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Theophylline/ephedrine
	Theophylline
	Ephedrine
Combination of
Theophylline	Adenosine receptor antagonist
Ephedrine	Norepinephrine releasing agent
Clinical data
Trade names	Franol, others
Other names	Theophylline/ephedrine; Theophylline-(–)-ephedrine compound; Theophylline-ephedrine
Identifiers
CAS Number	15766-94-6;
PubChem CID	86278139;
ChemSpider	34992091;
UNII	LMS3EG69X8;

Theophylline ephedrine (INNTooltip International Nonproprietary Name), or theophylline/ephedrine, sold under the brand name Franol among others,^[1] is a fixed-dose combination formulation of theophylline, an adenosine receptor antagonist, and ephedrine, a norepinephrine releasing agent and indirectly acting sympathomimetic agent, which has been used as a bronchodilator in the treatment of asthma and as a nasal decongestant.^[3]^[4]^[5]^[6]^[7]^[8]^[9]^[2] It was first studied and used to treat asthma in the 1930s or 1940s and combinations of the two drugs subsequently became widely used.^[9]^[7]^[10] A ratio of 5:1 theophylline to ephedrine is usually used in combinations of the drugs.^[11] Later research found that the combination was no more effective for asthma than theophylline alone but produced more side effects.^[9]^[1]^[12]^[7]

Combinations of theophylline, ephedrine, and phenobarbital (brand name Tedral among others) have also been widely used to treat asthma.^[12]^[13]^[14]^[15] Many such combinations have been marketed with numerous brand names.^[15] Theophylline has also been marketed in combination with other ephedrine-like sympathomimetics like racephedrine and pseudoephedrine and with other barbiturates such as amobarbital and butabarbital, among other drugs.^[15] A combination of theophylline, ephedrine, and hydroxyzine has been marketed under the brand name Marax among others as well.^[16]^[17]^[18] Combinations of theophylline, ephedrine, and a barbiturate were later phased out in favor of combinations of theophylline and ephedrine alone (e.g., brand name Franol).^[2]^[1] Fixed-dose combinations of theophylline and ephedrine were abandoned after the 1970s as they did not allow for dose titration in asthma therapy owing to the toxicity of ephedrine.^[19]

The effects of theophylline/ephedrine as a performance-enhancing drug in exercise and sports have been studied.^[20]^[21] Use of theophylline/ephedrine combinations has led to disqualification of elite athletes due to ephedrine being banned in competitive sports.^[22]

References

^ ^a ^b ^c ^d Mansfield PR (1991). "Classifying improvements to drug marketing and justifications for claims of efficacy". The International Journal of Risk & Safety in Medicine. 2 (4): 171–184. doi:10.3233/JRS-1991-2401. PMID 23511913. Dr Lathem, Sterling's Vice President for Scientific Affairs replied to MaLAM that "Franol is approved for marketing in the United Kingdom in a formulation containing theophylline and ephedrine. We have initiated a re-formulation worldwide to make all Franol formulations consistent with those of the U.K.". Weinberger and Bronsky (1974) compared theophylline and ephedrine separately and combined. They concluded that "the inclusion of ephedrine resulted in no further benefit but did appear to increase the frequency of adverse effects" [26].
^ ^a ^b ^c Head S (2022). "A breath of fresh air". Prescriber. 33 (2): 41–42. doi:10.1002/psb.1973. ISSN 0959-6682. Amesec contained ephedrine and amylobarbitone with a whiff of aminophylline. Franol contained ephedrine and theophylline, and earlier versions also contained phenobarbital.
^ Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1179. ISBN 978-1-4757-2085-3. Retrieved 29 August 2024.
^ "INN Proposed List 14". World Health Organization (WHO). 31 October 1964. Retrieved 29 August 2024.
^ National Archives (U.S.) (1978). Federal Register (in German). Office of the Federal Register, National Archives and Records Service, General Services Administration. pp. 12450–12382. Retrieved 30 August 2024.
^ Sims JA, doPico GA, Reed CE (July 1978). "Bronchodilating effect of oral theophylline-ephedrine combination". The Journal of Allergy and Clinical Immunology. 62 (1): 15–21. doi:10.1016/0091-6749(78)90066-0. PMID 350932.
^ ^a ^b ^c Weinberger M, Bronsky E, Bensch GW, Bock GN, Yecies JJ (May 1975). "Interaction of ephedrine and theophylline". Clinical Pharmacology and Therapeutics. 17 (5): 585–592. doi:10.1002/cpt1975175585. PMID 1092514. Brown1 reported uncontrolled clinical observations suggesting the apparent effectiveness of a fixed dose combination of ephedrine and theophylline in 1940, Such preparations have become very popular, though a search of the literature since that initial report unearthed only one controlled study (of very limited scope) that suggested additive effect from drug combination.15
^ Pinnas JL, Schachtel BP, Chen TM, Roseberry HR, Thoden WR (March 1991). "Inhaled epinephrine and oral theophylline-ephedrine in the treatment of asthma". Journal of Clinical Pharmacology. 31 (3): 243–247. doi:10.1002/j.1552-4604.1991.tb04969.x. PMID 2019665.
^ ^a ^b ^c Stargrove M, Treasure J, McKee D (2007). Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. Elsevier Health Sciences. p. 45. ISBN 978-0-323-02964-3. Retrieved 2024-08-31. Theophylline is generally more potent than caffeine in its effects; it was often combined with ephedrine in nasal decongestant products before more selective adrenergic blockers became available. An early study found the theophylline-ephedrine combination no more effective than theophylline alone in 23 asthmatic children, whereas the ADR rate was higher for the combination than for theophylline.40 Another study of asthmatic children, however, showed no additional adverse effects from the combination.
^ Weinberger M, Hendeles L (October 1986). "Therapeutic effect and dosing strategies for theophylline in the treatment of chronic asthma". The Journal of Allergy and Clinical Immunology. 78 (4 Pt 2): 762–768. doi:10.1016/0091-6749(86)90058-8. PMID 3534057. Theophylline has undergone a major transition in clinical use over the past 10 to 15 years. Used primarily for its cardiovascular effects in the early part of this century, theophylline was found in the 1920s to have clinically beneficial effects on acute bronchospasm.1 In the 1930s, theophylline became popular as an oral agent, particularly in fixed-dose combination with ephedrine. Its predominant use continued in this manner into the early 1970s. Since then, definition of the pharmacodynamics and pharmacokinetics of theophylline has led to its present use as a major prophylactic agent for the prevention of chronic asthma.
^ O'Loughlin JM (March 1979). "Drug therapy of bronchial asthma". The Medical Clinics of North America. 63 (2): 391–396. PMID 35721.
^ ^a ^b Hendeles L, Weinberger M (1980). "Avoidance of adverse effects during chronic therapy with theophylline". European Journal of Respiratory Diseases. Supplement. 109: 103–119. PMID 7002576. Until recently, combination products containing theophylline, ephedrine, and a "sedative" were the most frequently prescribed bronchodilators in the United States. Several studies, however, have documented that the combination of ephedrine and theophylline produce synergistic toxicity without significantly enhancing the therapeutic efficacy of theophylline alone (Figure 1).
^ Khouzam H, Tan D, Gill T (2007). Handbook of Emergency Psychiatry. Elsevier Health Sciences. p. 53. ISBN 978-0-323-07661-6. Retrieved 30 August 2024.
^ Heinzelman RV (1972). Annual Reports in Medicinal Chemistry. ISSN. Elsevier Science. p. 92. ISBN 978-0-08-058351-8. Retrieved 30 August 2024.
^ ^a ^b ^c Project Label: Alphabetical Listing by Drug Product. Department of Justice, Drug Enforcement Administration, Office of Compliance and Regulatory Affairs, Regulatory Support Division, Information Systems Section. 1979. Retrieved 2024-08-31.
^ Emergency Medical Care: A Manual for the Paramedic in the Field. Emergency Medical Care: A Manual for the Paramedic in the Field. U.S. Department of Transportation, National Highway Traffic Safety Administration. 1983. p. 3-PA33. Retrieved 31 August 2024.
^ Emergency Department Trends from the Drug Abuse Warning Network: Preliminary Estimates January-June 2001 with Revised Estimates 1994-2000. DHHS publication. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2002. p. 210. Retrieved 31 August 2024.
^ Mosby's Pocket Dictionary of Medicine, Nursing & Health Professions - E-Book: Mosby's Pocket Dictionary of Medicine, Nursing & Health Professions - E-Book. Elsevier Health Sciences. 2016. p. 810. ISBN 978-0-323-41427-2. Retrieved 31 August 2024.
^ Akazawa M, Stempel DA (2006). "Single-inhaler combination therapy for asthma: a review of cost effectiveness". PharmacoEconomics. 24 (10): 971–988. doi:10.2165/00019053-200624100-00005. PMID 17002480. The concept of using a single therapy and maximising the dose of ICS might have been driven by the desire to avoid fixed combinations. These were commonly used in the US during the 1970s with products such as Tedral®1 and Marax® that combined theophylline and ephedrine with a sedative. The earlier fixed combinations did not allow for significant dose titration, due to the toxicity of ephedrine, and thus the concept of fixed dosing combinations for asthma was relegated to an 'unacceptable' status.
^ Kennedy M (January 2021). "Effects of theophylline and theobromine on exercise performance and implications for competition sport: A systematic review". Drug Testing and Analysis. 13 (1): 36–43. doi:10.1002/dta.2970. PMID 33188564.
^ Sidney KH, Lefcoe NM (1978). "Effects of anti-asthmatic medication (ephedrine plus theophylline) upon the physical performance and work capacity of healthy track athletes". Can J Appl Sport Sci. 3: 93–97.
^ Helenius I, Haahtela T (September 2000). "Allergy and asthma in elite summer sport athletes". The Journal of Allergy and Clinical Immunology. 106 (3): 444–452. doi:10.1067/mai.2000.107749. PMID 10984362. Team physicians became interested in asthma in elite athletes after the 1972 Olympic Games in Munich. The winner of the men's 400 m freestyle swimming race was disqualified because a significant amount of a banned drug, ephedrine, was found in his postrace urinalysis sample. The swimmer had used a combination preparation of theophylline and ephedrine for the treatment of his asthma. Since then both US and Australian Olympic Committees have put special emphasis on the accurate diagnosis and treatment of asthma in their Olympic teams.1,2

[Mansfield1991-1] Mansfield PR (1991). "Classifying improvements to drug marketing and justifications for claims of efficacy". The International Journal of Risk & Safety in Medicine. 2 (4): 171–184. doi:10.3233/JRS-1991-2401. PMID 23511913. Dr Lathem, Sterling's Vice President for Scientific Affairs replied to MaLAM that "Franol is approved for marketing in the United Kingdom in a formulation containing theophylline and ephedrine. We have initiated a re-formulation worldwide to make all Franol formulations consistent with those of the U.K.". Weinberger and Bronsky (1974) compared theophylline and ephedrine separately and combined. They concluded that "the inclusion of ephedrine resulted in no further benefit but did appear to increase the frequency of adverse effects" [26].

[Head2022-2] Head S (2022). "A breath of fresh air". Prescriber. 33 (2): 41–42. doi:10.1002/psb.1973. ISSN 0959-6682. Amesec contained ephedrine and amylobarbitone with a whiff of aminophylline. Franol contained ephedrine and theophylline, and earlier versions also contained phenobarbital.

[Elks2014-3] Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1179. ISBN 978-1-4757-2085-3. Retrieved 29 August 2024.

[WHO-INN-1964-4] "INN Proposed List 14". World Health Organization (WHO). 31 October 1964. Retrieved 29 August 2024.

[FederalRegister1978-5] National Archives (U.S.) (1978). Federal Register (in German). Office of the Federal Register, National Archives and Records Service, General Services Administration. pp. 12450–12382. Retrieved 30 August 2024.

[SimsdoPicoReed1978-6] Sims JA, doPico GA, Reed CE (July 1978). "Bronchodilating effect of oral theophylline-ephedrine combination". The Journal of Allergy and Clinical Immunology. 62 (1): 15–21. doi:10.1016/0091-6749(78)90066-0. PMID 350932.

[WeinbergerBronskyBensch1975-7] Weinberger M, Bronsky E, Bensch GW, Bock GN, Yecies JJ (May 1975). "Interaction of ephedrine and theophylline". Clinical Pharmacology and Therapeutics. 17 (5): 585–592. doi:10.1002/cpt1975175585. PMID 1092514. Brown1 reported uncontrolled clinical observations suggesting the apparent effectiveness of a fixed dose combination of ephedrine and theophylline in 1940, Such preparations have become very popular, though a search of the literature since that initial report unearthed only one controlled study (of very limited scope) that suggested additive effect from drug combination.15

[PinnasSchachtelChen1991-8] Pinnas JL, Schachtel BP, Chen TM, Roseberry HR, Thoden WR (March 1991). "Inhaled epinephrine and oral theophylline-ephedrine in the treatment of asthma". Journal of Clinical Pharmacology. 31 (3): 243–247. doi:10.1002/j.1552-4604.1991.tb04969.x. PMID 2019665.

[StargroveTreasureMcKee2007-9] Stargrove M, Treasure J, McKee D (2007). Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. Elsevier Health Sciences. p. 45. ISBN 978-0-323-02964-3. Retrieved 2024-08-31. Theophylline is generally more potent than caffeine in its effects; it was often combined with ephedrine in nasal decongestant products before more selective adrenergic blockers became available. An early study found the theophylline-ephedrine combination no more effective than theophylline alone in 23 asthmatic children, whereas the ADR rate was higher for the combination than for theophylline.40 Another study of asthmatic children, however, showed no additional adverse effects from the combination.

[WeinbergerHendeles1986-10] Weinberger M, Hendeles L (October 1986). "Therapeutic effect and dosing strategies for theophylline in the treatment of chronic asthma". The Journal of Allergy and Clinical Immunology. 78 (4 Pt 2): 762–768. doi:10.1016/0091-6749(86)90058-8. PMID 3534057. Theophylline has undergone a major transition in clinical use over the past 10 to 15 years. Used primarily for its cardiovascular effects in the early part of this century, theophylline was found in the 1920s to have clinically beneficial effects on acute bronchospasm.1 In the 1930s, theophylline became popular as an oral agent, particularly in fixed-dose combination with ephedrine. Its predominant use continued in this manner into the early 1970s. Since then, definition of the pharmacodynamics and pharmacokinetics of theophylline has led to its present use as a major prophylactic agent for the prevention of chronic asthma.

[O'Loughlin1979-11] O'Loughlin JM (March 1979). "Drug therapy of bronchial asthma". The Medical Clinics of North America. 63 (2): 391–396. PMID 35721.

[HendelesWeinberger1980-12] Hendeles L, Weinberger M (1980). "Avoidance of adverse effects during chronic therapy with theophylline". European Journal of Respiratory Diseases. Supplement. 109: 103–119. PMID 7002576. Until recently, combination products containing theophylline, ephedrine, and a "sedative" were the most frequently prescribed bronchodilators in the United States. Several studies, however, have documented that the combination of ephedrine and theophylline produce synergistic toxicity without significantly enhancing the therapeutic efficacy of theophylline alone (Figure 1).

[KhouzamTanGill2007-13] Khouzam H, Tan D, Gill T (2007). Handbook of Emergency Psychiatry. Elsevier Health Sciences. p. 53. ISBN 978-0-323-07661-6. Retrieved 30 August 2024.

[Henzelman1972-14] Heinzelman RV (1972). Annual Reports in Medicinal Chemistry. ISSN. Elsevier Science. p. 92. ISBN 978-0-08-058351-8. Retrieved 30 August 2024.

[ProjectLabel1979-15] Project Label: Alphabetical Listing by Drug Product. Department of Justice, Drug Enforcement Administration, Office of Compliance and Regulatory Affairs, Regulatory Support Division, Information Systems Section. 1979. Retrieved 2024-08-31.

[EmergMedCare1983-16] Emergency Medical Care: A Manual for the Paramedic in the Field. Emergency Medical Care: A Manual for the Paramedic in the Field. U.S. Department of Transportation, National Highway Traffic Safety Administration. 1983. p. 3-PA33. Retrieved 31 August 2024.

[EmergDepTrends2002-17] Emergency Department Trends from the Drug Abuse Warning Network: Preliminary Estimates January-June 2001 with Revised Estimates 1994-2000. DHHS publication. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2002. p. 210. Retrieved 31 August 2024.

[Mosby2016-18] Mosby's Pocket Dictionary of Medicine, Nursing & Health Professions - E-Book: Mosby's Pocket Dictionary of Medicine, Nursing & Health Professions - E-Book. Elsevier Health Sciences. 2016. p. 810. ISBN 978-0-323-41427-2. Retrieved 31 August 2024.

[AkazawaStempel2006-19] Akazawa M, Stempel DA (2006). "Single-inhaler combination therapy for asthma: a review of cost effectiveness". PharmacoEconomics. 24 (10): 971–988. doi:10.2165/00019053-200624100-00005. PMID 17002480. The concept of using a single therapy and maximising the dose of ICS might have been driven by the desire to avoid fixed combinations. These were commonly used in the US during the 1970s with products such as Tedral®1 and Marax® that combined theophylline and ephedrine with a sedative. The earlier fixed combinations did not allow for significant dose titration, due to the toxicity of ephedrine, and thus the concept of fixed dosing combinations for asthma was relegated to an 'unacceptable' status.

[Kennedy2021-20] Kennedy M (January 2021). "Effects of theophylline and theobromine on exercise performance and implications for competition sport: A systematic review". Drug Testing and Analysis. 13 (1): 36–43. doi:10.1002/dta.2970. PMID 33188564.

[SidneyLefcoe1978-21] Sidney KH, Lefcoe NM (1978). "Effects of anti-asthmatic medication (ephedrine plus theophylline) upon the physical performance and work capacity of healthy track athletes". Can J Appl Sport Sci. 3: 93–97.

[HeleniusHaahtela2000-22] Helenius I, Haahtela T (September 2000). "Allergy and asthma in elite summer sport athletes". The Journal of Allergy and Clinical Immunology. 106 (3): 444–452. doi:10.1067/mai.2000.107749. PMID 10984362. Team physicians became interested in asthma in elite athletes after the 1972 Olympic Games in Munich. The winner of the men's 400 m freestyle swimming race was disqualified because a significant amount of a banned drug, ephedrine, was found in his postrace urinalysis sample. The swimmer had used a combination preparation of theophylline and ephedrine for the treatment of his asthma. Since then both US and Australian Olympic Committees have put special emphasis on the accurate diagnosis and treatment of asthma in their Olympic teams.1,2

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Theophylline/ephedrine

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