Han Wei, Beijing Armed Police General Hospital, several recent studies have shown that compiler
lower LDL levels as low as possible, followed by the doctors in the world began to increase the use of statin dose. However, if the LDL down to 70 mg / dL, then what will happen to the treatment of heart disease? majority opinion is to increase HDL cholesterol, and this relatively neglected in the past. Recently the preliminary results of several studies shocking now become the focus of HDL. John Kastelein (Academic Medical Center, Amsterdam, Netherlands), Professor, said, In all known risk factors play an important role in lipoprotein metabolism. in the diuretic treatment of hypertension on the basis of further improvement seems to be difficult, in terms of lowering therapy compared with practical significance. produced good results, but now we approach the treatment platform. We all know that statins in reducing LDL cholesterol effectively, including several studies currently being carried out confirmed that LDL levels as low as possible, but the LDL of gradually drawing to a close, then the next target for improving treatment of what is it, the most obvious answer is HDL. HDL by a low incidence of heart disease, HDL cholesterol for each additional 1 mg / dL, lower the incidence of heart disease, 2% -3%. but HDL cholesterol, the decisive factor in changing the benefit is uncertain.
HDL effect link
HDL cholesterol and reverse cholesterol transport to the main work through the upcoming transport of cholesterol within the arterial wall will discharge the liver. while HDL also has anti-inflammatory, antioxidant, anti-NO-induced thrombosis and a variety of features. These features of the benefits of the role of HDL unclear how much impact, but also the cardiovascular protective effect of HDL is not clear whether some or a few specific role of HDL components, which are the current focus of the study. HDL cholesterol, one of the researchers Dan Rader (Binxi Law Virginia University, Philadelphia), Professor said, the role of Professor characteristics induced NO may play an important role but he said the importance of these effects is not clear how much. He said, > Although it has long been recognized that HDL has a protective effect, but increased HDL levels to reduce the risk of heart disease has not been in-depth study, but now the situation has changed. ApoA-1 of last year with the release of a breakthrough in the field progress.
ApoA-1 Milano is an uncommon variant of ApoA-1, ApoA-1 is the main component of HDL, Milan University of Milan, the Italian variant of Professor Cesare Sirtori and Guido Francheschini first discovered, they in a significantly lower HDL levels but no signs of cardiovascular disease found in the Italian population variant. Los Angeles Cedars-Sinai Medical Center, Professor Prediman K Shah researchers speculate ApoA-1 Milano variant ApoA than normal -1 have a greater protective effect, they conducted studies have shown that in animal models injected with ApoA-1 Milano variant physical atherosclerotic lesions reduce lipid levels and inflammation, can block the progression of the disease and can reverse the atherosclerosis sclerosis.
Department of the Cleveland Clinic last year, Steven Nissen study group led by Professor repeat in the human out of the result. Their study used intravascular ultrasound techniques, the results show that recombinant ApoA-1 Milano is only injection of 5 weeks, 47 patients with acute coronary syndrome patients, 4% had coronary atherosclerosis reversal, the difference was not much but there are statistically significant. The study is the first human atherosclerotic lesions reversed the evidence indicates that HDL in the ascendant.
Nissen said, ; He added, The study also makes the whole world was shocked. begins to accelerate their HDL is now planned. The main stimulus.
HDL reversal of atherosclerosis is the key to you?
The most exciting is that increasing HDL can reverse the atherosclerosis is the key to whether interventions reduce LDL also not clear. In the Nissen and other recent IVUS trials conducted another that (REVERSAL) trial, the highest dose of statins reduced the greatest degree of LDL to block progress of atherosclerosis, but can not be reversed. Baylor Houston Christie Ballantyne School of Medicine, said, between more than that, and statins, but we need to increase the treatment of elevated HDL. LDL lowering reduces adverse events makes 35%, 35% less than for those patients, effect is excellent, but for the remaining 65% may not have much benefit. This some patients need additional treatment, that is, increased HDL. will not be reduced 20-30%, but reduced by 70%. This will have enormous significance. have the ability to coronary events by 70%, 80% or even 90%. LDL treatment over the past 20 years, the focus of the next 10 years will belong to the HDL points higher on cognitive and the elderly. Kastelein said, 1 is also true, ApoA-1 in most cases is beneficial. have not yet found increased HDL ApoA-1 and the clinical condition of no benefit. he believes the situation may be more complicated, he said, High HDL
ApoA-1 Milano study makes the world's pharmaceutical companies and cholesterol enthusiastic researchers develop new drugs that increase HDL, but even the most advanced research and development really can be used for clinical also need a few years time, so during this period, the help of doctors is still the greatest degree of existing instruments, lifestyle changes such as exercise, weight loss, moderate alcohol consumption and smoking cessation in the increase in HDL has modest benefits, but also try a variety of drugs.
niacin side effects and benefits of increasing HDL is now considered to drugs already on the market and niacin, but the side effects of the drug in the presence of so many people put off. Ballantyne that nicotinic acid there is still value in use, 2000mg of niacin can increase HDL 30%. poor. The main reaction is facial flushing, while not easy to use, due to give 500mg, and then gradually increased to 1000mg, and 2000mg, the drug can cause the body flushing, impaired glucose tolerance, uric acid levels and abnormal liver function. ;
He believes that the measures in the elevated HDL limited circumstances, the current joint use of statins and niacin is a good strategy. He said the role of nicotinic acid and statins are complementary. Preliminary Study (HATS) show that the joint can cause mild regression of atherosclerosis. acid is effective in increasing HDL drug, because of its low price, no drug company promotion, not many people know the benefits of the drug .1 / 3 of patients can not tolerate the drug, but also means that 2 / 3 patients can use. According to HATS study, niacin and statins have a very excellent strategy for the joint effect, the doctor should vigorously promote this combination therapy. use less of the drug in Europe. But he looked forward to long-acting formulations Niaspanr the market, the end of the drug this year in Europe, he believes the drug will be able to and joint use of statins. But he believes a better strategy is to develop a new drug without the side effects of nicotinic acid. Nicole has developed a new type of acid agonists. Ballantyne said, role, VA HIT study using gemfibrozil, results showed that the drug can significantly reduce adverse cardiac events. But as the University of California Professor Richard Havel pointed out, fibrates also lower triglycerides, Richard Havel HDL in the 50's original research. He said, drugs, but more needs to update the role of the drug. Ballantyne said, standards, we should achieve the highest quintile group of about 60-80mg/dl. but we can not yet close to the standard treatment. so that treatment is much room for improvement. drug development research and development currently under a variety of
may increase HDL drug, which is the most in-depth cholesterol ester transfer protein (CETP) inhibitors.
CETP inhibitors
CETP is a There are several features of the plasma glycoprotein, one of the functions in the transfer of cholesterol from HDL to LDL-mediated effects in the. CETP inhibitor can lead to higher HDL levels, there are two CETP inhibitors currently in advanced stages of clinical development, a species is Pfizer's torcetrapib, the other is Japan Tobacco's JJT-705. Pfizer pharmaceutical company has begun Phase 3 clinical trials, the drug company in Japan just after two clinical trials. Pfizer is also developing A atorvastatin and torcetrapib compound preparation that can significantly reduce both LDL and HDL increased role, Ballantyne think this is very exciting.
CETP inhibitor being developed by the name of the company in research and development
Phase 3 clinical
Torcetrapib Pfizer
JTT-705 Japan Tobacco, Phase 2 clinical
CETP vaccine Avant 2 of 2 clinical
Torcetrapib clinical results recently released, showing a significant increase in HDL levels can be. Nissen Determination is now hosting a plaque burden of IVUS3 clinical trials, 886 patients were selected, giving half of atorvastatin and the other half given atorvastatin and torcetrapib, the beginning of the trial results will be released in two years.
If the IVUS studies obtained positive results, and if the FDA accepted as a legitimate alternative to IVUS end point, torcetrapib will be certified in the next 2-3 years. Pfizer is also carrying out a test torcetrapib clinical endpoint, but the results in recent years will not release, Nissen that torcetrapib's certification is not necessary to wait for the results of the study. He said, certification, especially now REVERSAL and PROVE-IT studies have confirmed the role of IVUS. , he said, Corporation and Japan Tobacco (JT) test new drug development. He pointed out that the two test results show that the JT drug can increase HDL 35% or 40%, while Pfizer's drugs increased HDL levels higher. But he said it, and does not mean that torcetrapib in reducing coronary heart disease events better. There are many unknown place, Brown pointed out that the CETP inhibitor, the results of animal experiments are inconsistent, and even results show that the drug has an adverse effect. he explained, as LDL, if we give statins reduce LDL, but also to prevent the conversion of HDL to LDL, then we might have prevented the transfer of cholesterol to the liver. CETP in some animal models have a more serious treatment of atherosclerosis, in fact, rodents did not CETP, these studies also difficult to draw conclusions, but for some reason CETP in human evolution, and may have a useful role.
Shah also pointed out that there is not all caused by CETP gene mutation in high-HDL people can prevent heart disease. He said, high levels of HDL, but not clear whether it can avoid heart disease. high levels of HDL can not solve all of the risk. HDL is high and the inherent effects of HDL are the same. IVUS's main motive is that if found to have plaque reduction, then we can say that drugs are efficacious. results to determine how effective blocking the enzyme, Nissen's IVUS studies in this area is very good. will be eased.
Rader that if the study found no effect of CETP inhibitors, also can not deny other measures to increase HDL. He said, The most direct strategy, but without effect, we should not delay the increase of HDL, the difference in mechanism of action may explain the causes of invalidity. much discussion, some may also be unknown, but the CETP inhibitor is implementing an active development program, 2 years or so will come to the validity of the results. antibodies, animal experiments show that the drug can increase HDL levels, in the absence of a preliminary clinical trial showed that statin use in patients with the drug can increase HDL by about 8%, the company says can be used for the treatment of normal LDL and low HDL in patients . Nissen cautions that Avant is a small company with limited partnership may be required to successfully develop the drug. Brown that the development of antibodies are , and some people have used the antibody, it will cause irreparable harm. increased HDL drugs, PPARs is a nuclear receptor, can activate the ABC-A1 gene, and then induced the first step in reverse cholesterol transport - the cholesterol excreted from the cells and transferred to HDL particles.
are three types of PPARs that alpha, gamma, and delta-type, these are the targets of PPARs agonists. fibrates and PPAR alpha by binding to play a role, it could also lead to higher HDL and lower triglycerides, PPAR gamma only mild increase HDL, but its main effect seems to reduce insulin resistance, and PPAR delta seems the combination of these three roles.
PPARs effects of different types of receptor types that already exist
effect
Alpha beta agonist special class of lipid-lowering drugs to increase HDL, reduce triglycerides
Gamma Glitazones hypoglycemic agents reduced triglycerides and increased insulin resistance
Delta non-HDL, reduce triglycerides and insulin resistance
Rader pointed out that the study is PPAR attractive, The. simultaneously on two different targets may have the greatest effect, and now the early start of the study some clinical trials. low HDL in metabolic syndrome, it is possible indications of these drugs. recently abandoned its late-stage clinical research program.
Kastelein said, do not know what will happen. difficult, compared to selectively block an easier target, which is the majority of the reason drugs are blockers. agonist effect of more extensive and more receptors and can activate the enzyme pathway, which will bring about side effects. PPARs are agonists, I was working in this area, I certainly hope that these drugs will be successful, but have to wait. Name of company research stage agent
PPAR type
Tesaglitazar (Galida) AstraZeneca Phase 3 Alpha / gamma
GW-590735 GlaxoSmithKline Phase 2 Alpha
GW-501516 GlaxoSmithKline Phase 2 Delta
K-111 Roche Phase 1 Alpha
GW-641597 GlaxoSmithKline Phase 1 Alpha
LY-674 Ligand Phase 1 Mixed
LY-929 Ligand Phase 1 Mixed
GW- 409544 Ligand Phase 1 Alpha / gamma
LY-518674 Lilly Preclinical Alpha
DRF-4832 Dr Reddy's Preclinical Alpha / gamma
Brown said he was worried about the beginning of a new dual-agonist prior to, gamma and alpha joint excited study is not sufficient. He said, in-depth study to see if these two drugs have synergistic effect. to develop a patented new drugs can really bring more profit, but to make clear such a large investment should be based on the dual PPAR-alpha and ngamma excited whether the concept of agent science. the same civil liberties issues.
increased HDL in all measures, the most obvious direct to the main component of HDL or Apo-A1, or the simulation of these components of the drug. This is the Apo-A1 Milano on the basis of the study was conducted by Professor Nissen host, the use of IVUS studies synthesized Apo-A1 Milano model drugs Esperion's ETC-216.
there are several limitations of such drugs themselves, the molecules are too large, long-term oral treatment inconvenient and expensive, making cumbersome, But as a short-term treatment of drug still being studied. Shah pointed out that in patients hospitalized for acute coronary events can be intravenous application of the peptide, and then patients can be discharged from the treatment given to different drugs.
other orally active peptide material
Esperion and other units are also being conducted oral collaboration with the smaller active peptide molecules, which have a realistic hope. Kastelein said that if oral administration of peptide can be effective, there will be a very important meaning, but he said the clinical research effective before the release of his oral argument still hold a trace of doubt, potential applications, Pfizer acquired Esperion Company. oral drug development program is really attractive, but the rabbits orally active, oral administration of not necessarily have the same effect, to judge before I want to see in the study of human the data. , may have little practical significance. But the small molecular peptides is feasible. with a view of the D-amino acid peptide of type has some degree of intestinal absorption, but this is only some very early research.
Los Angeles Bruin drug companies to develop this peptide drug, the company is Professor UCLA cardiologist Alan Fogelman founded. The company claims to have orally active peptide D4F, animal studies have shown can reduce atherosclerosis in rats sclerosis. Shah also attended the D4F of research, he said, would be a great discovery. After the acquisition by Pfizer, they chose to leave and create a Esperion. The irony is that now Esperion Youyi price was 1.3 billion acquisition of Pfizer.
Esperion has developed four kinds of reverse cholesterol transport of drugs They are:
l ETC-216 recombinant ApoA-1 Milano molecules, is planning to implement a large-scale clinical trials, expected in 2007 listed.
l ETC-588 used in another ApoA-IV 1 Milan molecules, is vividly described as ; positive blood vessels change, l ESP 31015 orally active small molecule, can reduce animal experiments show that LDL, increased HDL and inhibiting the progress of atherosclerosis.
SR-BI receptor
Another more controversial measures to increase HDL is increased liver SR-BI receptor. one of the pioneer of this strategy is Krieger, he found that HDL receptor SR-BI. SR-BI to remove plasma HDL, which mediates cholesterol transport from blood to bile. Because plasma HDL levels can lead to reduced, but lower HDL Krieger that does not necessarily bad.
he said, Adsorption of cholesterol in the blood reduced.
some experts to SR-BI on the basis of this treatment is feasible and critical, as can lead to decreased HDL, increased HDL that strategy and the current phase wrong, but Kriger said it was unwise to say, will be promising.
said ApoA-1 Milano study confirms his view, help to better play the role of HDL, so do not need more HDL. This is a very risky strategy, but may be long-term solution, the cost is not high. What we need is long-term use of the carrier, there is now dawn. being carried out to ApoA-1 Milano gene-based gene therapy, indicating that after a single injection of the gene transfer is feasible, can reduce plaque accumulation. He said, Milan, which can produce their own ApoA-1. we have the evidence but not for humans, it is a promising treatment. :
l increase in endothelial cell lipase enzyme can lead to lower HDL, thus inhibiting the enzyme may be effective. Rader ongoing research in the area.
l LXR (another nuclear receptor) agonists and other small molecules These substances can increase peptide ABC-A1, resulting in outflow of cholesterol from the cells. have confirmed that a variety of molecules, but side effects prevented further development.
HDL lipid science companies Lipid Sciences fat strategy headquarters
In California, developed a plasma to lipid treatment, when the blood back to the enhanced role of HDL. The transfer of the patients treated, including the first part of the plasma, in vitro using the HDL particles to go back to lose fat. research shows that the HDL of these fat particles in the adsorbed HDL cholesterol more effectively than the natural, animal experiments show that the treatment can cause regression of atherosclerotic plaques. The company will be the treatment described as ; increase in lipid in patients with internal mechanisms
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