Goat beans are now all over the world. It was originally introduced as pasture by the US government. However, it is found that it can cause pulmonary edema, hypotension, paralysis and even death of livestock, because it is rich in guanidine compounds, a strong alkaline small molecular compound containing three nitrogen atoms. As a product of protein metabolism, it still exists in human urine.
In the 1920s, this kind of grass attracted the attention of German scientist Don Wright. Because, after goats eat this forage, the milk yield will increase, but there will be serious hypoglycemia and even death. Inspired by this, Tang Leite extracted goat's acid from goatee and found that it has obvious therapeutic effect on diabetes. The exact structure of caprine is isopentene guanidine, which is the earliest prototype of metformin.
During the period of 1927, some studies published in France found that rabbits and dogs injected with high doses of goastin could have symptoms similar to hypoglycemia, and subsequent human experiments also verified this conclusion. However, it doesn't make the goat bean alkali a medicine. After all, goat bean alkali is easy to cause hypoglycemia, and the risk of hypoglycemia is too high. Moreover, this natural substance can not only reduce blood sugar, but also has serious toxicity. So scientists can only start to transform this compound and find another way.
The popularity of insulin makes biguanide untimely.
In the case that goat amino acid is not suitable for drug use, scientists have continuously synthesized a series of guanidine derivatives on the basis of isopentene guanidine. In particular, biguanides have stronger hypoglycemic potential and better safety than guanidine, while decane biguanides have been found to have better tolerance and efficacy, and have been applied in clinic.
However, before the biguanides were introduced to the market, the problem came, and the faint light of biguanides was completely swallowed up by the superstar, insulin, which was born at the same time. Insulin is the only active substance in human body that can lower blood sugar and promote blood sugar utilization. The cause of diabetes is insufficient insulin secretion and/or function. Therefore, the use of drugs to restore insulin levels and promote glucose metabolism has become the basis of diabetes treatment.
In the first decade after the discovery of insulin, people once naively thought that the problem of diabetes had been completely solved. Under this trend, biguanides represented by metformin have to remain anonymous.
Looking back, E.P. jocelyn, the founder of modern diabetes, said that metformin was unlucky in the 1920s: "With the application of diet therapy and insulin, the treatment of diabetes has been significantly improved. In this case, it is difficult to evaluate the value of any other new therapy. " The struggle of "Sanguanidine Brothers"
With the deepening of the research on insulin, problems are constantly emerging: high incidence of severe hypoglycemia, weight gain, inconvenient use and so on.
During the second world war, when studying the antibacterial effect of sulfonamides, it was found that sulfonylureas could cause unexpected hypoglycemia, which pioneered the oral hypoglycemic agents of sulfonylureas and revived the upsurge of people's research on diabetes treatment drugs on a larger scale.
Jean Stern, a diabetic from France, is regarded as the key figure to discover the effect of metformin. He made the first human study on metformin and named it "Gehuazhi" (glucose devourer, Chinese trade name "Gehuazhi"), which has been in use ever since.
From 65438 to 0957, Stern published a research paper on metformin, but almost at the same time, the research papers of metformin's brothers phenformin and butylbiguanide were published at the same time.
With the support of Squibb, metformin was listed in France under the trade name of "Gehuazhi". However, in the initial competition, because of its weak hypoglycemic effect, metformin was almost uncompetitive compared with phenformin with strong hypoglycemic effect, and its application was almost limited to France. Phenylbiguanide was a sensation in the 1960s.
However, American scientists have gradually discovered that phenformin has a high risk of lactic acidosis, and the mortality rate of this complication is high. At the end of 1970s, phenformin almost completely withdrew from the market, and metformin belonging to the biguanide family was also affected. It was once suggested to withdraw from the market, so it was once again left out and misunderstood.
In this regard, Stern did not flinch and still insisted on further exploration. Subsequent research found that the mechanism of action of metformin and sulfonylurea oral hypoglycemic agents is completely different-because of their different molecular structures, it does not inhibit the release and oxidation of lactic acid, and the incidence of lactic acidosis is much lower than that of its two brothers, but this concern was subjectively exaggerated at that time.
Squibb's marketing was successful and Ge Huazhi joined the heavyweight club.
Due to the lactic acid poisoning caused by phenformin, Squibb's idea of listing Gehuazhi in the United States is almost impossible.
In the face of doubt, Squibb did not give up, but insisted on high-risk clinical research. This is the famous "UKPDS study" in the history of diabetes (prospective study of diabetes in Britain). As jocelyn said, "Behind every successful drug, there is a great experiment", which finally helped metformin to take the lead in treating type 2 diabetes.
This study started from 1977 and ended at 1997, and then followed up for 10 years, with a total duration of 30 years. It is not only the longest-lasting research in medical history, but also an epoch-making milestone in the development history of diabetes treatment, which has great influence on the formulation of diabetes prevention and control norms and guidelines. This experiment confirmed for the first time that metformin intensive therapy has cardiovascular protection while lowering blood sugar, which is especially obvious in overweight patients.
After seeing Squibb's efforts and determination, FDA initially released some data of UKPDS research, and affirmed the safety of Glucophanol. Finally, the controlled release dosage form of pueraria lobata was approved by FDA on February 29th, 1994.
Kochi means "people who eat sugar". After listing, in order to get enough returns as soon as possible before the patent expires, Squibb's advertisements are bold enough: "effective for all kinds of diabetes", "no side effects after long-term use", "safe and non-toxic" and "no danger of vascular injury". Today, these words are enough to make people doubt the status of the manufacturers, but at that time, these promotions really stood the test of time, and people gradually realized that Gehuazhi was "completely different from sulfonylureas" and "opened up a new direction for diabetes treatment". The prospect of metformin seems good.
With the release of UKPDS research results, the sales volume of Gehuazhi increased rapidly. In 200 1 year, its sales reached a record $2.7 billion, an increase of 42%, and the prescription amount exceeded one third of the total prescription amount of oral hypoglycemic drugs, making it the first choice among oral hypoglycemic drugs at that time.
Nowadays, metformin has become the cornerstone of diabetes treatment and the reference standard for the research and development of new drugs for diabetes. The evaluation of new oral hypoglycemic agents is to confirm that their efficacy is "no less than that of metformin", although it is as difficult as metformin coming out of the shadow of insulin and sulfonylurea drugs.
(Biological Exploration/Amy Poetry 20 15/07/ 15)