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Theophylline
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<h2 id="medical-uses">Medical uses</h2> <p>The main actions of theophylline involve:<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p> <ul><li>relaxing bronchial <a href="/facts/Smooth_muscle/mpcpTsHp">smooth muscle</a></li> <li>increasing heart muscle contractility and efficiency (positive <a href="/facts/Inotrope/A58XE1pa">inotrope</a>)</li> <li>increasing heart rate (positive <a href="/facts/Chronotropic/hRj7pBIC">chronotropic</a>)</li> <li>increasing <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a></li> <li>increasing <a href="/facts/Kidney/HBspPrv9">renal</a> blood flow</li> <li><a href="/facts/Anti-inflammatory/W27poSUd">anti-inflammatory</a> effects</li> <li><a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> stimulatory effect, mainly on the medullary <a href="/facts/Respiratory_center/PPxQf431">respiratory center</a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li></ul> <p>The main therapeutic uses of theophylline are for treating:<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <ul><li><a href="/facts/Chronic_obstructive_pulmonary_disease/ud3oXGCr">Chronic obstructive pulmonary disease</a> (COPD)<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li> <li><a href="/facts/Asthma/7GkJvxn3">Asthma</a></li> <li><a href="/facts/Apnea_of_prematurity/HUEM8dbD">infant apnea</a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a></li> <li>Blocks the action of <a href="/facts/Adenosine/MwyTJ2wR">adenosine</a>; an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.</li> <li>Treatment of post-dural puncture headache.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a></li></ul> <h2 id="performance-enhancement-in-sports">Performance enhancement in sports</h2> <p>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.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against <a href="/facts/Exercise-induced_bronchoconstriction/8tJSl7pv"> exercise-induced asthma</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="adverse-effects">Adverse effects</h2> <p>The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow <a href="/facts/Therapeutic_window/h311pqE5">therapeutic window</a> (<20 mcg/mL).<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Its use must be monitored by direct measurement of serum theophylline levels to avoid <a href="/facts/Toxicity/qa96rs60">toxicity</a>. It can also cause nausea, diarrhea, increase in heart rate, <a href="/facts/Heart_arrhythmia/ooEpr46Q">abnormal heart rhythms</a>, and CNS excitation (headaches, <a href="/facts/Insomnia/C1TnQTb2">insomnia</a>, irritability, <a href="/facts/Dizziness/eI8UvmS5">dizziness</a> and <a href="/facts/Lightheadedness/Gcuruugy">lightheadedness</a>).<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> <a href="/facts/Seizure/zuIrQyze">Seizures</a> can also occur in severe cases of toxicity, and are considered to be a neurological emergency.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p><p>Its toxicity is increased by <a href="/facts/Erythromycin/dPt7avsU">erythromycin</a>, cimetidine, and <a href="/facts/Fluoroquinolones/1jRTHzYW">fluoroquinolones</a>, such as <a href="/facts/Ciprofloxacin/RNAy8SHB">ciprofloxacin</a>. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called <a href="/facts/Dose_dumping/cGy0KqfL">dose dumping</a>, but this does not occur with most formulations of theophylline.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Theophylline toxicity can be treated with <a href="/facts/Beta_blocker/PRsWgpLV">beta blockers</a>. In addition to seizures, tachyarrhythmias are a major concern.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Theophylline should not be used in combination with the <a href="/facts/Selective_serotonin_reuptake_inhibitor/L6jjcmEH">SSRI</a> <a href="/facts/Fluvoxamine/1wmv6FLh">fluvoxamine</a>.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="spectroscopy">Spectroscopy</h2> <h3>UV-visible</h3> <p>Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1).<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h3>Proton NMR</h3> <p>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.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h3>13C-NMR</h3> <p>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.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="natural-occurrences">Natural occurrences</h2> <p>Theophylline is naturally found in <a href="/facts/Cocoa_bean/cAdQvQxy">cocoa beans</a>. Amounts as high as 3.7 mg/g have been reported in <a href="/facts/Criollo_(cocoa_bean)/cAdQvQxy">Criollo</a> cocoa beans.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p><p>Trace amounts of theophylline are also found in brewed <a href="/facts/Tea/oDQhcyrc">tea</a>, although brewed tea provides only about 1 mg/L,<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> which is significantly less than a therapeutic dose. </p><p>Trace amounts of theophylline are also found in guarana (<i><a href="/facts/Paullinia_cupana/PLLKGukE">Paullinia cupana</a></i>) and in <a href="/facts/Cola_(plant)/Io4FN1Sg">kola nuts</a>.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p> <h2 id="pharmacology">Pharmacology</h2> <h3>Pharmacodynamics</h3> <p>Like other methylated <a href="/facts/Xanthine/3ARA2QCg">xanthine derivatives</a>, theophylline is both a </p> <ol><li>competitive nonselective <a href="/facts/Phosphodiesterase_inhibitor/QIXRfPcb">phosphodiesterase inhibitor</a> which increases intracellular levels of <a href="/facts/Cyclic_adenosine_monophosphate/flK2vwUe">cAMP</a> and <a href="/facts/Cyclic_guanosine_monophosphate/zsge65d9">cGMP</a>,<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> activates <a href="/facts/CAMP-dependent_protein_kinase/kaKoYfbp">PKA</a>, <a href="/facts/TNF_inhibitor/LS7R0oA1">inhibits TNF-alpha</a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> and inhibits <a href="/facts/Leukotriene/PxNEg3IS">leukotriene</a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> synthesis, and <a href="/facts/Anti-inflammatory/W27poSUd">reduces inflammation</a> and <a href="/facts/Innate_immunity/lz4BpSQI">innate immunity</a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a></li> <li>nonselective <a href="/facts/Adenosine_receptor/TjlLlUD0">adenosine receptor</a> antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> Theophylline activates <a href="/facts/Histone_deacetylase/P38q78aV">histone deacetylases</a>.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li></ol> <h3>Pharmacokinetics</h3> <h4>Distribution</h4> <p>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%.[<i>medical citation needed</i>] </p> <h4>Metabolism</h4> <p>Theophylline is metabolized extensively in the liver.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> It undergoes <a href="/facts/N-demethylation/AvM5BLjD"><i>N</i>-demethylation</a> via <a href="/facts/Cytochrome/VF51IeGv">cytochrome</a> P450 <a href="/facts/CYP1A2/U69VPyRC">1A2</a>. It is metabolized by parallel <a href="/facts/Order_of_reaction/VK18zUhN">first order</a> and <a href="/facts/Michaelis-Menten_kinetics/lYFykW3p">Michaelis-Menten</a> pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration. <a href="/facts/Methylation/EvDMWVW5">Methylation</a> to caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> </p> <h4>Excretion</h4> <p>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 <a href="/facts/Cystic_fibrosis/tlNK5BAH">cystic fibrosis</a>, and <a href="/facts/Hyperthyroidism/H9Eqmbgk">hyperthyroidism</a>. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> </p><p>The elimination <a href="/facts/Half-life/kGVH8BAB">half-life</a> 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 <a href="/facts/Hepatic_impairment/NHtuS0gU">hepatic impairment</a>, 12 hours for those with congestive heart failure <a href="/facts/NYHA/l2TewHQH">NYHA</a> class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.[<i>medical citation needed</i>] </p> <h2 id="history">History</h2> <p>Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist <a href="/facts/Albrecht_Kossel/Q5Qe7Dyl">Albrecht Kossel</a>.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> Seven years later, a <a href="/facts/Chemical_synthesis/3KXsVVwC">chemical synthesis</a> starting with 1,3-dimethyluric acid was described by <a href="/facts/Hermann_Emil_Fischer/5wxbfBtu">Emil Fischer</a> and Lorenz Ach.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> The <a href="/facts/Traube_purine_synthesis/9ogLp0Wc">Traube purine synthesis</a>, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, <a href="/facts/Wilhelm_Traube/FSdg9ATI">Wilhelm Traube</a>.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> Theophylline's first clinical use came in 1902 as a <a href="/facts/Diuretic/x3j4I1Tg">diuretic</a>.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> It took an additional 20 years until it was first reported as an asthma treatment.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> The drug was prescribed in a <a href="/facts/Syrup/sYS48lTx">syrup</a> up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron. </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Theophylline%2fephedrine/vdW17Hho">Theophylline/ephedrine</a></li></ul> <h2 id="external-links">External links</h2> <ul><li> Media related to Theophylline at Wikimedia Commons</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Theophylline". PubChem, US National Library of Medicine. 26 August 2023. Retrieved 2 September 2023. <a href="https://pubchem.ncbi.nlm.nih.gov/compound/2153" target="_blank">https://pubchem.ncbi.nlm.nih.gov/compound/2153</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674. <a href="https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP" target="_blank">https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>"Theophylline". PubChem, US National Library of Medicine. 26 August 2023. Retrieved 2 September 2023. <a href="https://pubchem.ncbi.nlm.nih.gov/compound/2153" target="_blank">https://pubchem.ncbi.nlm.nih.gov/compound/2153</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"Theophylline". PubChem, US National Library of Medicine. 26 August 2023. Retrieved 2 September 2023. <a href="https://pubchem.ncbi.nlm.nih.gov/compound/2153" target="_blank">https://pubchem.ncbi.nlm.nih.gov/compound/2153</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1991). "Coffee, Tea, Mate, Methylxanthines and Methylglyoxal". IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 51. International Agency for Research on Cancer: 391–419. PMC 7681294. PMID 2033791. <a href="https://www.ncbi.nlm.nih.gov/books/NBK507021/#:~:text=Theophylline%20is%20found%20in%20black,used%20principally%20in%20pharmaceutical%20preparations." target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK507021/#:~:text=Theophylline%20is%20found%20in%20black,used%20principally%20in%20pharmaceutical%20preparations.</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674. <a href="https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP" target="_blank">https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Eldridge FL, Millhorn DE, Kiley JP (November 1985). "Antagonism by theophylline of respiratory inhibition induced by adenosine". Journal of Applied Physiology. 59 (5): 1428–1433. doi:10.1152/jappl.1985.59.5.1428. PMID 4066573. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Elder HJ, Walentiny DM, Beardsley PM (August 2023). "Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids". Pharmacology, Biochemistry, and Behavior. 229: 173601. doi:10.1016/j.pbb.2023.173601. PMC 10599235. PMID 37414364. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599235" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599235</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674. <a href="https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP" target="_blank">https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Mahemuti G, Zhang H, Li J, Tieliwaerdi N, Ren L (10 January 2018). "Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis". Drug Design, Development and Therapy. 12: 99–120. doi:10.2147/DDDT.S156509. PMC 5768195. PMID 29391776. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768195" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768195</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Miao Y, Zhou Y, Zhao S, Liu W, Wang A, Zhang Y, et al. (19 September 2022). "Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis". PLOS ONE. 17 (9): e0274882. Bibcode:2022PLoSO..1774882M. doi:10.1371/journal.pone.0274882. PMC 9484669. PMID 36121807. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484669" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484669</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Hung KC, Ho CN, Chen IW, Hung IY, Lin MC, Lin CM, et al. (August 2021). "The impact of aminophylline on incidence and severity of post-dural puncture headache: A meta-analysis of randomised controlled trials". Anaesthesia, Critical Care & Pain Medicine. 40 (4): 100920. doi:10.1016/j.accpm.2021.100920. PMID 34186265. S2CID 235686558. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Barati-Boldaji R, Shojaei-Zarghani S, Mehrabi M, Amini A, Safarpour AR (April 2023). "Post-dural puncture headache prevention and treatment with aminophylline or theophylline: a systematic review and meta-analysis". Anesthesia and Pain Medicine. 18 (2): 177–189. doi:10.17085/apm.22247. PMC 10183611. PMID 37183286. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183611" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183611</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Watson CJ, Stone GL, Overbeek DL, Chiba T, Burns MM (February 2022). "Performance-enhancing drugs and the Olympics". Journal of Internal Medicine. 291 (2): 181–196. doi:10.1111/joim.13431. PMID 35007384. S2CID 245855348. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Pigakis KM, Stavrou VT, Pantazopoulos I, Daniil Z, Kontopodi AK, Gourgoulianis K (January 2022). "Exercise-Induced Bronchospasm in Elite Athletes". Cureus. 14 (1): e20898. doi:10.7759/cureus.20898. PMC 8807463. PMID 35145802. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807463" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807463</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674. <a href="https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP" target="_blank">https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID 23672674. <a href="https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP" target="_blank">https://www.atsjournals.org/doi/10.1164/rccm.201302-0388PP</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>"Theophylline". MedlinePlus Drug Information. U.S. National Library of Medicine. Archived from the original on July 5, 2016. <a href="https://web.archive.org/web/20160705111407/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681006.html" target="_blank">https://web.archive.org/web/20160705111407/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681006.html</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. 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