L-amlodipine is an antihypertensive drug with independent intellectual property rights in China. It was listed for the first time in the world in 1999, and it belongs to the national Class 1.3 innovative drug. Through a series of basic and clinical studies, the reliable role of these drugs in the prevention and treatment of hypertension and cardiovascular diseases has been confirmed.
1. Pharmaceutical characteristics
(1) Levamlodipine is a chiral drug in antihypertensive drugs
Chiral drugs are used with a single enantiomer, so as to reduce the dosage, reduce the risk of adverse events, and eliminate the burden of drug metabolism. In 1992, the Food and Drug Administration of the United States required that racemic drugs must be marketed as optically pure single enantiomers. China Food and Drug Administration has also made similar provisions.
L-amlodipine, the first chiral antihypertensive drug independently developed in China, was obtained by Shihuida Pharmaceutical Group (Jilin) Co., Ltd. through chiral resolution technology, and the pure L-isomer was obtained for the first time, and the invention patent and intellectual property rights of the compound were obtained. Levamlodipine besylate (Shi Huida)? Named and listed.
In p>23, Unacon produced the second chiral levorotatory amlodipine drug by changing the acid radical, which was called? Levamlodipine maleate (Xuan Ning)? , and obtain intellectual property rights. These two drugs are innovative drugs with patent rights and independent intellectual property rights developed by China's pharmaceutical industry.
(2) Pharmaceutical characteristics of L-amlodipine:
① Pharmacodynamic characteristics: The antihypertensive effect of L-amlodipine besylate and L-amlodipine maleate is 1 times that of D-amlodipine besylate and twice that of 1: 1 racemate, and D-amlodipine has almost no antihypertensive effect, which can cause headache, edema of extremities, facial flushing and other symptoms in sensitive patients, but it is weaker than that of D-amlodipine besylate.
② Pharmacokinetic characteristics: After taking racemic amlodipine, the half-life of levorotatory is significantly longer than that of dextrorotatory, the former is 5.6 hours and the latter is 35.5 hours. And levorotatory absorption is superior to dextrorotatory absorption. The terminal elimination half-life is about 35 hours for healthy people, 5 hours for hypertensive patients, 65 hours for elderly patients, 6 hours for patients with impaired liver function, and renal insufficiency is not affected.
ii. pharmacological action and clinical evidence
(1) antihypertensive effect: the antihypertensive effect of racemic amlodipine was effectively retained by removing the dextrorotatory amlodipine by chiral drug resolution technology.
a randomized, double-blind parallel study of levoamlodipine besylate and amlodipine besylate in the treatment of primary mild to moderate hypertension in China showed that levoamlodipine besylate 2.5 mg and amlodipine besylate 5 mg had similar antihypertensive effects, and the total effective rates of the two drugs were 84.91% and 77.45% respectively. At the same time, it was found that the blood pressure could still be kept below 14/9 mmHg after 24 hours and 48 hours of drug leakage, suggesting that the drug has a long-lasting antihypertensive effect.
Another study, Levamlodipine Maleate and Amlodipine Benzenesulfonate in the Treatment of Mild and Moderate Essential Hypertension, shows that both of them have the same long-term and stable blood pressure reduction, and Levamlodipine Maleate has a stable, long-term and safe blood pressure reduction, which can not only effectively control 24-hour blood pressure, but also inhibit early morning hypertension. Due to the patent protection, the research on the clinical application of L-amlodipine in the world is mainly concentrated in Asian countries including South Korea and India.
Chinese research shows that the antihypertensive range and effective rate of levoamlodipine besylate are at least equal to other commonly used antihypertensive drugs. Levamlodipine besylate combined with antihypertensive drugs such as captopril, metoprolol, carvedilol or hydrochlorothiazide can further improve the antihypertensive effect.
country? Eleventh five-year plan? The research results of the sub-project "Reversal Effect of Levamlodipine on Microalbuminuria in Patients with Poor Blood Pressure Control" of the Comprehensive Prevention and Treatment Project of Hypertension show that Levamlodipine besylate combined with AT 1 receptor antagonist (sartan antihypertensive drugs) can significantly reduce microalbuminuria while reaching the standard of blood pressure; The research on non-dipper elderly patients with hypertension suggests that taking levoamlodipine besylate in the daytime or at night can better correct high-load blood pressure at night, improve the rate of reaching the standard at night and control blood pressure variability.
country? Twelfth five-year plan? A large-sample, multi-center and prospective comparative study of levoamlodipine maleate and amlodipine besylate in the treatment of hypertension (LEADER study), a major scientific and technological project of new drug creation, was conducted to explore an antihypertensive drug treatment scheme suitable for China. The study shows that levoamlodipine maleate has the same efficacy as imported amlodipine besylate, but the drug safety and pharmacoeconomics have differentiated advantages, and there are few adverse reactions of levoamlodipine maleate. Levamlodipine (2.5 ~ 5 mg once a day) is superior to lacidipine (4 ~ 8 mg once a day) in controlling blood pressure variability.
(2) Target organ protection: Levamlodipine (whether amlodipine besylate or amlodipine maleate) alone or in combination with other antihypertensive drugs can effectively reduce blood pressure, and at the same time, it can reverse left ventricular hypertrophy, reduce albuminuria and protect renal function. The corresponding clinical observation was made in improving dynamic arteriosclerosis index and protecting vascular endothelial function, and the organ protection effect of L-amlodipine was determined.
III. Tolerance and safety
Levamlodipine effectively retains the antihypertensive effect of racemic amlodipine, while reducing the dosage by 5%, reducing the incidence of treatment-related adverse reactions, making it more safe and tolerant. Compared with racemic amlodipine, levoamlodipine has lower incidence of side effects such as edema and facial flushing, higher compliance and better tolerance. The incidence of adverse reactions of edema in lower limbs was reduced after using amlodipine, nifedipine controlled release/sustained release tablets and felodipine sustained release tablets for patients with edema.
IV. Clinical application
(1) Indications: it is recommended for the treatment of hypertension, especially hypertension in the elderly; Recommended for the treatment of hypertension and angina pectoris of coronary heart disease; It is recommended for hypertensive patients with target organ damage (left ventricular hypertrophy, microalbuminuria, carotid atherosclerosis and plaque, etc.). For patients with mild hypertension, levoamlodipine can be the first choice for monotherapy. For patients with refractory hypertension or other high-risk factors, it can be combined with one or more other antihypertensive drugs to ensure that blood pressure reaches the standard.
(2) Administration method: Generally, the initial oral dose is 2.5 mg once a day, and the maximum dose is 5 mg once a day. The initial dose of thin people, weak people, elderly patients or patients with impaired liver function is 1.25 mg once a day. If the blood pressure reaches the standard after 1-2 weeks or the symptoms of angina pectoris are not satisfactorily controlled, the therapeutic dose can be gradually increased to the maximum dose. Renal insufficiency has no significant effect on the pharmacokinetic characteristics of this product and will not be removed by hemodialysis. Therefore, it can be used for patients with different degrees of renal insufficiency, and hemodialysis patients do not need to adjust the dose. The dosage of elderly patients is the same as that of ordinary adults, but the treatment should start with a small dose, and if the patient can tolerate it, it can be gradually increased to the therapeutic dose.
As a national innovative medicine, L-amlodipine can lower blood pressure with high quality and protect target organs, and its price is more reasonable. By November 216, there were 8,61 published academic papers on L-amlodipine, and so far there are 23 domestic invention patents and 12 international invention patents, which laid the foundation for the treatment of hypertension.