Chlorambucil for patients with primary biliary cirrhosis
ABSTRACT Chlorambucil has been used for patients with primary biliary cirrhosis as it possesses immunosuppressive properties. But it is unknown whether it benefits or harms these patients.
To evaluate the beneficial and any harmful effects of chlorambucil for primary biliary cirrhosis patients.
Eligible trials were identified by searching the Cochrane Hepato-Biliary Group Controlled Trials Register (March 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2012, Issue 2), MEDLINE (1946 to March 2012), EMBASE (1974 to March 2012), Science Citation Index EXPANDED (1900 to March 2012), The Chinese Biomedical Database (1976 to March 2012), The Chinese Medical Current Contents (1994 to March 2012), The China Hospital Knowledge Database (1994 to March 2012), and a database of ongoing trials (http://www.controlled-trials.com/mrct/) (accessed 6 March 2012). The reference lists of the retrieved publications and review articles were also read through, and pharmaceutical companies known to produce chlorambucil were contacted.
Randomised clinical trials, irrespective of language, year of publication, and publication status, comparing chlorambucil at any dose versus placebo, no intervention, another active drug, or one dose of chlorambucil with another dose.
We planned to assess continuous data with mean differences (MD), and dichotomous outcomes with relative risk (RR), both with 95% confidence intervals (CI). As we only identified one trial, Fisher's exact tests were employed.
Only one randomised trial was identified and included in the review. The bias risk in the trial was high. The trial compared chlorambucil versus no intervention in 24 patients with primary biliary cirrhosis. Fisher's exact test did not show a significant reduction of mortality when comparing chlorambucil with no treatment (0/13 (0%) versus (2/11 (18.2%); P = 0.20). There was no significant difference regarding adverse events for chlorambucil compared with no treatment, but all patients receiving chlorambucil experienced adverse events (13/13 (100%) versus (3/11 (27%); P = 0.1). According to the authors of the trial, chlorambucil led to a significant improvement in mean serum levels of bilirubin (P < 0.05), albumin (P < 0.05), immunoglobulin M (P < 0.01), serum aspartate aminotransferase activity (P < 0.01), and hepatic inflammatory infiltrates (P < 0.01).
There is not sufficient evidence to support or reject the use of chlorambucil for patients with primary biliary cirrhosis. Chlorambucil may show benefit in some unvalidated surrogate outcome measures (for example, serum bilirubin and immunoglobulin M levels). Chlorambucil is, however, connected with a number of adverse events. Bone marrow suppression should be noted in particular. Further randomised clinical trials are necessary to assess the benefits and harms of chlorambucil in this indication.
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ABSTRACT: Alkylating agents (e.g. sulfur and nitrogen mustards) cause a variety of cell and tissue damage including wound healing disorder. Migration of endothelial cells is of utmost importance for effective wound healing. In this study we investigated the effects of chlorambucil (a nitrogen mustard) on early endothelial cells (EEC) with special focus on cell migration. Chlorambucil significantly inhibited migration of EEC in Boyden chamber and wound healing experiments. Cell migration is linked to cytoskeletal organization. We therefore investigated the distribution pattern of the Golgi apparatus as a marker of cell polarity. Cells are polarized under control conditions, whereas chlorambucil caused an encircling perinuclear position of the Golgi apparatus, indicating non-polarized cells. ROS are discussed to be involved in the pathophysiology of alkylating substances and are linked to cell migration and cell polarity. Therefore we investigated the influence of ROS-scavengers (α-linolenic acid (ALA) and N-acetylcysteine (NAC)) on the impaired EEC migration. Both substances, in particular ALA, improved EEC migration. Notably ALA restored cell polarity. Remarkably, investigations of ROS and RNS biomarkers (8-isoprostane and nitrotyrosine) did not reveal a significant increase after chlorambucil exposure when assessed 24 h post exposure. A distinct breakdown of mitochondrial membrane potential (measured by TMRM) that recovered under ALA treatment was observed. In conclusion our results provide compelling evidence that the alkylating agent chlorambucil dramatically impairs directed cellular migration, which is accompanied by perturbations of cell polarity and mitochondrial membrane potential. ALA treatment was able to reconstitute cell polarity and to stabilize mitochondrial potential resulting in improved cell migration.Chemico-Biological Interactions 08/2014; DOI:10.1016/j.cbi.2014.05.015 · 2.98 Impact Factor
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ABSTRACT: Chlorambucil, (4-[4-[Bis (2-chloroethyl) amino] phenyl] butanoic acid), is a well established bifunctional alkylating agent indicated in chronic leukemia. Kolaviron (KV), a biflavonoid from Garcinia kola and L-ascorbic acid (ASA) are known to offer protection against oxidative damage in vivo. This study was designed to investigate the protective role of KV and ASA on chlorambucil (CLB)-induced toxicity in rat. Twenty male Wistar rats (180-200g) were randomized into four groups. Group - I animals served as control, Group - II received chlorambucil (0.2mg/kg b.w. p.o.), Group III (0.2mg/kg chlorambucil and 100mg/kg kolaviron p.o.), and Group IV (0.2mg/kg chlorambucil and 100mg/kg L - ascorbic acid p.o.) respectively for 14 days. Chlorambucil induced marked renal and liver damage as evident by a significant increase in plasma bilirubin, urea, and creatinine by 233%, 74% and 174% respectively (p˂0.05). Similarly, plasma ALP, ALT, and AST rose significantly by 103%, 43%, and 59% respectively (p˂0.05). However, co-treatment with KV and ASA caused reduction in the levels of urea, creatinine, bilirubin, ALP, ALT, and AST relative to chlorambucil rats. Also, hepatic malondialdehyde content of chlorambucil -treated rats increased significantly by 113% (p˂0.05). However, co-treatment with KV and ASA significantly attenuated chlorambucil-induced alteration in hepatic lipid peroxidation . Moreover, chlorambucil treatment caused a marked depletion in antioxidant status as hepatic vitamin C, GSH, GST, SOD and catalase activities by were significantly reduced 33%, 39%, 48.2%, 47.2%; and 55.8% respectively (p˂0.05). Co-treatment with KV and ASA however, significantly ameliorated the chlorambucil-induced reduction in vitamin C, GSH, GST, SOD and catalase levels. Overall, kolaviron and L-ascorbic acid protected against chlorambucil-induced damages in the liver and kidney of the rat.
Article: Primary biliary cirrhosis in adults.[Show abstract] [Hide abstract]
ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future.Expert review of gastroenterology & hepatology 03/2014; DOI:10.1586/17474124.2014.888950 · 2.55 Impact Factor