Olprinone [inn]
Olprinone
CAS: 106730-54-5
Molecular Formula: C14H10N4O
Olprinone [inn] - Names and Identifiers
Olprinone [inn] - Physico-chemical Properties
| Molecular Formula | C14H10N4O |
| Molar Mass | 250.26 |
| Density | 1.34±0.1 g/cm3(Predicted) |
| Melting Point | >300° |
| Solubility | DMSO |
| pKa | 6.59±0.10(Predicted) |
| Storage Condition | Sealed in dry,Store in freezer, under -20°C |
| Refractive Index | 1.702 |
| Physical and Chemical Properties | Crystallization from dimethylformamide, melting point> 300 °c. Olprinone Hydrochloride Monohydrate: C14H10N4O? HCl? H2O. White to yellowish white crystalline powder, odorless and tasteless. Melting point> 300 °c. Water solubility (Ph = 3~5) up to 3 mg/ml. Acute toxicity LD50 male and female rats, male and female mice (mg/kg):7804,10000,10000,>10000 oral; 176,240,242,269 intravenous injection; 2133,2890,3898,4479 subcutaneous injection. |
Olprinone [inn] - Introduction
Olprinone(Loprinone) is a phosphodiesterase 3(PDE3) inhibitor.
Last Update：2022-10-16 17:11:49
Olprinone [inn] - Reference Information
| background and overview | heart failure is not only pump failure, but also a complex group of clinical symptoms. the 5-year survival rate after clinical symptoms is similar to that of malignant tumors. In the treatment of congestive heart failure and heart failure, increasing myocardial contractility can improve hemodynamic stability, and increasing cyclic adenosine monophosphate cAMP can increase myocardial contractility. Usually, the increase of cAMP is through one of the following two ways: Promote its synthesis (such as catecholamines) and inhibit its degradation (such as phosphodiesterase PDEIII inhibitors). Specific phosphodiesterase III(PDEIII) inhibitor is a more effective inotropic drug in the past 30 years. Its mechanism of action is different from traditional digitalis and catecholamine drugs. It mainly improves cardiac function by enhancing myocardial contractility, improving ventricular diastolic compliance and dilating peripheral blood vessels. orglinone olprinone is an injection developed by Japan co., ltd. for the treatment of acute heart failure. it is a specific PDE Ⅲ inhibitor that selectively hinders cAMP and has a high selectivity for the inhibition of PDE Ⅲ in human heart. The drug was produced and marketed in Japan in 1996. The study found that Orpulinone improved the mechanical efficacy of the left ventricle better than dobutamine (dobutamine). The heart function improved while the relative changes in blood pressure, heart rate and myocardial oxygen consumption were not obvious. It has the advantage that other PDEIII inhibitors and catecholamines can replace catecholamines in short-term treatment, and are suitable for the treatment of acute heart failure and acute cardiac insufficiency after cardiac surgery. At present, the advantages and adverse reactions of Orpulinon in the treatment of heart failure have been clarified. In recent years, with the deepening of research, many foreign scholars have turned their attention to other pharmacological effects other than cardiotonic, such as direct expansion of cerebral arteries. It is more obvious in patients with impaired cerebral circulation; it improves the inappropriate distribution of cerebral perfusion, and selectively improves the dilatation of the carotid artery; at the same time, it can also be used to treat asthma and improve diaphragm contractility. The latest research focuses on the anti-inflammatory and organ protection effects of the drug during ischemia-reperfusion. If these pharmacological properties are well developed and the old drug is newly used, its clinical application will be greatly expanded. |
| traits | white to yellowish white crystalline powder, odorless and tasteless. Melting point> 300 ℃. The solubility in water (Ph = 3~5) can reach 3 mg/ml |
| pharmacological effects | enhance myocardial contractility: by selectively inhibiting the activity of PDEIII, the degradation of cyclic adenosine monophosphate (cAMP) is blocked, the intracellular CAMP concentration increases, and the Ca2 influx accelerates, thereby enhancing the excitation and contraction coupling process of myocardial cells and strengthening myocardial contractility. Vascular dilation: Cerebral blood flow and cardiac output increased significantly after intravenous administration of Orpulinon, but there was no obvious connection between the increase, suggesting that Orpulinon has a significant direct expansion of cerebral arteries. Orlinone was given to patients with cerebral hemorrhage after aneurysm clipping. It was found that the patient's cardiac output and cerebral blood flow increased while the balance of oxygen supply and demand in the brain did not change. It can be seen that the drug can increase brain metabolism and may be used as a new drug in the future. Used to treat cerebral vasospasm. A test comparing the drug's effect on different arterial dilation found that compared with the common carotid artery, the IC50 value of the renal artery is lower, and the maximum inhibition is greater, suggesting that it has a stronger expansion for the renal artery effect. It can be seen that the drug has a special vasodilator effect, and its vasodilator effect is different in different blood vessels, which is related to the different structural components of the blood vessel wall, collagen and elastic fibers, and the different distribution of PDE Ⅲ isoenzymes. Effects on the respiratory system 1) Bronchial dilation: Studies have found that Orpulinone can inhibit antigen-induced bronchoconstriction in asthmatic patients. In a randomized, double-blind trial. Asthmatic patients inhaled orpulinone or salbutamol (salbutamol), and there was no difference in the average maximum increase in forced expiratory volume FEV1 one second after the application of the two drugs. Nearly half of the patients in the orpulinone group had a greater bronchodilation effect than the salbutamol group, and did not affect heart rate and blood pressure; similarly, orpulinone and aminophylline (aminophyline) both showed dose-dependent bronchial expansion, but orpulinone did not affect plasma adrenaline levels; inhaled anesthetics sevoflurane (sevoflurane) and PDEIII can dilate bronchi, and the combined application of sevoflurane and orglinone has a synergistic effect in guinea pig airway hyperresponsiveness model. 2) increase diaphragmatic contractility: respiratory failure is often accompanied by diaphragmatic fatigue. Clinical studies have shown that intravenous pumping of low-dose oprinone 0.1 g/kg/min can increase the contractility of fatigue diaphragmatic muscle by affecting the transmembrane movement of calcium ions. Animal experiments have found that inhalation of Orpulinon can also increase the contractility of the fatigue diaphragm in a dose-dependent manner, but it cannot prevent the decrease in the contractility of the diaphragm induced by fatigue. Sepsis and septic shock patients are often accompanied by respiratory failure and diaphragm fatigue. Intraperitoneal injection of orcrinone can improve diaphragm fatigue, increase myeloperoxidase MPO activity, and reduce cytokine-induced neutrophil chemokine in septic model rats. It is suggested that orcrinone can treat respiratory failure with diaphragm fatigue by inhibiting the accumulation of neutrophils in diaphragm and inhibiting its activity. Inhaled anesthetic sevoflurane at the minimum alveolar effective concentration of 3-MAC can increase diaphragmatic fatigue caused by twitching and tension damage. Clinically relevant concentrations of olpulinone can improve the dysfunction of diaphragmatic fatigue induced by sevoflurane. Anti-inflammatory: After general anesthesia in patients with coronary artery bypass grafting, the level of interleukin-IL6 with pro-inflammatory effect did not rise significantly, while the IL-10 with anti-inflammatory effect reached a peak after extracorporeal circulation, suggesting that the drug has a certain anti-inflammatory effect; in the animal model of lipopolysaccharide LPS-induced pulmonary infection, pretreatment of Orpulinone and dexamethasone significantly reduced LPS-induced neutrophil intrapulmonary pool and inhibited the production of inflammatory factors. At the same time, IL-10 increased in Orpulinone group, suggesting that Orpulinone can strongly inhibit LPS-induced intrapulmonary infection, and its anti-inflammatory mechanism is different from hormone. Organ protection: Experiments show that intraperitoneal injection of 0.2 g/kg orcrinone in rats can reduce multiple organ failure induced by yeast, reduce the migration of neutrophils exuded from peritoneum, weaken lung, liver and pancreas injury, renal insufficiency, and reduce the increase of MPO activity in lung and small intestine caused by yeast. 1) cardiac protection: coronary artery ischemia-reperfusion will lead to serious adverse consequences in the early stage of myocardial ischemia or reperfusion to give Orpulinone can improve myocardial pump function and reduce myocardial injury. Studies have confirmed that Orglinone increases the concentration of cAMP in myocardium, improves the recovery of cardiac function after cardiac arrest, and prevents the increase of total myocardial calcium. Its protective effect may be mediated by the activation of phosphatidylinositol 3-kinase PI3K -Akt signaling pathway and mPTP inhibition, but not related to protein kinase CPKC or m-KATP channel. 2) Nervous system protection: Studies have shown that Orpulinon has a protective effect on various forms of damage to the central and peripheral nerves. In the rat cerebral ischemia model, the number of surviving CA1 neurons in the Opuli 30g/kg/min treatment group was significantly higher than that in the normal saline group, and the phosphorylation of cAMP response element binding protein was significantly increased. In addition, Orpulinone can inhibit the increase of intracellular Ca2 + concentration produced by the rapid separation of rat hippocampal pyramidal neurons during acute extracellular high K + depolarization, and inhibit the release of postsynaptic glutamate through cGMP /PKG pathway, which proves that the drug has neuronal protection in vivo and in vitro, especially in the fight against cerebral ischemia. The imbalance of cerebral oxygen supply and demand during cardiopulmonary bypass will promote neurophysiological dysfunction in patients after the establishment of hypothermic cardiopulmonary bypass. After the establishment of hypothermic cardiopulmonary bypass, Orpulinon is pumped and monitored for jugular vein oxygen saturation (SaO2) and local cerebral oxygen saturation (rSO2). Observation found that the drug can block the reduction of SaO2 during the cardiopulmonary bypass rewarming period and improve the balance of cerebral oxygen supply and demand. 3) liver protection: IRI is the main cause of abnormal liver function after liver transplantation and hepatectomy. Therefore, reducing IRI is the main goal to improve the outcome of these operations. Monitoring the blood oxygen in hepatic vein of postoperative patients in ICU and comparing the effects of intravenous administration of amrinone, milrinone and orienone. The results show that there is no difference in the increase of cardiac index of the three drugs, but the oxygen saturation of hepatic vein in orienone group increases significantly, the changes in blood flow in the liver of the Orpulinon group are significantly greater than those of other groups, suggesting that it may be beneficial to liver protection after surgery; the application of Orpulinon post-treatment in the pig endotoxemia model can improve liver blood flow and increase The transport of portal vein blood flow and liver oxygen prevents further increase in arterial lactic acid, blocks further disorders of liver blood flow, and increases liver mitochondrial oxidation; after most of the liver 90% is removed, excessive shear stress can lead to liver insufficiency, in the rat model, Orpulinone reduced shear stress and improved postoperative survival by up-regulating the expression of endothelial nitric oxide synthase eNOS. Recent studies have confirmed that Orpulinon may protect the liver by affecting the upstream mechanisms of p38MAPK JNK and NF-B signaling pathways, increasing cAMP levels, inhibiting ICAM-1 expression and cytokine production. 4) digestive tract protection: research [found that orglinone can slow down the progression of intestinal mucosal acidosis and protect the microstructure in acute progressive hypoxia model. Through blood flow-dependent and non-blood flow-dependent mechanisms, continuous pumping of Orpulinone during cardiac surgery, observation of gastric mucosal pH, systemic oxygen consumption, and systemic inflammatory response during surgery and cardiopulmonary bypass, found that Orpulinone can inhibit gastric mucosal acidosis and systemic inflammation after cardiopulmonary bypass. 5) renal protection: renal IRI is the main problem faced by renal transplantation. IRI induces renal tissue blood flow decline, increases renal vascular permeability and increases leukocyte activity. The experiment induced rat I/R reperfusion 30 min after pumping 0.2 g/kg/min, for 3 h, found that the IRI increased serum urea nitrogen, creatinine, improve the histological changes, and significantly reduce the level of MPO activity and cytokines in kidney tissue, and does not affect the hemodynamic state, suggesting that the ALP can reduce ischemia-reperfusion acute kidney injury, it is likely that the mechanism of inhibiting leukocyte activity can be explained by its effect on cAMP level. Experiments show that local and systemic application of Orpulinone has renal protective effect. |
| synthesis route | 2-amino -5-bromopyridine and bromoacetaldehyde diethanol are cyclized to obtain 6-bromoimidazolo [1,2-a] pyridine, and then the coupling reaction with methylallyl chloride to obtain 6-(2-methylallyl) imidazolo [1,2-a] pyridine, which is oxidized, 1- (imidazo [1,2-a] pyridine -6-yl)-2-acetone is obtained; it is subjected to methylation reaction with N,N-dimethylformamide and dimethyl alcohol to obtain (3Z)-4-(dimethylamino)-3-(imidazo [1,2-a] pyridine -6-yl)-3-butyene-2 ketone; cyanoacetamide for cyclization reaction, obthe Orpulinon, the specific reaction process is as follows: |
| indication | is used to treat acute myocardial insufficiency. |
| specification | water needle 5 mg/ml. |
| usage and dosage | adults, diluted by glucose injection or other diluent, and administered intravenously for 5 minutes at a dose of 10 µg/kg orprinone hydrochloride hydrate, followed by intravenous drip at a drop rate of 0.3-0.1 µg/kg/min.. According to the specific situation of the patient, the dose of instillation should be adjusted appropriately, and if necessary, it can be increased to 0.4 µg/kg/min. |
| adverse reactions | 1. when treating heart failure, the main adverse reactions of orpulinone are manifested in the circulatory system, including ventricular premature contraction (3.00%), tachycardia (2.15%), increased ventricular tachyarrhythmia (1.72%) and increased heart rate (1.29%). therefore, when orpulinone is applied, ECG monitoring should be closely monitored. 2. as a vasodilator, the incidence of hypotension is 2.15%. It has been reported that the incidence of thrombocytopenia is 0.43%. Opulinone is about 80% ~ 90%. It is excluded by urine as a prototype. Therefore, patients with renal insufficiency should be used at low doses. Long-term oral administration is due to large adverse reactions. It can lead to an increase in long-term mortality, so it is only used for a short time. |
| Drug interaction | 1. It is combined with catechol as a cardiotonic or adenylate cyclase activator: such as dopamine, hydraulic acyl chloride, Dobutamine hydrochloride, etc., the effect of both drugs is increased, and symptoms such as arrhythmia may occur. 2. Co-use with diisopyramide: may cause hypotension. |
| medication for pregnant and lactating women | pregnant women should be used with caution; lactating women should stop breastfeeding during the probation period. |
| medication for children | medication safety for children has not been established. |
| medication for elderly patients | due to the decline of liver and kidney function in the elderly, it is more likely to produce side effects. therefore, attention should be paid to the blood pressure and heart rate of elderly patients during administration, and the intravenous drip speed should be 0.1 µg/kg/min to avoid overdose. |
| main reference | [1] yang jianmin et al. clinical observation of orpulinone in improving the curative effect of heart failure. Clinical medical engineering. 2009,16(6):34-35. [2] Baonaren et al. New progress in the study of phosphodiesterase III inhibitor-Orpulinone. Chinese Journal of New Drugs and Clinology. 2011,30(9):657-662. [3] Opulinon Injection Drug Instructions (English). http://wenku.baidu.com/view/5e93080416fc700abb68fcb5.html [4] Zheng Huagan et al. A production process of naltroxaparin calcium with low ethanol residue. Application No. 201310145040.0, Application Date 2013-4-24. |
| use | for the treatment of acute myocardial insufficiency. |
| Production method | 4-(dimethylamino)-3-(pyrimido [1,2-α] pyridine-6-yl)-3-butene-2-one and cyanoacetamide are heated in dimethylformamide at 80~90 ℃ for 12h to obtain Orpulinon. |
Last Update：2024-04-09 19:05:09
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