Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.

Irinotecan-induced central nervous system toxicity: a case report.

Here we describe the first case, to our knowledge, of CNS [Central nervous system] toxicity in a patient treated with irinotecan.

Perioperative intravenous iron; an upfront therapy for treating anaemia and reducing transfusion requirements.

Perioperative anaemia, with iron deficiency being its leading cause, is a frequent condition among surgical patients, and has been linked to increased postoperative morbidity and mortality, and decreased quality of life. Postoperative anaemia is even more frequent and is mainly caused by perioperative blood loss, aggravated by inflammation-induced blunting of erythropoiesis. Allogenic transfusion is commonly used for treating acute perioperative anaemia, but it also increases the rate of morbidity and mortality in surgical and critically ill patients. Thus, overall concerns about adverse effects of both preoperative anaemia and allogeneic transfusion have prompted the review of transfusion practice and the search for safer and more biologically rational treatment options. In this paper, the role of intravenous iron therapy (mostly with iron sucrose and ferric carboxymaltose), as a safe and efficacious tool for treating anaemia and reducing transfusion requirements in surgical patients, as well as in other medical areas, has been reviewed. From the analysis of published data and despite the lack of high quality evidence in some areas, it seems fair to conclude that perioperative intravenous iron administration, with or without erythropoiesis stimulating agents, is safe, results in lower transfusion requirements and hastens recovery from postoperative anaemia. In addition, some studies have reported decreased rates of postoperative infection and mortality, and shorter length of hospital stay in surgical patients receiving intravenous iron.

Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat.

Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2'-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned locomotion but not with the prevention of cocaine-induced sensitization.

The rise of soluble TWEAK levels in severely obese subjects after bariatric surgery may affect adipocyte-cytokine production induced by TNFα.

CONTEXT Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells. OBJECTIVES The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity. DESIGN sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed. RESULTS sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events. CONCLUSION The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα.

Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results.

The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous) or incorporated through the diet and nutritional supplements (exogenous). In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency.