Novel safe antiemetic drug and application thereof

Abstract

The invention provides a novel safe antiemetic drug and application thereof. The novel safe antiemetic drug provided by the invention is a compound preparation containing the 5-hydroxytryptamine receptor antagonist and the potassium ion channel opener, can effectively avoid QT interval prolonging caused by the 5-hydroxytryptamine receptor antagonist ondansetron, and reduces the possibility of corresponding arrhythmia, tachycardia and sudden cardiac death. The invention also provides an application of the potassium channel opener in preparation of a medicine for reducing QT interval extension and a corresponding treatment method.

Description

Field of the invention:

[0001] The present application belongs to the field of western medicine. Specifically, the present application relates to a novel safe antiemetic and its application, and in particular to a compound preparation containing ondansetron and nicorandil and its application, which can effectively avoid QT interval prolongation caused by ondansetron, thereby preventing the possibility of inducing fatal ventricular arrhythmias and sudden death. Background technology:

[0002] Ondansetron, English name Ondansetron, chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one, chemical formula is C 18 H 19 N3O is a highly selective 5-hydroxytryptamine (5-HT3) receptor antagonist with high strength and selectivity. It can control vomiting caused by the stimulation of receptors in the small intestine and CTZ. At the same time, ondansetron can also enhance gastric emptying at antiemetic doses, which helps to relieve nausea; it also has an anti-anxiety effect on the central nervous system, which helps to inhibit the excitement of the vomiting center. Ondansetron is currently a first-line antiemetic drug used at home and abroad. It is widely used clinically to prevent or treat nausea and vomiting caused by chemotherapy drugs (such as cisplatin, doxorubicin, etc.), radiotherapy, surgery or anesthesia.

[0003] The QT interval is a key part of the surface electrocardiogram, and a prolonged QT interval is associated with a potentially fatal arrhythmia, Torsades de Pointes (TdP), and sudden cardiac death. For every 10 ms increase in the patient's QT interval, the risk of progression to TdP increases by 5%-7%. It is generally believed that when the QT interval is greater than 500 ms, the risk increases significantly and necessary intervention measures should be considered.

[0004] In patients treated with ondansetron, there have been reports of transient electrocardiographic changes including QT prolongation. In addition, in post-marketing case reports, patients treated with ondansetron have experienced torsade de pointes (TdP) (the FDA issued a special warning on this in 2012). Randomized, double-blind, cross-controlled clinical trials from the United States have confirmed that the QT prolongation caused by ondansetron is dose-dependent, especially for a single intravenous dose of 32 mg. After baseline correction, the maximum mean difference in QT prolongation was 20ms compared with placebo, while the maximum mean difference was 6ms at a lower dose (8mg) of intravenous injection. Patients with high-risk factors for QT prolongation (suffering from congenital long QT syndrome, electrolyte disorders, congestive heart failure, etc. or concurrent use of drugs that can cause QT prolongation) are more likely to experience QT prolongation when using ondansetron. Therefore, it is generally required that a single intravenous dose of ondansetron should not exceed 16mg. GlaxoSmithKline and other companies have also revised the ondansetron drug package insert, deleting the 32 mg single intravenous dose. The following table shows ondansetron adverse events and the FDA's response.

[0005] Adverse event reporting after the exclusivity period

[0006] 12 / 1 / 04-1 / 1 / 06

[0007]

[0008] Since marketing approval

[0009] and Adverse Event Reporting Prior to Pediatric Exclusivity

[0010] 1 / 4 / 91-12 / 1 / 04

[0011]

[0012] U.S. Food and Drug Administration (FDA) Actions on QT Interval Prolonging Drugs

[0013]

[0014] Non-drug risk factors for QT prolongation

[0015] Hypokalemia Structural heart disease Genetic polymorphism hypocalcemia Bradycardia female Hypomagnesemia Long QT syndrome Advanced age Summary of the invention

[0016] Although the adjusted dosage recommendation can reduce the probability of arrhythmia caused by ondansetron to a certain extent, it does not fundamentally avoid the possibility of arrhythmia and sudden death caused by it. Patients using this drug, especially those with congenital long QT syndrome, high-risk groups of other underlying diseases, and those who use drugs that can also cause QT interval prolongation, are still at considerable risk.

[0017] In response to the above problems, the applicant used the pluripotent stem cell cardiac electrophysiology research and development platform to design a new antiemetic drug that eliminates the cardiac toxic side effects of fatal arrhythmias, and unexpectedly found that Nicorandil can effectively avoid ondansetron-induced QT interval prolongation, thereby reducing the possibility of arrhythmias, sudden cardiac death and other problems. On the one hand, the present application provides a new safe antiemetic drug with reduced QT interval prolongation, which includes a 5-hydroxytryptamine receptor antagonist and a potassium ion channel opener.

[0018] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0019] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0020] Furthermore, the potassium ion channel opener is an ATP-sensitive potassium ion channel opener.

[0021] Furthermore, the potassium ion channel opener is nicorandil.

[0022] Furthermore, the novel safe antiemetic drug is a compound preparation.

[0023] Furthermore, the mass ratio of ondansetron to nicorandil in the novel safe antiemetic is 120:30 to 120:1000.

[0024] Furthermore, the mass ratio of ondansetron to nicorandil in the novel safe antiemetic is 120:40 to 120:500.

[0025] Furthermore, the mass ratio of ondansetron to nicorandil in the novel safe antiemetic is 120:80 to 120:350.

[0026] Furthermore, the novel safe antiemetic drug may be an oral preparation or an injection, a topical preparation, a spray, etc.; oral preparations include capsules, oral liquids, and tablets; injections include injections and powder injections.

[0027] In another aspect, the present application provides the use of Nicorandil in preparing a medicament for reducing QT interval prolongation.

[0028] Furthermore, the QT interval prolongation is QT interval prolongation caused by 5-hydroxytryptamine receptor antagonism.

[0029] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0030] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0031] Furthermore, the drug is an oral preparation or an injection, a local application preparation, a spray, etc.; oral preparations include capsules, oral liquids, and tablets; injections include injections and powder injections.

[0032] Furthermore, the administration dose of Nicorandil is 2-64 mg for a single oral preparation or 0.01-1 mg / kg / hr for an injection.

[0033] Furthermore, the administration dose of Nicorandil is 4-32 mg for a single oral formulation or 0.05-0.5 mg / kg / hr for an injection.

[0034] Furthermore, the blood concentration of Nicorandil in the compound preparation after entering the human body is 30 μg / L-1000 μg / L.

[0035] Furthermore, the blood concentration of Nicorandil in the compound preparation after entering the human body is 40 μg / L-500 μg / L.

[0036] In another aspect, the present application provides a method for reducing QT interval prolongation, comprising administering nicorandil to a subject at risk of QT interval prolongation or having symptoms of QT interval prolongation.

[0037] Furthermore, the subject is a human.

[0038] Furthermore, the subject is a female.

[0039] Furthermore, the QT interval prolongation is QT interval prolongation caused by 5-hydroxytryptamine receptor antagonism.

[0040] Furthermore, the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

[0041] Furthermore, the 5-hydroxytryptamine receptor antagonist is ondansetron.

[0042] Furthermore, the administration dose of Nicorandil is 2-64 mg for a single oral preparation or 0.01-1 mg / kg / hr for an injection.

[0043] Furthermore, the administration dose of Nicorandil is 4-32 mg for a single oral formulation or 0.05-0.5 mg / kg / hr for an injection.

[0044] Furthermore, the frequency and duration of administration of Nicorandil is once to four times a day, for 1 to 60 consecutive days.

[0045] Furthermore, the frequency and duration of administration of Nicorandil is once to three times a day, for 1-14 consecutive days.

[0046] The English name of ondansetron in this application is Ondansetron, the corresponding CAS number is 99614-02-5, and the molecular formula is C 18 H 19 N3O; the English name of Nicorandil in this application is Nicorandil, the corresponding CAS number is 65141-46-0, and the molecular formula is C8H9N3O4; the above-mentioned various numbers, names, combinations with different anions or chelates, and other aliases and trade names of products on the market, including but not limited to Nicorandil, Nitrosyl, Xigemai, Sudan, Obei, etc., can be used interchangeably to represent the same drug.

[0047] In the present application, 5-hydroxytryptamine and 5-HT represent the same meaning and can be used interchangeably.

[0048] Ondansetron and nicorandil in the present application can be prepared in the same pharmaceutical composition / compound preparation; can also be provided in the form of two drugs in the same package; can also be packaged separately and used in combination according to the doctor's advice or instructions; various feasible combination forms known in the art are applicable to the present invention.

[0049] The dosage forms applicable in the present application include, but are not limited to, oral preparations and injections. The compound preparations, ondansetron preparations and nicorandil preparations of the present application can be applicable to any specific dosage forms acceptable clinically, including, but not limited to, tablets, capsules, oral liquids, injections, powder injections, topical preparations, sprays, etc. When the ondansetron preparation and the nicorandil preparation are provided separately in the same package or in various packages, the dosage forms of the two may be the same or different.

[0050] Depending on the dosage form to be prepared / administered, various pharmaceutically acceptable excipients may be selected in the preparation, including but not limited to coating materials, solvents, solubilizers, adhesives, stabilizers, antioxidants, pH adjusters, and flavoring agents. Those skilled in the art may select these excipient ingredients based on common knowledge in pharmacy.

[0051] In addition to the above-mentioned auxiliary ingredients, the preparation of the present application may also include, or be provided separately, or other known drugs or therapies for inhibiting vomiting may be administered simultaneously when implementing the method of the present application, including but not limited to other 5-HT receptor antagonists, NK-1 receptor antagonists, dopamine receptor blockers, glucocorticoids, etc., such as granisetron, dolasetron, ramosetron, tropisetron, palonosetron, aprepitant, metoclopramide, dexamethasone, etc.; and other drugs or therapies for reducing QT interval prolongation, including but not limited to beta-blockers, sympathetic nerve blockers, such as propranolol, phenytoin sodium, reserpine, epinephrine, atropine, verapamil, sympathetic ganglionectomy, etc.

[0052] Beneficial effects:

[0053] 1. It avoids the prolongation of QT interval caused by ondansetron, thereby reducing the possibility of arrhythmia, tachycardia, sudden cardiac death and other problems.

[0054] 2. Retain the efficacy of ondansetron in preventing and treating vomiting.

[0055] 3. For high-risk groups with congenital long QT syndrome or other underlying diseases, patients taking other drugs that cause QT prolongation at the same time, or patients with electrolyte imbalance (hypokalemia, hypocalcemia, hypomagnesemia), liver and kidney function decline, heart failure, left ventricular hypertrophy, myocardial infarction and other heart diseases that form a QT prolongation susceptibility state, the drugs or methods of this application can also be safely used.

[0056] 4. Nicorandil has a certain effect of dilating coronary arteries and improving myocardial blood supply, and has a cardioprotective effect. Compound preparations containing Nicorandil are more suitable for middle-aged and elderly people or patients with heart disease.

[0057] 5. Women have a higher risk of drug-induced TdP than men, and the present invention provides more significant protection for the female patient group. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 Schematic diagram of electrocardiogram (ECG). A is a normal ECG diagram of a healthy human individual. B is an ECG diagram of a prolonged QT interval.

[0059] Figure 2 The electrocardiogram showed torsade de pointes (TdP).

[0060] Figure 3 The field potential characteristics (Field Potential, FP) of induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) were recorded by multi-electrode array (MEA); A: a representative normal MEA signal recording of hiPSC-CMs field potential electrical signals; B: a representative arrhythmia MEA signal recording of hiPSC-CMs field potential electrical signals, which can detect arrhythmia events; C: MEA signal traces can be analyzed to obtain field potential parameters: field potential duration (Field Potential Duration, FPD), beating period and corrected field potential duration (Corrected Field Potential Duration, FPDc).

[0061] Figure 4Nicorandil can effectively reverse the QT interval prolongation of human induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) induced by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that the use of ondansetron alone can significantly prolong FPDc compared with the control group, while the combination of ondansetron and nicorandil does not significantly change FPDc compared with the control group. B shows that the use of ondansetron alone can significantly prolong FPDc compared with the control group, while the combination of ondansetron and nicorandil does not significantly change FPDc compared with the control group. FPDc is the heart rate corrected field potential duration, which is equivalent to the QT interval in the electrocardiogram. The Fridericia formula is used to correct the FPD value, and the calculation method of FPDc is FPDc=FPD / (ISI^0.33). ISI is the interspike interval, which represents the duration of a cardiomyocyte beating cycle. In this figure, the ondansetron concentration is 120 μg / L and the nicorandil concentration is 422 μg / L, and the mass ratio of the two is 120:422.

[0062] Figure 5 In the process of finding an effective combination, the field potential data of cardiomyocytes differentiated from human induced stem cells were used to compare the effects of several other drugs combined with ondansetron. A indicates that mexiletine cannot eliminate the toxicity of ondansetron. B indicates that nadolol cannot eliminate the toxicity of ondansetron. In this figure, the concentration of ondansetron is 120μg / L, the concentration of mexiletine is 179μg / L, and the concentration of nadolol is 155μg / L.

[0063] Figure 6 It is a record of the original signal of the surface electrocardiogram of the experimental rabbit, as well as the commonly used measurement indicators for identifying the electrocardiogram and evaluating the possibility of arrhythmia. The QT interval of the electrocardiogram is the time from the starting point of the QRS wave to the end point of the T wave, representing the total time course of ventricular depolarization and repolarization. Its changes are sometimes related to the high and low heart rate. The heart rate-corrected QT interval (QTc) is often used clinically to evaluate QT changes. The extension of the QT and QTc intervals is of great significance for estimating the incidence of malignant arrhythmias and sudden cardiac death. Based on the Fridericia formula, the calculation method of QTc is QTc=QT / (RR^0.33). The RR interval is the distance between the R waves in the two QRS wave groups on the electrocardiogram, representing the duration of a cardiac cycle. 60 divided by the RR interval can be used to obtain the ventricular beat frequency.

[0064] Figure 7The adverse effects of ondansetron on the QT interval of the electrocardiogram and the QT interval (QTc) corrected for heart rate in whole animals (experimental rabbits) indicate that ondansetron has toxic effects on the animal heart and may induce severe arrhythmias or sudden death caused by prolonged QT interval. A shows that the use of ondansetron alone can significantly prolong the QT interval of the electrocardiogram compared with the control group. B shows that the use of ondansetron alone can significantly prolong the QTc interval of the electrocardiogram compared with the control group. QTc is the QT interval corrected for heart rate measured by the electrocardiogram of whole animals. The dose of ondansetron in this figure is 0.66 mg / kg body weight.

[0065] Figure 8 The effect of the compound preparation of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction of whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not significantly change the electrocardiogram QT interval compared with the control group. B shows that the compound preparation using ondansetron and nicorandil did not significantly change the electrocardiogram QTc interval compared with the control group. In this figure, the dose of ondansetron is 0.66 mg / kg body weight, and the dose of nicorandil is 0.47 mg / kg body weight, and the mass ratio of the two is 120:85.

[0066] Fig. 9 The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the compound preparation of ondansetron and nicorandil in this ratio did not change the electrocardiogram QTc interval statistically significantly compared with the control group. In this figure, the dose of ondansetron is 0.66 mg / kg body weight, and the dose of nicorandil is 0.93 mg / kg body weight, and the mass ratio of the two is 120:169.

[0067] Fig.10The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the compound preparation of ondansetron and nicorandil in this ratio did not change the electrocardiogram QTc interval statistically significantly compared with the control group. In this figure, the dose of ondansetron is 0.66 mg / kg body weight, and the dose of nicorandil is 1.40 mg / kg body weight, and the mass ratio of the two is 120:254.

[0068] Fig.11 The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the use of this ratio of ondansetron and nicorandil The compound preparation is compared with the control group, and there is no statistically significant change in the electrocardiogram QTc interval. In this figure, the dose of ondansetron is 0.66mg / kg body weight, and the dose of nicorandil is 1.87mg / kg body weight, and the mass ratio of the two is 120:339.

[0069] Fig.12The effect of the compound preparation of ondansetron and nicorandil on the incidence of arrhythmia in whole animals (experimental rabbits) indicates that this drug combination can effectively avoid the occurrence of cardiac arrhythmias induced by ondansetron, thereby preventing the possibility of sudden cardiac death caused by drug toxicity and side effects. The administration method is through the ear vein injection of the experimental rabbit. After the anesthesia is stable, the animal surface electrocardiogram signal is continuously recorded using a small animal electrocardiograph, and the total number of ventricular arrhythmias occurring in the 5-minute interval of 5 minutes before administration and 25 to 30 minutes after administration is analyzed as a percentage of the total number of heartbeats. As shown in this figure, the incidence of arrhythmias in all experimental groups before administration was 0, that is, no arrhythmias occurred. In the statistics after administration, the incidence of arrhythmias in the group using ondansetron alone was 6.92%; while the incidence of arrhythmias in the negative control group, the compound combination of ondansetron and nicorandil group 1 and group 2 was 0, that is, no arrhythmias occurred. This shows that the ondansetron alone group significantly increased the incidence of arrhythmias compared with the control group; while the combination of ondansetron and nicorandil significantly reduced the incidence of arrhythmias compared with the ondansetron alone group; the combination of ondansetron and nicorandil did not significantly change the incidence of arrhythmias in animals compared with the control group. In this figure, the negative control is 0.9% normal saline; in the ondansetron alone group, the ondansetron dose is 0.66 mg / kg body weight; in the ondansetron and nicorandil combination group 1, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 0.47 mg / kg body weight; in the ondansetron and nicorandil combination group 2, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 0.93 mg / kg body weight; in the ondansetron and nicorandil combination group 3, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 1.40 mg / kg body weight; in the ondansetron and nicorandil combination group 4, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 1.87 mg / kg body weight. DETAILED DESCRIPTION

[0070] Example 1 Drug Screening

[0071] ECG reference for normal people, QT prolongation and TdP Figure 1 and Figure 2 shown.

[0072] Based on induced pluripotent stem cell technology, combined with the latest international electrophysiology, pharmacology and other high-tech, we have established a pluripotent stem cell cardiac electrophysiology research and development platform that focuses on the world's advanced precision drug screening and development, thereby designing a new antiemetic drug that eliminates the cardiac toxic side effects of fatal arrhythmias. The platform can record and analyze parameters such as heart rate, QT, QTc (Corrected QT Interval), Beating Period, etc.; analyze the changes in heart rate, QT, QTc, Beating Period and other parameters caused by drugs.

[0073] Use the stem cell cardiac electrophysiology platform to screen drug combination solutions. The basic process is:

[0074] (1) Cardiomyocytes differentiated from human induced stem cells were thawed and seeded on Multi-Electrode Array (MEA) cell culture plates, and the cell culture medium was replaced daily.

[0075] (2) After about 4-8 days, the heart cell electrical signals are recorded. The heart cell electrical signals before the addition of drugs are recorded, as well as the heart cell electrical signals after the addition of ondansetron and nicorandil.

[0076] (3) Compare the differences in electrical signals under the action of different drugs, analyze the data, and make graphical comparisons.

[0077] Figure 3 The multi-electrode array (MEA) was used to record the field potential characteristics (FP) of induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs).

[0078] Example 2 Effect of the compound medicine in human myocardial cell experiment

[0079] The hiPSC-CMs differentiated from human induced stem cells were thawed and planted on the Multi-Electrode Array (MEA) cell culture plate with the base solution of the hiPSC-CMs differentiated from human induced stem cells. The culture medium was replaced with the culture medium of the hiPSC-CMs differentiated from human induced stem cells. After that, the cell culture medium was replaced every day until the addition of drugs and the recording was completed. The myocardial cells were planted on the MEA plate for 4-8 days, and the electrical signals of the cardiac cells could be recorded. The baseline cardiac cell electrical signals were recorded before the addition of drugs. After the addition of ondansetron, the cardiac cell electrical signal data were recorded. After that, drugs such as nicorandil were added to record the cardiac cell electrical signal data. After the recorded electrical signal data was analyzed, the data was imported into an Excel spreadsheet, and then graphed using Graph Pad.

[0080] Figure 4 The field potential data of cardiomyocytes differentiated from human induced stem cells showed that nicorandil can effectively reverse the QT interval prolongation of cardiomyocytes induced by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. Figure 4 A shows that the original field potential recording diagram shows that ondansetron alone can significantly prolong FPDc compared with the control group, while the combination of ondansetron and nicorandil did not significantly change FPDc compared with the control group. Figure 4 B shows that the use of ondansetron alone can significantly prolong FPDc compared with the control group, while the combination of ondansetron and nicorandil did not significantly change FPDc compared with the control group. FPDc (Corrected Field Potential Duration) is the duration of the heart rate corrected field potential, which is equivalent to the QTc interval (Corrected QT Interval) in the electrocardiogram, that is, the QT interval corrected for heart rate. The Fridericia formula is used to correct the FPD value, and the calculation method of FPDc is FPDc = FPD / (ISI^0.33). ISI is the interspike interval, which represents the duration of a myocardial cell beating cycle. In this figure, the ondansetron concentration is 120μg / L and the nicorandil concentration is 422μg / L, and the mass ratio of the two is 120:422.

[0081] Figure 5 This figure shows the field potential data of cardiomyocytes differentiated from human induced stem cells to compare the effects of several other drugs combined with ondansetron. A indicates that mexiletine cannot eliminate the toxicity of ondansetron. B indicates that nadolol cannot eliminate the toxicity of ondansetron. In this figure, the ondansetron concentration is 120μg / L, the mexiletine concentration is 179μg / L, and the nadolol concentration is 155μg / L.

[0082] Example 3 Effect of the compound medicine in the present application on the electrocardiogram test of the animal (rabbit) surface

[0083] The basic waveform of the rabbit ECG is similar to that of humans, both of which are sinus rhythms, and the distribution of ion channels on their hearts is closest to that of humans, so the rabbit ECG is used to compare drug effects, which is closest to human data. The whole animal ECG experiment uses healthy, adult New Zealand rabbits weighing 2.0-2.5 kg, with equal gender. 20% urethane solution is anesthetized and intraperitoneally injected, and the surface ECG signals of the experimental rabbits are continuously recorded using a small animal ECG machine. After the rabbits are anesthetized stably, they are fixed using a heated temperature-controlled rabbit table. The baseline ECG signal is recorded for 30 minutes, and then the drug is injected through the ear vein. 0.9% saline (control group), ondansetron alone group, and a compound preparation of ondansetron and nicorandil are given at one time. The ECG signals of the rabbits are continuously recorded for 30 minutes at the baseline state and 2 hours after intravenous injection of the drug, and the differences in ECG indicators between different experimental groups are analyzed. The ECG indicators used are mainly: QT, heart rate (HR), QTc, RR, etc. After the recorded electrical signal data were analyzed, the data were imported into Excel and then analyzed using Graph Pad. The drug dosage for the experimental rabbits was converted from the human drug dosage based on the body surface area.

[0084] Figure 6 It is a record of the original signal of the surface electrocardiogram of the experimental rabbit, as well as the commonly used measurement indicators for identifying the electrocardiogram and evaluating the possibility of arrhythmia. The QT interval of the electrocardiogram is the time from the starting point of the QRS wave to the end point of the T wave, representing the total time course of ventricular depolarization and repolarization. Its changes are sometimes related to the high and low heart rate. The heart rate-corrected QT interval (QTc) is often used clinically to evaluate QT changes. The extension of the QT and QTc intervals is of great significance for estimating the incidence of malignant arrhythmias and sudden cardiac death. Based on the Fridericia formula, the calculation method of QTc is QTc=QT / (RR^0.33). The RR interval is the distance between the R waves in the two QRS wave groups on the electrocardiogram, representing the duration of a cardiac cycle. 60 divided by the RR interval can be used to obtain the ventricular beat frequency.

[0085] Figure 7The effect of ondansetron on the QT interval of the electrocardiogram and the QT interval (QTc) corrected for heart rate in whole animals (experimental rabbits). Physiological saline (control group) and ondansetron solution were administered once through the ear vein, and the electrocardiogram signals before and after administration were recorded. By comparing the electrocardiogram signals at the baseline before administration and 30 minutes after administration, the effect of the ondansetron group on the growth rate (Percentage of Increase%) of the QT and QTc intervals of the surface electrocardiogram data of the whole animal was analyzed, and it was found that ondansetron had a toxic effect on the animal heart, which may induce severe arrhythmias or sudden death caused by prolonged QT interval. A shows that the use of ondansetron alone can significantly prolong the QT interval of the electrocardiogram compared with the control group. B shows that the use of ondansetron alone can significantly prolong the QTc interval of the electrocardiogram compared with the control group. QTc is the QT interval corrected for heart rate measured by the electrocardiogram of the whole animal. The ondansetron dose in this figure is 0.66 mg / kg body weight.

[0086] Figure 8 The effect of the compound preparation of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction of whole animals (experimental rabbits). Through the ear vein, physiological saline (control group) and the compound preparation of ondansetron plus nicorandil were administered once, and the electrocardiogram signals before and after administration were recorded. By comparing the electrocardiogram signals of the baseline before administration and 30 minutes after administration, the effect of the compound on the growth rate (Percentage of Increase%) of the QT and QTc intervals of the surface electrocardiogram data of the whole animal was analyzed, and it was found that the compound can effectively reverse the prolongation of the cardiac QT interval caused by ondansetron, thereby preventing the development of related arrhythmias, and thus avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that the use of the compound preparation of ondansetron and nicorandil did not significantly change the electrocardiogram QT interval compared with the control group. B shows that the use of the compound preparation of ondansetron and nicorandil did not significantly change the electrocardiogram QTc interval compared with the control group. In this figure, the dosage of ondansetron is 0.66 mg / kg body weight, and the dosage of nicorandil is 0.47 mg / kg body weight, and the mass ratio of the two is 120:85.

[0087] Fig. 9The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the compound preparation of ondansetron and nicorandil in this ratio did not change the electrocardiogram QTc interval statistically significantly compared with the control group. In this figure, the dose of ondansetron is 0.66 mg / kg body weight, and the dose of nicorandil is 0.93 mg / kg body weight, and the mass ratio of the two is 120:169.

[0088] Fig.10 The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the compound preparation of ondansetron and nicorandil in this ratio did not change the electrocardiogram QTc interval statistically significantly compared with the control group. In this figure, the dose of ondansetron is 0.66 mg / kg body weight, and the dose of nicorandil is 1.40 mg / kg body weight, and the mass ratio of the two is 120:254.

[0089] Fig.11 The effect of another ratio of ondansetron and nicorandil on the QT interval of the electrocardiogram and the QT interval of heart rate correction in whole animals (experimental rabbits) indicates that the compound preparation can effectively reverse the cardiac QT interval prolongation caused by ondansetron, thereby preventing the development of related arrhythmias and avoiding the occurrence of sudden cardiac death caused by drug side effects. A shows that a group of compound preparations using ondansetron and nicorandil did not change the electrocardiogram QT interval statistically significantly compared with the control group. B shows that the use of this ratio of ondansetron and nicorandil The compound preparation is compared with the control group, and there is no statistically significant change in the electrocardiogram QTc interval. In this figure, the dose of ondansetron is 0.66mg / kg body weight, and the dose of nicorandil is 1.87mg / kg body weight, and the mass ratio of the two is 120:339.

[0090] Fig.12The effect of the compound preparation of ondansetron and nicorandil on the incidence of arrhythmia in whole animals (experimental rabbits) indicates that this drug combination can effectively avoid the occurrence of cardiac arrhythmias induced by ondansetron, thereby preventing the possibility of sudden cardiac death caused by drug toxicity and side effects. The administration method is through the ear vein injection of the experimental rabbit. After the anesthesia is stable, the animal surface electrocardiogram signal is continuously recorded using a small animal electrocardiograph, and the total number of ventricular arrhythmias occurring in the 5-minute interval of 5 minutes before administration and 25 to 30 minutes after administration is analyzed as a percentage of the total number of heartbeats. As shown in this figure, the incidence of arrhythmias in all experimental groups before administration was 0, that is, no arrhythmias occurred. In the statistics after administration, the incidence of arrhythmias in the group using ondansetron alone was 6.92%; while the incidence of arrhythmias in the negative control group, the compound combination of ondansetron and nicorandil group 1 and group 2 was 0, that is, no arrhythmias occurred. This shows that the ondansetron alone group significantly increased the incidence of arrhythmias compared with the control group; while the combination of ondansetron and nicorandil significantly reduced the incidence of arrhythmias compared with the ondansetron alone group; the combination of ondansetron and nicorandil did not significantly change the incidence of arrhythmias in animals compared with the control group. In this figure, the negative control is 0.9% normal saline; in the ondansetron alone group, the ondansetron dose is 0.66 mg / kg body weight; in the ondansetron and nicorandil combination group 1, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 0.47 mg / kg body weight; in the ondansetron and nicorandil combination group 2, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 0.93 mg / kg body weight; in the ondansetron and nicorandil combination group 3, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 1.40 mg / kg body weight; in the ondansetron and nicorandil combination group 4, the ondansetron dose is 0.66 mg / kg body weight, and the nicorandil dose is 1.87 mg / kg body weight.

Claims

1. A new type of safe antiemetic drug, which includes a 5-hydroxytryptamine receptor antagonist and a potassium ion channel opener.

2. The novel safe antiemetic according to claim 1, wherein the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

3. The novel safe antiemetic according to claim 2, wherein the 5-hydroxytryptamine receptor antagonist is ondansetron.

4. The potassium ion channel opener according to claim 1 is an ATP-sensitive potassium ion channel opener.

5. The potassium ion channel opener according to claim 1 or 4 is nicorandil.

6. The novel safe antiemetic according to any one of claims 1 to 5, which is a compound preparation.

7. The novel safe antiemetic according to claim 6, wherein the mass ratio of ondansetron to nicorandil in the compound preparation is 120:30 to 120:1000.

8. The novel safe antiemetic according to claim 7, wherein the mass ratio of ondansetron to nicorandil in the compound preparation is 120:40 to 120:

500.

9. The novel safe antiemetic according to claim 8, wherein the mass ratio of ondansetron to nicorandil in the compound preparation is 120:80 to 120:

350.

10. The novel safe antiemetic according to any one of claims 1 to 9, wherein the compound preparation is an oral preparation or an injection, a topical preparation, or a spray; the oral preparation includes capsules, oral liquids, and tablets; the injection includes injections and powder injections.

11. The novel safe antiemetic according to claim 9, wherein the concentration of nicorandil in the compound preparation after entering the human body is 30 μg / L-1000 μg / L in blood.

12. The novel safe antiemetic according to claim 11, wherein the blood concentration of nicorandil in the compound preparation after entering the human body is 40 μg / L-500 μg / L.

13. Use of Nicorandil in the preparation of a drug for reducing QT interval prolongation.

14. The use according to claim 13, wherein the QT interval prolongation is QT interval prolongation caused by 5-hydroxytryptamine receptor antagonism.

15. The use according to claim 14, wherein the 5-hydroxytryptamine receptor antagonist is a 5-hydroxytryptamine 3 receptor antagonist.

16. The use according to claim 15, wherein the 5-hydroxytryptamine receptor antagonist is ondansetron.

17. The use according to any one of claims 13 to 16, wherein the drug is an oral preparation or an injection, a local application preparation, or a spray; the oral preparation includes capsules, oral liquids, and tablets; the injection includes injections and powder injections.

18. The use according to any one of claims 13 to 17, wherein the dosage of Nicorandil is 2 to 64 mg for a single oral preparation or 0.01 to 1 mg / kg / hr for an injection.

19. The use according to claim 18, wherein the dosage of Nicorandil is 4-32 mg for a single oral preparation or 0.05-0.5 mg / kg / hr for an injection.

20. A method for reducing QT interval prolongation, characterized in that: The method comprises administering a potassium channel opener to a subject at risk for, or experiencing symptoms of, a prolonged QT interval.

21. The method of claim 20, wherein the potassium ion channel opener is an ATP-sensitive potassium ion channel opener.

22. The method of claim 21, wherein the potassium channel opener is nicorandil.

23. The method of claim 22, wherein the subject is a human.

24. The method of claim 23, wherein the subject is a female.

25. The method according to any one of claims 20 to 24, wherein the QT interval prolongation is QT interval prolongation caused by 5-hydroxytryptamine receptor antagonism.

26. The method of claim 25, wherein the serotonin receptor antagonist is a serotonin 3 receptor antagonist.

27. The method of claim 26, wherein the serotonin receptor antagonist is ondansetron.

28. The method according to any one of claims 20 to 27, wherein the dosage of Nicorandil administered is 2 to 64 mg as a single oral formulation or 0.01 to 1 mg / kg / hr as an injection.

29. The method of claim 28, wherein the dosage of Nicorandil administered is 4-32 mg as a single oral formulation or 0.05-0.5 mg / kg / hr as an injection.

30. The method according to any one of claims 20 to 29, wherein the frequency and duration of administration of Nicorandil is from once to four times a day for 1 to 60 consecutive days.

31. The method of claim 30, wherein the frequency and duration of administration of Nicorandil is from once to three times a day for 1-14 consecutive days.

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