Ramatroban as a potential treatment for Cardiovascular Disease

Atherosclerosis is the deposition of cholesterol plaque in the inner walls of the arteries, occurring with aging or obesity. The plaque consists of swollen foam cells which are macrophages that have phagocytosed low density lipoprotein (LDL). LDL is found in the diet and is absorbed into the blood stream or is synthesized by the body. Formation of foam cells in the arteries can obstruct blood flow and cause inflammation. 

Sepsis is an extreme response to infection including bacterial infection where that body releases cytokines and lipid mediators that cause widespread inflammation and thrombosis (blood clotting) in the body. 

Coronary artery disease is the stiffening of arteries referred to as vascular calcification caused by arterial calcium phosphate deposition.   

A disease that causes inflammation and weakening of the blood vessel walls in children leading to the formation of aneurysms. 

High blood pressure caused by a variety of risk factors including obesity, diabetes, old age, etc. 

Brain damage due to impaired blood flow to the brain caused by bleeding or clotting in the cerebral blood vessels.

Aspirin is widely used for a variety of cardiovascular diseases by inhibiting the production of thromboxane A2 (TxA2), which stimulates platelet activation and constriction of blood vessels. However, aspirin resistance may occur if aspirin cannot sufficiently block the production of thromboxane in certain individuals, especially in the elderly and obese. Ramatroban directly inhibits the effects of thromboxane by blocking its receptor (TPr). Ramatroban is 100 times more potent than Aspirin in inhibiting platelet activation (Kariyazono et al, Blood Coagulation and Fibrinolysis, 2004) and promotes relaxation of blood vessels by increasing vasodilatory nitric oxide (Shiokoshi et al, J Hypertens, 2002). Therefore, Ramatroban has great potential in reducing hypertension and platelet activation in cardiovascular disease more effectively than Aspirin.  

Thromboxane A2 (TxA2) is significantly increased in obesity (Petrucci et al, J Thromb Haemost, 2019) and plays a role in atherosclerosis and cardiovascular disease. Blocking the thromboxane A2 receptor (TPr) with ramatroban ameliorates atherosclerotic disease by restoring vascular reactivity responses that are impaired in hypercholesterolemia. Administration of ramatroban, 4 weeks after balloon angioplasty in atherosclerotic rabbits prevented macrophage infiltration by downregulating MCP-1 expression and promoting neointimal formation (Ishizuka et al, Cardiovascular Drug Reviews, 2006). Therefore, Ramatroban prevents macrophage recruitment and subsequent accumulation of foam cells. 

Expression of adhesion molecules on the walls of blood vessels allows pro-inflammatory immune cells including macrophages to adhere and travel along the vessel walls. This further contributes to the formation of pro-inflammatory atherosclerotic plaque. These adhesion molecules include ICAM-1 and VCAM-1. Ramatroban, by blocking the thromboxane receptor, suppresses the expression of these adhesion molecules, thus potentially ameliorating inflammation in cardiovascular disease (Ishizuka et al, Cardiovascular Drug Reviews, 2006). 

Blood clots can obstruct blood flow to the organs, starving cells of oxygen and causing ischemia. In rats with splanchnic artery ischemia-reperfusion injury, while blood levels of thromboxane B2 were increased about 7-fold, ramatroban prevented hypotension, improved survival, restored phagocytic function of peritoneal macrophages partially, and inhibited tissue infiltration by neutrophils in the ilium and lung  (Canale et al, Pharmacology, 1994). Similar results with Ramatroban were demonstrated in a rat model of endotoxic shock in addition to reducing serum TNF-alpha levels and neutrophil infiltration in the heart (Altavilla et al, Pharmacol Res, 1994). Therefore, as an anti-platelet agent, Ramatroban has the potential to prevent organ damage during sepsis and other clotting disorders.

In myocardial ischemia-reperfusion injury of rats, ramatroban significantly increased survival rate, lowered areas of myocardial necrosis, blunted increased serum creatine phosphokinase (CPK) activity and reduced elevated myeloperoxidase levels (a marker of neutrophil infiltration) in the area-at-risk and necrotic area (Squadrito et al, Agents Actions, 1993). Therefore, Ramatroban has the potential to reduce risk and severity of heart attacks.