Spread the love

In 2001, Bush was elected president of the United States and became the first “president of the second generation” in the history of the United States. His running mate, the vice president, was the old Republican politician Dick Cheney.

Cheney once served as secretary of defense in President Bush’s cabinet, participated in planning the famous “Desert Storm” and captured the major military operations in Panama, including Nolega, and was deeply appreciated by the old Bush. He returned to the American political arena with great strength and fully assisted the younger Bush, who has not yet done so. He has endured the test of major crisis events that shocked the world, such as 9/11, and assisted Bush in his reelection in the next general election. He once again became president and vice president.

During the 8 years of his tenure as Vice President, Cheney left the public with an old-fashioned, hard-line, conservative image and was rated by the media as the most influential vice president in US history. What is little known, however, is that in the 8 years he served as Vice President, Cheney had been carrying a resignation letter that had been written before he took office.

After Cheney was elected, he discovered a gap in the U.S. Constitution. If the vice president is still alive but incapacitated, there is no provision in the constitution to allow the person to leave. Because he had had a history of three myocardial infarctions, Cheney feared that it might happen to him, so he wrote down this unprecedented resignation letter and gave it to his lawyer.

At the age of 37, Cheney unfortunately suffered his first infarct during the election of a member of the National Assembly. Later in 1984 and 1988, he suffered another two myocardial infarctions and performed a bypass operation. In the 2000 presidential election, after George W. Bush announced Cheney as a running partner, his health issue became a hot topic in the media. As the election just ended, there was an abnormality in Florida’s vote counting and it was impossible to determine the result for a time.

The State Supreme Court ruled that some counties would be allowed to recount manually. This bad news, which was not conducive to Bush and Cheney, came soon. Cheney was hospitalized for the fourth myocardial infarction. The doctor installed Cheney’s cardiovascular stent. When she was discharged two days later, Cheney himself told the media that he would soon be able to resume his daily work. He also revealed that he would continue to take Plavix to reduce the risk of future myocardial infarction.

According to the decision of the Federal Supreme Court, George W. Bush was successfully elected as the 42nd president of the United States. Cheney, who had had 4 MIs, couldn’t carelessly wrote the secret letter of resignation mentioned above before he became vice president.

Plavix-based post-surgery medications have enabled Cheney to bring his heart with four infarcts. He has successfully served as vice president of the United States for eight years. It can be said to be a miracle. Undoubtedly, the emergence of anti-platelet aggregation drugs represented by clopidogrel has fundamentally changed the treatment of cardiovascular diseases, especially ischemic heart disease. “Miracle” like Cheney is getting more and more happened around us.

Lucky hit

Plavix’s R&D is an example of mutual promotion between basic research and clinical trials. It is roughly in sync with our understanding of the molecular mechanisms of platelet aggregation and its relevance to cardiovascular events.

In 1972, Sanofi decided to make a generic version of Tinoridine, an analgesic and anti-inflammatory drug (don’t think that big companies wouldn’t do Me Too). Tenoridine belongs to a class of compounds known as “Thienopyridine,” and the stability is not good, so Sanofi’s project team believes there is room for improvement.

They synthesized a large number of thienopyridine derivatives. Since there were no micro-high-throughput screenings at the time, and cell-level screening was rare, the synthesis of these derivatives was in the order of grams, which was labor- and time-consuming. But when done well, almost all derivatives can be tested in vivo or ex vivo directly on a mouse or rat disease model, and as long as there is an animal disease model on hand (no total A few) can go and try it.

Looking back to the past is really amazing. At that time, none of the thienopyridine derivatives synthesized by the project team showed significant anti-inflammatory or analgesic effects. However, there were several unexpected findings. Not show the effect of anti-platelet aggregation.

This was only a small surprise at the time, because platelet aggregation has not been linked to thrombosis and cardiovascular events. The mainstream opinion of the medical community is that vasospasm is the main cause of clinical complications of atherosclerosis, so it is also No pharmaceutical company was specifically looking for new antiplatelet drugs at that time.

Since “Lucky hit” has been discovered, antiplatelet drugs still have some development value at that time. For example, in patients undergoing cardiopulmonary bypass surgery or during hemodialysis, their blood contact with some artificial surfaces can cause platelet aggregation. Thrombotic complications. So the project team selected the best of them for clinical development and marketed it in France as Ticlopidine in 1978, becoming a niche drug for restrictive clinical indications only.

Stand out for Plavix

After ticlopidine was nominated as a clinical drug candidate, Sanofi’s project team continued to synthesize thienopyridine derivatives in an attempt to obtain a second-generation antiplatelet drug with a higher activity/toxicity ratio in animal experiments because A few patients have severe blood disorders after taking ticlopidine, including leukopenia, thrombocytopenia, agranulocytosis, and pancytopenia, these potentially life-threatening adverse reactions in subsequent large clinical trials and postmarketing The drug tracking study was confirmed and quantified.

At the same time, there has been a keen interest in the role of platelet and platelet inhibitors in the treatment of atherosclerotic diseases in the medical community because of the preliminary confirmation of the protective effect of aspirin on cardiovascular disease in clinical research, and aspirin may be One of the targets is probably platelets!

The project team synthesized a total of more than 1,000 analogues of ticlopidine and tested its antiplatelet and antithrombotic effects in animal models. Of these, eight compounds entered the clinical phase and were administered to healthy volunteers. In the test, only the last test drug coded PCR4099 showed higher efficacy and better tolerability than ticlopidine. A further Phase II clinical study confirmed its strong anti-platelet aggregation in patients who had previously experienced another thrombotic event.

At the same time, the role of platelet aggregation in arterial thrombosis has been widely accepted by the industry, providing a theoretical basis for many drugs that inhibit platelet function. In various arterial thrombosis models, PCR4099 showed dose-related antithrombotic activity, which was more effective than ticlopidine and was about 100 times that of aspirin.

PCR4099 is a racemate (an equal mixture of a pair of mirror image enantiomers) in which the dextrorotatory enantiomer has antiplatelet and antithrombotic effects and the inactive L-enantiomer is tolerated in animal experiments. Poor sex. As a result, they stopped the clinical study of PCR4099. Since 1987, it began to develop the dextrorotatory enantiomer. After 10 years of clinical research, this dextrorotatory enantiomer was named Plavix, marketed globally in 1998 for secondary prevention of ischemic cardiovascular events.

In a phase III clinical trial named “CAPRIE”, studies in more than 19,000 patients with atherosclerosis showed that Plavix is ​​more likely than aspirin to reduce the risk of ischemic stroke, myocardial infarction, or vascular death. Effective, can be widely used to prevent fatal or non-fatal systemic ischemic events. The results of the CAPRIE study also show that Plavix’s overall safety is at least equivalent to that of medium-dose aspirin, paving the way for Plavix to become a big drug.

God’s way is higher than man’s

If you think that Plavix is ​​a heavy drug when it was born, it would be a big mistake.

It is still in the pre-clinical development stage, there are a lot of possible problems, not be optimistic. First, its mechanism of action is unclear, but it is certainly different from known antiplatelet drugs (such as aspirin). This uncertainty increases the blindness and risk of clinical development; second, clopidogrel is inactive in vitro. Yes, it is almost certainly a prodrug that must be metabolized by the liver before it is put into effect. Which metabolizing enzyme acts and what structure of the metabolite is not known, which in turn increases the risk of drug interactions and patients. The effect of diversity on the efficacy of the population; also, Plavix inhibition of platelets is irreversible.

Although there are successful examples, many drug development teams are still reluctant to develop irreversible “covalent drugs,” one of which is because of serious adverse reactions (such as bleeding caused by antiplatelet drugs) if excessive pharmacological effects occur. There is no way (such as antidote) that can immediately neutralize the effect of the drug, and persistent effects may cause permanent damage to the body. What is even more disturbing is that most of these active metabolites are non-selective and are likely to react with other cells and/or circulating macromolecules, such as DNA or proteins, resulting in specific toxicity.

If today’s criteria are used, Plavix is ​​unlikely to even qualify as a clinical candidate, but not so many “rules” of the year, Plavix not only became a candidate, but also entered the clinic, showing good efficacy and tolerance. In 2000, under the unremitting efforts of the project team, the secretive metabolite that produced pharmacodynamics finally surfaced, was isolated and characterized, and its platelet target was cloned in 2001 and confirmed as the P2Y12 receptor of ADP, involving Plavix. Active metabolic enzymes were not confirmed until 2011. In other words, the mechanism of action of these two representative anti-platelet drugs was elucidated in the 30 years after the discovery of the niche ticlopidine, more than 10 years after the synthesis of the big-name Plavix.

The application of Plavix under the guidance of clinical research has confirmed the key role of platelets in coronary artery thrombosis. On the other hand, it also proves the benefits of antiplatelet drugs in the treatment of acute coronary syndrome and coronary intervention. The role of adjuvant drugs and coronary thrombolysis. Further clinical studies have also shown that the combination of Plavix and aspirin has a good synergy.

Accumulated clinical data eventually led to the consensus of the medical community and fully affirmed the positive effects of anti-platelet drugs represented by Plavix. It has been the world’s second-best-selling drug for many years, with more than $9 billion in global sales in 2010 alone, saving the lives of countless MI patients.

Staying healthy from heart disease

Ischemic heart attacks have long been the “biggest killer” of humans. With the unremitting efforts of medical researchers, in the past 20 years or so, the death rate of MI in developed countries and regions has continued to decline. However, according to the 2016 China Cardiovascular Disease Report, the mortality rate of acute myocardial infarction patients in urban and rural areas of China is still on the rise, and everyone should pay attention to it.

In 2001, Plavix was approved to be listed in China, and aspirin achieved double-antibody treatment, which solved the acute thrombosis problem caused by stent implantation and helped China to further mature its interventional treatment. Today, China’s intervention surgery has reached a world-class level. It is estimated that about 6 million Chinese patients with acute coronary syndrome (ACS) and 3 million with stroke have benefited from Plavix.

In 2012, Plavix’s compound invention patent expired. From its original exclusive production, it entered a new stage of competition. Competition will undoubtedly bring benefits to consumers. The emergence of generic drugs will enable more patients to receive timely treatment, and it will also greatly reduce the economic burden on the health care sector. From the time of listing in 1998 to the expiration of patents in 2012, a very wide and long-term clinical use has accumulated a large amount of data for Plavix, and medical personnel have a comprehensive range of important parameters such as their drug properties, dosage, applicable population, and possible side effects. Learn, so use it more at ease. Although the original research drugs are expensive, they are often recommended by doctors. Many patients also have this tendency when economic conditions permit.

In addition, although Plavix’s compound invention patent has expired, the special crystal form of Plavix original drug is still under patent protection. It is certainly true that pharmaceutical companies have applied for patent protection for a particular crystal form. For example, Plavix’s orthogonal patent crystal form has more significant advantages in stability and hygroscopicity than other non-patent crystal forms.

Innovation drugs such as Plavix, which have preventive effects, are leaving us with heart disease. Staying away from heart disease, more people can enjoy the pleasure of healthy life. Far from the risk of myocardial infarction, our lives will certainly bloom more beautiful colors.

Leave a Reply

Your email address will not be published. Required fields are marked *