Editing Digitalis (section)

==Uses==

===Historical uses===
[[Nicholas Culpeper]] included Foxglove in his 1652 herbal medicine guide, ''The English Physician''. He cited its use for healing wounds (both fresh and old), as a purgative, for "the King's Evil" ([[mycobacterial cervical lymphadenitis]]), for "the falling sickness" ([[epilepsy]]), and for "a scabby head".<ref>{{cite book |last1=Culpeper |first1=Nicholas |title=The English Physician, Etc |date=1652 |publisher=William Bentley |location=London |pages=97–98 |edition=1st |url=https://books.google.com/books?id=WuyUw_5Hd8cC&pg=RA1-PA173 |access-date=22 January 2023 |language=en}}</ref> There is no empirical evidence for these claims, and it is not used for these conditions in modern medicine, only for slowing excessive heart rate in certain circumstances and/or strengthening heart muscle contraction in heart failure.<ref>{{cite web |title=BNF (only available in the UK) |url=https://bnf.nice.org.uk/drugs/digoxin/#indications-and-dose |website=NICE |publisher=BMJ & Pharmaceutical Press |access-date=20 February 2023}}</ref>

===Medicinal uses===
Digitalis is an example of a drug derived from a plant that was formerly used by [[herbalist]]s; herbalists have largely abandoned its use because of its narrow [[therapeutic index]] and the difficulty of determining the amount of active drug in herbal preparations. Once the usefulness of digitalis in regulating the human pulse was understood, it was employed for a variety of purposes, including the treatment of [[epilepsy]] and other seizure disorders, which are now considered to be inappropriate treatments.

A group of medicines extracted from foxglove plants are called [[digitalin]]. The use of ''[[Digitalis purpurea|D. purpurea]]'' extract containing [[cardiac glycoside]]s for the treatment of heart conditions was first described in the English-speaking medical literature by [[William Withering]], in 1785,<ref>{{cite book | first1 = William | last1 = Withering | url = https://books.google.com/books?id=VgIta49rzT4C&pg=PR3 | title = An Account of the Foxglove and some of its Medical Uses | location = Birmingham, England | publisher = M. Swinney | date = 1785 }}</ref><ref>{{Cite journal|last1=Goldthorp |first1=W. O. |title=Medical Classics: An Account of the Foxglove and Some of its Medicinal Uses by William Withering, published 1785|journal=British Medical Journal |year=2009 |volume=338 |pages=b2189 |doi=10.1136/bmj.b2189 |s2cid=72429441}}</ref><ref>{{cite book|last1=Simpson |first1=Beryl Brintnall |last2=Ogorzaly |first2=Molly Coner |title=Economic Botany |date=2001 |publisher=Mc Graw Hill |location=Boston |isbn=9780072909388 |page=529 |edition=3rd}}</ref> which is considered the beginning of modern therapeutics. In contemporary medicine, digitalis (usually [[digoxin]]) is obtained from ''D. lanata''.<ref name="Hollman">{{cite journal |last1=Hollman |first1=A. |title=Drugs for atrial fibrillation. Digoxin comes from ''Digitalis lanata'' | journal = BMJ (Clinical Research Ed.) | volume = 312 | issue = 7035 | pages = 912 | date = April 1996 | pmid = 8611904 | pmc = 2350584 | doi = 10.1136/bmj.312.7035.912 }}</ref><ref name=Weisse2010>{{cite journal |last1=Weisse |first1=Allen B. |date=January 2010 |title=A Fond Farewell to the Foxglove? The Decline in the Use of Digitalis |journal=Journal of Cardiac Failure |volume=16 |issue=1 |pages=45–48 |doi=10.1016/j.cardfail.2009.08.001 |pmid=20123317|doi-access=free }}</ref> It is used to increase cardiac contractility (it is a positive [[inotrope]]) and as an [[antiarrhythmic agent]] to control the heart rate, particularly in the irregular (and often fast) [[atrial fibrillation]]. Digitalis is hence often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with [[congestive heart failure]]. Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of prospective, randomized study and clinical trials. It was also approved for the control of ventricular response rate for patients with atrial fibrillation. American College of Cardiology/American Heart Association guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function, preservation of systolic function, and/or rate control for atrial fibrillation with a rapid ventricular response. [[Heart Failure Society of America]] guidelines for heart failure provide similar recommendations. Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, the therapeutic use of digoxin is declining in patients with heart failure—likely the result of several factors. The main factor is the more recent introduction of several drugs shown in randomised controlled studies to improve outcomes in heart failure.<ref>{{cite web |last1=Anon. |title=Medications Used to Treat Heart Failure |url=https://www.heart.org/en/health-topics/heart-failure/treatment-options-for-heart-failure/medications-used-to-treat-heart-failure |website=www.heart.org |publisher=American Heart Association |access-date=13 August 2020 |language=en}}</ref> Safety concerns regarding a proposed link between digoxin therapy and increased mortality seen in observational studies may have contributed to the decline in therapeutic use of digoxin, however a systematic review of 75 studies including four million patient years of patient follow-up showed that in properly designed randomised controlled studies, mortality was no higher in patients given digoxin than in those given placebo.<ref>{{cite journal |last1=Ziff |first1=Oliver J. |last2=Lane |first2=Deirdre A. |last3=Samra |first3=Monica |last4=Griffith |first4=Michael |last5=Kirchhof |first5=Paulus |last6=Lip |first6=Gregory Y. H. |last7=Steeds |first7=Richard P. |last8=Townend |first8=Jonathan |last9=Kotecha |first9=Dipak |title=Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data |journal=British Medical Journal |language=en |doi=10.1136/bmj.h4451 |date=30 August 2015 |volume=351 |pages=h4451 |pmid=26321114 |pmc=4553205 |s2cid=9995597}}</ref>

[[Romani people]] use foxglove to treat eczema.<ref>{{cite book|url=https://books.google.com/books?id=WAagnZNb0cAC&dq=gypsies+foxglove+eczema&pg=PA129|title=Dictionary of Plant Lore|page=129|isbn=978-0-08-054602-5 |last1=Watts |first1=D. C. |date=2 May 2007 |publisher=Elsevier }}</ref>

====Variations====
[[File:Foxglove - Digitalis purpurea.jpg|thumb|Digitalis purpurea -- light purple]]
A group of pharmacologically active compounds are extracted mostly from the leaves of the second year's growth, and in pure form are referred to by common chemical names, such as [[digitoxin]] or [[digoxin]], or by brand names such as Crystodigin and Lanoxin, respectively. The two drugs differ in that digoxin has an additional [[hydroxyl]] group at the C-3 position on the B-ring (adjacent to the pentane). This results in digoxin having a half-life of about one day (and increasing with impaired kidney function), whereas digitoxin's is about 7 days and not affected by kidney function. Both molecules include a [[lactone]] and a triple-repeating sugar called a [[glycoside]].

====Mechanism of action====
Digitalis works by inhibiting [[sodium-potassium ATPase]]. This results in an increased intracellular concentration of sodium ions and thus a decreased concentration gradient across the cell membrane. This increase in intracellular sodium causes the Na/Ca exchanger to reverse potential, i.e., transition from pumping sodium into the cell in exchange for pumping calcium out of the cell, to pumping sodium out of the cell in exchange for pumping calcium into the cell. This leads to an increase in cytoplasmic calcium concentration, which improves cardiac contractility.<ref>{{cite journal |doi=10.1016/0165-6147(85)90136-1 |title=Sodium ion and the cardiac actions of digitalis |journal=Trends in Pharmacological Sciences |year=1985 |pages=296–298 |volume=6 |last1=Akera |first1=Tai |last2=Brody |first2=Theodore M.}}</ref> Under normal physiological conditions, the cytoplasmic calcium used in cardiac contractions originates from the [[sarcoplasmic reticulum]], an intracellular organelle that stores calcium. Human newborns, some animals, and patients with chronic heart failure lack well developed and fully functioning sarcoplasmic reticula and must rely on the Na/Ca exchanger to provide all or a majority of the cytoplasmic calcium required for cardiac contraction. For this to occur, cytoplasmic sodium must exceed its typical concentration to favour a reversal in potential, which naturally occurs in human newborns and some animals primarily through an elevated heart rate; in patients with chronic heart failure it occurs through the administration of digitalis. As a result of increased contractility, [[stroke volume]] is increased. Ultimately, digitalis increases cardiac output (cardiac output = stroke volume x heart rate). This is the mechanism that makes this drug a popular treatment for congestive heart failure, which is characterized by low cardiac output.

Digitalis also has a vagal effect on the [[parasympathetic nervous system]], and can be used to slow the ventricular rate during [[atrial fibrillation]] (unless there's [[Wolff–Parkinson–White syndrome|an accessory pathway]], when it can paradoxically increase the heart rate).<ref>{{cite journal |last1=Fuster |first1=Valentin |last2=Rydén |first2=Lars E. |last3=Asinger |first3=Richard W. |last4=Cannom |first4=David S. |last5=Crijns |first5=Harry J. |last6=Frye |first6=Robert L. |last7=Halperin |first7=Jonathan L. |last8=Kay |first8=G. Neal |last9=Klein |first9=Werner W. |last10=Lévy |first10=Samuel |last11=McNamara |first11=Robert L. |last12=Prystowsky |first12=Eric N. |last13=Wann |first13=L. Samuel |last14=Wyse |first14=D. George |last15=Gibbons |first15=Raymond J. |last16=Antman |first16=Elliott M. |last17=Alpert |first17=Joseph S. |last18=Faxon |first18=David P. |last19=Fuster |first19=Valentin |last20=Gregoratos |first20=Gabriel |last21=Hiratzka |first21=Loren F. |last22=Jacobs |first22=Alice K. |last23=Russell |first23=Richard O. |last24=Smith |first24=Sidney C. |last25=Klein |first25=Werner W. |last26=Alonso-Garcia |first26=Angeles |last27=Blomström-Lundqvist |first27=Carina |last28=de Backer |first28=Guy |last29=Flather |first29=Marcus |last30=Hradec |first30=Jaromir |last31=Oto |first31=Ali |last32=Parkhomenko |first32=Alexander |last33=Silber |first33=Sigmund |last34=Torbicki |first34=Adam |title=ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology |journal=Circulation |date=23 October 2001 |volume=104 |issue=17 |pages=2118–2150 |doi=10.1161/circ.104.17.2118 |pmid=11673357 |language=en |issn=0009-7322|doi-access=free }}</ref> The dependence on the vagal effect means digitalis is not effective when a patient has a high [[sympathetic nervous system]] drive, which is the case with acutely ill persons, and also during exercise.<ref>{{Cite journal |date=1985-05-01 |title=Digitalis and the autonomic nervous system |journal=Journal of the American College of Cardiology |language=en |volume=5 |issue=5 |pages=35A–42A |doi=10.1016/S0735-1097(85)80461-7 |issn=0735-1097 |last1=Watanabe |first1=August M. |pmid=3886751|doi-access=free }}</ref><ref>{{Cite journal |last1=Tonkon |first1=M. J. |last2=Lee |first2=G. |last3=DeMaria |first3=A. N. |last4=Miller |first4=R. R. |last5=Mason |first5=D. T. |date=December 1977 |title=Effects of digitalis on the exercise electrocardiogram in normal adult subjects |url=https://pubmed.ncbi.nlm.nih.gov/923306/ |journal=Chest |volume=72 |issue=6 |pages=714–718|doi=10.1378/chest.72.6.714 |issn=0012-3692 |pmid=923306}}</ref>

===Molecular probes===
[[Digoxigenin]] (DIG) is a steroid found in the flowers and leaves of ''Digitalis'' species, and is extracted from ''D. lanata''. Digoxigenin can be used as a [[molecular probe]] to detect [[mRNA]] in situ and label DNA, RNA, and [[oligonucleotides]].<ref name="Glick2018">{{cite book|last=Glick |first=Bernard R. |title=Methods in Plant Molecular Biology and Biotechnology |url=https://books.google.com/books?id=u0paDwAAQBAJ&pg=PA183 |date=4 May 2018 |publisher=CRC Press |isbn=978-1-351-09139-8 |pages=183}}</ref> It can easily be attached to nucleotides such as [[uridine]] by chemical modifications. DIG molecules are often linked to nucleotides; DIG-labelled uridine can then be incorporated into RNA via ''[[in vitro]]'' [[transcription (genetics)|transcription]]. Once [[Nucleic acid hybridization|hybridisation]] occurs, RNA with the incorporated DIG-U can be detected with anti-DIG [[antibodies]] conjugated to [[alkaline phosphatase]]. To reveal the hybridised transcripts, a [[chromogen]] can be used which reacts with the alkaline phosphatase to produce a coloured precipitate.<ref>{{Cite journal |last1=Lauter |first1=Gilbert |last2=Söll |first2=Iris |last3=Hauptmann |first3=Giselbert |date=2011-07-04 |title=Two-color fluorescent in situ hybridization in the embryonic zebrafish brain using differential detection systems |journal=BMC Developmental Biology |language=en |volume=11 |issue=1 |page=43 |doi=10.1186/1471-213X-11-43 |doi-access=free |pmid=21726453 |pmc=3141750 |issn=1471-213X }}</ref>