Editing Theophylline

{{Short description|Drug used to treat respiratory diseases}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{infobox drug
| Watchedfields      = changed
| verifiedrevid      = 470606142
| IUPAC_name         = 1,3-dimethyl-7H-purine-2,6-dione
| image              = Theophylline.svg
| image_class        = skin-invert-image
| width              = 150
| image2             = Theophylline 3D ball.png
| width2             = 180

<!--Clinical data-->| tradename          = Theolair, Slo-Bid
| Drugs.com          = {{drugs.com|monograph|theophyllines}}
| MedlinePlus        = a681006
| pregnancy_AU       = A
| pregnancy_AU_comment = {{citation needed|date=April 2015}}
| pregnancy_US       = C
| pregnancy_category = 
| legal_AU           = S4
| legal_CA           = Rx-only
| legal_UK           = P
| legal_US           = Rx-only
| legal_status       = 
| routes_of_administration = [[Oral administration|oral]], [[Intravenous therapy|IV]], [[Rectal administration|rectal]]

<!--Pharmacokinetic data-->| bioavailability    = 100% ([[Oral administration|oral]])
| protein_bound      = 40% (primarily to albumin)
| metabolism         = [[Liver|Hepatic]]: [[CYP1A2]], [[CYP2E1]], [[CYP3A4]]
| metabolites        = • 1,3-Dimethyluric acid <br> • 1-Methyixanthine<br> • 3-Methylxanthine
| elimination_half-life = 5–8 hours

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 58-55-9
| ATC_prefix         = R03
| ATC_suffix         = DA04
| ATC_supplemental   = R03DB04
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 28177
| PubChem            = 2153
| IUPHAR_ligand      = 413
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00277
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 2068
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 0I55128JYK
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D00371
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 190

<!--Chemical data-->| C                  = 7
| H                  = 8
| N                  = 4
| O                  = 2
| smiles             = Cn1c2c(c(=O)n(c1=O)C)[nH]cn2
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9)
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = ZFXYFBGIUFBOJW-UHFFFAOYSA-N
| drug_name          = 
| alt                = 
| caption            = 
| type               = 
| licence_EU         = 
| licence_US         = 
}}

[[File:Cylmin 100mg by Tsuruhara.jpg|thumb|right|upright|Theophylline extended-release tablets in Japan]]
'''Theophylline''', also known as '''1,3-dimethylxanthine''', is a drug that inhibits [[phosphodiesterase]] and blocks [[adenosine receptors]].<ref name="pubchem">{{cite web |title=Theophylline |url=https://pubchem.ncbi.nlm.nih.gov/compound/2153 |publisher=PubChem, US National Library of Medicine |access-date=2 September 2023 |date=26 August 2023}}</ref> It is used to treat [[chronic obstructive pulmonary disease]] (COPD) and [[asthma]].<ref name="barnes">{{cite journal | vauthors = Barnes PJ | title = Theophylline | journal = American Journal of Respiratory and Critical Care Medicine | volume = 188 | issue = 8 | pages = 901–906 | date = October 2013 | pmid = 23672674 | doi = 10.1164/rccm.201302-0388PP|url=https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP}}</ref> Its pharmacology is similar to other [[xanthine|methylxanthine]] drugs (e.g., [[theobromine]] and [[caffeine]]).<ref name=pubchem/> Trace amounts of theophylline are naturally present in [[tea]], [[coffee]], [[chocolate]], [[Yerba mate|yerba maté]], [[guarana]], and [[kola nut]].<ref name=pubchem/><ref>{{cite journal | vauthors = ((IARC Working Group on the Evaluation of Carcinogenic Risks to Humans)) | title = Coffee, Tea, Mate, Methylxanthines and Methylglyoxal. | journal = IARC Monographs on the Evaluation of Carcinogenic Risks to Humans | volume = 51 | pages = 391–419 | date = 1991 | pmid = 2033791 | pmc = 7681294 | url = https://www.ncbi.nlm.nih.gov/books/NBK507021/#:~:text=Theophylline%20is%20found%20in%20black,used%20principally%20in%20pharmaceutical%20preparations. | publisher = International Agency for Research on Cancer }}</ref>

The name 'theophylline' derives from "Thea"—the former genus name for [[Camellia sinensis|tea]] + Legacy Greek φύλλον (phúllon, "leaf") + -ine.

== Medical uses ==
The main actions of theophylline involve:<ref name=barnes/>
* relaxing bronchial [[smooth muscle]]
* increasing heart muscle contractility and efficiency (positive [[inotrope]])
* increasing heart rate (positive [[chronotropic]])
* increasing [[blood pressure]]
* increasing [[kidney|renal]] blood flow
* [[anti-inflammatory]] effects
* [[central nervous system]] stimulatory effect, mainly on the medullary [[respiratory center]]<ref>{{cite journal | vauthors = Eldridge FL, Millhorn DE, Kiley JP | title = Antagonism by theophylline of respiratory inhibition induced by adenosine | journal = Journal of Applied Physiology | volume = 59 | issue = 5 | pages = 1428–1433 | date = November 1985 | pmid = 4066573 | doi = 10.1152/jappl.1985.59.5.1428 }}</ref><ref>{{cite journal | vauthors = Elder HJ, Walentiny DM, Beardsley PM | title = Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids | journal = Pharmacology, Biochemistry, and Behavior | volume = 229 | pages = 173601 | date = August 2023 | pmid = 37414364 | pmc = 10599235 | doi = 10.1016/j.pbb.2023.173601 }}</ref>

The main therapeutic uses of theophylline are for treating:<ref name=barnes/>

* [[Chronic obstructive pulmonary disease]] (COPD)<ref>{{cite journal | vauthors = Mahemuti G, Zhang H, Li J, Tieliwaerdi N, Ren L | title = Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis | journal = Drug Design, Development and Therapy | volume = 12 | pages = 99–120 | date = 10 January 2018 | pmid = 29391776 | pmc = 5768195 | doi = 10.2147/DDDT.S156509 | doi-access = free }}</ref>
* [[Asthma]]
* [[Apnea of prematurity|infant apnea]]<ref>{{cite journal | vauthors = Miao Y, Zhou Y, Zhao S, Liu W, Wang A, Zhang Y, Li Y, Jiang H | title = Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis | journal = PLOS ONE | volume = 17 | issue = 9 | pages = e0274882 | date = 19 September 2022 | pmid = 36121807 | pmc = 9484669 | doi = 10.1371/journal.pone.0274882 | doi-access = free | bibcode = 2022PLoSO..1774882M }}</ref>
* Blocks the action of [[adenosine]]; an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.
* Treatment of post-dural puncture headache.<ref>{{cite journal | vauthors = Hung KC, Ho CN, Chen IW, Hung IY, Lin MC, Lin CM, Wang LK, Chen JY, Sun CK | title = The impact of aminophylline on incidence and severity of post-dural puncture headache: A meta-analysis of randomised controlled trials | journal = Anaesthesia, Critical Care & Pain Medicine | volume = 40 | issue = 4 | pages = 100920 | date = August 2021 | pmid = 34186265 | doi = 10.1016/j.accpm.2021.100920 | s2cid = 235686558 }}</ref><ref>{{cite journal | vauthors = Barati-Boldaji R, Shojaei-Zarghani S, Mehrabi M, Amini A, Safarpour AR | title = Post-dural puncture headache prevention and treatment with aminophylline or theophylline: a systematic review and meta-analysis | journal = Anesthesia and Pain Medicine | volume = 18 | issue = 2 | pages = 177–189 | date = April 2023 | pmid = 37183286 | doi = 10.17085/apm.22247 | pmc = 10183611 }}</ref>

== Performance enhancement in sports ==
Theophylline and other methylxanthines are often used for their performance-enhancing effects in sports, as these drugs increase alertness, bronchodilation, and increase the rate and force of heart contraction.<ref>{{cite journal | vauthors = Watson CJ, Stone GL, Overbeek DL, Chiba T, Burns MM | title = Performance-enhancing drugs and the Olympics | journal = Journal of Internal Medicine | volume = 291 | issue = 2 | pages = 181–196 | date = February 2022 | pmid = 35007384 | doi = 10.1111/joim.13431 | s2cid = 245855348 }}</ref> There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against [[Exercise-induced bronchoconstriction | exercise-induced asthma]].<ref>{{cite journal | vauthors = Pigakis KM, Stavrou VT, Pantazopoulos I, Daniil Z, Kontopodi AK, Gourgoulianis K | title = Exercise-Induced Bronchospasm in Elite Athletes | journal = Cureus | volume = 14 | issue = 1 | pages = e20898 | date = January 2022 | pmid = 35145802 | doi = 10.7759/cureus.20898 | doi-access = free | pmc = 8807463 }}</ref>

==Adverse effects==
The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow [[therapeutic window]] (<20 mcg/mL).<ref name=barnes/> Its use must be monitored by direct measurement of serum theophylline levels to avoid [[toxicity]]. It can also cause nausea, diarrhea, increase in heart rate, [[Heart arrhythmia|abnormal heart rhythms]], and CNS excitation (headaches, [[insomnia]], irritability, [[dizziness]] and [[lightheadedness]]).<ref name=barnes/><ref>{{Cite web|url=https://medlineplus.gov/druginfo/meds/a681006.html|archive-url=https://web.archive.org/web/20160705111407/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681006.html |title=Theophylline | work = MedlinePlus Drug Information|archive-date=July 5, 2016| publisher = U.S. National Library of Medicine }}</ref> [[Seizure]]s can also occur in severe cases of toxicity, and are considered to be a neurological emergency.<ref name=barnes/> 

Its toxicity is increased by [[erythromycin]], cimetidine, and [[fluoroquinolones]], such as [[ciprofloxacin]]. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called [[dose dumping]], but this does not occur with most formulations of theophylline.<ref>{{cite journal | vauthors = Hendeles L, Weinberger M, Milavetz G, Hill M, Vaughan L | title = Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity | journal = Chest | volume = 87 | issue = 6 | pages = 758–765 | date = June 1985 | pmid = 3996063 | doi = 10.1378/chest.87.6.758 | s2cid = 1133968 }}</ref> Theophylline toxicity can be treated with [[beta blocker]]s. In addition to seizures, tachyarrhythmias are a major concern.<ref>{{cite journal | vauthors = Seneff M, Scott J, Friedman B, Smith M | title = Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability | journal = Annals of Emergency Medicine | volume = 19 | issue = 6 | pages = 671–673 | date = June 1990 | pmid = 1971502 | doi = 10.1016/s0196-0644(05)82474-6 }}</ref> Theophylline should not be used in combination with the [[Selective serotonin reuptake inhibitor|SSRI]] [[fluvoxamine]].<ref>{{cite journal | vauthors = DeVane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS | title = Fluvoxamine-induced theophylline toxicity | journal = The American Journal of Psychiatry | volume = 154 | issue = 9 | pages = 1317–1318 | date = September 1997 | pmid = 9286199 | doi = 10.1176/ajp.154.9.1317b | doi-access =  }}</ref><ref>{{cite journal | vauthors = Sperber AD | title = Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy | journal = Drug Safety | volume = 6 | issue = 6 | pages = 460–462 | date = November 1991 | pmid = 1793525 | doi = 10.2165/00002018-199106060-00006 | s2cid = 21875026 }}</ref>

== Spectroscopy ==
=== UV-visible  ===
Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277&nbsp;nm with an extinction coefficient of 10,200 (cm<sup>−1</sup> M<sup>−1</sup>).<ref name="pmid15392550">{{cite journal | vauthors = Schack JA, Waxler SH | title = An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 97 | issue = 3 | pages = 283–291 | date = November 1949 | pmid = 15392550 | doi =  }}</ref>

=== Proton NMR ===
The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions.<ref name="pmid27320965">{{cite journal | vauthors = Shelke RU, Degani MS, Raju A, Ray MK, Rajan MG | title = Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors | journal = Archiv der Pharmazie | volume = 349 | issue = 8 | pages = 602–613 | date = August 2016 | pmid = 27320965 | doi = 10.1002/ardp.201600066 | s2cid = 40014874 }}</ref>

=== <sup>13</sup>C-NMR ===
The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone.<ref>{{cite journal | vauthors = Pfleiderer W | title = Pteridines. Part CXIX. A New Pteridine–Purine Transformation. | journal = Helvetica Chimica Acta | date = February 2008 | volume = 91 | issue = 2 | pages = 338–353 | doi = 10.1002/hlca.200890039 }}</ref>

== Natural occurrences ==
Theophylline is naturally found in [[cocoa bean]]s. Amounts as high as 3.7&nbsp;mg/g have been reported in [[Criollo (cocoa bean)|Criollo]] cocoa beans.<ref name="ApgarTarka">{{Cite book | title = Caffeine | chapter = Methylxanthine composition and consumption patterns of cocoa and chocolate products and their uses | vauthors = Apgar JL, Tarka Jr SM | veditors = Spiller GA | publisher = CRC Press | year = 1998 | isbn = 978-0-8493-2647-9 | page = 171 | chapter-url = https://books.google.com/books?id=WxmBmvhsoZ8C&pg=PA171 | access-date = 2013-11-10 }}</ref>

Trace amounts of theophylline are also found in brewed [[tea]], although brewed tea provides only about 1&nbsp;mg/L,<ref>{{cite web | title = TABLE 2a: Concentrations of caffeine, theobromine and theophylline in tea products. | work = Food Surveillance Information Sheet Number 103 | publisher = MAFF, Department of Health and the Scottish Executive | url = http://archive.food.gov.uk/maff/archive/food/infsheet/1997/no103/table2a.htm | archive-url = https://web.archive.org/web/20060927200412/http://archive.food.gov.uk/maff/archive/food/infsheet/1997/no103/table2a.htm | archive-date=2006-09-27 }}</ref> which is significantly less than a therapeutic dose.

Trace amounts of theophylline are also found in guarana (''[[Paullinia cupana]]'') and in [[cola (plant)|kola nuts]].<ref name="pmid4013524">{{cite journal | vauthors = Belliardo F, Martelli A, Valle MG | title = HPLC determination of caffeine and theophylline in Paullinia cupana Kunth (guarana) and Cola spp. samples | journal = Zeitschrift für Lebensmittel-Untersuchung und -Forschung | volume = 180 | issue = 5 | pages = 398–401 | date = May 1985 | pmid = 4013524 | doi = 10.1007/BF01027774 | s2cid = 40205323 }}</ref>

==Pharmacology==
===Pharmacodynamics===
Like other methylated [[xanthine|xanthine derivatives]], theophylline is both a

# competitive nonselective [[phosphodiesterase inhibitor]] which increases intracellular levels of [[Cyclic adenosine monophosphate|cAMP]] and [[Cyclic guanosine monophosphate|cGMP]],<ref name=barnes/><ref name="PDEs-Essayan">{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–680 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | doi-access = free }}</ref> activates [[cAMP-dependent protein kinase|PKA]], [[TNF inhibitor|inhibits TNF-alpha]]<ref name="PTX-Deree">{{cite journal | vauthors = Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R | title = Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition | journal = Clinics | volume = 63 | issue = 3 | pages = 321–328 | date = June 2008 | pmid = 18568240 | pmc = 2664230 | doi = 10.1590/S1807-59322008000300006 }}</ref><ref name="pmid9927365">{{cite journal | vauthors = Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U | title = Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages | journal = American Journal of Respiratory and Critical Care Medicine | volume = 159 | issue = 2 | pages = 508–511 | date = February 1999 | pmid = 9927365 | doi = 10.1164/ajrccm.159.2.9804085 }}</ref> and inhibits [[leukotriene]]<ref name="LT-Peters-Golden">{{cite journal | vauthors = Peters-Golden M, Canetti C, Mancuso P, Coffey MJ | title = Leukotrienes: underappreciated mediators of innate immune responses | journal = Journal of Immunology | volume = 174 | issue = 2 | pages = 589–594 | date = January 2005 | pmid = 15634873 | doi = 10.4049/jimmunol.174.2.589 | doi-access = free }}</ref> synthesis, and [[Anti-inflammatory|reduces inflammation]] and [[innate immunity]]<ref name="LT-Peters-Golden"/>
# nonselective [[adenosine receptor]] antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.<ref name=barnes/><ref name="AR-Daly">{{cite journal | vauthors = Daly JW, Jacobson KA, Ukena D | title = Adenosine receptors: development of selective agonists and antagonists | journal = Progress in Clinical and Biological Research | volume = 230 | issue = 1 | pages = 41–63 | year = 1987 | pmid = 3588607 }}</ref> Theophylline activates [[histone deacetylase]]s.<ref name=barnes/>

===Pharmacokinetics===
====Distribution====
Theophylline is distributed in the extracellular fluid, in the placenta, in the mother's milk and in the central nervous system. The volume of distribution is 0.5 L/kg. The protein binding is 40%.{{medical citation needed|date=September 2023}}

====Metabolism====
Theophylline is metabolized extensively in the liver.<ref name=barnes/> It undergoes [[N-demethylation|''N''-demethylation]] via [[cytochrome]] P450 [[CYP1A2|1A2]]. It is metabolized by parallel [[Order of reaction|first order]] and [[Michaelis-Menten kinetics|Michaelis-Menten]] pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration. [[Methylation]] to caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently.<ref name=barnes/> Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.<ref>{{cite journal | vauthors = Jenne JW, Nagasawa HT, Thompson RD | title = Relationship of urinary metabolites of theophylline to serum theophylline levels | journal = Clinical Pharmacology and Therapeutics | volume = 19 | issue = 3 | pages = 375–381 | date = March 1976 | pmid = 1261172 | doi = 10.1002/cpt1976193375 | s2cid = 33943915 }}</ref><ref>{{cite journal | vauthors = Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM | title = Enhanced biotransformation of theophylline in marihuana and tobacco smokers | journal = Clinical Pharmacology and Therapeutics | volume = 24 | issue = 4 | pages = 405–410 | date = October 1978 | pmid = 688731 | doi = 10.1002/cpt1978244406 | s2cid = 44613672 }}</ref>

====Excretion====
Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in children (age 1 to 12), teenagers (12 to 16), adult smokers, elderly smokers, as well as in [[cystic fibrosis]], and [[hyperthyroidism]]. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.<ref name=barnes/>

The elimination [[half-life]] varies: 30 hours for premature neonates, 24 hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for adult non-smokers, 5 hours for adult smokers, 24 hours for those with [[hepatic impairment]], 12 hours for those with congestive heart failure [[NYHA]] class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.{{medical citation needed|date=February 2022}}

==History==
Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist [[Albrecht Kossel]].<ref>{{cite journal | vauthors = Kossel A | title = Über eine neue Base aus dem Pflanzenreich | trans-title = About a new base from the plant kingdom | language = de | journal = Berichte der Deutschen Chemischen Gesellschaft | trans-journal = Reports of the German Chemical Society | volume = 21 | pages = 2164–2167 | year = 1888 | doi = 10.1002/cber.188802101422 | url = https://zenodo.org/record/1425531 }}</ref><ref>{{cite journal | vauthors = Kossel A | title = Über das Theophyllin, einen neuen Bestandtheil des Thees | trans-title = On theophylline, a new component of tea | language = de | journal = Hoppe-Seyler's Zeitschrift für Physiologische Chemie | trans-journal = Hoppe-Seyler's Journal of Physiological Chemistry | volume = 13 | pages = 298–308 | year = 1889 }}</ref> Seven years later, a [[chemical synthesis]] starting with 1,3-dimethyluric acid was described by [[Hermann Emil Fischer|Emil Fischer]] and [[Lorenz Ach]].<ref>{{cite journal |vauthors=Fischer E, Ach L | title = Synthese des Caffeins | trans-title =Synthesis of caffeine | language = de | journal = Berichte der Deutschen Chemischen Gesellschaft | trans-journal = Reports of the German Chemical Society | volume = 28 | issue = 3| page = 3139 | year = 1895 | doi=10.1002/cber.189502803156}}</ref> The [[Traube purine synthesis]], an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, [[Wilhelm Traube]].<ref name="Traube2">{{cite journal | vauthors = Traube W | title = Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure | trans-title = The synthetic structure of uric acid, xanthine, theobromine, theophylline and caffeine from cyanoacetic acid | language = de| journal = Berichte der Deutschen Chemischen Gesellschaft | trans-journal = Reports of the German Chemical Society | volume = 33 | issue = 3 | pages = 3035–3056 | year = 1900 | doi = 10.1002/cber.19000330352 | url = https://zenodo.org/record/1425990 }}</ref> Theophylline's first clinical use came in 1902 as a [[diuretic]].<ref>{{cite journal | vauthors = Minkowski O | title = Über Theocin (Theophyllin) als Diureticum | trans-title = About theocine (theophylline) as a diuretic | language = de | journal = Therapie der Gegenwart | trans-journal = Therapy of the Present | volume = 43 | pages = 490–493 | year = 1902 }}</ref> It took an additional 20 years until it was first reported as an asthma treatment.<ref>{{cite journal | vauthors = Schultze-Werninghaus G, Meier-Sydow J | title = The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S. R. Hirsch in Frankfurt (Main) 1922 | journal = Clinical Allergy | volume = 12 | issue = 2 | pages = 211–215 | date = March 1982 | pmid = 7042115 | doi = 10.1111/j.1365-2222.1982.tb01641.x | s2cid = 38178598 }}</ref> The drug was prescribed in a [[syrup]] up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron. 

==See also==
* [[Theophylline/ephedrine]]

== References ==
{{Reflist}}

== External links ==
* {{Commons category inline}}

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[[Category:Drugs developed by Merck]]
[[Category:Histone Acetyltransferase Inhibitor]]
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[[Category:Phosphodiesterase inhibitors]]
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[[Category:Wakefulness-promoting agents]]
[[Category:Xanthines]]