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US5153178.Pdf ||||||||||| USOO5153178A United States Patent (19) 11) Patent Number: 5,153,178 Maroko (45) Date of Patent: * Oct. 6, 1992 54) COMPOSITIONS AND METHOD OF 58) Field of Search ................. 514/280, 284, 821, 26; TREATMENT FOR IMPROVING 424/10 CRCULATORY PERFORMANCE (56) References Cited 76 Inventor: Peter R. Maroko, 1765 Garwood Dr., Cherry Hill, N.J. 08003 U.S. PATENT DOCUMENTS 4,761,417 8/1988 Maroko ............................... 514/284 *) Notice: The portion of the term of this patent subsequent to Aug. 2, 2005 has been Primary Examiner-Frederick E. Waddell disclaimed. Assistant Examiner-Diane Gardner Attorney, Agent, or Firm-Weiser & Stapler 21 Appl. No.: 226,630 57 ABSTRACT 22 Filed: Aug. 1, 1988 Compositions and methods for increasing the contrac tility of the mammalian heart as shown by a positive Related U.S. Application Data inotropic effect are disclosed, employing protoberbe 63 Continuation of Ser. No. 788,507, Oct. 18, 1985, Pat. rine alkaloids such as berberine, discretine, xylopinine, No. 4,761,417. berrberubine, tetrahydropalmatine, and stepharotine in 51 Int, Cl. ................... A61K 31/705; A61K 31/44; combination with cardiac glycosides such as ouabain, A61K 49/OO digoxin, digitoxin, deslanoside and digitalis. 52 U.S. Cl. ...................................... 514/26; 514/280; 514/284; 514/821; 424/10 17 Claims, 17 Drawing Sheets U.S. Patent Oct. 6, 1992 Sheet 4 of 17 5,153,178 ”SOME(SB10NIW)EWIJLt» NOISf^-}NISTOTINILNOO9NIMITOBIVAJLAJVEHNISE9NvHO BQI&JOTHOO8QAHBNIM39839JO Og+ O2+ O2+ ol+ U.S. Patent Oct. 6, 1992 Sheet 5 of 17 5,153,178 EFFECTS OF CONTINUOUS INTRAVENOUS ADMINISTRATION OF BERBERNE HYDROCHLORIDE (O.7mg/kg/min, n=7) -- O sh OO + 90 + 8O - 70 sh 6O 4O N A% + 3O --- 5 O 5 2O 25 3O 35 - 20 a-la HEART RATE v - 3O D----O LV dp/dt mox y a 4O O-O AORTIC FLOW A-a PULSE PRESSURE FIG. 5 U.S. Patent Oct. 6, 1992 Sheet 8 of 17 5,153,178 * BVT001B1N3^133TNOBOIMOTHOOM@AHBNIAJBGJBGJO1034-13 B80SS3\ldOITOLSVIOONE 9"91:099]O d0EATV7 (6Huuuu) U.S. Patent Oct. 6, 1992 Sheet 11 of 17 5,153,178 103333ENIMJ38838-30IMOTHOOMJOAHEQ EXO}JLSNOEWOTOA ENIMEBHB9•|OH TOMINOO[] 2+ V7AS (100g/Iuj) U.S. Patent Oct. 6, 1992 Sheet 12 of 17 5,153,178 {»+£2+|-O]-Ç–çÇ-9- 2]^9|E|(ôHulu)dQBATK7 NO30180THOOMQAHENIMEQJ39-JO1OB-J-JE „3A8nO9NITAJvIS-XINwM3, [OHENIM,30}}E{}e TOHINOO[] |'O+ 2°O- r???????????????????????????????????????????????????????????????????????????????????????????????????????????????n |’O- OOOV7 (NiW/SMJELIT) U.S. Patent Oct. 6, 1992 Sheet 13 of 17 5,153,178 ?y+£2IO-?-t>9 NOBOIJOTHOOM@AHBNIJ38838Jo103333 „BAHÍnO9NITAJV1S-XNvH+, TOMLNOODE ©2-ENIMEEM/38 |+ —r–r??????????????????????????????????????????????????????????????????????????????????n U.S. Patent Oct. 6, 1992 Sheet 14 of 17 5,153,178 STRENUOUS ACT WITY CARDAC STROKE NDEX VOLUME L/min/m2 m / m2 4. 5O - - - rew stre v- now - - - - - - - - - - - - - - - - a . a- - - - - - NORMA ACT WITY 3 REDUCED 2 - - -7--------------- 25- - - - PHYSICAL O ACT WITY 1. L s O CONGESTIVE ot SYMPTOMS ol O O 2O 3O LVEDP, mm Hg FIG. 4 5,153,178 1. 2 ence. For further details relating to disorders of the COMPOSITIONS AND METHOD OF TREATMENT heart, reference is made to Harrison's Principles of Inter FOR IMPROVING CIRCULATORY nal Medicine, Thorne, Adams, Braunwald, Isselbacher PERFORMANCE and Petersdorf, McGraw-Hill Book Company, 8th Ed., Part 7, ("Harrison's') Disease of the Organ Systems, This is a continuation of application Ser. No. 788,507, Disorder of the Heart, Chap. 231 through 248, which are filed Oct. 18, 1985, now U.S. Pat. No. 4,761,47. referred to specifically herein and incorporated herein This invention relates to berberine-type alkaloids, by reference. particularly protoberberine drug compositions and their Reference shall also be made herein to the following use in the treatment and diagnosis of circulatory disor 10 clinical books, namely Veterinary Pharmacology and d ders. The compounds of the invention are of special Therapeutics, Jones, Booth and McDonald, Iowa State interest in prophylactic, therapeutic and other applica University Press, 4th Ed., 1977; Physicians' Desk Refer tions to prevent, minimize, control, alleviate, correct, ence "PDR' Medical Economics Company, 36th Ed. remedy and so on, various disorders or symptoms of 1982; and Veterinary Pharmaceuticals and Biologicals, circulatory disorders, including cardiovascular origins 15 “VPB", 1980/1981, Aronson, Harwal Publishing Com or types. The invention relates in terms of subjects (or pany, Media, Pa., 1980. patients) to the field of mammals, i.e. human and veteri The direct cardiac action of drugs may be divided nary fields. into four major areas: (1) an effedt on contractility (ino The invention also encompasses distinct and valuable tropic effect), reflecting alterations in the myocardial embodiments like compositions (and compounds and force-velocity relation at any given initial muscle methods of use) for chronic and acute heart failure and length; (2) an effect on heart rate expressed as an alter other pathologic states that will benefit from an im ation in the rhythmicity, i.e., the frequency of discharge provement in cardiac performance; for the treatment of of normal pacemaker tissue, generally in the sinoatrial shock (cardiogenic and non-cardiogenic shock); for the node; (3) an effect on conductivity, i.e., on the velocity treatment of arrythmias (whether of natural causes or 25 with which the depolarization wave travels through the caused by a drug); for increasing the usefulness of car myocardium and the atrial ventricular conduction sys diac glycosides (like of the digitalis types) including tem; (4) an effect on irritability, i.e. the tendency to broadening their usually limited therapeutic index; for provoke ectopic pacemaker activity, which is depen controlling or correcting A-V (atrio-ventricular blocks, dent on the rate of diastolic depolarization and the to be defined later herein) block in mammals. 30 threshold potential. The unique, unobvious and remarkable aspects of the One of the most serious consequences of all types of invention are quite numerous and will become apparent cardiovascular diseases involves the pathophysiological hereinafter, but at the outset it is most noteworthy that state in which the heart fails in its prime function as a the compounds of the invention are antiarrhythmo muscle acting as a pump. In general, heart failure is the genic, a remarkable utility in and by itself. Another result of severe primary depression of myocardial con aspect, is that the compounds of the invention have a tractility or extreme ventricular hemodynamic over remarkable combination of beneficial properties, such load combined with secondary diminution of the con as, concurrently, having a positive inotropic effect and tractile state. For a description of the basics and disor being antiarrythmogenic. Another unusual aspect is that ders of the myocardial function, especially cardiac con the compounds of the invention are useful both in acute traction see Harrison's, chapter 236. ventricular failure and also in chronic congestive heart Knowledge of the biochemical and physiological failure. These aspects are of course described in greater changes in heart failure has advanced considerably in detail hereinafter. recent years. Unfortunately, the development of phar The invention also relates to other biochemical or macological agents with clinically useful positive prop biomedical applications. The other aspects, to which 45 erties on cardiac contractility (positive inotropic the invention relates, will become apparent to one of agents) has not kept pace. Nearly two centuries have average skill in the art from the teaching herein. passed since W. Withering described the cardiovascular One important, but not the only important field to effects of Digitalis purpurea in 1787. Since then, the which the invention relates is the cardiovascular field, basic treatment of congestive heart failure remains with both in humans and animals. Today cardiovascular 50 the cardiac glycosides as is described in greater detail diseases, which have reached epidemic proportions, herein. Although literally hundreds of cardiac glyco account for a very high proportion of all deaths in the sides have been investigated, not one has been found world, especially in industrialized nations. Approxi with a wide therapeutic index. The most commonly mately one of every five persons has some form of car used cardiac glycosides digoxin and digitoxin, have a diovascular ailment such as heart disease, cerebrovascu 55 very narrow therapeutic index of less than 2, with life lar disease or hypertension. threatening cardiac arrhythmias as the first manifesta Cardiovascular disease not only is fatal but causes tion of toxicity. It is clear that a cardiotonic agent with prolonged suffering and disability in even a larger pro a wide therapeutic index is needed, especially one that portion of the population. In the United States alone, does not have the drawbacks of the glycosides at all or cardiovascular disease was responsible for almost one has them at least to a milder extent. million fatalities in 1979, well over one-half of all re For the treatment of vascular diseases and the phar ported deaths. Almost 5 million persons afflicted with macology of cardiac glycosides, reference is made here cardiovascular disease are hospitalized annually. The to Braunwald, Chapter 16, pages 515-538; Harrison, cost of this disease in terms of human annual costs due chapter 239, pages 1207-1210 and Goodman and to morbidity amount to over
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