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Gut. 2008 Apr 8

Emerging Role of Cannabinoids in Gastrointestinal and Liver Diseases: Basic and Clinical Aspects.

Izzo AA, Camilleri M. Italy.

A multitude of physiological effects and putative pathophysiological roles have been proposed for the endogenous cannabinoid system in the gastrointestinal tract, liver and pancreas. These range from effects on epithelial growth and regeneration, immune function, motor function, appetite control, fibrogenesis and secretion. Cannabinoids have the potential for therapeutic application in gut and liver diseases. Two exciting therapeutic applications in the area of reversing hepatic fibrosis as well as anti-neoplastic effects may have a significant impact in these significant diseases. This review critically appraises the experimental and clinical evidence supporting clinical application of cannabinoid receptor-based drugs on gastrointestinal, liver and pancreatic diseases. Application of modern pharmacological principles will most likely expand the selective modulation of cannabinoid system peripherally in humans. We anticipate that in addition to the approval in several countries of the CB1 antagonist, rimonabant, for the treatment of obesity and associated metabolic dysfunctions, other cannabinoid modulators are likely to have an impact on human disease in the future, including hepatic fibrosis and neoplasia.

Mol Pharmacol. 2008 Apr 3

Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: Involvement of regulatory T cells.

Hegde VL, Hegde S, Cravatt BF, Hofseth LJ, Nagarkatti M, Nagarkatti PS. University of South Carolina.

Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. Natural cannabinoids such as Delta(9)-tetrahydrocannabinol (THC) effectively modulate immune cell function and have shown therapeutic potential in treating inflammatory diseases. We investigated the effects of THC in a murine model of Concanavalin A-induced hepatitis. Intraperitoneal administration of THC after ConA challenge inhibited hepatitis as shown by significant decrease in liver enzymes and reduced liver tissue injury. Furthermore, THC treatment resulted in significant suppression of crucial inflammatory cytokines in ConA-hepatitis. Interestingly, THC treatment in ConA-injected mice led to significant increase in absolute number of Foxp3(+) T regulatory cells in liver. Surprisingly, select cannabinoid receptor (CB1 or CB2) agonists were not able to block hepatitis either independently or in combination. However, CB1/CB2 mixed agonists were able to efficiently attenuate hepatitis similar to THC. The modulatory effect of THC in ConA-induced hepatitis was reversed by both CB1 and CB2 antagonists. We also observed that endogenous cannabinoid anandamide was able to reduce hepatitis by suppressing cytokine levels. Also, deficiency or inhibition of endocannabinoid hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), which leads to increased levels of endogenous cannabinoids, resulted in decreased liver injury upon ConA challenge. Our data demonstrate that targeting cannabinoid receptors using exogenous or endogenous cannabinoids and use of FAAH inhibitors may constitute novel therapeutic modalities to treat immune-mediated liver inflammation.

IACM-Bulletin of 27 April 2008
3. Science: Cannabinoids may be helpful in the treatment of side effects of anti-viral medications in patients with hepatitis C

According to researchers of the University of Ottawa, Canada, the use of cannabinoids may be helpful in the treatment of appetite loss and nausea observed in patients with hepatitis C, who undergo an anti-viral treatment. The medical records of all hepatitis C patients, who received a treatment with ribavirin and interferon between August 2003 and January 2007, were reviewed. Of the 191 patients identified, 25 received oral cannabinoid containing medications. Cannabinoid treatment was initiated at a median time of seven weeks after initiation of anti-viral treatment. The main reasons for cannabinoid treatment were appetite loss (72 per cent) and nausea (32 per cent).

64 per cent of all patients who received cannabinoids experienced subjective improvement in symptoms. The median weight loss before this therapy was 4.5 kg. Weight loss stabilized one month after cannabinoid initiation. Interferon dose reductions were rare and did not differ between patients who received cannabinoids compared to those not using cannabinoids. The proportions of patients completing a full course of anti-viral hepatitis C therapy and achieving a sustained virological response were greater in cannabinoid recipients compared to the control group.

(Source: Costiniuk CT, Mills E, Cooper CL. Evaluation of oral cannabinoid-containing medications for the management of interferon and ribavirin-induced anorexia, nausea and weight loss in patients treated for chronic hepatitis C virus. Can J Gastroenterol 2008;22(4):376-80.)

Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases. March 2007

Mallat A, Teixeira-Clerc F, Deveaux V, Lotersztajn S.

1INSERM, Unite 841, Institut Mondor de Recherche Biomedicale, Universite Paris XII - Val de Marne, Creteil, F-94000, France. 2AP-HP, Groupe Hospitalier Henri-Mondor-Albert Chenevier, Service d'Hepatologie et de Gastroenterologie, Creteil, F-94000 France.

Chronic liver injury exposes the patient to liver fibrosis and its end stage, cirrhosis, is a major public health problem worldwide. In western countries, prevailing causes of cirrhosis include chronic alcohol consumption, hepatitis C virus infection and non-alcoholic steatohepatitis. Current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Nevertheless, suppression of the cause of hepatic injury is not always feasible and numerous efforts are directed at the development of liver-specific antifibrotic therapies. Along these lines, the authors recently demonstrated that the endocannabinoid system shows promise as a novel target for antifibrotic therapy during chronic liver injury. Indeed, cannabinoid receptors CB(1) and CB(2) promote dual pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies, combining CB(2) agonists and CB(1) antagonists may open novel therapeutic perspectives for the treatment of chronic liver diseases.

PMID: 17298297 [PubMed - as supplied by publisher]

Endocannabinoids as novel mediators of liver diseases.

J Endocrinol Invest. 2006;29(3 Suppl):58-65.

Mallat A, Lotersztajn S.

Unite INSERM 581, Hopital Henri Mondor, 94010 Creteil, France.

In the past two decades, cannabinoids have emerged as crucial mediators in a variety of pathophysiological conditions. Awareness of their critical functions in liver pathophysiology is only recent, probably given the low level of expression of cannabinoid receptor type 1 (CB1 receptor) and type 2 (CB2 receptor) in normal liver. However, it has been shown that non-alcoholic fatty liver disease and cirrhosis are associated to a marked upregulation of the hepatic endocannabinoid system, including increases in endocannabinoids and in hepatic CB receptors, both in humans and in rodents. Consequently, a growing number of cannabinoid-related hepatic effects are being unravelled. Hence, hepatic CB1 receptors enhance liver steatogenesis in a mouse model of high fat-induced obesity, and contribute to peripheral arterial vasodilation in cirrhosis, thereby promoting portal hypertension. In addition, CB1 and CB2 receptors elicit dual opposite effects on fibrogenesis associated to chronic liver injury, by promoting pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies may open novel therapeutic avenues in the treatment of chronic liver diseases.

PMID: 16751709 [PubMed - in process]