Simendan
Simendan
CAS: 131741-08-7
Molecular Formula: C14H12N6O
Simendan - Names and Identifiers
Simendan - Physico-chemical Properties
| Molecular Formula | C14H12N6O |
| Molar Mass | 280.28 |
| Density | 1.33±0.1 g/cm3(Predicted) |
| Melting Point | >238°C (dec.) |
| Solubility | DMSO (Slightly), THF (Slightly, Sonicated) |
| Appearance | Solid |
| Color | Yellow to Dark Yellow |
| pKa | 6.12±0.10(Predicted) |
| Storage Condition | Hygroscopic, -20°C Freezer, Under inert atmosphere |
| Physical and Chemical Properties | Yellow powder. |
Simendan - References
| calcium sensitizers | in the Eighties of the 20th century, in the study of drugs for the treatment of congestive heart failure (CHF), A new class of cardiotonic drugs has been discovered, which increase the cardiac contractility mainly by increasing the sensitivity of cardiac contractile proteins to Ca2, thus being called calcium sensitizers. Calcium sensitizer is the release of Ca2, which reduces the energy demand of the heart, so it is considered to avoid arrhythmia, myocardial cell injury and even death caused by positive inotropic drugs. Studies have shown that calcium sensitizers can reverse myocardial systolic dysfunction under pathological conditions such as acidosis and temporary myocardial dysfunction. Multi-target action of anti-heart failure drugs such as Levosimendan (Levosimendan). levosimendan is a new generation of cardiotonic drugs-calcium sensitizers in the class of the first species on the market, clinical mainly for the treatment of a variety of acute heart failure. The drug was first launched in Sweden in October 2000, after being developed by the Finnish company Oreon. At present, domestic Qilu Pharmaceutical Co., Ltd. and Chengdu shengnuo Biological Pharmaceutical Co., Ltd. two companies can provide levosimendan injection. levosimendan is the optical isomer of simendan, which is a new positive inotropic agent. It increases the sensitivity of cardiac contractile proteins to Ca2 and opens the adenosine triphosphate (ATP) enzyme-sensitive K channels on the cell membrane, thereby increasing myocardial contractility while expanding the peripheral vessels and coronary arteries, reducing the load of the heart before and after. In addition, levosimendan has anti-inflammatory, antioxidant, anti-apoptotic, anti-Myocardial stunning and other pharmacological effects. The drug can effectively enhance myocardial contractility, but does not increase myocardial oxygen consumption, no significant effect on heart rate. In the effective relief of symptoms at the same time can improve the prognosis, reduced by Mortality Rate. Clinical studies have shown that levosimendan can reduce heart failure by Mortality Rate. Various clinical trials have shown that levosimendan can improve hemodynamics, improve arrhythmia, chest pain and other related symptoms, and shorten hospital stay. Less interaction with other cardiovascular drugs, does not affect the use of other drugs (heart failure patients often need to apply a large number of different drugs at the same time treatment), good safety. Compared with the commonly used drugs for acute heart failure, such as dobutamine and milrinone, it has obvious advantages. The adverse reactions of levosimendan were mild, and the serious adverse reactions were few. The common adverse reactions were Head Pain, tachycardia and so on. |
| mechanism of action | levosimendan it does not directly increase the intracellular calcium concentration or increase the affinity of troponin and Ca2, instead, it binds to the amino-terminal amino acid of Troponin C(Tnc) on the myocardial filaments, increasing the conformational stability of the Tnc-Ca2 complex. After Tnc binds to Ca2, the molecular conformation of tropomyosin changes, which removes its blocking effect on the binding of myofibrillin and transverse Bridge. The transverse bridge combines with the Myofilament, the Myofilament widens, and the myocardial fiber contracts. In addition, the binding of levosimendan to Tnc is Ca2 concentration dependent, that is, when the Ca2 concentration in the myocardial cells is high (when the myocardial cells contract), its affinity to Tnc is high, when the Ca2 concentration in the cardiac muscle cells is low (when the cardiac muscle cells are relaxed), its affinity to Tnc is low. Therefore, it has the strongest effect in the systolic phase and the weaker effect in the diastolic phase, thus preventing or reducing the possible impairment of diastolic function. inflammatory cytokines, oxidative stress and myocardial apoptosis play an important role in the process of myocardial remodeling, and myocardial remodeling is the basic pathophysiological basis leading to the progression of heart failure. Levosimendan can reduce interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), malondialdehyde (MDA), brain natriuretic titanium (BNP) in patients with heart failure as well as reducing the soluble apoptotic signaling factor Fas/Fas ligand, thereby having anti-inflammatory, anti-oxidative and anti-cardiomyocyte apoptosis effects. In addition to its calcium-sensitizing effect on cardiac myofilaments, levosimendan inhibits the activity of cardiac phosphodiesterases (mainly phosphodiesterase III), production and phosphodiesterase inhibitors have the same effect: blocking the degradation of cAMP, increasing the content of cAMP, further increasing the activity of protein kinase on the cell membrane, and then acting on the cAMP mediated information transmission, the content of intracellular cAMP is increased, the phosphorylation of calcium channel membrane protein is promoted, Ca2 influx is increased, and myocardial contraction is strengthened. levosimendan was found to selectively inhibit type III phosphodiesterase activity in vitro, but this effect was only evident when the recommended therapeutic dose was exceeded. Therefore, the positive inotropic effect is not related to the inhibition of phosphodiesterase in clinical application dose. The above information was edited and organized by Jane. |
| toxicological studies | in animal experiments, there were no drug-related deaths in the experimental animals after oral and intravenous levosimendan (doses of 250 and 400 times the clinical therapeutic concentration in humans, respectively), there was no change in the appearance and activity of the rats. Long-term treatment with levosimendan is well tolerated and has minimal side effects. Ames test showed that levosimendan had no mutagenicity. No teratogenicity and embryotoxicity were found in rats and rabbits given levosimendan during organ formation. Levosimendan had no adverse effect on the reproductive capacity of male rats. Long-term use of levosimendan on intrauterine survival of the offspring without any damage. [acute toxicity] The results showed that the median lethal dose (LD50) of levosimendan administered orally to male mice, female mice and male rats was 156,152,103mg/KG, when administered intravenously (LD50): 32,50,57mg/KG, the animals mainly died of cardiopulmonary failure. [reproductive toxicity] After 8 weeks of continuous administration of sub-lethal dose of levosimendan, no adverse effect on fertility was found, no abnormal changes were found in the anatomical structure and histological examination. The use of this drug in pre-pregnant rats and early pregnant rats can reduce the number of implantation of fertilized eggs, and reduce the viability of rats in the uterus, this effect was dose-related, but no adverse effect of the drug on surviving pups was found. The teratogenic effect and embryotoxicity of levosimendan were not found when levosimendan was used in rat and rabbit fetal organ formation period, but the high dose of levosimendan in pregnant rats could cause multiple osteogenesis block. |
| Usage | levosimendan for short-term use after cardiac surgery or heart failure in patients with dilated cardiomyopathy. The first 12g/kg intravenous injection, after the maintenance of 0.1~0.2g/kg per minute intravenous infusion, generally used 24 hours. The dose and duration of application of levosimendan should be determined according to its pharmacological properties. The half-life of the prototype levosimendan is 1H, and it takes 4H to achieve a stable plasma concentration. However, the half-life of the active metabolite OR-1896 of levosimendan is as long as 80H, the blood concentration will continue to increase after stopping the infusion. The combination of levosimendan and dobutamine can further improve hemodynamics, and the combination of levosimendan and norepinephrine can maintain organ and tissue perfusion. The effect of levosimendan is not attenuated by beta blockers; Instead, even patients with severe heart failure may be considered for beta blockers under the protection of levosimendan, the patient gradually transitions to a state of conventional therapy. The indications of levosimendan are: decompensated acute heart failure, with decreased cardiac output and high perfusion pressure, heart failure after cardiac surgery (stunning), heart failure after acute myocardial infarction. The recommended dosage is: When systolic blood pressure is more than 100mmHg, loading dose of 6~12 μg · kg-1 is given, and intravenous injection is given within 10 min; followed by 0.05~0.2 mg · kg-1 · min-1 continuous intravenous infusion, according to the blood pressure to adjust the dose. Drug combination: hypotension patients can be applied norepinephrine levosimendan, levosimendan in the application of dobutamine can be gradually withdrawn. |
Last Update：2024-04-10 22:29:15
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CAS: 131741-08-7
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CAS: 131741-08-7
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
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