Hemolytic uremic syndrome (HUS) comprises hemolytic anemia (anemia caused by destruction of red blood cells), acute kidney failure (uremia), and a low platelet count (thrombocytopenia). It predominantly affects children. Most often the disease is caused by food or water-borne pathogenic bacteria producing Shiga or Shiga-like toxins, for example the bacteria S. dysenteriae and the shigatoxigenic group of Escherichia coli (STEC), which includes serotypes O157:H7, O104:H4, and other enterohemorrhagic E. coli (EHEC), and (rarely) some Campylobacter strains. The most common source of Shiga or Shiga-like toxins is E. coli O157:H7. Approximately 5% of HUS cases appear to result from infection by Streptococcus pneumoniae, the agent that causes traditional lobar pneumonia. Atypical HUS (aHUS) represents 5-10% of HUS cases, and is caused by genetic defects resulting in chronic, uncontrolled complement activation.
HUS is the most common cause of acquired acute renal failure in childhood. It is a medical emergency and carries a 5-10% mortality. Shiga toxins and Shiga-like toxins can kill cells directly by blocking protein synthesis. Vascular endothelial cells are particularly vulnerable, and the destruction of these cells causes lesions in the endothelial wall and separation of the basement membrane of the endothelial layer, activating the coagulation cascade. They also trigger a complex cascade of damage to blood cells. The toxins bind to the globotriaosylceramide (Gb3) receptor on the surface of the glomerular endothelium, which initiates a signal cascade leading to apoptosis and binding of leukocytes to endothelial cells, as well as inducing the release of cytokines and chemokines involved in platelet activation and inhibiting ADAMTS13, causing microthrombus formation. Clumps of platelets adhere to the endothelia of small blood vessels, destroying erythrocytes (microangiopathic hemolysis), and producing characteristic fragments of sheared erythrocytes (schistocytes). The end result is anemia due to destruction of erythrocytes, thromobocytopenia due to the destruction of platelets, and damage to tissue, particularly the kidneys, due to impaired blood flow. This process is known as thrombotic microangiopathy (TMA). Finally, Shiga toxin also activates the alternative complement pathway and interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade.
In atypical HUS, the uncontrolled activation of complement leads to a similar end result: complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis.
Currently, there is no cure for HUS. Treatment is generally supportive, with dialysis if needed. Antibiotics to kill the bacteria may exacerbate the condition by stimulating further production and release of toxin. Platelet transfusion may simply increase the incidence of microthrombi, further exacerbating the TMA.
New approaches to treatment and management of HUS are needed.
Deer antler is a traditionally widely used Asian medicine, prepared by drying uncornified antler of a deer. Deer antler has been acclaimed to have various medical effects, such as growth- and development-promoting effects, promoting hematopoietic function, treating nervous breakdown, benefiting cardiac insufficiency, improving the function of five viscera and six entrails, as described in the Dong-eui Bogam, a Korean medical book first published in 1613. Moreover, deer antler has been known to have various medical effects such as elongation of power and endurance, improvement of myocardial motion, fatigue recovery and enlargement of immune system. Active components of deer antler and effects thereof have been researched. For example, it has been reported that certain components of deer antler, including rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol (PLAG) obtained from chloroform extracts of the deer antler, have growth-stimulating activities of hematopoietic stem cells and megakaryocytes (WO 99/26640). It is also reported that monoacetyldiacylglycerol derivatives which are active components of the deer antlers are effective in treating autoimmune diseases, sepsis, cancers such as bile duct cancer, kidney cancer or malignant melanoma, and so on (WO 2005/112912). Use of certain monoacetyldiacylglycerol derivatives for treatment of leukopenia and/or thrombocytopenia is described, e.g., in International Application No. PCT/US2015/031204, the contents of which are incorporated herein by reference.
USPTO Backgrounds
USPTO Backgrounds