请输入您要查询的百科知识：

　

词条 Theophylline
释义

  1. Medical uses

      Uses under investigation  

  2. Adverse effects

  3. Spectroscopy

      UV-Visible Spectroscopy    Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR)   Carbon Nuclear Magnetic Resonance Spectroscopy (13C-NMR) 

  4. Natural occurrences

  5. Pharmacology

     Pharmacodynamics  Pharmacokinetics  Absorption  Distribution  Metabolism  Elimination 

  6. History

  7. Future Studies

  8. References

  9. External links

{{drugbox | Watchedfields = changed
| verifiedrevid = 470606142
| IUPAC_name = 1,3-dimethyl-7H-purine-2,6-dione
| image = Theophylline.svg
| width = 150
| image2 = Theophylline 3D ball.png
| width2 = 180
| 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 = By mouth, IV, rectal
| bioavailability = 100% (IV)
| protein_bound = 40% (primarily to albumin)
| metabolism = Hepatic to 1-methyluric acid
| elimination_half-life = 5–8 hours
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 58-55-9
| ATC_prefix = R03
| ATC_suffix = DA04
| ATC_supplemental =
| 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
| C=7 | H=8 | N=4 | O=2
| molecular_weight = 180.164 g/mol
| 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=}}Theophylline, also known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine, and is readily found in nature, and is present in tea (Camellia sinensis) and cocoa (Theobroma cacao). A small amount of theophylline is one of the products of caffeine metabolic processing in the liver.[1]

Medical uses

The main actions of theophylline involve:

  • relaxing bronchial smooth muscle
  • increasing heart muscle contractility and efficiency (positive inotrope)
  • increasing heart rate (positive chronotropic)[2]
  • 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 inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.

Uses under investigation

A clinical study reported in 2008 that theophylline was helpful in improving the sense of smell in study subjects with anosmia.[3]

In 2004, a small clinical study compared theophylline to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents.[4]

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.{{how much|date=March 2018}} 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, abnormal heart rhythms, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness).[5][6] Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[7] 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.[8] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[9] Theophylline should not be used in combination with SSRI Fluvoxamine.[10][11][12]

Spectroscopy

UV-Visible Spectroscopy

Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1/M).[13]

Proton Nuclear Magnetic Resonance Spectroscopy (1H-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.[14]

Carbon Nuclear Magnetic Resonance Spectroscopy (13C-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.[15]

Natural occurrences

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.[16]

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L,[17] which is significantly less than a therapeutic dose.

Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts cola (plant) [18]

Pharmacology

Pharmacodynamics

Like other methylated xanthine derivatives, theophylline is both a

  1. competitive nonselective phosphodiesterase inhibitor,&91;19&93; which raises intracellular cAMP, activates PKA, inhibits TNF-alpha&91;20&93;&91;21&93; and inhibits leukotriene&91;22&93; synthesis, and reduces inflammation and innate immunity&91;22&93;
  2. nonselective adenosine receptor antagonist,&91;23&93; 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.[24]

It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics who 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.[25] Furthermore, theophylline has been shown to directly activate HDAC2.[25] (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.)

Pharmacokinetics

Absorption

When theophylline is administered intravenously, bioavailability is 100%.

[26]

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%. 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

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.[27]

Elimination

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 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

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel.[28][29] Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.[30] The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube.[31] Theophylline's first clinical use came in 1902 as a diuretic.[32] It took an additional 20 years until it was first reported as an asthma treatment.[33] 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.

Future Studies

Theophylline, despite its adverse effects and narrow therapeutic range, as discussed above, is still a potent bronchodilator. Current research regarding theophylline-based therapies are oriented towards employing theophylline, as well as other methylxanthines as natural scaffolding for new bronchodilatory pharmaceuticals. In 2017, Mohammed, et al.[34] demonstrated potential derivitization of methylxanthines to produce significant broncodilatory effects in a small mouse study group. However, additional work is oriented towards limiting the interactions of theophylline-based therapies with other drugs and structures, as theophylline has been demonstrated as an effective adjunctive therapy[35] in various diseases. These interactions include maintaining, for example, its activity with HDAC, but eliminating its stimulatory behavior (or rather its adenosine-antagonist behavior).[36]

References

1. ^{{cite web |url=http://www.news-medical.net/health/Caffeine-Pharmacology.aspx |title=Caffeine Pharmacology |first=Ananya |last=Mandal |website=Website Medical News |deadurl=no |archiveurl=https://web.archive.org/web/20160531230958/http://www.news-medical.net/health/Caffeine-Pharmacology.aspx |archivedate=2016-05-31 |df= }}
2. ^Alboni et al. Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome The THEOPACE Study: A Randomized Controlled Trial {{webarchive|url=http://archive.wikiwix.com/cache/20130802024155/http://circ.ahajournals.org/content/96/1/260.abstract?ijkey=3d1da68d05ba3840295f835f12eb8b899200a1c7&keytype2=tf_ipsecsha |date=2013-08-02 }}
3. ^[https://www.sciencedaily.com/releases/2008/04/080407114619.htm For Some Who Have Lost Their Sense Of Smell, A Once Popular Asthma Drug Could Help. Science Daily, American Physiological Society] {{webarchive|url=https://web.archive.org/web/20160821182128/https://www.sciencedaily.com/releases/2008/04/080407114619.htm |date=2016-08-21 }}
4. ^{{cite journal |last1=Mohammadi |first1=M. R. |last2=Kashani |first2=L. |last3=Akhondzadeh |first3=S. |last4=Izadian |first4=E. S. |last5=Ohadinia |first5=S. |title=Efficacy of theophylline compared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: a pilot double-blind randomized trial |journal=Journal of Clinical Pharmacy and Therapeutics |date=2004 |volume=29 |issue=2 |pages=139–144 |doi=10.1111/j.1365-2710.2004.00545.x |pmid=15068402 |issn=0269-4727 |quote=The results suggest that theophylline may be a useful for the treatment of ADHD. […] Nevertheless, our study is small and our results would need to be confirmed in a larger study.}}
5. ^[https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681006.html MedlinePlus Drug Information: Theophylline] {{webarchive|url=https://web.archive.org/web/20160705111407/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681006.html |date=2016-07-05 }}
6. ^THEOPHYLLINE - ORAL 24 HOUR TABLET (Uni-Dur) side effects, medical uses, and drug interactions {{webarchive|url=https://web.archive.org/web/20080509083232/http://www.medicinenet.com/theophylline-oral_24_hour_tablet/article.htm |date=2008-05-09 }}
7. ^{{cite journal | author = Yoshikawa H | title = First-line therapy for theophylline-associated seizures | journal = Acta Neurol Scand | volume = 115 | issue = 4 Suppl | pages = 57–61 |date=Apr 2007 | pmid = 17362277 | doi = 10.1111/j.1600-0404.2007.00810.x }}
8. ^{{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 = 758–65 | year = 1985 | pmid = 3996063 | doi = 10.1378/chest.87.6.758 }}
9. ^{{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 = 671–3 | year = 1990 | pmid = 1971502 | doi = 10.1016/s0196-0644(05)82474-6}}
10. ^{{Cite journal|date=September 1997|title=Fluvoxamine-induced theophylline toxicity|journal=American Journal of Psychiatry|language=en|volume=154|issue=9|pages=1317b–1318|doi=10.1176/ajp.154.9.1317b|issn=0002-953X}}
11. ^{{Cite journal|last=Sperber|first=A. D.|date=November 1991|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|issn=0114-5916|pmid=1793525}}
12. ^{{Cite journal|last=Brøsen|first=K.|date=September 1998|title=Differences in interactions of SSRIs|journal=International Clinical Psychopharmacology|volume=13 Suppl 5|pages=S45–47|issn=0268-1315|pmid=9817620}}
13. ^Schack, Jerome A., and Samuel H. Waxler. "An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues." Journal of pharmacology and experimental therapeutics 97.3 (1949): 283-291.
14. ^Shelke, R. U.; Degani, M. S.; Raju, A.; Ray, M. K.; Rajan, M. G. R. Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors. Archiv der Pharmazie 2016, 349, 602-613.
15. ^Pfleiderer, W. Pteridines. Part CXIX. Helvetica Chimica Acta 2008, 91, 338-353.
16. ^{{Cite book|title=Caffeine|chapter=Methylxanthine composition and consumption patterns of cocoa and chocolate products and their uses|first1=Joan L|last1=Apgar|first2=Stanly M. Jr.|last2=Tarka|editor=Gene A. Spiller|author=|publisher=CRC Press|year=1998|isbn=978-0-8493-2647-9|page=171|url=https://books.google.com/books?id=WxmBmvhsoZ8C&pg=PA171|postscript=|accessdate=2013-11-10}}
17. ^MAFF Food Surveillance Information Sheet {{webarchive|url=https://web.archive.org/web/20060927200412/http://archive.food.gov.uk/maff/archive/food/infsheet/1997/no103/table2a.htm |date=2006-09-27 }}
18. ^Belliardo F, Martelli A, Valle MG. HPLC determination of caffeine and theophylline in Paullinia cupana Kunth (guarana) and Cola spp. samples. Z Lebensm Unters Forsch. 1985 May;180(5):398-401.
19. ^{{cite journal | author = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = J Allergy Clin Immunol | volume = 108 | issue = 5 | pages = 671–80 | year = 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 }}
20. ^{{cite journal |vauthors=Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R | title = Insights into the Regulation of TNF-α Production in Human Mononuclear Cells: The Effects of Non-Specific Phosphodiesterase Inhibition | journal = Clinics (Sao Paulo). | volume = 63 | issue = 3 | pages = 321–8 | year = 2008 | pmid = 18568240 | pmc = 2664230 | doi = 10.1590/S1807-59322008000300006 }}
21. ^{{cite journal |vauthors=Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U | title = Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages | journal = Am. J. Respir. Crit. Care Med. | volume = 159 | issue = 2 | pages = 508–11 |date=February 1999 | pmid = 9927365 | doi = 10.1164/ajrccm.159.2.9804085| url = http://www.atsjournals.org/?journalCode=ajrccm&view=long&pmid=9927365& }}
22. ^1 {{cite journal | vauthors = Peters-Golden M, Canetti C, Mancuso P, Coffey MJ | title = Leukotrienes: underappreciated mediators of innate immune responses | journal = J. Immunol. | volume = 174 | issue = 2 | pages = 589–94 | year = 2005 | pmid = 15634873 | doi = 10.4049/jimmunol.174.2.589 | url = http://www.jimmunol.org/content/174/2/589.full | deadurl = no | archiveurl = https://web.archive.org/web/20140120010737/http://www.jimmunol.org/content/174/2/589.full | archivedate = 2014-01-20 | df = }}
23. ^{{cite journal |vauthors=Daly JW, Jacobson KA, Ukena D | title = Adenosine receptors: development of selective agonists and antagonists | journal = Prog Clin Biol Res. | volume = 230 | issue = 1 | pages = 41–63 | year = 1987 | pmid = 3588607 | doi = }}
24. ^{{cite journal |vauthors=Yano Y, Yoshida M, Hoshino S, Inoue K, Kida H, Yanagita M, Takimoto T, Hirata H, Kijima T | title = Anti-fibrotic effects of theophylline on lung fibroblasts | journal = Biochemical and Biophysical Research Communications | volume = 341 | issue = 3 | pages = 684–90 | year = 2006 | pmid = 16430859 | doi = 10.1016/j.bbrc.2006.01.018 }}
25. ^1 {{cite journal |vauthors=Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ | title = A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 13 | pages = 8921–6 | year = 2002 | pmid = 12070353 | pmc = 124399 | doi = 10.1073/pnas.132556899 }}
26. ^Griffin, J. P. The Textbook of Pharmaceutical Medicine (6th ed.). New Jersey: BMJ Books. {{ISBN|978-1-4051-8035-1}}
27. ^{{cite web|url=http://www.rxlist.com/marinol-drug/side-effects-interactions.htm|title=RxList Marinol Interactions|date=2008-05-29|accessdate=2013-06-02|deadurl=no|archiveurl=https://web.archive.org/web/20130706112952/http://www.rxlist.com/marinol-drug/side-effects-interactions.htm|archivedate=2013-07-06|df=}} (accessdate may be 2013-02-06)
28. ^{{cite journal | author = Kossel A | title = Über eine neue Base aus dem Pflanzenreich | journal = Ber. Dtsch. Chem. Ges. | volume = 21 | issue = | pages = 2164–2167 | year = 1888 | doi = 10.1002/cber.188802101422 }}
29. ^{{cite journal | author = Kossel A | title = Über das Theophyllin, einen neuen Bestandtheil des Thees | journal = Hoppe-Seyler's Z. Physiol. Chem. | volume = 13 | issue = | pages = 298–308 | year = 1889 }}
30. ^{{cite journal |vauthors=Fischer E, Ach L | title = Synthese des Caffeins | journal = Ber. Dtsch. Chem. Ges. | volume = 28 | issue = 3| page = 3139 | year = 1895 | doi=10.1002/cber.189502803156}}
31. ^{{cite journal | author = Traube W | title = Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure] | journal = Chem. Ber. | volume = 33 | issue = 3 | pages = 3035–3056 | year = 1900 | doi = 10.1002/cber.19000330352 }}
32. ^{{cite journal | author = Minkowski O | title = Über Theocin (Theophyllin) als Diureticum | journal = Ther. Gegenwart | volume = 43 | issue = | pages = 490–493 | year = 1902 }}
33. ^{{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 = Clin. Allergy | volume = 12 | issue = 2 | pages = 211–215 | year = 1982 | pmid = 7042115 | doi = 10.1111/j.1365-2222.1982.tb01641.x }}
34. ^Mohamed, A. R.; Georgey, H. H.; George, R. F.; El-Eraky, W. I.; Saleh, D. O.; Abdel Gawad, N. M. Identification of some novel xanthine-based derivatives with bronchodilator activity. Future Medicinal Chemistry 2017, 9, 1731-1747.
35. ^João Monteiro; Marco G Alves; Pedro F Oliveira; Branca M Silva Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Critical reviews in food science and nutrition 2018, 58, 1-29.
36. ^Barnes, P. J. Theophylline in Chronic Obstructive Pulmonary Disease: New Horizons. Proceedings of the American Thoracic Society 2005, 2, 1.

External links

{{Commons category}}{{Asthma and copd rx}}{{Adenosinergics}}{{Phosphodiesterase inhibitors}}{{Stimulants}}{{Authority control}}

7 : Adenosine receptor antagonists|Beta1-adrenergic agonists|Bitter compounds|Bronchodilators|Phosphodiesterase inhibitors|Xanthines|Histone Acetyltransferase Inhibitor
随便看

　

开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。

　

Copyright © 2023 OENC.NET All Rights Reserved
京ICP备2021023879号 更新时间：2024/11/13 1:37:50