has announced preclinical results indicating that histamine may prevent lipopolysaccharide (LPS)-induced liver injury. The results were presented at the 39th annual European Association for the Study of the Liver (EASL) meeting in Berlin, Germany. In this preclinical study, LPS is used to increase the severity of alcohol-induced damage. These new results demonstrate the ability of histamine to prevent LPS-induced liver injury in a rodent model by showing efficacy
when delivered in a manner mimicking oral administration.
Maxim scientists have previously shown that histamine is protective against early alcohol-induced liver injury in rats. Histamine is known to inhibit reactive oxygen species and LPS-induced pro-inflammatory cytokines like TNF-(alpha) in circulating inflammatory cell types in blood. Similar cells in the liver called Kupffer cells, also mediate inflammation by releasing pro-inflammatory cytokines when stimulated by LPS. Maxim researchers tested histamine in a rat model using alcohol in combination with a high-fat diet to create liver injury. LPS was administered as a "second insult" to dramatically increase damage and the markers that measure this damage. Subcutaneous histamine pre-treatment at all doses prevented serum transaminase (ALT, AST) levels from elevating compared to when LPS was given alone. When histamine was directly given into the intestine, a dose-dependent protection was achieved. Histamine also dose-dependently decreased LPS-induced TNF-(alpha) and IL-6 mRNA levels in the liver.
"These continued results were used to support our oral histamine program now in phase 1 human trials and the continued understanding of histamine's mechanism of action in chronic liver diseases," says Kurt R. Gehlsen, Senior Vice President and Chief Scientific Officer. "This work will help to advance toward clinical trials of our oral product candidate in the treatment of chronic liver diseases including Hepatitis C, alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH)."
Chronic liver diseases, including hepatitis, ALD and NASH, affect an estimated 25 million people in the U.S., approximately one in every ten. Hepatitis C is the leading blood-borne infection in the United States. The U.S. Center for Disease Control and Prevention estimates that over 4.5 million Americans are infected with the hepatitis C virus. The World Health Organization and other sources estimate that at least 200 million people are infected worldwide. Some experts estimate that without substantial improvements in treatment, deaths from hepatitis C will surpass those from HIV. Hepatitis C is the leading cause of liver cancer and the primary reason for liver transplantation in many countries. Even with recent advances, approximately half of patients still do not attain a sustained response with current therapies. NASH, non-alcoholic steatohepatitis, also called 'fatty liver,' is an inflammation of the liver associated with an increase of fat deposits in liver cells that may lead to severe liver damage and cirrhosis. NASH may occur in middle-aged, overweight, and often in diabetic patients who do not drink alcohol. ALD, caused by alcohol abuse, is one of the ten leading causes of death in the United States.