Theophylline

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Theophylline
Theophylline.svg
Theophylline 3D ball.png
Clinical data
Trade names Theolair, Slo-Bid
AHFS/Drugs.com Monograph
MedlinePlus a681006
Pregnancy
category
Routes of
administration 		oral, IV, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (oral)
Protein binding 40% (primarily to albumin)
Metabolism Hepatic: CYP1A2, CYP2E1, CYP3A4
Metabolites • 1,3-Dimethyluric acid
• 1-Methyixanthine
• 3-Methylxanthine
Elimination half-life 5–8 hours
Identifiers
  • 1,3-dimethyl-7H-purine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.350 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H8N4O2
Molar mass 180.167 g·mol−1
3D model (JSmol)
  • Cn1c2c(c(=O)n(c1=O)C)[nH]cn2
  • InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9) Yes check.svgY
  • Key:ZFXYFBGIUFBOJW-UHFFFAOYSA-N Yes check.svgY
   (verify)
Theophylline extended-release tablets in Japan Cylmin 100mg by Tsuruhara.jpg
Theophylline extended-release tablets in Japan

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. [1] It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. [2] Its pharmacology is similar to other methylxanthine drugs (e.g., theobromine and caffeine). [1] Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut. [1] [3]

Contents

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

Medical uses

The main actions of theophylline involve: [2]

The main therapeutic uses of theophylline are for treating: [2]

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. [9] There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against exercise-induced asthma. [10]

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). [2] 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). [2] [11] Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency. [2]

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. [12] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern. [13] Theophylline should not be used in combination with the SSRI fluvoxamine. [14] [15]

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−1). [16]

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. [17]

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. [18]

Natural occurrences

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans. [19]

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L, [20] which is significantly less than a therapeutic dose.

Trace amounts of theophylline are also found in guarana ( Paullinia cupana ) and in kola nuts. [21]

Pharmacology

Pharmacodynamics

Like other methylated xanthine derivatives, theophylline is both a

  1. competitive nonselective phosphodiesterase inhibitor which increases intracellular levels of cAMP and cGMP, [2] [22] activates PKA, inhibits TNF-alpha [23] [24] and inhibits leukotriene [25] synthesis, and reduces inflammation and innate immunity [25]
  2. nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects. [2] [26] Theophylline activates histone deacetylases. [2]

Pharmacokinetics

Absorption

When theophylline is administered intravenously, bioavailability is 100%. [27]

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 ]

Metabolism

Theophylline is metabolized extensively in the liver. [2] 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. [2] Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance. [28] [29]

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. [2]

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 ]

History

Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel. [30] [31] Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach. [32] The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube. [33] Theophylline's first clinical use came in 1902 as a diuretic. [34] It took an additional 20 years until it was first reported as an asthma treatment. [35] 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.

Related Research Articles

<span class="mw-page-title-main">Caffeine</span> Central nervous system stimulant

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used as a eugeroic (wakefulness promoter) or as a mild cognitive enhancer to increase alertness and attentional performance. Caffeine acts by blocking binding of adenosine to the adenosine A1 receptor, which enhances release of the neurotransmitter acetylcholine. Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors. Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase.

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Theobromine</span> Bitter alkaloid of the cacao plant

Theobromine, also known as xantheose, is the principal alkaloid of Theobroma cacao. Theobromine is slightly water-soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to some cosmetics. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut. It is a white or colourless solid, but commercial samples can appear yellowish.

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

<span class="mw-page-title-main">Adenosine</span> Chemical compound

Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life on Earth. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<span class="mw-page-title-main">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

<span class="mw-page-title-main">Zileuton</span> Chemical compound

Zileuton (trade name Zyflo) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation, used for the maintenance treatment of asthma. Zileuton was introduced in 1996 by Abbott Laboratories and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names Zyflo and Zyflo CR. The original immediate-release formulation, Zyflo, is taken four times per day. The extended-release formulation, Zyflo CR, is taken twice daily.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Aminophylline</span> Chemical compound

Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.

<span class="mw-page-title-main">Paraxanthine</span> Chemical compound

Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.

<span class="mw-page-title-main">Analeptic</span> Drug class

An analeptic, in medicine, is a central nervous system stimulant. The term "analeptic" typically refers to respiratory stimulants. Analeptics are central nervous system (CNS) stimulants that include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (ADHD), and respiratory depression. Analeptics can also be used as convulsants, with low doses causing patients to experience heightened awareness, restlessness, and rapid breathing. The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency respiratory depression. Other drugs of this category are prethcamide, pentylenetetrazole, and nikethamide. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a barbiturate overdose. Through the use of agents, researchers were able to treat obtundation and respiratory depression.

<span class="mw-page-title-main">Hexoprenaline</span> Chemical compound

Hexoprenaline is a selective β2 adrenergic receptor agonist used in the treatment of asthma. Hexoprenaline is also used in some countries as a tocolytic agent, with the most common trade name being Gynipral. It is not approved by the United States Food and Drug Administration.

<span class="mw-page-title-main">Doxofylline</span> Chemical compound

Doxofylline is a phosphodiesterase inhibiting bronchodilator used in the treatment of chronic respiratory diseases such as asthma and COPD. Like theophylline, it is a xanthine derivative.

<span class="mw-page-title-main">Phosphodiesterase-4 inhibitor</span> Class of chemical compounds

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

<span class="mw-page-title-main">CGS-15943</span> Chemical compound

CGS-15943 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A, having a Ki of 3.3nM at A2A and 21nM at A1. It was one of the first adenosine receptor antagonists discovered that is not a xanthine derivative, instead being a triazoloquinazoline. Consequently, CGS-15943 has the advantage over most xanthine derivatives that it is not a phosphodiesterase inhibitor, and so has more a specific pharmacological effects profile. It produces similar effects to caffeine in animal studies, though with higher potency.

<span class="mw-page-title-main">8-Phenyltheophylline</span> Chemical compound

8-Phenyltheophylline (8-phenyl-1,3-dimethylxanthine, 8-PT) is a drug derived from the xanthine family which acts as a potent and selective antagonist for the adenosine receptors A1 and A2A, but unlike other xanthine derivatives has virtually no activity as a phosphodiesterase inhibitor. It has stimulant effects in animals with similar potency to caffeine. Coincidentally 8-phenyltheophylline has also been found to be a potent and selective inhibitor of the liver enzyme CYP1A2 which makes it likely to cause interactions with other drugs which are normally metabolised by CYP1A2.

<span class="mw-page-title-main">Theacrine</span> Chemical compound

Theacrine, also known as 1,3,7,9-tetramethyluric acid, is a purine alkaloid found in Cupuaçu and in a Chinese tea known as kucha. It shows anti-inflammatory and analgesic effects and appears to affect adenosine signalling in a manner similar to caffeine. In kucha leaves, theacrine is synthesized from caffeine in what is thought to be a three-step pathway. Theacrine and caffeine are structurally similar.

An adenosine receptor antagonist is a drug which acts as an antagonist of one or more of the adenosine receptors. The best known are xanthines and their derivatives, but there are also non-xanthine representatives

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.

References

  1. 1 2 3 "Theophylline". PubChem, US National Library of Medicine. 26 August 2023. Retrieved 2 September 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Miao Y, Zhou Y, Zhao S, 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
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  12. ↑ Hendeles L, Weinberger M, Milavetz G, Hill M, Vaughan L (June 1985). "Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity". Chest. 87 (6): 758–765. doi:10.1378/chest.87.6.758. PMID   3996063. S2CID   1133968.
  13. ↑ Seneff M, Scott J, Friedman B, Smith M (June 1990). "Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability". Annals of Emergency Medicine. 19 (6): 671–673. doi:10.1016/s0196-0644(05)82474-6. PMID   1971502.
  14. ↑ DeVane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS (September 1997). "Fluvoxamine-induced theophylline toxicity". The American Journal of Psychiatry. 154 (9): 1317–1318. doi:10.1176/ajp.154.9.1317b. PMID   9286199.
  15. ↑ Sperber AD (November 1991). "Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy". Drug Safety. 6 (6): 460–462. doi:10.2165/00002018-199106060-00006. PMID   1793525. S2CID   21875026.
  16. ↑ Schack JA, Waxler SH (November 1949). "An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues". The Journal of Pharmacology and Experimental Therapeutics. 97 (3): 283–291. PMID   15392550.
  17. ↑ Shelke RU, Degani MS, Raju A, Ray MK, Rajan MG (August 2016). "Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors". Archiv der Pharmazie. 349 (8): 602–613. doi:10.1002/ardp.201600066. PMID   27320965. S2CID   40014874.
  18. ↑ Pfleiderer W (February 2008). "Pteridines. Part CXIX. A New Pteridine–Purine Transformation". Helvetica Chimica Acta. 91 (2): 338–353. doi:10.1002/hlca.200890039.
  19. ↑ Apgar JL, Tarka Jr SM (1998). "Methylxanthine composition and consumption patterns of cocoa and chocolate products and their uses". In Spiller GA (ed.). Caffeine. CRC Press. p. 171. ISBN   978-0-8493-2647-9 . Retrieved 2013-11-10.
  20. ↑ "TABLE 2a: Concentrations of caffeine, theobromine and theophylline in tea products". Food Surveillance Information Sheet Number 103. MAFF, Department of Health and the Scottish Executive. Archived from the original on 2006-09-27.
  21. ↑ Belliardo F, Martelli A, Valle MG (May 1985). "HPLC determination of caffeine and theophylline in Paullinia cupana Kunth (guarana) and Cola spp. samples". Zeitschrift für Lebensmittel-Untersuchung und -Forschung. 180 (5): 398–401. doi:10.1007/BF01027774. PMID   4013524. S2CID   40205323.
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  24. ↑ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–511. doi:10.1164/ajrccm.159.2.9804085. PMID   9927365.
  25. 1 2 Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–594. doi: 10.4049/jimmunol.174.2.589 . PMID   15634873.
  26. ↑ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230 (1): 41–63. PMID   3588607.
  27. ↑ Griffin JP (2009). The Textbook of Pharmaceutical Medicine (6th ed.). Chichester: Wiley-Blackwell. ISBN   978-1-4051-8035-1.
  28. ↑ Jenne JW, Nagasawa HT, Thompson RD (March 1976). "Relationship of urinary metabolites of theophylline to serum theophylline levels". Clinical Pharmacology and Therapeutics. 19 (3): 375–381. doi:10.1002/cpt1976193375. PMID   1261172. S2CID   33943915.
  29. ↑ Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM (October 1978). "Enhanced biotransformation of theophylline in marihuana and tobacco smokers". Clinical Pharmacology and Therapeutics. 24 (4): 405–410. doi:10.1002/cpt1978244406. PMID   688731. S2CID   44613672.
  30. ↑ Kossel A (1888). "Über eine neue Base aus dem Pflanzenreich" [About a new base from the plant kingdom]. Berichte der Deutschen Chemischen Gesellschaft[Reports of the German Chemical Society] (in German). 21: 2164–2167. doi:10.1002/cber.188802101422.
  31. ↑ Kossel A (1889). "Über das Theophyllin, einen neuen Bestandtheil des Thees" [On theophylline, a new component of tea]. Hoppe-Seyler's Zeitschrift für Physiologische Chemie[Hoppe-Seyler's Journal of Physiological Chemistry] (in German). 13: 298–308.
  32. ↑ Fischer E, Ach L (1895). "Synthese des Caffeins" [Synthesis of caffeine]. Berichte der Deutschen Chemischen Gesellschaft[Reports of the German Chemical Society] (in German). 28 (3): 3139. doi:10.1002/cber.189502803156.
  33. ↑ Traube W (1900). "Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure" [The synthetic structure of uric acid, xanthine, theobromine, theophylline and caffeine from cyanoacetic acid]. Berichte der Deutschen Chemischen Gesellschaft[Reports of the German Chemical Society] (in German). 33 (3): 3035–3056. doi:10.1002/cber.19000330352.
  34. ↑ Minkowski O (1902). "Über Theocin (Theophyllin) als Diureticum" [About theocine (theophylline) as a diuretic]. Therapie der Gegenwart[Therapy of the Present] (in German). 43: 490–493.
  35. ↑ Schultze-Werninghaus G, Meier-Sydow J (March 1982). "The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S. R. Hirsch in Frankfurt (Main) 1922". Clinical Allergy. 12 (2): 211–215. doi:10.1111/j.1365-2222.1982.tb01641.x. PMID   7042115. S2CID   38178598.
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