The Alteon Corporation in the USA currently has aminoguanidine (Pimagidine) in stage III trials for diabetes. Interestingly it has also developed ALT-711 (thiazolium salt) which is now in stage II trials. Whilst aminoguanidine and other agents (such as Carnosine and Acetyl-L-Carnitine) have been shown to help prevent cross-linking, ALT-711 is claimed to break existing links. If this is substantiated, this could be a major anti-aging medicine of the future.
It is becoming clear that agents that can slow, prevent and even reverse the effects of cross-linking will have a major impact in the role of preventative medicine, and indeed could be one of the keys to true anti-aging medicine.
A new class of anti-aging supplements, called AGE blockers, works by helping to stop the glycation chain reaction started by glucose metabolism just prior to the formation of the AGE molecules.*
Although stopping glycation reactions at the Advanced Stage does not break up cross-links that have already formed, it does limit the formation and accumulation of AGEs throughout the body without interfering with normal bodily function.*
There are a few drugs that are in various stages of approval that are purported to actually be cross-link breakers. One such drug, called ALT 711, appears to do just that, but may not be available on the market for some time. Another drug, aminoguanidine, is also in the midst of drug approval trials, but it has only been shown to be an inhibitor of AGE, not a cross-link breaker.
An array of substances have been tested for effectiveness at preventing AGE formation. Many of those tested work well in vitro (in the laboratory test tube) but fail in vivo (in living organisms).
Alagebrium (formerly known as ALT-711) is a drug produced by Alteon Corporation, which was evaluated in clinical trials. It was the first drug to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (A.G.E.s), thereby reversing one of the main mechanisms of aging. Through this effect Alagebrium is designed to reverse the stiffening of blood vessel walls that contributes to hypertension and cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking.
A.G.E.s are permanent carbohydrate structures that form when carbohydrates bind to proteins, lipids and DNA. Many proteins, including structural proteins such as collagen and elastin, play an integral role in the architecture of tissues and organs and maintenance of cardiovascular elasticity and vascular wall integrity. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than non-diabetic individuals. This process can impair the normal function of organs that depend on flexibility for normal function, such as blood vessels and cardiac muscle. The formation of A.G.E. crosslinks leads to increased stiffness and loss of function of tissues and organs, and abnormal protein accumulation, which together cause many of the complications of aging and diabetes. A.G.E.s are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation.
Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the A.G.E.s by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of A.G.E. crosslinks also renders tissues and organs less susceptible to normal turnover thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intra-molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced.
The chemical compound had been discovered many years ago, and had traveled a circuitous route through academia, research firms, and finally, Alteon. There are two prominent attributes to Alagebrium (as Alteon renamed it). The first is that it is not a difficult compound to synthesize. An active black market rose very quickly after the early Phase I and II tests came in. Independent, lab-tested, certified for purity product was available for a short time on the grey market at about $3 per gram.
Although Alagebrium has shown very promising Phase I and II clinical trials, active research stopped because Alteon had run out of operating cash. Alteon, having a huge amount of convertible preferred stock hanging over its head (held by Genentech), had increasing difficulty raising subsequent levels of venture capital until finally, it was unavailable at any price. On 25 July, 2007 Alteon was essentially bought for its corporate shell by a three-man operation developing another medication that needed a corporate shell in order to move fast. The company changed its name to Synvista Therapeutics, Inc. now with perhaps three employees in the United States, and outsources its research, (probably none of it on Alagebrium, despite the website’s assertions).
One conclusion that could easily be derived from the published research is that Alagebrium works first and fastest on those areas with the most blood-to-surface coverage and that are constantly in a state of higher levels of hemodynamic pressure, such as the large and small chambers of the heart, as well as the atriums, and potentially, the valves. Because testing for regulatory approval looks for quick answers for severe problems in order to meet the ‘need’ hurdles of the FDA, and given the impatience of the venture capital markets, Alteon never engaged in long-term tests seeking FDA approval of the medication for conditions other than heart treatment, so the patent applied for was a ‘use’ patent for just that. Given the relationship between surface-area coverage under pressure and short-terms results, testing for conditions such as diabetic neuropathy, or long-term low-dose prohylactic use for aging hearts, which would have taken years, was never an option for Alteon. Although the medication had dramatic positive results in the tests for efficacy, the molecule is not difficult to replicate, which is a negative vis-a-vis obtaining approval and satisfying investors that they are buying into an exclusively-owned product. So a lack of patent protection, and ease of replication by others, obviously made the venture investment community lose faith before an approved product arrived.