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United States Patent [191 [11] Patent Number: 4,761,417 Maroko [45] Date of Patent: Aug

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United States Patent [191 [11] Patent Number: 4,761,417 Maroko [45] Date of Patent: Aug United States Patent [191 [11] Patent Number: 4,761,417 Maroko [45] Date of Patent: Aug. 2, 1988 [54] COMPOUNDS, COMPOSITIONS AND 1187733 4/1970 United Kingdom ................ .. 546/71 METHOD OF TREATMENTS FOR IMPROVING CIRCULATORY OTHER PUBLICATIONS PERFORMANCE Soto et al—-Rev. Assoc. Med Argent, 41:3062-3068 Inventor: Peter R. Maroko, 1765 Garwood (1933). [76] Soto et al-Rev. Assoc. Med Argent 47: 2494-2501, Dr., Cherry Hill, NJ. 08003 (1933). [21] App]. No.: 788,507 Chopra-4nd. Jour. Med. Res., XIX, 4, Apr. 1932, pp. 1193-1203. [22] Filed: Oct. 18, 1985 Williams-Jour. A.M.A., Jan. 4, 1908. Kulkarni et al—Japan J. Pharmacol. 22, 11-16 (1972). Related US. Application Data Chemical & Pharmaceutical Bulletin, vol. 18, No. 7, Jul. [63] Continuation of Ser. No. 378,122, May 14, 1982, aban 1970, pp. 1299—1304—Fukuda et al. doned. J. Pharmacol. Exp. Then, 71: 178-186 (1941), Jang. Mercier et al-Comptes Rendus Societe de Biologie, [51] Int. Cl.4 .................. .. A61K 31/44; A61K 31/705 127: 1022-1024, (1938). [52] US. Cl. ................................... .. 514/284; 514/280 [58] Field of Search ........................ .. 514/280, 284, 26 Primary Examiner-Frederick E. Waddell Attorney, Agent, or Firm—Weiser & Stapler [56] References Cited U.S. PATENT DOCUMENTS [57] ABSTRACT 3,326,920 6/1967 Stanaback et a1. .................. .. 546/71 A method of increasing the contractility of the mamma~ 3,346,582 10/1967 Brown et al. .. lian heart as shown by a positive inotropic affect is 3,933,826 1/ 1976 Karnetani .. 424/258 disclosed, employing protoberberine alkaloids such as 4,013,666 3/1977 Lenz .................................... .. 546/71 berberrubine or tetrahydropalmitane, alone or in combi nation with cardiac glycosides such as ouabain, digoxin, FOREIGN PATENT DOCUMENTS digitoxin or delanoside. 37976 4/ 1967 Japan ................................... .. 546/71 105699 7/1972 Japan ................................... .. 546/71 18 Claims, 17 Drawing Sheets US. Patent Aug. 2, 1988 Sheet 1 0f 17 4,761,417 6252.3:m2;, vlOm+ IOw+ ION+ lOm+ US. Patent Aug. 2, 1988 Sheet 5 0f 17 4,761,417 EFFECTS OF CONTINUOUS INTRAVENOUS ADMINISTRATION OF BERBERINE HYDROCHLORIDE (O.7mg/kg/min, n=7) + IOO + 90 + 80 + 70 + 60 + 50 + 40 /'\ Ao/o +30 r" + 20 / ‘I’ I0 1/ 5 ID l's 2'0 25 3'0 35 _ |Q . - 2O A——-—A HEART RATE _ 30 m----c| LV dp/dt max _ 4O <>—O AORTIC FLOW A—A PULSE PRESSURE FIG. 5 US. Patent Aug. 2, 1988 Sheet 8 of 17 4,761,417 m 9 ii» u. S $5.325.m2; 9O |_uImziwmmmmO J_ DJOE-Z00 US. Patent Aug. 2, 1988 Sheet 9 of 17 4,761,417 06E 65.32:):m2; 40:wziwmmmmO 20 405.200D 00m+ 03+ . com4. Com| OOvI 00ml 00m1 mmkq $-69.538m US. Patent Aug. 2, 1988 ‘Sheet 10 of 17 4,761,417 6E10- __ 0m_On 35.32:):m2; .0:0mziummmmI U16528 o m.O+ _.o| No| no| .20| US. Patent M % % e a 0 7 2, 4 6 U, 0.3* H,__9-h-GMSZEGE; w~+I HN..| H6:wziwmmwmQ 7,omm__w| U.6528 V+l .ql...I.. 0I 285.5 >m< US. Patent Aug. 2, 1988 Sheet 13 of 17 4,761,417 mziummwma U.6528 >m< 225:5. US. Patent Aug. 2, 1988 Sheet 15 0f 17 4,761,417 mmO, 6-“m- US. Patent Aug. 2, 1988 Sheet 16 0f 17 4,761,417 $ @0pm0.“Qo.”OW0.. 55.32:):mi; rON.O 9.0| $66 US. Patent Aug. 2, 1988 Sheet 17 0f 17 4,761,417 On _T 0vOmON9O 9.0| no.0I 4,761,417 1 2 ence. For further details relating to disorders of the COMPOUNDS, COMPOSITIONS AND METHOD heart, reference is made to Harrison ’s Principles of Inter OF TREATMENTS FOR IMPROVING nal Medicine, Thorne, Adams, Braunwald, Isselbacher CIRCULATORY PERFORMANCE and Petersdorf, McGraw-Hill Book Company, 8th Ed., Part 7, (“Harrison’s”) Disease of the Organ Systems, This application is a continuation of application Ser. Disorder of the Heart, Chap. 231 through 248, which are No. 378,122 ?led May 14, 1982, now abandoned. referred to speci?cally 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 clinical books, namely Veterinary Pharmacology and 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, corect, 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 “VPB”, 1980/ 1981, Aronson, Harwal Publishing Com or types. The invention relates in terms of subjects (or pany, Media, Pa., 1980. patients) to the ?eld of mammals, i.e. human and veteri The direct cardiac action of drugs may be divided nary ?elds. into four major areas: (1) an effect on contractility (ino The invention also encompasses distinct and valuable tropic effect), re?ecting alterations in the myocardial embodiments like compositions (and compounds and 20 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 bene?t 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 de?ned 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 40 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 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 ?eld to effects of Digitalis purpurea in 1787. Since then, the which the invention relates is the cardiovascular ?eld, basic treatment of congestive heart failure remains with both in humans and animals. Today cardiovascular 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 ?ve persons has some form of car used cardia 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 ?rst 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 8 billion dollars.
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