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digitalis preparation used to treat congestive heart failure or cardiac arrhythmia

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/03 00:04:19」(JST)

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Digitoxin is a cardiac glycoside. It has similar structure and effects to digoxin (though the effects are longer-lasting). Unlike digoxin (which is eliminated from the body via the kidneys), it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current Western medical practice. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.^[1]

Toxicity

Digitoxin exhibits similar toxic effects to the more commonly used digoxin, namely: anorexia, nausea, vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmias. Antidigoxin antibody fragments, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.^[2]

History

The first description of the use of foxglove dates back to 1775.^[3] For quite some time, the active compound was not isolated. Oswald Schmiedeberg was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist Claude-Adolphe Nativelle (1812-1889). The first structural analysis was done by Adolf Otto Reinhold Windaus in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962.^[4]^[5]

Use in fiction

Digitoxin is used as the murder weapon in Agatha Christie's Appointment with Death, Elizabeth Peters' Die For Love and CSI, season 9, episode 19: "The Descent of Man". It was also used as a poison in "Uneasy Lies the Crown" on Columbo, season 9, episode 5 (1990), "Affair of the Heart" on McMillan and Wife, season 6, episode 5 (1977) and on Murder 101: "College can be a Murder". Also used in several episodes of Murder She Wrote.

In The Decemberists's song, "The Rake's Song" on the The Hazards of Love album, the narrator murders his daughter by feeding her foxglove.

Use in cancer chemotherapy

Digitoxin and related cardenolides display potent anticancer activity against a range of human cancer cell lines in vitro but the clinical use of digitoxin to treat cancer has been restricted by its narrow therapeutic index.^[6]^[7] Digitoxin glycorandomization led to the discovery of novel digitoxigenin neoglycosides which displayed improved anticancer potency and reduced ionotropic activity (the perceived mechanism of general toxicity).^[8] Steroidal glycosides based upon this latter discovery served as the basis for the development of a new class of antibody-drug conjugate known as extracellular drug conjugates (EDCs) as first in class agents to treat cancer by the biotechnology company Centrose.

References

^ Belz, G. G.; Breithaupt-Grögler, K.; Osowski, U. (2001). "Treatment of congestive heart failure—current status of use of digitoxin". European Journal of Clinical Investigation 31 (Suppl 2): 10–17. doi:10.1046/j.1365-2362.2001.0310s2010.x. PMID 11525233.
^ Kurowski, V.; Iven, H.; Djonlagic, H. (1992). "Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies". Intensive Care Medicine 18 (7): 439–442. doi:10.1007/BF01694351. PMID 1469187.
^ Withering, William (1785). An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and other Diseases.
^ Diefenbach, W. C.; Meneely Jr, J. K. (1949). "Digitoxin; a critical review" (PDF). The Yale Journal of Biology and Medicine 21 (5): 421–431. PMC 2598854. PMID 18127991. edit
^ Sneader, Walter (2005). Drug discovery: A history. p. 107. ISBN 978-0-471-89980-8.
^ Menger, L; Vacchelli, E; Kepp, O; Eggermont, A; Tartour, E; Zitvogel, L; Kroemer, G; Galluzzi, L (Feb 1, 2013). "Trial watch: Cardiac glycosides and cancer therapy". Oncoimmunology 2 (2): e23082. doi:10.4161/onci.23082. PMID 23525565.
^ Elbaz, HA; Stueckle, TA; Tse, W; Rojanasakul, Y; Dinu, CZ (Apr 5, 2012). "Digitoxin and its analogs as novel cancer therapeutics". Experimental Hematology & Oncology 1 (1): 4. doi:10.1186/2162-3619-1-4. PMID 23210930.
^ Langenhan, JM; Peters, NR; Guzei, IA; Hoffmann, FM; Thorson, JS (Aug 30, 2005). "Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization". Proceedings of the National Academy of Sciences of the United States of America 102 (35): 12305–10. doi:10.1073/pnas.0503270102. PMID 16105948.

Johansson, S.; Lindholm, P.; Gullbo, J.; Larsson, R.; Bohlin, L.; Claeson, P. (2001). "Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells". Anticancer Drugs 12 (5): 475–483. doi:10.1097/00001813-200106000-00009. PMID 11395576.
Hippius, M.; Humaid, B.; Sicker, T.; Hoffmann, A.; Göttler, M.; Hasford, J. (2001). "Adverse drug reaction monitoring--digitoxin overdosage in the elderly". International Journal of Clinical Pharmacology and Therapeutics 39 (8): 336–343. doi:10.5414/cpp39336. PMID 11515708.
Haux, J.; Klepp, O.; Spigset, O.; Tretli, S. (2001). "Digitoxin medication and cancer; case control and internal dose-response studies" (PDF). BMC Cancer 1: 11. doi:10.1186/1471-2407-1-11. PMC 48150. PMID 11532201.
Srivastava, M.; Eidelman, O.; Zhang, J.; Paweletz, C.; Caohuy, H.; Yang, Q.; Jacobson, K. A.; Heldman, E.; Huang, W.; Jozwik, C.; Pollard, B. S.; Pollard, H. B. (2004). "Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells". Proceedings of the National Academy of Science of the United States of America 101 (20): 7693–7698. doi:10.1073/pnas.0402030101. PMC 419668. PMID 15136726.

External links

"Comparing the Toxicity of Digoxin and Digitoxin in a Geriatric Population: Should an Old Drug Be Rediscovered?". Medscape.
Official Centrose website

UpToDate Contents

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1. ジゴキシンによる治療：初回投与、モニタリング、および用量変更 treatment with digoxin initial dosing monitoring and dose modification
2. ジギタリス（強心配糖体）中毒 digitalis cardiac glycoside poisoning
3. ジゴキシン中毒患者におけるジゴキシン特異的抗体（Fab）フラグメントに対する投与レジメン dosing regimen for digoxin specific antibody fab fragments in patients with digoxin toxicity
4. ジゴキシン中毒による不整脈 cardiac arrhythmias due to digoxin toxicity
5. 小児における毒性植物摂取およびニコチン中毒のマネージメント management of toxic plant ingestions and nicotine poisoning in children

English Journal

Simultaneous quantification of digoxin, digitoxin, and their metabolites in serum using high performance liquid chromatography-tandem mass spectrometry.

Bylda C1, Thiele R, Kobold U, Volmer DA.
Drug testing and analysis.Drug Test Anal.2015 Mar 4. doi: 10.1002/dta.1781. [Epub ahead of print]
The study describes an LC-MS/MS method for simultaneous quantification of the cardiac glycosidic drugs digoxin and digitoxin and several of their metabolites. The assay represents a useful reference method for immunoassay-based tests, which are easily biased by the presence of metabolites of the tar
PMID 25735870

Cardiac glycoside activities link Na(+)/K(+) ATPase ion-transport to breast cancer cell migration via correlative SAR.

Magpusao AN1, Omolloh G, Johnson J, Gascón J, Peczuh MW, Fenteany G.
ACS chemical biology.ACS Chem Biol.2015 Feb 20;10(2):561-9. doi: 10.1021/cb500665r. Epub 2014 Nov 26.
The cardiac glycosides ouabain and digitoxin, established Na(+)/K(+) ATPase inhibitors, were found to inhibit MDA-MB-231 breast cancer cell migration through an unbiased chemical genetics screen for cell motility. The Na(+)/K(+) ATPase acts both as an ion-transporter and as a receptor for cardiac gl
PMID 25334087

Rapid quantification of digitoxin and its metabolites using differential ion mobility spectrometry-tandem mass spectrometry.

Bylda C1, Thiele R, Kobold U, Bujotzek A, Volmer DA.
Analytical chemistry.Anal Chem.2015 Feb 17;87(4):2121-8. doi: 10.1021/ac503187z. Epub 2015 Jan 26.
This study focuses on the quantitative analysis of the cardiac glycoside drug digitoxin and its three main metabolites digitoxigenin-bisdigitoxose, digitoxigenin-monodigitoxose, and digitoxigenin using electrospray ionization-differential ion mobility spectrometry-tandem mass spectrometry (ESI-DMS-M
PMID 25588102

Japanese Journal

Perfectly regioselective acylation of a cardiac glycoside, digitoxin, via catalytic amplification of the intrinsic reactivity

Yoshida Keisuke,Furuta Takumi,Kawabata Takeo
Tetrahedron Letters 51(37), 4830-4832, 2010-09-15
… Organocatalytic regioselective acylation of digitoxin has been developed. …
NAID 120002484958

Interaction of Polyphenols with Proteins : Binding of (-)-Epigallocatechin Gallate to Serum Albumin, Estimated by Induced Circular Dichroism

NOZAKI Akiko,HORI Mami,KIMURA Toshikiro,ITO Hideyuki,HATANO Tsutomu
Chemical & pharmaceutical bulletin 57(2), 224-228, 2009-02-01
… Double-reciprocal plot analyses showed the competitive relations with the site-I-(PB and tolbutamide, TB) and site-II-binding drugs (DP and ibuprofen, IP) indicating the binding of EGCG to sites I and II on HSA, while digitoxin (DG), a site-III-binding drug, did not affect the binding of EGCG. …
NAID 110007042056

Interaction of Polyphenolic Metabolites with Human Serum Albumin: A Circular Dichroism Study

Nozaki Akiko,Kimura Toshikiro,Ito Hideyuki,Hatano Tsutomu
Chemical and Pharmaceutical Bulletin 57(9), 1019-1023, 2009
… The addition of digitoxin did not affect the induced CD of the polyphenolic acids examined. …
NAID 130000124205

Related Pictures

★リンクテーブル★

リンク元	「強心配糖体」「ジギトキシン」
拡張検索	「acetyldigitoxin」

「強心配糖体」

Digitoxin
Systematic (IUPAC) name
	(3β,5β)-3-[(O-2,6-dideoxy-; β-D-ribo-hexapyranosyl-(1->4)-; 2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-; 14-hydroxycard-20(22)-enolide
Clinical data
Trade names	Digitaline
Pharmacokinetic data
Bioavailability	95% (Oral)
Metabolism	Liver
Biological half-life	5~7 days
Identifiers
CAS Registry Number	71-63-6
ATC code	C01AA04
PubChem	CID: 441207
IUPHAR/BPS	6782
DrugBank	DB01396
ChemSpider	389987
UNII	E90NZP2L9U
KEGG	D00297
ChEBI	CHEBI:28544
ChEMBL	CHEMBL254219
Chemical data
Formula	C41H64O13
Molecular mass	764.939 g/mol
	SMILES O=C\1OC/C(=C/1)[C@H]2CC[C@@]8(O)[C@]2(C)CC[C@H]7[C@H]8CC[C@H]6[C@]7(C)CC[C@H](O[C@@H]5O[C@H](C)[C@@H](O[C@@H]4O[C@@H]([C@@H](O[C@@H]3O[C@@H]([C@@H](O)[C@@H](O)C3)C)[C@@H](O)C4)C)[C@@H](O)C5)C6 ;
	InChI InChI=1S/C41H64O13/c1-20-36(46)29(42)16-34(49-20)53-38-22(3)51-35(18-31(38)44)54-37-21(2)50-33(17-30(37)43)52-25-8-11-39(4)24(15-25)6-7-28-27(39)9-12-40(5)26(10-13-41(28,40)47)23-14-32(45)48-19-23/h14,20-22,24-31,33-38,42-44,46-47H,6-13,15-19H2,1-5H3/t20-,21-,22-,24-,25+,26-,27+,28-,29+,30+,31+,33+,34+,35+,36-,37-,38-,39+,40-,41+/m1/s1 ; Key:WDJUZGPOPHTGOT-XUDUSOBPSA-N ;
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英: cardiac glycoside, cardiotonic glycoside
同: 強心ステロイド cardiotonic steroid、植物心臓毒 plant heart poison
関

ジギタリス digitalis
- ジゴキシン digoxin
- ジギトキシン digitoxin

「ジギトキシン」

　　[★]

英: digitoxin
関: ジギタリス、強心薬

「acetyldigitoxin」

　　[★]

アセチルジギトキシン

[Belz-1] Belz, G. G.; Breithaupt-Grögler, K.; Osowski, U. (2001). "Treatment of congestive heart failure—current status of use of digitoxin". European Journal of Clinical Investigation 31 (Suppl 2): 10–17. doi:10.1046/j.1365-2362.2001.0310s2010.x. PMID 11525233.

[Kurowsky-2] Kurowski, V.; Iven, H.; Djonlagic, H. (1992). "Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies". Intensive Care Medicine 18 (7): 439–442. doi:10.1007/BF01694351. PMID 1469187.

[3] Withering, William (1785). An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and other Diseases.

[4] Diefenbach, W. C.; Meneely Jr, J. K. (1949). "Digitoxin; a critical review" (PDF). The Yale Journal of Biology and Medicine 21 (5): 421–431. PMC 2598854. PMID 18127991. edit

[5] Sneader, Walter (2005). Drug discovery: A history. p. 107. ISBN 978-0-471-89980-8.

[6] Menger, L; Vacchelli, E; Kepp, O; Eggermont, A; Tartour, E; Zitvogel, L; Kroemer, G; Galluzzi, L (Feb 1, 2013). "Trial watch: Cardiac glycosides and cancer therapy". Oncoimmunology 2 (2): e23082. doi:10.4161/onci.23082. PMID 23525565.

[7] Elbaz, HA; Stueckle, TA; Tse, W; Rojanasakul, Y; Dinu, CZ (Apr 5, 2012). "Digitoxin and its analogs as novel cancer therapeutics". Experimental Hematology & Oncology 1 (1): 4. doi:10.1186/2162-3619-1-4. PMID 23210930.

[8] Langenhan, JM; Peters, NR; Guzei, IA; Hoffmann, FM; Thorson, JS (Aug 30, 2005). "Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization". Proceedings of the National Academy of Sciences of the United States of America 102 (35): 12305–10. doi:10.1073/pnas.0503270102. PMID 16105948.

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案内

digitoxin