![]() | |
![]() | |
Combination of | |
---|---|
Theophylline | Adenosine receptor antagonist |
Ephedrine | Norepinephrine releasing agent |
Clinical data | |
Trade names | Franol, others [1] [2] |
Other names | Theophylline/ephedrine; Theophylline-(–)-ephedrine compound; Theophylline-ephedrine |
Identifiers | |
CAS Number | |
PubChem CID | |
ChemSpider | |
UNII |
Theophylline ephedrine (INN ), 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]
Asthma is a common long-term inflammatory disease of the airways of the lungs. Asthma occurs when allergens, pollen, dust, or other particles, are inhaled into the lungs, causing the bronchioles to constrict and produce mucus, which then restricts oxygen flow to the alveoli. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.
Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.
A bronchodilator or broncholytic is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be originating naturally within the body, or they may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions. They may be useful in bronchiolitis and bronchiectasis, although this remains somewhat controversial. They are often prescribed but of unproven significance in restrictive lung diseases.
Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label for certain other indications, like treatment of low blood pressure. At higher doses, it may produce various additional effects including stimulant, appetite suppressant, and performance-enhancing effects. In relation to this, non-medical use of pseudoephedrine has been encountered. The medication is taken by mouth.
Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. It can be taken by mouth or by injection into a muscle, vein, or just under the skin. Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, and by mouth can take an hour for effect. When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.
Theophylline/ephedra/hydroxyzine is a drug that was used for the treatment of asthma. It was a combination of theophylline, ephedra, and hydroxyzine, and taken by mouth. It is no longer manufactured in the US due to approval of ephedra being withdrawn by the FDA.
Azithromycin, sold under the brand names Zithromax and Azasite, is an antibiotic medication used for the treatment of several bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler's diarrhea, and certain other intestinal infections. Along with other medications, it may also be used for malaria. It is administered by mouth, into a vein, or into the eye.
Guaifenesin, also known as glyceryl guaiacolate, is an expectorant medication taken by mouth and marketed as an aid to eliminate sputum from the respiratory tract. Chemically, it is an ether of guaiacol and glycerine. It may be used in combination with other medications. A 2014 study found that guaifenesin does not affect sputum volume in upper respiratory infections.
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.
Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among others, is a medication used as a decongestant for uncomplicated nasal congestion, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, applied to the skin, or as a rectal suppository.
Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response.
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.
Dorzolamide/timolol, sold under the brand name Cosopt among others, is a medication used to treat high pressure inside the eye including glaucoma. It is a combination of dorzolamide hydrochloride and timolol maleate. It may be used when a beta blocker, like timolol, is not sufficient alone. It is used as an eye drop.
Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.
Azelastine, sold under the brand name Astelin among others, is a H1 receptor-blocking medication primarily used as a nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis. Other uses may include asthma and skin rashes for which it is taken by mouth. Onset of effects is within minutes when used in the eyes and within an hour when used in the nose. Effects last for up to 12 hours.
Bitolterol mesylate (Tornalate) is a short-acting β2 adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD. In these disorders there is a narrowing of the airways that carry air to the lungs. Muscle spasm and inflammation within the bronchi worsen this narrowing. Bitolterol relaxes the smooth muscles present continuously around the bronchi and bronchioles facilitating the flow of air through them.
Mometasone, also known as mometasone furoate, is a steroid medication used to treat certain skin conditions, hay fever, and asthma. Specifically it is used to prevent rather than treat asthma attacks. It can be applied to the skin, inhaled, or used in the nose. Mometasone furoate, not mometasone, is used in medical products.
Budesonide, sold under the brand name Pulmicort, among others, is a steroid medication. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The nasal spray is used for allergic rhinitis and nasal polyps. Modified-release pills or capsules and rectal forms may be used for inflammatory bowel disease including Crohn's disease, ulcerative colitis, and microscopic colitis.
Tedral, or theophylline/ephedrine/phenobarbital, is a medicine formerly used to treat respiratory diseases such as asthma, chronic obstructive lung disease (COPD), chronic bronchitis, and emphysema. It is a combination drug containing three active ingredients - theophylline, ephedrine, phenobarbital. This medication relaxes the smooth muscle of the airways, making breathing easier. The common side effects of Tedral include gastrointestinal disturbances, dizziness, headache and lightheadedness. However, at high dose, it may lead to cardiac arrhythmias, hypertension, seizures or other serious cardiovascular and/or central nervous system adverse effects. Tedral is contraindicated in individuals with hypersensitivity to theophylline, ephedrine and/or phenobarbital. It should be also used in caution in patients with cardiovascular complications, such as ischemic heart disease and heart failure and/or other disease conditions. It can cause a lot of drug–drug interactions. Therefore, before prescribing patient with Tedral, drug interactions profile should be carefully checked if the patient had other concurrent medication(s). Being used as a treatment option for respiratory diseases for decades, Tedral was withdrawn from the US market in 2006 due to safety concerns.
An anti-asthmatic agent, also known as an anti-asthma drug, refers to a drug that can aid in airway smooth muscle dilation to allow normal breathing during an asthma attack or reduce inflammation on the airway to decrease airway resistance for asthmatic patients, or both. The goal of asthmatic agents is to reduce asthma exacerbation frequencies and related hospital visits.
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].
Amesec contained ephedrine and amylobarbitone with a whiff of aminophylline. Franol contained ephedrine and theophylline, and earlier versions also contained phenobarbital.
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
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.
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.
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).
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.
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