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Ouabain - the Insulin of the Heart Hauke Fürstenwerth

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Ouabain - The Insulin of the Heart Hauke Fürstenwerth To cite this version: Hauke Fürstenwerth. Ouabain - The Insulin of the Heart. International Journal of Clinical Practice, Wiley, 2010, 64 (12), pp.1591. 10.1111/j.1742-1241.2010.02395.x. hal-00599542 HAL Id: hal-00599542 https://hal.archives-ouvertes.fr/hal-00599542 Submitted on 10 Jun 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. International Journal of Clinical Practice For PeerOuabain – TheReview Insulin of the HeartOnly Journal: International Journal of Clinical Practice Manuscript ID: IJCP-12-09-0760.R1 Manuscript Type: Perspective Date Submitted by the 18-Jan-2010 Author: Complete List of Authors: Fürstenwerth, Hauke; Hauke Fürstenwerth, consultant Specialty area: International Journal of Clinical Practice Page 1 of 9 International Journal of Clinical Practice 1 2 Title: Ouabain – The Insulin of the Heart 3 4 Author: Dr. Hauke Fürstenwerth 5 6 Unterölbach 3A 7 D-51381 Leverkusen 8 Germany 9 Phone: +49-2171-733740 10 e-mail: [email protected] 11 12 corresponding author: Dr. Hauke Fürstenwerth 13 Unterölbach 3A 14 15 D-51381 Leverkusen 16 For Germany Peer Review Only 17 Phone: +49-2171-733740 18 e-mail: [email protected] 19 20 21 22 disclosure: no conflict of interest 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 1 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice Page 2 of 9 1 2 3 Abstract: 4 Prior to the introduction of modern drugs like angiotensin converting enzyme inhibitors and 5 6 β-adrenergic receptor antagonists, the cardiac glycoside ouabain (referred to as g- 7 Strophanthin in German) has routinely been used in treatment of heart diseases. Decades of 8 practical use indicate benefits in prevention and treatment of acute heart attacks. Prophylactic 9 and therapeutic use of ouabain was recommended in insufficiencies of the left ventricle. This Deleted: is 10 clinical experience disappeared in time, yet there is mounting evidence that supports a re- 11 evaluation of ouabain in the treatment of heart disease. In 1991 ouabain was identified as an 12 endogenous hormone. This discovery has lead to an intense re-examination of the drug, its 13 14 physiological functions and its mode of action. New research illustrates the uniqueness of 15 ouabain and thus confirms the extensive clinical experiences. Moreover, a recent study 16 confirmed the long-knownFor clinical Peer observation that Reviewouabain has an inhibitory Onlyeffect on 17 cardiotoxicity induced by other digitalis glycosides. 18 19 Mechanistic studies have validated the clinical experience that ouabain is different from other 20 cardiac glycosides. In contrast to digitalis glycosides ouabain modulates the metabolism of 21 the heart; it stimulates substrate utilization of the myocardium, removes lactate accumulated 22 23 during heart diseases, and reduces the amount of fatty acids in the blood. This profile makes 24 ouabain a valuable prototype for new drugs, which offer new approaches for causal treatment 25 of heart diseases. Clinical studies with ouabain that correspond to current standards are 26 warranted. 27 28 29 30 Review Criteria: 31 32 An excessive literature research was performed on clinical experience with ouabain as well as 33 on research on mode of action of ouabain and related cardiac steroids. 34 35 36 Message for the clinic: 37 Clinical experience suggests that ouabain has a favorable therapeutic profile in treatment of 38 insufficiencies of the left ventricle. Ouabain modulates the metabolism of the heart. Clinical 39 40 studies that correspond to current standards are warranted. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 2 55 56 57 58 59 60 International Journal of Clinical Practice Page 3 of 9 International Journal of Clinical Practice 1 2 Ouabain – The Insulin of the Heart 3 4 Today, medical therapies for heart disease are based on a diverse range of drugs. Angiotensin 5 6 converting enzyme inhibitors, angiotensin II receptor antagonists, β-adrenergic receptor 7 antagonists, aldosterone receptor antagonists, as well as diuretics, and inotropic agents 8 improve clinical symptoms and slow the progression of contractile dysfunction. Despite these 9 therapeutic advances, heart failure is still associated with an annual mortality rate of 10% [1]. 10 The search for better treatments and optimization of existing ones remain major challenges in 11 cardiology. 12 13 14 Modulation of myocardial metabolism has become an accepted new approach to improve the 15 performance of the dysfunctional myocardium [2]. Alternatively, proven agents such as 16 digitalis glycosides continueFor to be Peerof interest. Digoxin Review is still used extensively Only worldwide and Deleted: very 17 it remains one of the most commonly prescribed drugs. The Digitalis Investigation Group trial 18 has indicated that digoxin is quite effective in reducing cardiovascular hospitalizations [3]. A 19 proposal for a large digoxin study is being considered for funding in Europe [4]. However, 20 21 arrhythmia and a narrow therapeutic index limit its therapeutic application [5, 6 ]. 22 23 Although often used as research tool, the cardiac glycoside ouabain (referred to as g- 24 Strophanthin in German) has become a niche product in treatment of heart diseases. Decades 25 of practical use indicate benefits in prevention and treatment of acute heart attacks. 26 Prophylactic and therapeutic use of ouabain is recommended in insufficiencies of the left 27 ventricle. Several clinical studies with orally administered ouabain report exceptionally 28 29 positive results for treatment of cardiovascular diseases [7-9]. 30 31 This clinical experience disappeared in time, yet there is mounting evidence that supports a 32 re-evaluation of ouabain in the treatment of heart disease. In 1991 ouabain was identified as 33 an endogenous hormone. This discovery has lead to an intense re-examination of the drug, its 34 physiological functions and its mode of action [10 - 12 ]. Deleted: , 11 35 36 37 Based on its chemical structure ouabain is considered a typical digitalis derivative. All 38 digitalis derivatives bind to and inhibit the ubiquitous transmembrane protein Na+, K+- 39 ATPase and increase the force of contraction of heart muscle. However, there are diverse 40 biological responses to different derivatives both at the cellular and at the molecular level 41 [13]. There are marked differences between the effects of digoxin and ouabain. Only ouabain Deleted: 2 42 in small doses stimulates the sodium pump [1 4, 1 5]; digoxin does not show this effect [1 6]. Deleted: 3 43 Deleted: 4 44 Moreover, digoxin was shown to induce changes in intracellular membrane traffic in neuronal Deleted: 45 cells, while ouabain does not possess this ability and even antagonized digoxin effect [17]. A 5 46 recent study confirmed the long-known clinical experience that ouabain has an inhibitory Deleted: it was shown that ouabain inhibits digoxin-induced 47 effect on cardiotoxicity induced by digitalis glycosides. Ouabain at a low dosage delayed the changes in membrane traffic 48 start of arrythmia induced by digoxin on guinea pig papillary muscle. In addition, ouabain at a Deleted: 6 49 low dosage but not at a high dosage delayed the development of digoxin-induced arrhythmia 50 in anaesthetized guinea pigs [18]. Thus the long-known characteristic dose dependency of Deleted: 7 51 Deleted: 0 52 ouabain effects [21] has been confirmed. 53 54 3 55 56 57 58 59 60 International Journal of Clinical Practice International Journal of Clinical Practice Page 4 of 9 1 2 3 Clinical Experience with Ouabain 4 5 6 According to canonical explanations, ouabain and other digitalis derivatives should have 7 similar therapeutic effects. However, clinical experience clearly indicates that ouabain is 8 different from other digitalis derivatives . A most pronounced difference is the fast onset of 9 action by ouabain. This effect was the basis for the chance discovery of ouabain in 1859 by 10 the English botanist Kirk. He had discovered the fast onset of action of ouabain on the heart 11 by using a toothbrush contaminated with Strophanthus seeds. The rapid onset of effect of oral 12 ouabain was used in medical practice for a "Strophanthin-quick-test": patients with suspected 13 heart disease were given two tablets of 3 mg that they had to chew and distribute in the 14 15 mouth. In the case of heart disease a relief of complaints was observed within 5-10 minutes. 16 This test was used routinelyFor in German Peer physicians' officesReview well into the 1970s. Only 17 18 Based on decades of extensive clinical experience with ouabain the therapeutic profile of the 19 drug and the disease profiles for which the use of ouabain is appropriate have been 20 summarized in monographs and reviews [19-21]. The main benefit is in prevention and Deleted: 8 21 treatment of acute heart attacks. Prophylactic and therapeutic use of ouabain is recommended Deleted: 0 22 23 in: congestive heart insufficiency without pronounced hypertrophy, coronary sclerosis, 24 cardiogenic hypertension, asthma cardiale, exercise-induced cardiac insufficiency, angina 25 pectoris and arrhythmias, including those that occur on treatment with digitalis. It is stated 26 that ouabain “has proven to be the most acceptable, most effective antidote for digitalis 27 intoxication.” 28 29 Edens described “the intravenous Strophanthin treatment as the safest treatment of organic- 30 induced angina pectoris, including heart attack." Digitalis causes a worsening of symptoms 31 32 and is therefore contra-indicated.
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  • Quo Vadis Cardiac Glycoside Research?

    Quo Vadis Cardiac Glycoside Research?

    toxins Review Quo vadis Cardiac Glycoside Research? Jiˇrí Bejˇcek 1, Michal Jurášek 2 , VojtˇechSpiwok 1 and Silvie Rimpelová 1,* 1 Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, Prague 6, Czech Republic; [email protected] (J.B.); [email protected] (V.S.) 2 Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 3, Prague 6, Czech Republic; [email protected] * Correspondence: [email protected]; Tel.: +420-220-444-360 Abstract: AbstractCardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG’s toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG’s toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations.