against acetaminophen hepatotoxicity in mice.

There is evidence that an increase in cytosolic Ca++ concentration is a terminal event in the progression to cell death in toxic liver injury. We have compared the hepatoprotective effects of N-acetylcysteine (1 g/kg) and the calcium channel blocking agent, diltiazem (24 mg/kg), when given at 30 min, 3 h and 6 h after single intraperitoneal overdoses of acetaminophen (500 mg/kg) in mice. Overall beneficial effects on mortality, liver necrosis score, and plasma alanine aminotransferase (ALT) activity were found in diltiazem-treated mice 24 h after acetaminophen overdose. However, the most marked effects were obtained when diltiazem was given 6 h after acetaminophen. N-acetylcysteine was more effective than diltiazem at 30 min and 3 h, although it was less effective at 6 h. Mean plasma concentrations of the mercapturate metabolite (hepatic oxidative metabolism) were not significantly different among animals receiving acetaminophen alone or in combination with diltiazem, which suggests that the hepatoprotective effects of diltiazem are not exerted by inhibition of drug metabolic enzymes.

Prevalence of macroprolactin detected by Elecsys 2010.

BACKGROUND: Macroprolactin or big-big PRL is, usually, a complex of little prolactin (PRL) with anti-PRL autoantibody. There are some patients with hyperprolactinemia showing a high proportion of serum macroprolactin. However, its clinical significance is not clear. Immunoassays used to determine PRL differ in their ability to detect macroprolactin. Moreover, in recent years, PRL assays have changed from isotopic methods (radioimmunoassays and immunoradiometric assays) to non-isotopic automated immunoassays. The effect of macroprolactin on currently used methods is often unknown. The aim of this work was to study the different reactivity of macroprolactin in two immunoassays systems, Elecsys 2010 and ACS Centaur, and to assess the clinical repercussion of this condition. METHODS: We studied retrospectively 956 consecutive routine patients. Samples with a PRL value >636 mIU/l (211 samples) were subjected to the polyethylene glycol (PEG) precipitation test to detect macroprolactin, and 2 of them also to gel filtration chromatography for further confirmation. PRL was measured by Elecsys 2010 and, alternatively, by ACS Centaur. RESULTS: By Elecsys 2010, macroprolactin was detected in 19 patients (9%). After removing macroprolactin, PRL levels were within the normal range in every case but one. When original sera from patients with macroprolactin were processed with ACS Centaur. PRL levels were normal or only marginally elevated. The correlation of PRL values in samples with and without macroprolactin assayed by both systems was 0.64 and 0.98, respectively. CONCLUSIONS: Nearly 9% of hyperprolactinemic patients detected by Elecsys 2010 may have macroprolactin, but the detection rate obtained using ACS Centaur is much lower. As macroprolactin seems to have minimal clinical relevance, it would be important that the users of PRL assays be aware to what extent macroprolactin interferes with their assays, and have available a validated method, such as the PEG precipitation test, to confirm the presence of macroprolactin.

Effect of exogenous cholecystokinin and secretin on pancreatic secretion of insulin and glucagon in rats: in vivo model without hepatic filter.

In order to study the effect of cholecystokinin and secretin on the endocrine function of the pancreas, we have developed an experimental model that we have applied to a total of 30 anesthetized rats stimulated with physiological or supraphysiological doses of cholecystokinin and secretin administered intravenously by continuous infusion. Our results show that the serum insulin concentration increases after the supramaximum dose of cholecystokinin is infused, while that of glucagon increases after the maximum dose of this hormone. In case of secretin, the serum glucagon level increases after the supramaximum dose, while that of insulin is not affected by any dose. We conclude that after infusion of physiological doses of cholecystokinin, the pancreatic secretion of glucagon is modified but not that of insulin, while secretin has no effect on the endocrine pancreatic secretion of either insulin or glucagon upon the same conditions.

Changes in P-glycoprotein expression in gastric carcinoma with respect to distant gastric mucosa may be influenced by p53.

BACKGROUND: The effectiveness of some chemotherapeutic agents used to treat gastric carcinoma patients may be impaired by the presence of P-glycoprotein (P-gp) and the status of p53. A modulation of P-gp expression by p53 or other alterations during tumorigenesis have been reported. The authors analyzed P-gp expression in relation to p53 and histopathologic features in gastric carcinoma. METHODS: Forty-one resected gastric carcinomas and mucosa distant from the tumor were assessed for P-gp expression by immunohistochemistry with C494 and JSB-1 antibodies. p53 expression was also immunohistochemically assessed by DO7 antibody in tumor samples. P-gp and p53 expression were semiquantitatively analyzed according to the percentage of stained cells. Histologic type, grade, vessel invasion, and stage were also studied. RESULTS: Moderate or high P-gp expression was detected in gastric carcinoma in 29 cases (71%) and in gastric mucosa remote from the tumor in 36 cases (88%). This reduction in P-gp expression was observed in 22% of the carcinomas, all but 1 being p53 immunonegative tumors. Thus, 8 (42%) of the p53 immunonegative carcinomas showed a loss of P-gp expression compared with their distant gastric mucosa. All p53 immunopositive carcinomas coexpressed P-gp. No correlation between P-gp expression and histologic type, grade, vessel invasion, or stage was found. CONCLUSIONS: P-gp expression in gastric carcinomas is frequent and coexpression with p53 is found. The analysis of P-gp expression in carcinomas and distant mucosa show that it is not regulated by p53, but a loss of P-gp detected in some of these carcinomas is mainly associated with a lack of p53 protein accumulation.

Lupus eritematoso sistémico, con síndrome antifosfolípido asociado / Systemic lupus erythematosus with antiphospholipid syndrome

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