Here's an interesting but dated article ('97) from the New Scientist.
Fix for furry arteries
By Andy Coghlan
A double-barrelled assault on coronary heart disease will begin next month, when doctors in Scotland begin testing a pioneering drug to tackle both the root cause of blockages in coronary arteries, and suppress levels of cholesterol--the fatty substance in blood which aggravates furring of the arteries.
Developed in the US by AtheroGenics, a biotechnology company in Norcross, Georgia, the drug snuffs out any inflammation in the endothelial cells that line the artery walls. Chemical and mechanical stresses normally trigger this inflammation, which the company believes leads to the build-up of plaque.
Most existing drugs attempt to treat atherosclerosis by reducing levels of cholesterol in the blood, says Russell Medford, the president and founder of AtheroGenics. This fatty substance accumulates in plaque, but Medford argues that the underlying inflammation causes the build-up.
To back up his case, Medford and his colleagues showed that if they disrupted the endothelial inflammation in rabbits, they could prevent plaque from forming, even if the animals had high levels of cholesterol in their bloodstream.
The drug, codenamed AGI-1067, prevents the activation of a cascade of genes in endothelial cells which amplifies inflammation. The cascade is inactive until an endothelial cell is exposed to mechanical or chemical stress. There are many possible causes of stress, including exposure of the cells to oxidants--reactive chemicals that often accumulate in blood of people on high-fat diets. Mechanical stresses caused by high blood pressure also trigger the cascade.
When activated, the cascade of genes manufactures several proteins that summon cells of the immune system. One key protein, called vascular cell adhesion molecule-1, or VCAM-1, serves as a docking point on the cell surface for white blood cells called leucocytes. Another protein, called monocyte chemoattractant protein, or MCP-1, sends out chemical signals to attract yet more leucocytes.
Once the leucocytes dock on VCAM-1, they mature and embed themselves deep in the artery wall, sending out chemical signals summoning additional leucocytes, which act as a seed for plaque to form.
If oxidised low-density cholesterol is in the vicinity, white blood cells called macrophages gorge themselves and become fat-laden "foam cells", which also embed themselves in the growing plaque. Other blood components join the throng, as do cells of body linings called smooth muscle cells. As the plaque expands, more immune cells arrive, creating a vicious cycle that hastens growth of the plaque.
But AGI-1067 nips this whole process in the bud by stopping the cascade of genes. It does so by neutralising fatty substances called lipid peroxides, which accumulate in endothelial cells when the bloodstream is laden with the oxidants that come from a fatty diet. Unchecked, these lipid peroxides trip nuclear factor kappa-B, the genetic switch or "transcription factor" which activates the gene cascade.
The beauty of the new treatment, says Medford, is that it lowers cholesterol levels as well as attacking the inflammatory roots of atherosclerosis. This might make it easier for patients who find it difficult to control their disease by following a strict low-cholesterol diet. "I wouldn't look at any drug as a panacea which would allow you to carry on smoking and eating fatty food," cautions Medford. "But this should make it much easier for people to control their disease."
He hopes that AGI-1067 might also cause pre-existing plaques to recede, but says that there is no evidence for this yet.
Brian Pickering, medical director at the British Heart Foundation, says that tackling heart disease by combating the underlying inflammation is gaining favour over traditional treatments which simply control cholesterol levels. He says that the VCAM-1 cascade neutralised by AGI-1067 is a "very promising target".
But Pickering is concerned about the effects that long-term use might have on patients' immune systems. Inflammation of the endothelial cells is a normal immune response, and the danger is that the drug could damp down immune responses elsewhere in the body. Medford says that there is no evidence that this will be a problem: the experiments in animals suggest that "global" immunity is not affected.
He adds that tests in animals have not revealed any significant side effects. But Medford acknowledges that the safety of the drug is paramount, because patients may need to take it for many years.
related sites:
CardioVascular Diseases (Statistics)--WHO
Blood Cholesterol--Know The Facts
From New Scientist, 15 November 1997
newscientist.com |
