In order to control diseases, many people need to take drugs for a long time, the most common ones are antihypertensive drugs and antithrombotic drugs (anticoagulants). My mother has been taking antihypertensive drugs every day for more than twenty years. My father had a stroke seven years ago and this year, so he has to take aspirin and warfarin every day.
However, these two widely used anticoagulants have little effect on my father. After consulting many literatures related to drugs and heredity, it is found that other patients have encountered the same problem, and the reason may be "gene mismatch".
Aspirin: Legend has it that it will also encounter "resistance"
Let's start with the "magic medicine" aspirin.
Since the advent of 1897, the legend of aspirin has never ended. If each tablet contains 50 mg of aspirin, the global annual consumption of aspirin will exceed 654.38+000 billion tablets. No wonder 654.38+0950 was selected as the "best-selling drug" in Guinness World Records. In 2004, Englishman jeffries wrote the history of aspirin into the legend of aspirin. Until today, people's interest in it has not diminished, and relevant scientific research papers are published every year.
Aspirin was not an antithrombotic drug at first, but a family drug to deal with headache and brain fever. The earliest aspirin was extracted from willow bark. In 400 BC, Hippocrates, a famous Greek doctor, described the medicinal value of willow bark. However, acetylsalicylic acid, the active ingredient of aspirin, was successfully synthesized in 1853. 1897, chemist of Bayer company and synthesizer of heroin "cough medicine" fenix? Felix hoffman finally synthesized a stable acetylsalicylic acid. Less than two years later, Bayer introduced a painkiller called aspirin.
Aspirin is a combination of the initial "a" of acetyl and the word "spir" in the word Spiraea (the source of salicin), with a common suffix "in" at the end.
Since 1980s, the use of aspirin has gradually expanded to prevent myocardial infarction, stroke, venous thrombosis, and even some cancers and Alzheimer's disease.
Pharmacologically speaking, aspirin can prevent platelet adhesion and blockage, so it can prevent cardiovascular and cerebrovascular diseases, especially for the elderly and diabetic patients with family history of cardiovascular and cerebrovascular diseases.
Aspirin, as a basic drug to prevent and treat arterial thrombotic diseases, can be called "countless living people". A meta-analysis showed that aspirin antiplatelet therapy reduced nonfatal myocardial infarction 1? 3, non-fatal stroke reduction 1? 4, vascular disease mortality decreased 1? 6。
But aspirin is not effective for all patients with thrombosis, and some patients can't benefit from it. Even taking aspirin can not inhibit platelet aggregation and prevent thrombosis. Studies have reported that 5%-40% people have aspirin resistance (AR).
What caused this "resistance"? Some studies believe that smoking, diabetes, hyperlipidemia and other factors weaken the efficacy of aspirin. At the same time, some studies believe that the most important factor to predict the individual difference of aspirin's antiplatelet effect is the genetic background difference.
At present, aspirin can inhibit platelet aggregation by inhibiting the activity of a protein called cyclooxygenase (COX). At present, there are three kinds of COX isoenzymes: COX- 1, COX-2 and COX-3. COX- 1 is considered as a beneficial enzyme, which exists in most mammalian cells, while COX-2 is an inducible enzyme whose function is to activate macrophages or other cells, and it is full of inflammatory tissues. There is little research on COX-3.
COX is activated when body tissues are stimulated, such as trauma and infection. COX can catalyze the synthesis of various prostaglandins-don't think that only men have prostaglandins. In fact, prostaglandin is widely distributed in various tissues of human body and is the key to inflammatory reaction. Aspirin can inhibit COX, and COX can also inhibit prostaglandin, thus inhibiting inflammation and pain, and playing an anti-inflammatory and analgesic role.
Both aspirin and ibuprofen can inhibit COX protein. Image source: circres.ahajournals.org
The problem is the COX gene.
At the genome level, single nucleotide variations often occur. For example, at the same locus, one group of people is A and the other group is G. This is called single nucleotide polymorphism (SNP), which is the most common genetic variation in human beings, accounting for more than 90% of all known polymorphisms.
A nucleotide seems insignificant. However, studies have shown that the polymorphism of COX- 1 gene may prevent aspirin from acetylating it and affect its function. Another study found that the single nucleotide polymorphism of COX- 1 gene-1676 a >:G locus has a strong correlation with aspirin resistance, and patients with this genotype are more prone to aspirin resistance.
In addition, the inhibitory effect of aspirin on COX- 1 was 70 times stronger than that of COX-21. In other words, aspirin has no effect on COX-2. Generally speaking, COX-2 is rarely or not expressed in normal tissues and cells. However, under some pathological conditions, COX-2 can be overexpressed due to the stimulation of various internal and external environments. Another study found that the overexpression of the mutant allele -765g >: COX-2 in the carrier of C locus rs204 17 is one of the reasons for the poor efficacy of aspirin.
At present, there is not much research on COX-3, but it is not difficult to imagine that its mutation or polymorphism will also affect the use of aspirin.
Warfarin: testing genes before taking medicine.
Compared with the original positioning of aspirin as "anti-inflammatory and analgesic", the origin of another anticoagulant sounds even more frightening. Warfarin became a rodenticide as early as 1948. Although other more effective rodenticides have been developed, warfarin is still a good method to kill rodents.
Warfarin is an anticoagulant drug, which is used to prevent thrombosis and thromboembolism, blood coagulation and migration of thrombus in blood vessels. In 1950s, warfarin was proved to be effective and safe in preventing thrombosis and thromboembolism. Warfarin was approved for listing on 1954 and is still in use today. Today, warfarin is the most widely used oral anticoagulant in North America.
Warfarin has obvious curative effect, but it also has many shortcomings. For example, it interacts with many drugs, even the green leaf food rich in vitamin K 1 may reduce the curative effect. Coupled with individual differences of each person, the dosage of warfarin is particularly difficult to control. Eating less is useless, and eating too much is an accident. Therefore, warfarin needs to pass the international standardized ratio (INR) of blood test to ensure the safe dose. Above INR, there may be a risk of bleeding, while below INR, there may be a risk of thrombosis.
Clinical observation in recent years shows that although there are the same symptoms, different patients have great differences in the use of warfarin, and these differences are directly related to the genetic background of the patients themselves.
Therefore, on February 20 10, the FDA revised the drug instructions of warfarin. Because of the gene specificity of the dose, it is suggested that genetic tests should be carried out on CYP2C9 and VCORC 1 before warfarin is prescribed, and the drug dose should be adjusted according to different gene types.
Protein encoded by CYP2C9 gene is responsible for metabolizing 80-85% of L- warfarin, and S- warfarin is more easily excreted after metabolism. This protein belongs to cytochrome P450 enzyme family, which is responsible for oxidizing exogenous and endogenous compounds, and is also the main enzyme system of drug metabolism in vivo. In liver microsomes, CYP2C9 can metabolize 100 kinds of therapeutic drugs. In addition to warfarin, there are phenytoin for convulsions and epilepsy, as well as conventional prescription drugs such as acetaminophen, tolbutamide, glipizide losartan and some non-steroidal anti-inflammatory drugs. Extrahepatic CYP2C9 metabolizes some important endogenous compounds, such as arachidonic acid, serotonin and linoleic acid.
As for VKORC 1, it is the target of warfarin, and its full name is "vitamin K epoxide reductase complex subunit 1" gene. Vitamin K is necessary for blood coagulation, but it needs to be activated by enzymes. Protein encoded by VKORC 1 gene is responsible for activating vitamin K. If the VKORC 1 gene is mutated, vitamin K cannot be activated, resulting in the lack of coagulation factors dependent on vitamin K, thus preventing coagulation.
Pharmacologically speaking, the target of warfarin is protein encoded by VKORC 1 Warfarin inhibits vitamin K by affecting VKORC 1 protein, thus interfering with the carboxylation of vitamin K-dependent coagulation factors Ⅱ, ⅶ, ⅸ and ⅹ, so that these coagulation factors cannot be activated and only stay in the precursor stage, thus achieving the purpose of anticoagulation. However, the activity of VKORC 1 protein produced by different people is different, which leads to different doses of warfarin.
The latest edition of FDA catalogue also adds PROS and PROC genes as warfarin early warning and early warning scope, because these two genes are also involved in the process of blood coagulation, and these two genes encode vitamin K-dependent proteins existing in plasma. If their genetic mutation increases the tendency to form blood clots, then the use of warfarin must be different.
Polivi: the protagonist of court disputes
Plavix, also known as clopidogrel, is also a very popular anticoagulant, which is suitable for stroke, myocardial infarction and peripheral arterial disease. Pharmacologically, Plavix belongs to adenosine diphosphate (ADP) receptor antagonist, which inhibits platelet aggregation by preventing ADP from binding with its platelet receptor.
There is a famous lawsuit about Boliwei, that is, Hawaiian islanders sued the pharmaceutical companies Bristol-Myers Squibb and Sanofi-Aventis on March 9, 20 14 for concealing that Boliwei was invalid for Hawaiian islanders.
According to the drug price, poliovir is more expensive than aspirin 100 times, but many islanders use poliovir instead of aspirin because they see that drugs promote better anticoagulant effect than aspirin.
However, due to the low genetic susceptibility of 38-79% Pacific islanders and 40-50% East Asians, "Polivik" has insufficient metabolism in many East Asian and Pacific islanders, so it cannot take effect. Aspirin can actually protect them from thrombosis, but Polivik can't.
However, since 1998, pharmaceutical companies deliberately concealed this information, which led to a large number of patients abusing the drug, increasing the economic burden of patients and putting patients at risk. The pharmaceutical company even hid one thing. The validity of Polivik can be clearly judged by simply detecting CYP2C 19 gene (rs4244285).
As I said before, protein encoded by CYP2C 19 can metabolize drugs. Generally speaking, the result of metabolism is to make drugs more easily excreted and reduce the efficacy of drugs, but this is not the case in polivy. Polivir itself is an "inactive precursor", which will only take effect after metabolism. Therefore, some people with CYP2C 19 genotype belong to "slow metabolizers", and they take the recommended dose of wave.
Although the relationship between genes and drugs was neglected before, it is gradually recognized and understood by people. For different people, the efficacy of the same drug is different. This difference is not only "effective" or "ineffective", but also the strength of "side effects", as well as the length of time that drugs stay in the body and whether different drugs can be taken together. Through gene expression and single nucleotide polymorphism, it can be confirmed whether there are genetic or acquired genetic changes and how these changes will affect the absorption, distribution, metabolism and excretion of drugs by patients. This is called pharmacogenomics.
Today, according to the regulations of the US Food and Drug Administration (FDA), there are 166 drugs with pertinence, and 65 drugs need genetic testing before use. In fact, the effectiveness of the above three widely used anticoagulants can be determined by genetic testing, especially warfarin and plavix. The evidence is very obvious. People who take these two drugs for a long time strongly recommend genetic testing. If the curative effect is not necessarily good, they need to discuss with clinicians and decide whether to change the dosage or change the medicine according to their own specific conditions.
For other drugs that have been approved by FDA and have a clear genetic relationship, it is also recommended that you carry out corresponding genetic testing before taking the drug to determine the effectiveness and or reasonable dosage of the drug. This is the real individualized medication and precise treatment.
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