Hepatitis C

[EDDIEKIRK]

Hepatitis C





Is marijuana an effective treatment for the symptoms of hepatitis C?





General Reference (not clearly pro or con)



The US National Institute of Health stated on its website (accessed Sep. 29, 2006): "Hepatitis C is an inflammation of the liver caused by infection with the hepatitis C virus (HCV).[...] There are approximately 4 million people in the United States who are infected with hepatitis C (about 1 in 70 to 100 people). Other hepatitis virus infections include hepatitis A and hepatitis B. Each viral hepatitis infection is caused by a different virus.



Many people who are infected with the hepatitis C do not have symptoms. Hepatitis C is often detected during blood tests for a routine physical or other medical procedure. If the infection has been present for many years, the liver may be permanently scarred -- a condition called cirrhosis. In many cases, there may be no symptoms of the disease until cirrhosis has developed.



The following symptoms could occur with hepatitis C infection: Jaundice, Abdominal pain (right upper abdomen), Fatigue, Loss of appetite, Nausea, Vomiting, Low-grade fever, Pale or clay-colored stools, Dark urine, Generalized itching, Ascites, Bleeding varices (dilated veins in the esophagus)."









More on Pro's and Con's



PRO (yes) CON (no) Diana L. Sylvestre, MD, Assistant Clinical Professor in the Department of Medicine at the University of California, San Francisco, et al. stated in the Oct. 2006 article "Cannabis Use Improves Retention and Virological Outcomes in Patients Treated for Hepatitis C," published in the European Journal of Gastroenterology & Hepatology:



"Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen."






More









Medical Marijuana and Hepatitis C





What Is Hepatitis C ?


Hepatitis C is an often chronic infection of the liver caused by the hepatitis C virus (HCV), which can result in cirrhosis of the liver. Hepatitus C is responsible for most of the liver transplants conducted each year.








Medical Marijuana and Hepatitis C


Hepatitis C is a liver disease that affects 300 million people worldwide. Based on current statistics for hepatitis C, it is estimated that 8,000 to 10,000 people die each year from chronic liver disease caused by this condition.





Hepatitis C is typically treated with interferon medication, but many patients are unable to complete the full treatment regimen due to the severe side effects it can induce, such as fatigue, insomnia, loss of appetite, nausea, muscle and joint pain, and depression. Because of these side effects, many patients are forced to reduce their doses or discontinue treatment altogetherboth of which deter interferons effectiveness against the Hepatitis C virus.





There is strong scientific and anecdotal evidence that
medical marijuana is a safe, effective medicine that helps patients with Hepatitis C endure the side effects of treatmentthereby helping patients complete the full treatment regimen. Many
marijuana states include Hepatitis C on their list of qualifying conditions. Additionally, marijuana side effects are typically mild and are classified as "low risk," with euphoric mood changes among the most frequent side effects.








Hepatitis C - The Silent Killer


Can Medical Cannabis Help?








Jay R. Cavanaugh, PhD








Hepatitis C (HCV) is a blood borne pathogen that presently infects some four to eight million Americans making it the leading blood borne virus in America. HCV is the primary cause of liver cancer and cirrhosis and kills over 10,000 Americans each year. Hepatitis C is the leading factor in patients who require liver transplant. Some 80% of those who contract HCV will go on to develop chronic infection and 20% of these will develop cirrhosis, liver cancer, or liver failure. A slim 20% of those infected will eliminate the virus from their body on their own.





Patients can contract Hepatitis C from using shared needles, accidental needle stick injuries, blood transfusions (prior to 1990), and to a minor degree from unprotected sex. HCV can be transmitted from an infected tattoo needle, dental instruments, or tools used in commercial nail care. Anything that assists the transfer of HCV infected blood from one person to another can be a vector. The blood of a patient with HCV can be highly contagious and precautions should be taken to not come in contact with it.





Hepatitis C usually produces no early symptoms. The disease can go unrecognized for decades. This is why HCV is termed a "silent killer". During the decades of quiescence the virus can continue to slowly destroy liver cells without the patient having any idea this is happening. The following groups are considered "high risk" and should be tested for the virus:





IV drug users who have shared needles


Sexual partners of HCV patients


Family members of HCV patients


Individuals receiving a blood transfusion prior to 1990


Patients who undergo dialysis


Individuals with tattoos or who have their nails frequently done


Individuals who have suffered a needle stick incident


Patients who have been diagnosed with any liver disease


Symptoms:





While patients are generally unaware of HCV infection for many years, some 80% may eventually develop symptoms which can include:





Fatigue and malaise


Loss of appetite


Weight loss


Jaundice


Joint pain and headache


Fluid retention in the abdomen (ascites)


Nausea and vomiting


Itching


Diagnosis:





Diagnosis begins with a simple history and blood test. The history looks at risk factors and symptoms. The blood test is generally to measure both liver enzymes (produced when the liver is damaged) and to detect antibodies to the Hepatitis C virus and/or to quantify the amount of virus present in the blood stream. The amount of virus is called the "titer" and is determined using the polymerase chain reaction (PCR) with HCV "primers". Additional blood tests can determine the specific strain of virus present (some strains are more pathogenic than others). A physical examination will be conducted that includes probing the liver for enlargement and looking for other possible factors such as swelling in the legs and feet and jaundice.





Prior to the initiation of treatment, it is common practice to conduct additional tests to more closely ascertain the status of the liver and the need for treatment. A liver scan using radioactive isotopes and X-ray can highlight liver structures and blood flow. A CAT scan may be conducted to look for tumors or blockage. The definitive diagnostic procedure is a liver biopsy where small samples of the liver are extracted through an office surgical procedure and examined for pathology. A liver biopsy taken from different quadrants of the liver can reveal hepatocarcinoma (liver cancer), fatty deposits, and cirrhosis (scarring).





Why is the liver important?





The liver is the largest internal organ. It is within the liver that medications and toxins are neutralized, metabolized, and eliminated (with the help of the kidneys). The liver is the site of sugar storage (glycogen) and plays a vital role in maintaining normal blood sugar along with the pancreas. The bodys fluid balance and blood clotting are largely controlled by the liver as is the processing of proteins. Bile produced in the liver aides in the digestion of food. Most noticeable is the role of the liver in energy production which is why fatigue is so common in liver disease.





Treatment for Hepatitis C:





Current therapy focuses on the subcutaneous administration of a combination of Interferon alpha (an immunomodulator) and the anti-viral drug Ribavirin. Depending upon the type of Interferon used, dosing can be one to three times a week for six to 18 months. Approximately 50% of those treated respond although it is not yet known how long the response might last. Combination drug therapy is usually not attempted when there is no sign of liver damage as determined by histopathology following biopsy. Drug therapy is also contraindicated when patients have long standing problems with depression or heart disease. The major side effects of the therapy include flu like symptoms, joint pain, nausea, anemia and depression. The decision to undergo combination therapy is a very serious one and should be done only under the supervision of a qualified and experienced physician. HCV patients with liver impairment must avoid hepatotoxins, particularly alcohol and acetaminophen (Tylenol).





Alcohol is a key toxin that damages the liver. Normal healthy adults are advised to drink no more than two drinks a day for men and one for women. With liver disease that recommendation drops to zero. Yet, many in the general population and the HCV population are heavy drinkers. Cannabis can be an effective harm reduction agent for those with alcohol problems along with therapy and self help.





Long term Complications of Hepatitis C:





Cirrhosis - As liver cells are destroyed by virally induced inflammation, they can be replaced by scar tissue (hence the name) which does not function to conduct normal liver functions. Cirrhosis is chronic and progressive. Cirrhosis occurs in approximately 20% of all HCV cases and may lead to cancer. The course of cirrhosis is variable but usually includes fluid build up in the abdomen (ascites), portal hypertension, and esophageal varices (swollen blood vessels). Treatment is limited to alleviating symptoms. Fluid may be periodically drained and medicines provided to reduce hypertension and fluid imbalances. Cirrhosis can cause uncontrolled bleeding, coma, and death.





Hepatocellular carcinoma (liver cancer) - Constant cell death and division caused by HCV can lead to tumors in 1-5% of all patients. Liver cancer is curable only in its earliest stages if it is contained within the liver in an area approachable by surgery. In other cases various treatments can be used including cryotherapy (freezing) and ethanol ablation. Chemotherapy, at present, is not usually effective with liver tumor. Liver cancer is generally terminal with treatment limited to symptomatic relief and improving the quality and length of life.





Liver failure and transplantation - As HCV destroys liver tissue; liver function can be increasingly compromised leading to failure. As the liver fails toxins can circulate that harm other organs and effect perception and behavior. Medications are not metabolized normally and have an increased risk of side effects and adverse reaction. Essential clotting factors may not be produced leading to uncontrolled internal bleeding. Complete failure results in coma and death. Patients with cirrhosis, cancer, and/or liver failure can sometimes be helped by a liver transplant. Hard to come by, transplants are usually restricted to those cases where they may materially help. Patients who continue to abuse alcohol or drugs are often excluded from transplant waiting lists as are those whose cancer has spread beyond the liver. Others excluded are surgical risks (usually those with cardiac disease) and those with compromised immune systems. Patients survive transplantation in nearly 80% of trials although continued use of immunosuppressants is needed.











Can medical cannabis help?





The short answer is yes. The primary role of cannabis is to stimulate appetite, reduce nausea and vomiting, and treat joint pain. This role is applicable to HCV patients undergoing chemotherapy, those with cancer or cirrhosis, and those with joint pain and headache. Cannabis is far less toxic than other medications that might be prescribed for these conditions and where liver impairment is concerned, it is vital to avoid toxicity. Cannabis may help alleviate the depression often produced by chronic illness and by combination drug therapy. Additionally, cannabis based food products may provide needed extra nutrition without taxing the liver. Using cannabis in place of alcohol is an established harm reduction technique particularly important when liver disease is present.





Perhaps more important but still unknown is the possibility that some of the chemical components of cannabis (the Cannabinoids) may actually reduce liver inflammation and slow the progression of both cirrhosis and Hepatocellular carcinoma. The cannabinoids have been shown to be powerful anti-inflammatories and anti-oxidants. They have also been shown to have anti-neoplastic activity, at least in gliomas (a form of brain cancer). Cannabinoids both slow programmed cell death (apoptosis) in normal cells while accelerating apoptosis in cancer cells.





Since cannabis is nontoxic it might as well be tried, particularly in patients who have chronic progressive disease that is likely to result in death. It is important to point out that whole cannabis (whether smoked, vaporized, elixir, or in food products) is preferable to Marinol. The prescription drug Marinol contains only one cannabinoid (THC) and lacks the other healing properties of the whole herb and its extracts. Dosing is up to the physician and patient. Usually patients "self-titrate" or use only what they feel they need for symptomatic relief. This may be a mistake as the protective effects of cannabis are best achieved with a steady state minimal blood level of Cannabinoids. It is recommended that a base line level of Cannabinoids be maintained with regular doses of oral cannabis products and the smoked or vaporized form of cannabis used for acute symptomatic relief.





source:
http://www.letfreedo...hepatitis_c.htm











(Marijuana/Hash) Endocannabinoids and liver disease - review








Liver International


Volume 25 Issue 5 Page 921 - October 2005





Ezra Gabbay1,2, Yosefa Avraham1, Yaron Ilan2, Eran Israeli and Elliot M. Berry1 1Department of Metabolism and Human Nutrition, Hadassah-Hebrew University Medical School, 2The Liver Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel





Abstract: Aims: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease.





Methods: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered.





Results: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function.





Conclusions: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.





ARTICLE TEXT





Cannabis has been used for psychoactive and recreational purposes as well as in traditional medicine, long before the advent of modern medicine and scientific research (1, 2). The active component of cannabis, tetra-hydro-cannabinol (THC) was discovered in 1964 (3). This finding led to the discovery of two specific receptors to cannabinoids. The cannabinoid receptor antagonist (CB1) receptor was found initially in the brain (4) and subsequently in the gut and vascular endothelium (5-7). The CB2 receptor was isolated primarily in the immune system (8). Both receptors are coupled to G-proteins and act via adenylate cyclase and calcium channels (4). The first endogenous ligand for these receptors was found in 1992, and designated as Anandamide (from the Sanskrit 'Ananda'-bliss) (9). This compound is an amide of arachidonic acid and ethanolamine, and is a member of the fatty acid amide (FAA) family. Following this breakthrough, several other ligands were reported, e.g. 2-arachidonyl-glycerol (2-AG), noladine and oleamide (10-13). Specific antagonists to each subtype of cannabinoid receptors were also found: SR141716A for the CB1 receptor and SR 14452 for the CB2 receptor (14, 15).





Cannabinoids have been studied extensively in recent years and have been found to have important functions in many physiological and pathophysiolocal processes. They have been found throughout the CNS, and effect many neurological and psychological phenomena such as mood, appetite, emesis control, memory, spatial coordination muscle tone and analgesia (5, 16-29). These effects are mediated primarily through the CB1 receptor. Outside the CNS, cannabinoids exert immunomodulatory and anti-inflammatory effects via CB2 receptors found in lymphocytes, monocytes and neutrophils (30-34). Other effects include vasodilation of splanchnic vessels via receptors on the surface of endothelial cells (7, 35), and inhibition of gut motility by anadamide released from nerve ends (10, 16). In this review, we examine the implications of basic-science and clinical research of cannabinoids' role in hepatic physiology and disease.





Endocannabinoids and liver disease





Portal hypertension, a complication of cirrhosis, is caused by both increased resistance to flow in the portal vein, and, at a later stage, by increased flow in the mesenteric vasculature. Systemic vasodilation further complicates this condition, causing a decrease in effective blood volume, hypotension, fluid and salt retention, worsening ascites and deterioration of renal function (36).





Ascites is associated with increased plasma levels of the bacterial endotoxin lipopolysaccharide (LPS). In a study designed to assess the prognostic value of plasma endotoxin levels, it was found that plasma endotoxin levels increased progressively as liver function deteriorated. In short-term survival analysis, plasma endotoxin levels were significantly higher in non-survivors than in survivors. In long-term survival analysis, plasma endotoxin levels did not differ significantly between survivors and non-survivors, and was not an independent predictor of long-term survival. The authors concluded that in patients with cirrhosis, plasma endotoxin levels progressively increase as liver function deteriorates and may be useful in predicting short-term survival (37). LPS appears to contribute to the hemodynamic changes observed in cirrhosis, possibly mediated via enhanced nitric oxide (NO) production (38). LPS acts on macrophages, in a complex mechanism involving the CD14 protein expressed on their membranes, resulting in increased production of cytokines, including interleukin (IL) 1-beta and tumor necrosis factor-alpha (39, 40). Anandamide is found in macrophages (41). The finding that activation of peripheral CB1 receptors in rats by macrophage- and platelet-derived substances contributes to the hypotension in hemorrhagic shock (42) prompted the investigation of the possible role of endocannabinoids in endotoxin-induced shock. In that study, rat platelets were found to contain 2-AG. In vitro exposure of platelets to LPS markedly increases 2-AG levels. Prolonged hypotension and tachycardia were elicited in rats treated with LPS, as well as by macrophages plus platelets isolated from LPS-treated donor rats; rat macrophages or platelets preincubated in vitro with LPS had a similar effect. In all four cases, the hypotension but not the tachycardia was prevented by pretreatment of the recipient rat with the CB1 receptor antagonist SR141716A (3 mg/kg i.v.), which also inhibits the hypotensive response to anandamide or 2-AG. The hypotension elicited by LPS-treated macrophages or platelets remains unchanged in the absence of sympathetic tone or after blockade of NO synthetase. These findings indicate that platelets and macrophages generate different endogenous cannabinoids, and that both 2-AG and anandamide may be paracrine mediators of endotoxin-induced hypotension via activation of vascular CB1 receptors (43).





These results led to further studies designed to explore the possible role of endocannabinoids in the hemodynamic changes in chronic liver disease.





Hypotension in rats with biliary cirrhosis was improved by the CB1 receptor antagonist SR141716A. Similar results were also observed in rats with CCl4-induced cirrhosis, wherein SR141716A also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic humans and rats elicited SR141716A-sensitive hypotension in normal recipient rats. Significantly elevated levels of anandamide were found in these cells. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells indicating up-regulation of these receptors in chronic liver disease (44).





In a similar study, arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of SR141716A to cirrhotic rats with ascites, and to control rats. CB1 receptor blockade increased arterial pressure and peripheral resistance in cirrhotic animals, but not in healthy ones. A suspension of blood cells from cirrhotic rats induced hypotension in recipient rats. Monocyte levels of anandamide were significantly elevated in cirrhotic animals as compared to those in healthy controls. Here too, the conclusion was that in cirrhosis, monocytes increase their production of anandamide, and that this process contributes to hypotension and hemodynamic deterioration (45).





It would thus seem that endocannabinoids are involved in the hemodynamic alterations of cirrhosis by acting as mediators between endotoxin/LPS and blood vessels. LPS acts on monocytes and platelets, thereby increasing production of anandamide and 2-AG, respectively. The endocannabinoids produced in response to LPS may then act on systemic and mesenteric vasculature, decreasing blood pressure and effective blood volume, increasing fluid and solute retention, thereby worsening ascites and contributing to renal dysfunction. The mechanism of vasodilation is at least partially mediated by the CB1 receptor, as demonstrated by the effects of SR141716A. However, a non-CB1 receptor mechanism cannot be ruled out as a contributor to these processes. One such mechanism may be via the vanniloid receptor and possibly by the subsequent release of CGRP that requires NO production, as demonstrated in endothelium-denuded aortic rings in rabbits (46). Given the central role of NO in the hemodynamics of cirrhosis, such a mechanism would seem plausible.





The development of new chromatographic techniques has allowed for more accurate measurements of serum cannabinoids. Using this method, four-fold and three-fold increased levels of ANA and 2-AG, respectively, were found in the sera of patients with endotoxic shock compared to healthy subjects (47). In a subsequent study, the investigators demonstrated that compared to serum anandamide levels in healthy humans (4.00.79 nM), a significant increase was seen in acute non-severe hepatitis (8.8 0.98 nM), with a further rise in severe acute hepatitis (15.810.25 nM). In chronic cirrhosis, anandamide levels were also elevated at 11.641.93 nM. In the acute hepatitis group, serum anandamide levels were found to correlate with the extent of tissue damage as indicated by serum ALT levels. Furthermore, tissue samples from the cirrhotic patients showed massive hepatocellular apoptosis and liver fibrosis. Since anandamide has been known to induce apoptosis, particularly of lymphocytes (48), the effect of anadamide on hepatocellular apoptosis was therefore assessed. Anandamide induced apoptosis of human heptaoma cells (HepG2) in a dose-dependent manner. This was preceded by G0/G1 cell cycle arrest, and the activation of pro-apoptotic signaling pathways such as p38mitogen-activated protein kinase. The mechanism of apoptosis was thought to be either CB receptor-mediated as in thymic lymphocytes (48) or vanilloid receptor (VR1) mediated, as seen in human neuroblastoma CHP100 and lymphoma U937 cells (49). As neither SR141716A nor SR144528 produced significant inhibition of apoptosis in VR1 knock-out mice, it was concluded that the principal mechanism of apoptosis was non-receptor mediated. Depletion of membrane cholesterol by MCD or treatment with HMG-coA-reductase inhibitors, did result in suppression of apoptosis, as did treatment with the antioxidant N-acetyl-cystein. Polymixin binding studies indicated that anadamide interacts with membrane cholesterol. Similar results were observed in normal rat hepatocytes. This indicated that the apoptotic effect of anandamide on liver cells is mediated through a direct effect on membrane cholesterol designated as lipid-lipid plasma membrane interaction and not through specific receptors. The effect seems to involve enhanced susceptibility to oxidative stress (50).





The effects of endocannabinoids on neurological and cognitive aspects of hepatic encephalopathy (HE) were studied in an animal model of acute hepatic failure. The pathogenesis of HE is a complex process involving several mechanisms including functional changes in neurotransmitter systems such as the opiodergic (51, 52) and gamma amino butyric acid (GABA-ergic) (53-58) systems that are known to interact with the endocannabinergic system (16, 59).





Fulminant hepatic failure (FHF) was induced by thioacetamide (TAA). Neurological performance (assessed by a fourteen point scale based on reflexes and task performance), activity (evaluated in an infra red maze), and cognitive function (performance in an eight arm maze) were measured after administration of the 2-AG SR141716A or both. Encephalopathic mice treated with SR141716A or 2-AG or both, showed improved neurological function, activity and cognitive function compared to untreated animals. SR141716A showed a dose-response pattern in the improvement of neurological function. CNS levels of 2-AG were found to be elevated in mice with TAA induced liver failure when compared to healthy mice. Administration of exogenous 2-AG resulted in decreased brain levels of endogenous 2-AG. The endocannabinoid system may therefore have a role in the pathogenesis of hepatic encephalopthy. The similar effect of 2-AG and SR141716A could be explained by two hypotheses: end-product inhibition of 2-AG and exertion of the effect through a non-CB1-receptor target (60).





Other publications have shown that certain cannabinoid compounds decrease the extent of experimental hepatitis. The synthetic, non-psychotropic cannabinoid (PRS-211,092) decreased concanavalin A-induced liver injury in mice that was accompanied by promotion of early gene exp
<b></b>ression of IL-6 and IL-10, induction of early gene exp
<b></b>ression of the suppressors of cytokine signaling (SOCS-1 and 3), and inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1beta, interferon-gamma, and tumor necrosis factor alpha. PRS-211,092 inhibited IL-2 production and nuclear factor of activated T cells activity in cultured T cells (61).





A recently published study, examined the potential hepatotoxic effects of marijuana use in humans. A transversal study was conducted among 123 patients over 2 years in Sao-Paolo, Brazil. The patients were divided into three groups: 26 (21%) using only marijuana, 83 (67.5%) using marijuana and crack, and 14 (11.4%) consuming marijuana and alcohol. Among patients who reported using marijuana alone, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%. These patients were found to have slightly elevated AST (42.3%), ALT (34.6%) and AP (53.8%). The prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly was not different in the three groups. Patients who consumed both marijuana and alcohol had the highest levels of aminotransferases. These results suggest that chronic marijuana use, alone or in combination with alcohol or other drugs, may have hepatotoxic effects (62). The methodological issues involved, particularly the isolation of cannabis use from the use of other substances warrants caution as to the interpretation of these results.





What are the therapeutic implications of these data for patients with liver disease? Very little clinical data are available as to the efficacy of endocannabinoids or their receptor antagonists in humans with hepatic disease.





THC treatment for intractable cholestatic-related pruritus (ICRP) was evaluated in a report of three patients who had previously been treated with standard therapies for ICRP including: diphenhydramine, chlorpheniramine, cholestyramine, rifampicin, phenobarbital, doxepin, naltrexone, UV therapy, topical lotions and plasmapheresis. Patients were given 5 mg of delta-9-THC (Marinol) at bedtime. All three patients reported a decrease in pruritus, marked improvement in sleep, and were eventually able to return to work. Resolution of depression occurred in two of three. Side effects related to the drug included coordination disturbance in one patient. Marinol dosage was decreased to 2.5 mg in this patient with resolution of symptoms. The duration of antipruritic effect was approximately 4-6 h in all three patients suggesting that frequent dosing may be needed (63). One possible mechanism for the beneficial effect on cholestasis may be related to an increase in the threshold for nociception. This hypothesis was tested in rats with bile-duct-resection induced cholestasis and in sham-resected controls. Administration of the cannabinoid agonist WIN 55, 212-2 resulted in an increase in the tail-flick latency - an index of the nociception threshold - in both groups as compared to baseline. These results support the notion that the analgesic effect of cannabinoids may be of use in treating pruritus, a nociceptive stimulus, in patients with liver disease (64).





Despite the scarcity of information, certain conclusions may be drawn from clinical experience in other fields. Cannabinoids such as THC, cannabis and nabilone have been tried in patients with multiple sclerosis with some success (28). The safety profile of these agents may also prove problematic. A review of cannabinoids in clinical practice found that some patients, particularly women and the elderly had panic or anxiety attacks. Psychosis is also a possible consequence of cannabis use that must be considered. The slow elimination time of cannabinoids from the body may impair task performance and driving (65). The development of new, non-psychotropic cannabinoids such as HU-320 (66) may enable the development of new therapeutic agents, while avoiding the legal and social issues that may be associated with the use of compounds derived from illicit drugs.





SR141716A, the CB1 receptor antagonist is currently under investigation for treatment of obesity and for smoking cessation, given the cannabinoids' known effect in appetite stimulation and reward (1, 5, 16, 67). Preliminary results of the RIO-Europe trial, now in phase III show that this agent (labeled Rimonabant) was safe and effective in achieving weight reduction, improved lipid profile and amelioration of the metabolic syndrome compared to placebo (68, 69).





In summary, endocannabinoids are relatively recently discovered compounds, that have many physiological and pathophysiological functions. Though much has been learned about their effects in the CNS, immune system and gut, relatively little is known about their role in liver physiology and disease. There is convincing evidence for their role in the hemodynamic compromise as seen in cirrhosis. The mechanism underlying this phenomenon appears to involve an increase in production of 2-AG and anandamide in platelets and macrophages, respectively, and a subsequent vasodilation, at least partially mediated by CB1 receptors on endothelial cells. Studies have revealed an increase in serum anandamide concentration in both acute and chronic liver disease in humans, as well as an apoptotic effect of anandamide on liver cells, via a direct interaction with membrane cholesterol. The endocannabiod system may also be involved in the pathogenesis of HE, as are several other neurotransmitter systems. Some epidemiological data supports the notion of a hepatotoxic effect for marijuana; however, methodological problems preclude conclusion in this context. Certain cannabinoids may improve hepatic inflammation and pruritus secondary to liver disease, but more data are needed to substantiate these propositions. The development of therapeutic modalities based on cannabinoids or their antagonists depends on their safety as well as efficacy. Synthetic, non-psychotropic cannabinoids may be better tolerated and reduce social and legal tensions that may impede the pharmacological use of substances derived from illicit drugs.





source:
http://www.natap.org...V/091905_01.htm








A Novel Synthetic Cannabinoid Derivative Inhibits Inflammatory Liver Damage via Negative Cytokine Regulation


Iris Lavon, Tatiana Sheinin, Sigal Meilin, Efrat Biton, Ayelet Weksler, Gilat Efroni, Avi Bar-Joseph, George Fink, and Ayelet Avraham





Pharmos Limited, Kiryat Weizmann, Rehovot, Israel





The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene exp
<b></b>ression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene exp
<b></b>ression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1{beta}, interferon-{gamma}, and tumor necrosis factor {alpha}. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the exp
<b></b>ression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the exp
<b></b>ression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.





source:
http://molpharm.aspe...tract/64/6/1334





June 02, 2008


Marijuana Use Sparks Liver Transplant Controversy


Despite its legality in 12 states, learn why medical marijuana use may render a person with Hepatitis C ineligible for a liver transplant.





by Nicole Cutler, L.Ac.





Hepatitis C is not only the leading cause of chronic liver disease in the United States, it is also the most common reason for liver transplants in this country. Unfortunately, some with Hepatitis C are being denied access to liver transplants because of their use of a controversial type of symptom relief.





Although transplantation is considered a last resort for liver disease, the number of people waiting for a new organ far outnumbers the supply. Since donated livers are in such high demand, a complex system of prioritizing who gets transplant surgery has evolved. Obviously, great deliberation is involved in deciphering transplant eligibility and recipient ranking. However, the ethics of this process has been called into question for those using medical marijuana. Occasionally used to ease Hepatitis C symptoms, patients legally using medical marijuana are at high risk of being denied a spot on the liver transplant recipient queue.





UNOS


The United Network for Organ Sharing (UNOS) is a non-profit, scientific and educational organization that administers the nation's only Organ Procurement and Transplantation Network. UNOS is responsible for organ matching and placement throughout the United States. According to the UNOS website, over 98,000 people are currently on an organ transplant waiting list. Many people wait for years for a new liver, often not surviving the wait. According to the Scientific Registry of Transplant Recipients, less than a third of those waiting for a liver actually receive one.





The UNOS entrusts individual hospitals and transplant centers to develop their own criteria for transplant candidates. Some of these institutions automatically reject people who use "illicit substances" including those legally prescribed medical marijuana. "Most transplant centers struggle with issues of how to deal with people who are known to use marijuana, whether or not it's with a doctor's prescription," said Dr. Robert Sade, director of the Institute of Human Values in Health Care at the Medical University of South Carolina. "Marijuana, unlike alcohol, has no direct effect on the liver. It is, however, a concern ... in that it's a potential indicator of an addictive personality."





Medical Marijuana


Marijuana has been used for medicinal purposes for approximately 4,000 years. Surviving texts from ancient India confirm that its psychoactive properties were recognized, and doctors used it for a variety of illnesses and ailments. These included a whole host of gastrointestinal disorders, nausea, low appetite, insomnia, headaches and as a pain reliever.





People with Hepatitis C have reported using marijuana (cannabis) to treat both symptoms of the disease as well as the nausea associated with antiviral therapy. An observational study by investigators at the University of California at San Francisco (UCSF) found that Hepatitis C patients who used cannabis were significantly more likely to adhere to their treatment regimen than patients who didn't use it. Despite this support for medical marijuana, several trials reported an association between daily cannabis use and the development of liver fibrosis in Hepatitis C. Aside from the question of legality, experts disagree on the therapeutic use of cannabinoids for Hepatitis C treatment.





The medical use of cannabis has been legalized in several countries including Canada, Belgium, Australia, the Netherlands, the United Kingdom, New Zealand and Spain. Since 1996, twelve U.S. states have legalized medical marijuana use: Alaska, California, Colorado, Hawaii, Maine, Montana, Nevada, New Mexico, Oregon, Rhode Island, Vermont and Washington. Doctors in these states can write a prescription for marijuana for a legitimate medical issue. However, the United States Supreme Court ruled that the federal government has the right to regulate and criminalize marijuana in these states, even for medical purposes.





Sad Outcome in Washington


The debate about medical marijuanas impact on liver transplant eligibility jumped to center stage in May of 2008 when Washington state resident Timothy Garon passed away. To combat his Hepatitis C symptoms, Garons physician had authorized medical marijuana for alleviating his nausea and stomach pain and to stimulate his appetite. Legally authorized in Washington state since 1998, Garons attorney believes that his clients medical marijuana use kept him off of the liver transplant list, a decision that ultimately cost Garon a chance for survival.





No one tracks how many patients are denied transplants over medical marijuana use. Pro-marijuana groups have cited a handful of cases, including at least two patient deaths, in Oregon and California, since the mid- to late 1990s, when states began adopting medical marijuana laws.





With the nations shortage of transplantable livers, some administrators may be using their moral judgment to decide who gets on an eligibility list. Thus, using medical marijuana to ease advanced Hepatitis C symptoms may put some people at a disadvantage. Until our nations lawmakers, physicians and administrators are all in agreement about the use of cannabis for certain illnesses, those in need of a liver transplant may wish to think ahead and either choose a different medicine for symptom relief or consult with their chosen hospital about their view on medical marijuana as a factor in transplant eligibility.








References:



http://en.wikipedia.org

, Medical Cannabis, Wikimedia Foundation Inc., 2008.



http://norml.org

, Hepatitis C, The National Organization for the Reform of Marijuana Laws, 2008.



http://seattletimes.newsource.com

, Is medical-marijuana use reason to deny someone an organ transplant?, Seattle Times Staff and Associated Press, The Seattle Times Company, May 2008.



http://stopthedrugwar.com

, Marinol Death Sentence: Oregon Man Denied Liver Transplant Because of Prescription -- He's Not the Only One, stopthedrugwar.com, 2008.





Sylvestre, et al, Cannabis use improves retention and virological outcomes in patients treated for hepatitis C, European Journal of Gastroenterology & Hepatology, 2006.





www.cbhd.org, Liver Transplants: How Do We Choose Who Should Live When Not All Can?, Gregory W. Rutecki, The Center for Bioethics and Human Dignity, 2008.





www.drugwarfacts.org, Medical Marijuana, Common Sense for Drug Policy, 2008.





www.unos.org, Who We Are, United Network for Organ Sharing, 2008.





www.usatoday.com, Playing field for liver transplants is not level, studies find, Robert Davis, USA Today, 2008.





SOURCE:
http://www.hepatitis...uana_use_s.html











Moderate Cannabis Use Associated with Improved Treatment Response in Hepatitis C Patients on Methadone





By Liz Highleyman





Interferon-based therapy for chronic hepatitis C virus (HCV) infection is often limited by side effects including flu-like symptoms, fatigue, insomnia, loss of appetite, nausea, muscle and joint pain, and depression, which can lead to poor adherence, dose reduction, or treatment discontinuation.











Medicinal cannabis may relieve such side effects and help patients stay on treatment, according to a study published in the October 2006 European Journal of Gastroenterology and Hepatology.





Several studies - as well as ample anecdotal evidence - have demonstrated that medical marijuana can reduce nausea, increase appetite, and improve wasting in people with HIV.





Diana Sylvestre, MD, of the University of California at San Francisco and colleagues conducted a study to define the impact of cannabis use during HCV treatment. The prospective observational study included 71 patients at OASIS (Organization to Achieve Solutions in Substance Abuse), a community-based clinic providing medical and psychiatric treatment to substance users in Oakland, California.





Patient Demographics





Eligible participants were recovering substance users with HCV who had been on methadone maintenance therapy for at least 3 months. Patients with non-HCV-related liver disease or decompensated cirrhosis were excluded. Among the 30 patients with liver biopsy results, the mean Metavir inflammation grade was 2.4 and the mean fibrosis stage was 2.6. Subjects with untreated depression were first stabilized on antidepressants.





Use of cannabis during the study was "neither endorsed nor prohibited." About one-third of participants used marijuana during hepatitis C treatment. "Regular" marijuana use was defined as every day or every other day for at least 4 weeks. Drug and alcohol use were assessed by self-report and random monthly urine testing.





22 patients (31%) reported cannabis use during ant-HCV treatment, while 49 (69%) did not.





Baseline characteristics were generally similar between marijuana users and non-users.





The median age was about 50 years in both groups.





Compared with non-users, cannabis users were somewhat more likely to be male (68% vs 57%) and Caucasian (86% vs 69%), but less likely to have genotype 1 HCV (48% vs 61%).





About 60% of participants reported a previous psychiatric diagnosis (usually depression); cannabis users and non-users had similar rates of psychiatric diagnosis and antidepressant use.





32% of cannabis users and 37% of non-users reported use of other illicit substances during HCV treatment (including heroin, cocaine, and methamphetamine), while 14% and 24%, respectively, reported alcohol consumption; these differences were not statistically significant.





Participants were treated with conventional interferon alfa-2b (3 million units 3 times weekly) plus 1000-1200 mg daily ribavirin. Patients were initially treated for 48 weeks regardless of genotype, but the protocol was later amended to allow 24-week therapy for those with genotypes 2 or 3.





Adherence to therapy was assessed by self-report, ribavirin pill counts, and returned empty interferon vials. Participants were considered adherent if they took 80% or more of prescribed interferon and ribavirin for at least 80% of the projected treatment course.





Results





In an intent-to-treat analysis, 37 patients (52%) achieved an end-of-treatment response (undetectable HCV RNA at the end of 24 or 48 weeks of therapy):





- 14 cannabis users (64%);


- 23 non-users (47%) (P = 0.21).





Overall, 21 out of 71 participants (30%) achieved sustained virological response (SVR), or continued undetectable HCV RNA 6 months after the end of therapy:





- 12 of 22 cannabis users (54%);


- 9 of 49 non-users (18%) (P = 0.009).





Post-treatment virological relapse rates were 14% for cannabis users and 61% for non-users (P = 0.009).





End-of-treatment response rates were similar among occasional cannabis users (10 of 16; 62%) and regular users (4 of 6; 67%).





10 of 16 occasional users (62%) went on to achieve SVR, compared with 2 of 6 regular users (33%), but the difference was not statistically significant.





Most patients (93%) reported at least one treatment-related side-effect, with similar rates among cannabis users and non-users.





Overall, 17 of 71 patients (24%) discontinued therapy early:





- 1 cannabis user (5%);


- 16 cannabis non-users (33%) (P = 0.01).





Overall, 48 patients were adherent (68%):





- 19 cannabis users (86%);


- 29 non-users (59%) (P = 0.03).





There was no significant difference in adherence between occasional and regular cannabis users (87% vs 83%)





91% of cannabis users took at least 80% of prescribed interferon, compared with 76% of non-users. For ribavirin, the corresponding rates were 91% and 84%; these differences were not statistically significant.





However, cannabis users were significantly more likely than non-users to remain on therapy for at least 80% of the projected treatment duration (95% vs 67%; P = 0.01).





The average duration of HCV treatment was 38 weeks for cannabis users, compared with 33 weeks for non-users.








Conclusion





In conclusion, the authors wrote, "Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen."





Discussion





In their discussion, the authors wrote that their results "suggest that the use of cannabis during HCV treatment can improve adherence by increasing the duration of time that patients remain on therapy; this translates to reduced rates of post-treatment virological relapse and improved SVR."





"Although other potential mechanisms may contribute to its enhancement of treatment outcomes, such as altered immunological function and improved nutritional status," they added, "it appears that the moderate use of cannabis during HCV treatment does not lead to deleterious consequences."





In this study, it appears that the treatment response benefit was primarily due to improved ability to stay on adequate doses of interferon and/or ribavirin. Sylvestre told HIV and Hepatitis.com that the researchers could not judge whether there was a direct antiviral effect. "It was probably more of a side-effect management effect than an antiviral effect, but we can't rule out the latter," she said.





There remain concerns about the safety of marijuana use by individuals with chronic hepatitis C. Cannabinoid receptors are present on immune cells, and use of the drug may suppress immune function. In addition, there is some evidence that frequent marijuana use may contribute to liver fibrosis. As reported in the July 2005 issue of Hepatology, French researchers found that HCV positive individuals who smoked cannabis daily were more likely to have severe fibrosis and were at higher risk for rapid fibrosis progression than those who used marijuana only occasionally or not at all. However, the participants in that study were not receiving treatment for hepatitis C.





Notably, in the current study, there was no direct dose-response relationship between the amount of cannabis consumed and the likelihood of sustained virological response. In fact, the patients who used the largest amounts of cannabis did not show as much benefit from hepatitis C therapy. The researchers did not perform pre- and post-treatment histological assessments using paired liver biopsies, and did not measure immune parameters.





"The lack of dose response in our study argues against specific receptor or metabolism-related effects, and suggests instead that cannabis exerted its benefit by non-specific improvements in symptom management," the authors stated. "Interestingly, because the benefits of heavy cannabis use were less apparent, we cannot rule out the possibility that detrimental biological or immunological mechanisms may be relevant at higher levels of consumption. Obviously, further study is needed."





Unfortunately, because cannabis is strictly controlled in the U.S. and the federal government considers the drug illegal even in states with medical marijuana laws, it is difficult to conduct randomized, controlled trials.





Editorial





In an accompanying editorial, a group of hepatitis C experts from Canada and Germany noted that people who use illicit drugs are the main risk group for new hepatitis C infections, and "will form the largest HCV treatment population for years to come."





While past treatment guidelines advised against hepatitis C treatment for active substance users and those with a recent history of active use, this categorical recommendation is no longer in effect in the U.S. and Europe, since recent studies have shown that such patients can achieve good treatment outcomes as long as they are able to maintain adequate adherence. Treatment remains a challenge for this population, however, in part because substance users have a higher prevalence of depression and other psychiatric conditions, which are associated with an increased likelihood of neuropsychological side effects during interferon therapy.





Sylvestre's study, the editorial authors wrote, "suggests that cannabis use may benefit treatment retention and outcomes in illicit drug users undergoing HCV treatment" and that "there is substantial evidence that cannabis use may help address key challenges faced by drug users in HCV treatment." Several recent studies have demonstrated the benefits of combining anti-HCV therapy with methadone maintenance, in effect offering "one-stop shopping."





The authors suggested that the therapeutic effects of cannabis "may be of principal importance and benefit for the distinct needs of illicit drug users" on methadone maintenance, because methadone itself is associated with some of the same side effects as interferon (bone aches, loss of energy, depression).





"Overall, cannabis use may thus even offer dual benefits, in facilitating adherence to both methadone maintenance therapy and HCV treatment in the HCV-infected drug user, and thus contribute to public health benefits related to both these interventions," they noted.





"While further research is required on the biological and clinical aspects of the benefits of cannabis use for HCV treatment, and the effectiveness of cannabis use for HCV treatment needs to be explored in larger study populations," they concluded, "we advocate that in the interim existing barriers to cannabis use are removed for drug users undergoing HCV treatment until the conclusive empirical basis for evidence-based guidance is available."





In particular, they suggested that medical marijuana laws and programs that specify its use for patients with specific conditions such as AIDS and cancer should also include people with hepatitis C.





9/15/06





References





D L Sylvestre, B J Clements, Y Malibu. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. European Journal of Gastroenterology and Hepatology 18(10): 1057-1063. October 2006.





B Fischer, J Reimer, M Firestone, and others. Treatment for hepatitis C virus and cannabis use in illicit drug user patients: implications and questions. European Journal of Gastroenterology and Hepatology 18(10): 1039-1042. October 2006.





C Hezode, F Roudot-Thoraval, S Nguyen, and others. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 42(1): 63-71. July 2005.








SOURCE:
http://www.hivandhep...6/091506_a.html