Patent Application
20170304388
The present invention provides new clinical indication of cardiovascular drugs, which were approved by FDA. Particularly, the present invention demonstrates that the cardiovascular drugs can effectively inhibit a variety of cancers.
Cancer is the most popular disease cause of death in the world. The cancer patients are gradually increase yearly, therefore the treatment method of the cancer has become an important issue. The medical treatments of cancer can be classified as surgical treatment, radiation therapy, chemotherapy and target therapy.
Generally, the cancer drug, whether chemotherapy drug or target therapy drug, is inhibit the cancer cells' duplication and split to prevent the tumor growth and metastasis. In clinical treatment options, the combination of chemotherapies and several targeted therapies were selected; try to eliminate cancer cells more effectively, by means of different mechanisms. Furthermore, if the cancer patients happen the drug resistance, that would reduce the effectiveness of the drugs and result in the medical treatment failure.
On the other side, treatment of cardiovascular disease aims to prevent or delay the progression of the disease. Also, it aims to reduce the risk of developing cardiovascular diseases. For example, some cardiovascular drugs can treat high blood pressure, and other cardiovascular drugs can promote blood flow in patients with heart failure.
Based on the many years' experience of inventors, the human cancer cells and normal cells often have different characteristics, the differences in patterns or mechanism variation might be seen as a foreign invader. The different cancel cells are located in different locations and the statuses of variations are related to the located environment. Thus, the inventors are the first person to propose the use of antibiotic drugs to inhibit the cancer cell growth.
In contrast, these cardiovascular drugs have been used for decades and are recognized by FDA long time ago. These cardiovascular drugs already have been researched and analyzed to know the mechanism on human body. Therefore, the groundbreaking new application would be time-saving and cost effective if these drugs applied in treating cancer. Besides, the treatment effect would be improved if these drugs are used to combine with other treating method.
Otherwise, the manufacturing of the drug is also a big problem. When the drug starting the clinical trials, there are lots of problems need to overcome, such as drug safety, patient selection, trial dose and other issues. Even the drug has approved by the FDA and sales on the market, there still possibly face the situation of the poor drug response in patients. Furthermore, if the cancer patients happen the drug resistance, that would reduce the effectiveness of the drugs and result in the medical treatment failure. Therefore, the new drug development is very difficult.
To solve the above problems, the present invention provides a usage of existing cardiovascular drugs, which have passed clinical trials.
The experiment results showed that the cardiovascular drugs had no toxicity or only little toxicity to normal cells. However, there are more studies need to be test to know that whether the cardiovascular drugs have selection between normal cells and cancer cells. Besides, not all the cardiovascular drugs could inhibit the growth of cancer cells under same condition, there are still lots of problems need to be overcame.
Term Definition
The cardiovascular drugs can be classified to ten categories based on the features, includes: peripheral vasodilator reaming enhancer, angiotensin converting agent inhibitor, hypotension and shock therapeutic agent, diuretic, antiarrhythmic agent, antiarralciton drug, antihypertensive agent, anticoagulant and thrombolytic agent, cardiac tonic, intravenous (hemorrhoids) therapeutic agent.
(1) Peripheral vasodilator reaming enhancer, which can directly or indirectly effect on peripheral blood vessels to increase blood flow, includes: Cilnidipine, Minoxidil, Prazosin HCl, Sildenafil citrate, Tadalafil (Cialis), Nicorandil (Ikorel), Lacidipine (Lacipil, Motens), Benidipine hydrochloride, Cilazapril monohydrate (Inhibace), Fosinopril sodium (Monopril), Almotriptan malate (Axert), Milrinone (Primacor), Avanafil, Lomerizine HCl, Histamine Phosphate, Chromocarb and Pinacidil.
(2) Angiotensin converting agent inhibitor, which is used to inhibit ACE activity and reduce the production of vasopressin II, so as to reduce the bradykinin hydrolysis, lead to vasodilatation, blood volume, and decrease blood pressure, includes: Benazepril hydrochloride, Losartan potassium, Perindopril Erbumine (Aceon), Irbesartan (Avapro), Candesartan (Atacand), Olmesartan medoxomil (Benicar), Enalaprilat dehydrate, Telmisartan (Micardis), Ramipril (Altace), Valsartan (Diovan), Enalapril maleate (Vasotec), Candesartan cilexetil (Atacand), Conivaptan HCl (Vaprisol), Azilsartan Medoxomil (TAK-491) and Eprosartan Mesylate.
(3) Hypotension and shock therapeutic agent, which includes: L-Adrenaline (Epinephrine), DL-Adrenaline and Methoxamine HCl.
(4) Diuretic, which is used to increase the generation of urine and increase the excretion of human body water, includes: Bumetanide, Furosemide (Lasix), Metolazone(Zaroxolyn), Silodosin (Rapaflo), Chlorothiazide, Trichlormethiazide (Achletin), Torsemide (Demadex), Hydrochlorothiazide, Indapamide (Lozol), Dichlorphenamide (Diclofenamide), Amiloride hydrochloride dehydrate, Solifenacin succinate, Methyclothiazide, Benzthiazide, Meticrane, Bendroflumethiazide and Potassium Canrenoate.
(5) Antiarrhythmic agent, which is used to inhibit abnormal heartbeat rhythm (arrhythmia), such as atrial fibrillation, atrial flutter, and ventricular tachycardia (ventricular tachycardia) and ventricular fibrillation, includes: Adenosine (Adenocard), Dofetilide (Tikosyn), Amiodarone HCl, Ibutilide fumarate, Propafenone (Rytmonorm) and Disopyramide Phosphate.
(6) Antiarralciton drug, which is used to treat ischemic heart disease symptoms, includes Dexrazoxane Hydrochloride, Ranolazine dihydrochloride, Nisoldipine (Sular), Ranolazine (Ranexa), Acadesine, Nifedipine (Adalat), Amlodipine besylate (Norvasc), Diltiazem HCl (Tiazac), Ticagrelor and Oxprenolol HCl
(7) Antihypertensive agent is a medicament for hypertension treatment, which is used to prevent high blood pressure complications, such as stroke and myocardial infarction, includes: Bisoprolol, Doxazosin mesylate, Alfuzosin hydrochloride (Uroxatral), Nebivolol (Bystolic), Reserpine, Methyldopa (Aldomet), Eplerenon, Nimodipine (Nimotop), Betaxolol hydrochloride (Betoptic), Carvedilol, Metoprolol tartrate, Felodipine (Plendil), Amlodipine (Norvasc), Phentolamine mesilate, Imidapril (Tanatril) HCl, Aliskiren hemifumarate, Sodium Nitroprusside, Propranolol HCl, Levobetaxolol HCl, Esmolol HCl, (R)-(+)-Atenolol, Guanethidine Sulfate and Lofexidine HCl.
(8) Anticoagulant, thrombolytic agent is the flag used to prevent blood coagulation (coagulation). Those substances exist in leeches and blood-sucking insects. Anticoagulants can treat thrombotic diseases, include: Prasugrel (Effient), Cilostazol, Nafamostat mesylate, Clopidogrel (Plavix), Apixaban, Aminocaproic acid (Amicar), Dipyridamole (Persantine), Phenindione (Rectadione), Ticlopidine HCl, Ozagrel HCl, Argatroban, Bexarotene, Gabexate mesylate and Ozagrel and Anisindione.
(9) Cardiac tonic includes: Pimobendan (Vetmedin), Ampiroxicam, Digoxigenin and Pindolol.
(10) Intravenous (hemorrhoids) therapeutic agent includes: Edaravone (MCI-186), Daidzein, Ginkgolide A and Bisacodyl.
In one of the embodiments, the cancer is selected from lung cancer, intestinal cancer, colorectal cancer, prostate cancer, liver cancer, bladder cancer, cervical cancer, breast cancer and blood cancer.
In one of the embodiment of the present invention, wherein the effect concentration of the drug in the present invention is 20 mg/kg/day˜500 mg/kg/day.
The present invention provides a usage of cardiovascular drugs for cancer inhibition pharmaceutical composition preparation, which feature is the pharmaceutical composition composed by an effective dosage of cardiovascular drug and a pharmaceutical acceptable salt.
The cardiovascular drug of the present invention includes: Lenalidomide Valproic acid sodium salt (Sodium valproate), Decitabine, Bisoprolol, Dexrazoxane Hydrochloride, Prasugrel (Effient), Benazepril hydrochloride, Bumetanide, Cilnidipine, Cilostazol, Doxazosin mesylate, Edaravone (MCI-186), Losartan potassium, Minoxidil, Nafamostat mesylate, Bimatoprost, Alfuzosin hydrochloride (Uroxatral), Clopidogrel (Plavix), Prazosin HCl, Ranolazine dihydrochloride, Sildenafil citrate, Perindopril Erbumine (Aceon), Irbesartan (Avapro), Tadalafil (Cialis), Nebivolol (Bystolic), Pimobendan (Vetmedin), Candesartan (Atacand), Apixaban, Reserpine, Furosemide (Lasix), Olmesartan medoxomil (Benicar), Pyridostigmine Bromide (Mestinon), Metolazone (Zaroxolyn), Silodosin (Rapaflo), Chlorothiazide, Methyldopa (Aldomet), Adenosine (Adenocard), Ezetimibe (Zetia), Enalaprilat dehydrate, Dofetilide (Tikosyn), Trichlormethiazide (Achletin), Aminocaproic acid (Amicar), Busulfan (Myleran, Busulfex), Torsemide (Demadex), Eplerenone, Hydrochlorothiazide, Gemfibrozil (Lopid), Indapamide (Lozol), Telmisartan (Micardis), Nimodipine (Nimotop), Nisoldipine (Sular), Pitavastatin calcium (Livalo), Simvastatin (Zocor), Ramipril (Altace), Fenofibrate (Tricor, Trilipix), Ranolazine (Ranexa), Acadesine, Acipimox, Nifedipine (Adalat), Amlodipine besylate (Norvasc), Clofibrate (Atromid-S), Betaxolol hydrochloride (Betoptic), Carvedilol, Daidzein, toprolol tartrate, Diltiazem HCl (Tiazac), Tranexamic acid (Transamin), Felodipine (Plendil), Valsartan (Diovan), Dipyridamole (Persantine), Amlodipine (Norvasc), Fluvastatin sodium (Lescol), Phenindione (Rectadione), Enalapril maleate (Vasotec), Nicorandil (Ikorel), Amiodarone HCl, Ticlopidine HCl, Lacidipine (Lacipil, Motens), Suplatast tosylate, Benidipine hydrochloride, Ginkgolide A, Candesartan cilexetil (Atacand), Phentolamine mesilate, Nimesulide, Cytidine, Bromhexine HCl, Tiopronin (Thiola), Ozagrel HCl, Argatroban, Mitiglinide calcium, Rosiglitazone HCl, Atorvastatin calcium (Lipitor), Famotidine (Pepcid), Cleviprex (Clevidipine), Cilazapril monohydrate (Inhibace), Adiphenine HCl, Rivastigmine tartrate (Exelon), Detomidine HCl, Fosinopril sodium (Monopril), Almotriptan malate (Axert), Bexarotene, Gabexate mesylate, Rasagiline mesylate, Imidapril (Tanatril) HCl, Conivaptan HCl (Vaprisol), Ibutilide fumarate, Probucol, Arbidol HCl, S-(+)-Rolipram, Tebipenem pivoxil (L-084), Dichlorphenamide (Diclofenamide), Aliskiren hemifumarate, DL-Carnitine hydrochloride, D-Mannitol (Osmitrol), L-carnitine (Levocarnitine), Amantadine hydrochloride (Symmetrel), Clozapine (Clozaril), Milrinone (Primacor), Mitoxantrone Hydrochloride, Novobiocin sodium (Albamycin), Ozagrel, Pancuronium (Pavulon), Propafenone (Rytmonorm), Quinine hydrochloride dehydrate, Spectinomycin hydrochloride, Xylazine HCl, L-Adrenaline (Epinephrine), DL-Adrenaline, Trospium chloride (Sanctura), Amiloride hydrochloride dehydrate, Cloxacillin sodium (Cloxacap), Zidovudine (Retrovir), Thiamphenicol (Thiophenicol), Oseltamivir phosphate (Tamiflu), Lonidamine, Peramivir Trihydrate, Carfilzomib (PR-171), Pazopanib, Fosaprepitant dimeglumine, Otilonium Bromide, Solifenacin succinate, Besifloxacin HCl (Besivance), Azilsartan Medoxomil (TAK-491), Creatinine, Adrenalone HCl, Ampiroxicam, Desloratadine, Avanafil, Bisacodyl, Methyclothiazide, Sodium Nitroprusside, Vitamin D3 (Cholecalciferol), Deferiprone, Propranolol HCl, Mefenamic acid, Ticagrelor, sulfacetamide sodium, Lomerizine HCl, Levobetaxolol HCl, Dexlansoprazole, Esmolol HCl, Eprosartan Mesylate, Histamine Phosphate, Sevelamer HCl, Deoxyarbutin, Clorprenaline HCL, Ethamsylate, Chromocarb, Mevastatin, Mexiletine HCl, Phenazopyridine HCl, (R)-(+)-Atenolol, Anisindione, Benzthiazide, Disopyramide Phosphate, Guanethidine Sulfate, Isoetharine Mesylate, Methoxamine HCl, Meticrane, Oxprenolol HCl, Pinacidil, Bendroflumethiazide, Potassium Canrenoate, Digoxigenin, Lofexidine HCl and Pindolol.
Cell Culture
Subculture the different types of cancer cells. The cancer cells includes lung cancer, gastric cancer, hepatic cancer, colon cancer, skin cancer, cervical cancer, prostate cancer, bladder cancer, breast cancer, leukemia, pancreatic cancer, ovarian cancer, tongue cancer, osteosarcoma, and renal cancer. Cancer cell lines were cultured in different culture medium according to different characteristics (as shown in Table 1). The cell numbers were counted and reseed as 2×106 in cell culture plate/flask. Then, the culture medium for culturing the cell lines was added to a volume of 10 ml, and the cells were cultured for 2-3 days. Then, the cells were suspended for loading into 96-well plates. The cell number was 3000 cells and the volume of the culture medium was 100 ul each well.
Cell Viability Analysis
Removing the original culture medium from 96-well plate. Then add 100 μl of commercially drug at a concentration of 10 μM per well. After 72 hours, add the diluted WST-1 reagent to the well with 100 μl/well, and the diluted WST-1 reagent was acquired from the dilution of 9:1 medium and WST-1 stock reagent. Finally, the total volume of each well are 200 μl/well. Culture the 96-well plate at 37° C. for 30 to 90 minutes. Detecting and calculating the survival rate of each cancer cells with an ELISA reader at OD450 nm. The lower viability of cancer cells represents better inhibition effect via the drugs. Otherwise, the higher viability of cancer cells represents worse inhibition effect via the drugs.
Growth Inhibitory Effects on Cancer Cell Lines by Various Cardiovascular Drugs in the Present Invention
For cell viability analysis, the cardiovascular drugs include peripheral vasodilator reaming enhancer, angiotensin converting agent inhibitor, hypotension and shock therapeutic agent, diuretic, antiarrhythmic agent, antiarralciton drug, antihypertensive agent, anticoagulant thrombolytic agent, cardiac tonic, intravenous (hemorrhoids) therapeutic agent, are used to test the inhibition effect of cancer cell.
The test result showed that lots of cardiovascular drugs had no effect on cancer cell lines growth inhibition (Table 2).
Besides, the inhibition effects of different cardiovascular drugs on different cancer cells were different (shown as
Although the present invention has been described in terms of specific exemplary embodiments and examples, it will be appreciated that the embodiments disclosed herein are for illustrative purposes only, and various modifications might be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the following claims.
Repeated experiments for growth inhibitory effects on cancer cell lines by various cardiovascular drugs in the present invention
According to the above mentioned cardiovascular drugs for cancer growth inhibition in Table 3, the inventors took the repeat experiments for the cardiovascular drugs to check the growth inhibitory effects of cancer cells by the cardiovascular drugs. The results were showed as Table. 4.
This is a National Phase Application filed under 35 U.S.C. 371 as a national stage of PCT/CN2015/092768 filed Oct. 23, 2015, an application claiming the benefit under 35 USC 119(e) to the following U.S. Provisional Applications No. 62/068,298 filed Oct. 24, 2014, the content of each of which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2015/092768 | 10/23/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62068298 | Oct 2014 | US |
