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a colorless crystalline alkaloid derived from tea leaves or made synthetically; used in medicine as a bronchial dilator (同)Elixophyllin, Slo-Bid, Theobid

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/12 06:36:49」(JST)

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Theophylline extended-release tablets in Japan

Theophylline, also known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine.

Natural occurrences[edit]

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.^[1]

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L,^[2] which is significantly less than a therapeutic dose.

Medical uses[edit]

The main actions of theophylline involve:

relaxing bronchial smooth muscle
increasing heart muscle contractility and efficiency; as a positive inotropic
increasing heart rate: (positive chronotropic)^[3]
increasing blood pressure
increasing renal blood flow
anti-inflammatory effects
central nervous system stimulatory effect mainly on the medullary respiratory center.

The main therapeutic uses of theophylline are aimed at:

chronic obstructive pulmonary disease (COPD)
asthma
infant apnea
Blocks the action of adenosine, an inhibitor neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.

Uses under investigation[edit]

A clinical study reported in 2008 that theophylline was helpful in improving the sense of smell in study subjects with anosmia.^[4]

Adverse effects[edit]

The use of theophylline is complicated by its interaction with various drugs, chiefly cimetidine and phenytoin, and that it has a narrow therapeutic index, so, as in the case with many other asthma drugs, its use must be monitored to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, arrhythmias, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness).^[5]^[6] Seizures can also occur in severe cases of toxicity and is considered to be a neurological emergency.^[7] Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. It can reach toxic levels when taken with fatty meals, an effect called dose dumping.^[8] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.^[9]

Mechanisms of action[edit]

Like other methylated xanthine derivatives, theophylline is both a

competitive nonselective phosphodiesterase inhibitor,^[10] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha ^[11]^[12] and inhibits leukotriene ^[13] synthesis, and reduces inflammation and innate immunity ^[13]
nonselective adenosine receptor antagonist,^[14] antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects

Theophylline has been shown to inhibit TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD and asthma via cAMP-PKA pathway and suppresses COL1 mRNA, which codes for the protein collagen.^[15]

It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics that are active smokers (a condition resulting in oxidative stress) via a distinctly separate mechanism. Theophylline in vitro can restore the reduced HDAC (histone deacetylase) activity that is induced by oxidative stress (i.e., in smokers), returning steroid responsiveness toward normal.^[16] Furthermore, theophylline has been shown to directly activate HDAC2.^[16] (Corticosteroids switch off the inflammatory response by blocking the expression of inflammatory mediators through deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity. It has recently been shown that the oxidative stress associated with cigarette smoke can inhibit the activity of HDAC2, thereby blocking the anti-inflammatory effects of corticosteroids.) Thus theophylline could prove to be a novel form of adjunct therapy in improving the clinical response to steroids in smoking asthmatics.^{[citation needed]}The use of theophylline is complicated by its interaction with various drugs, chiefly cimetidine and phenytoin, and that it has a narrow therapeutic index, so, as in the case with many other asthma drugs, its use must be monitored to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, arrhythmias, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness).[5][6] Seizures can also occur in severe cases of toxicity and is considered to be a neurological emergency.[7] Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. It can reach toxic levels when taken with fatty meals, an effect called dose dumping.[8] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[9]

Pharmacokinetics[edit]

Absorption[edit]

When theophylline is administered intravenously, bioavailability is 100%, as with all intravenously administered drugs. However, if taken orally, taking the drug late in the evening may slow the absorption process, without affecting the bioavailability.^{[citation needed]}

Distribution[edit]

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%. The volume of distribution may increase in neonates and those suffering from cirrhosis or malnutrition, whereas the volume of distribution may decrease in those who are obese.

Metabolism[edit]

Theophylline is metabolized extensively in the liver (up to 70%). It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and 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. Both THC and nicotine have been shown to increase the rate of theophylline metabolism.^[17]

Elimination[edit]

Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in these conditions: children 1 to 12, teenagers 12 to 16, adult smokers, elderly smokers, cystic fibrosis, hyperthyroidism. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illness.

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.

History[edit]

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel.^[18]^[19] Just seven years after its discovery, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.^[20] The Traube synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube.^[21] Theophylline's first clinical use came in 1902 as diuretic.^[22] It took an additional 20 years until its first description in asthma treatment.^[23] The drug was prescribed in a liquid syrup by the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron.

Synthesis[edit]

Theophylline can be prepared synthetically starting from dimethylurea and ethyl 2-cyanoacetate.

References[edit]

^ Apgar, Joan L.; Tarka, Jr., Stanly M. (1998). "Methylxanthine composition and consumption patterns of cocoa and chocolate products". In Gene A. Spiller. Caffeine. CRC Press. p. 171. ISBN 0-8493-2647-8
^ MAFF Food Surveillance Information Sheet
^ Alboni et al. Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome The THEOPACE Study: A Randomized Controlled Trial
^ For Some Who Have Lost Their Sense Of Smell, A Once Popular Asthma Drug Could Help. Science Daily, American Physiological Society
^ MedlinePlus Drug Information: Theophylline
^ THEOPHYLLINE - ORAL 24 HOUR TABLET (Uni-Dur) side effects, medical uses, and drug interactions
^ Yoshikawa H (Apr 2007). "First-line therapy for theophylline-associated seizures.". Acta Neurol Scand 115 (4 Suppl): 57–61. doi:10.1111/j.1600-0404.2007.00810.x. PMID 17362277.
^ Hendeles L, Weinberger M, Milavetz G, Hill M, Vaughan L (1985). "Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity". Chest 87 (6): 758–65. doi:10.1378/chest.87.6.758. PMID 3996063.
^ Seneff M, Scott J, Friedman B, Smith M (1990). "Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability". Annals of emergency medicine 19 (6): 671–3. PMID 1971502.
^ Essayan DM (2001). "Cyclic nucleotide phosphodiesterases". J Allergy Clin Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (2008). "Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition". Clinics (Sao Paulo). 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. PMID 9927365.
^ ^a ^b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". J Immunol. 174 (2): 589–94. PMID 15634873.
^ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.
^ Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, Takimoto T, Hirata H, Kijima T (2006). "Anti-fibrotic effects of theophylline on lung fibroblasts". Biochemical and Biophysical Research Communications 341 (3): 684–90. doi:10.1016/j.bbrc.2006.01.018. PMID 16430859.
^ ^a ^b Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002). "A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression". Proceedings of the National Academy of Sciences of the United States of America 99 (13): 8921–6. doi:10.1073/pnas.132556899. PMC 124399. PMID 12070353.
^ "RxList Marinol Interactions". 5/29/2008. Retrieved 2/06/2013.
^ Kossel A (1888). "Über eine neue Base aus dem Pflanzenreich". Ber. Dtsch. Chem. Ges. 21: 2164–2167. doi:10.1002/cber.188802101422.
^ Kossel A (1889). "Über das Theophyllin, einen neuen Bestandtheil des Thees". Hoppe Seylers Z. Physiol. Chem. 13: 298–308.
^ Fischer E, Ach L (1895). "Synthese des Caffeins". Ber. Dtsch. Chem. Ges. 28: 3139.
^ Traube W (1900). "Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure]". Chem. Ber. 33 (3): 3035–3056. doi:10.1002/cber.19000330352.
^ Minkowski O (1902). "Über Theocin (Theophyllin) als Diureticum". Ther. Gegenwart 43: 490–493.
^ Schultze-Werninghaus G, Meier-Sydow J (1982). "The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S. R. Hirsch in Frankfurt (Main) 1922". Clin. Allergy 12 (2): 211–215. doi:10.1111/j.1365-2222.1982.tb01641.x. PMID 7042115. .

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UpToDate Contents

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1. 喘息におけるテオフィリン使用 theophylline use in asthma
2. テオフィリン中毒 theophylline poisoning
3. 慢性閉塞性肺疾患（COPD）治療におけるメチルキサンチンの役割 role of methylxanthines in the treatment of copd
4. I群抗不整脈薬の主な副作用 major side effects of class i antiarrhythmic drugs
5. 成人における胆嚢機能障害 functional gallbladder disorder in adults

English Journal

Further Studies on the Hypothesis of PARP-1 Inhibition as a Strategy for Lessening the Long-Term Effects Produced by Perinatal Asphyxia: Effects of Nicotinamide and Theophylline on PARP-1 Activity in Brain and Peripheral Tissue : Nicotinamide and Theophylline on PARP-1 Activity.

Allende-Castro C, Espina-Marchant P, Bustamante D, Rojas-Mancilla E, Neira T, Gutierrez-Hernandez MA, Esmar D, Valdes JL, Morales P, Gebicke-Haerter PJ, Herrera-Marschitz M.SourceProgramme of Molecular & Clinical Pharmacology, ICBM, BNI, Medical Faculty, University of Chile, P.O. Box 70.000, Santiago 7, Chile, allende.camilo@gmail.com.
Neurotoxicity research.Neurotox Res.2012 Jul;22(1):79-90. Epub 2012 Feb 4.
Oxygen interruption leads to death when re-oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis. The effects observed long after perinatal asphyxia (PA) have been explained by over-expression of
PMID 22311271

Association between asthma medications and suicidal ideation in adult asthmatics.

Favreau H, Bacon SL, Joseph M, Labrecque M, Lavoie KL.SourceMontreal Behavioural Medicine Centre, Montreal, Canada; Research Centre, Hôpital du Sacré-Cœur de Montréal - A University of Montreal affiliated Hospital, 5400 Gouin West, Montréal, Québec H4J 1C5, Canada; Department of Psychology, University of Quebec at Montreal (UQAM), P.O. Box 8888, Succursale Centre-Ville, Montreal, Quebec H3C 3P8, Canada.
Respiratory medicine.Respir Med.2012 Jul;106(7):933-41. Epub 2012 Apr 10.
BACKGROUND: Asthma has been associated with suicidal ideation (SI), though the mechanisms remain poorly understood. Some asthma medications (e.g., theophylline and beta-2 adrenergic agonists) have been shown to provoke feelings of anxiety, fear, and irritability, but their link to SI among asthmatic
PMID 22495109

Japanese Journal

多項目自動血球分析装置XE-5000を用いた幼若血小板比率(IPF%)測定における抗凝固剤と保存温度の影響 : 抗凝固剤CTADと室温保存の有用性

西山美保,林悟,兜森修,山西八郎,末久悦次,倉田義之,柏木浩和,冨山佳昭
臨床病理 59(5), 452-458, 2011-05-25
NAID 10029427358

テオフィリン薬の出番はあるか (AYUMI 最新の喘息治療薬--使い方のコツ)

黨康夫
医学のあゆみ 239(4), 277-282, 2011-10-22
NAID 40019027960

Related Pictures

★リンクテーブル★

リンク元	「薬理学」「メチルキサンチン」「テオフィリン」「中枢神経興奮薬」
拡張検索	「theophylline ethylenediamine」「choline theophylline」「determination of blood theophylline」

「薬理学」

Theophylline
Systematic (IUPAC) name
	1,3-dimethyl-7H-purine-2,6-dione
Clinical data
Trade names	Theolair, Slo-Bid
AHFS/Drugs.com	monograph
MedlinePlus	a681006
Pregnancy cat.	A (AU) C (US)
Legal status	P (UK) ℞-only (US)
Routes	oral, IV, rectal
Pharmacokinetic data
Bioavailability	100%
Protein binding	40%, primarily to albumin
Metabolism	hepatic to 1-methyluric acid
Half-life	5-8 hours
Identifiers
CAS number	58-55-9
ATC code	R03DA04
PubChem	CID 2153
IUPHAR ligand	413
DrugBank	DB00277
ChemSpider	2068
UNII	0I55128JYK
KEGG	D00371
ChEBI	CHEBI:28177
ChEMBL	CHEMBL190
Chemical data
Formula	C7H8N4O2
Mol. mass	180.164 g/mol
	SMILES Cn1c2c(c(=O)n(c1=O)C)[nH]cn2;
	InChI InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9) ; Key:ZFXYFBGIUFBOJW-UHFFFAOYSA-N ;
(what is this?) (verify);

　　[★]

英: pharmacology
関: drug entries

定義

生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

薬の生物系に対する相互作用：薬理作用 <-化学の視点
生物系の薬に対する相互作用：薬物動態 <-生物の視点

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β₂ agonist	albuterol
～tidine	H₂ antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a₁ antagonist	prazosin

薬一覧

薬物代謝

薬理動態

神経伝達物質

貧血治療薬

甲状腺関連物質

甲状腺ホルモン製剤

レボチロキシン levothyroxine
リオチニシン liothyronine

抗甲状腺薬

痛風治療薬

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol

「メチルキサンチン」

　　[★]

英: methylxanthine
関

概念

ホスホジエステラーゼ阻害作用を有する化合物の一群

誘導体

構造

メチルキサンチン系

作用機序 (SPC.211)

飲料として摂取した場合血中濃度は<50μM

血中濃度	作用
0.5-1.0mM	[Ca²⁺]_i↑
>50μM	ホスホジエステラーゼの阻害
<50μM	アデノシン受容体の拮抗

cAMP↑－(+cAMP)→ホルモン受容体↑、(+cAMP)βアドレナリン受容体↑
アデノシン受容体の非特異的拮抗、細胞内Ca2+遊離

薬理作用 (SPC.211,212)

中枢作用　　　：眠気消失、知的活動↑、興奮、不眠、振戦、神経過敏、けいれん、胃腸障害
心血管系作用　：陽性変力作用、陽性変時作用
気管支拡張作用：気管支平滑筋の弛緩
利尿作用
高濃度：SRからCa²⁺を放出→骨格筋拘縮、胃酸分泌促進

	カフェイン	テオフィリン	テオブロミン
中枢作用	◎	○	△
心血管系作用	○	◎	△
気管支拡張作用	△	◎	○
利尿作用	○	◎	△

副作用

肝臓で代謝されるので肝不全では中毒症状を呈する

「テオフィリン」

　　[★]

英: theophylline, 1,3-dimethylxanthine
ラ: theophyllinum
同: 1,3-ジメチルキサンチン 1,3-dimethylxanthine
商: アーデフィリン、アプネカット、スロービッド、セキロイド、チルミン、テオドール、テオドリップ、テオフルマートL、テオフルマート、テオロング、テルダン小児用、テルバンス、ユニコンCR、ユニコン、ユニフィルLA、ユニフィル
関: メチルキサンチン; 気管支拡張剤

概念

メチルキサンチン誘導体
心血管系作用、気管支拡張作用、利尿作用が強い。中枢作用もやや強い

動態

血中半減期の上昇：肝硬変、うっ血性心不全、急性肺浮腫
クリアランスの上昇：フェニトイン、バルビツール酸系薬。(作用は小さい)喫煙、リファンピン、経口避妊薬

適応

気管支喘息

テオフィリンの気管支拡張作用

副作用

LES圧を低下させる作用や胃酸分泌を亢進させる作用を有するとされており、GERDとの関連が指摘されている。

「中枢神経興奮薬」

　　[★]

英: cerntral nervous system stimulant, CNS stimulant
同: 中枢興奮薬
関: 薬理学

中枢神経系の機能を亢進する薬物の総称

中枢神経興奮薬

メチルキサンチン誘導体(methylxanthine)

覚醒アミン

「theophylline ethylenediamine」

　　[★] テオフィリンエチレンジアミン、アミノフィリン

「choline theophylline」

　　[★]

コリンテオフィリン

関: choline theophyllinate

「determination of blood theophylline」

　　[★] 血中テオフィリン濃度測定

[ApgarTarka-1] Apgar, Joan L.; Tarka, Jr., Stanly M. (1998). "Methylxanthine composition and consumption patterns of cocoa and chocolate products". In Gene A. Spiller. Caffeine. CRC Press. p. 171. ISBN 0-8493-2647-8

[2] MAFF Food Surveillance Information Sheet

[3] Alboni et al. Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome The THEOPACE Study: A Randomized Controlled Trial

[4] For Some Who Have Lost Their Sense Of Smell, A Once Popular Asthma Drug Could Help. Science Daily, American Physiological Society

[5] MedlinePlus Drug Information: Theophylline

[6] THEOPHYLLINE - ORAL 24 HOUR TABLET (Uni-Dur) side effects, medical uses, and drug interactions

[Yoshikawa-2007-7] Yoshikawa H (Apr 2007). "First-line therapy for theophylline-associated seizures.". Acta Neurol Scand 115 (4 Suppl): 57–61. doi:10.1111/j.1600-0404.2007.00810.x. PMID 17362277.

[8] Hendeles L, Weinberger M, Milavetz G, Hill M, Vaughan L (1985). "Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity". Chest 87 (6): 758–65. doi:10.1378/chest.87.6.758. PMID 3996063.

[9] Seneff M, Scott J, Friedman B, Smith M (1990). "Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability". Annals of emergency medicine 19 (6): 671–3. PMID 1971502.

[PDEs-Essayan-10] Essayan DM (2001). "Cyclic nucleotide phosphodiesterases". J Allergy Clin Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.

[PTX-Deree-11] Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (2008). "Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition". Clinics (Sao Paulo). 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.

[pmid9927365-12] Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. PMID 9927365.

[LT-Peters-Golden-13] Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". J Immunol. 174 (2): 589–94. PMID 15634873.

[AR-Daly-14] Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.

[15] Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, Takimoto T, Hirata H, Kijima T (2006). "Anti-fibrotic effects of theophylline on lung fibroblasts". Biochemical and Biophysical Research Communications 341 (3): 684–90. doi:10.1016/j.bbrc.2006.01.018. PMID 16430859.

[Ito-16] Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002). "A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression". Proceedings of the National Academy of Sciences of the United States of America 99 (13): 8921–6. doi:10.1073/pnas.132556899. PMC 124399. PMID 12070353.

[17] "RxList Marinol Interactions". 5/29/2008. Retrieved 2/06/2013.

[18] Kossel A (1888). "Über eine neue Base aus dem Pflanzenreich". Ber. Dtsch. Chem. Ges. 21: 2164–2167. doi:10.1002/cber.188802101422.

[19] Kossel A (1889). "Über das Theophyllin, einen neuen Bestandtheil des Thees". Hoppe Seylers Z. Physiol. Chem. 13: 298–308.

[20] Fischer E, Ach L (1895). "Synthese des Caffeins". Ber. Dtsch. Chem. Ges. 28: 3139.

[Traube2-21] Traube W (1900). "Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure]". Chem. Ber. 33 (3): 3035–3056. doi:10.1002/cber.19000330352.

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theophylline