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Drug Profile

10.1586/17476348.2.3.305 2008 Expert Reviews Ltd ISSN 1747-6348 305www.expert-reviews.com

Aminophylline for treatingasthma and chronic obstructivepulmonary diseaseExpert Rev. Resp. Med.2(3), 305313 (2008)

Yonca NuhogluandCagatay NuhogluAuthor for correspondence

Yesilbahar Sokak, Savas

Apartment, Number 16/16Goztepe Kadikoy, 34730Istanbul, Turkey

Tel.: +90 216 363 4273

Fax: +90 216 369 3235

[email protected]

Aminophylline is a complex of theophylline and ethylenediamine. Its main pharmacologicalaction is relaxation of bronchial smooth muscle. Two meta-analyses examining the efficacy of

aminophylline in acute asthma attacks in children and in adults have been reported by the

Cochrane Collaboration. In the meta-analysis reporting results from studies in children, it was

concluded that aminophylline does not add any benefit to standard care. Yet one study, which

has the largest patient population, reports that aminophylline improves lung functions within

68 h and reduces the risk of intubation. The meta-analysis examining adult studies revealed

that there is no outstanding difference between aminophylline and standard therapy in the

management of adult acute asthma. In conclusion, aminophylline may be an alternative to

intravenous infusion of -agonists, heliox or magnesium sulfate administration in children in

whom respiratory fatigue begins to develop and intensive-care unit admission and mechanical

ventilation seems to be the next treatment in line. However, in adults, it is not recommended

for use in the treatment of acute asthma owing to its possible adverse effects.

KEYWORDS:aminophylline asthma COPD theophylline

Aminophylline is a 2:1 complex of theophylline

and ethylenediamine (FIGURE

1). Aminophyllinehas greater water solubility than theophylline. Inbiological fluids, aminophylline dissociates totheophylline; therefore, the pharmacologicaleffects of aminophylline belong mainly to theo-phylline. Theophylline is a xanthine derivative,its main pharmacological action is direct relaxa-tion of bronchial smooth muscle, relieving bron-chospasm. Theophylline has been used in thetreatment of obstructive pulmonary diseases formore than 50 years [1]. Although it has been tra-ditionally classified as a bronchodilator agent, itis now known that theophylline also has some

anti-inflammatory properties and immunomod-ulatory actions [24], which adds new perspectivesto its use in the treatment of obstructive pulmo-nary diseases. This article evaluates aminophyl-line, the intravenous form of theophylline, in thetreatment of acute asthma.

History

Theophylline was first extracted from tea leavesin the early 1900s. Herrmann et al. were thefirst to discover the pharmacological effects of

theophylline in the treatment of asthma in

1937 [5]. After the introduction of aminophyl-line in the treatment of acute asthma, seriousclinical side effects began to be reported. In thelate 1900s, an effective concentration range wasestablished [4]. Over the last decade, as newbronchodilators and better anti-inflammatoryagents have been introduced for the treatmentof respiratory diseases, the use of this drug hasdeclined. The narrow therapeutic window oftheophylline, which has typically been classifiedas being 1020 g/ml in plasma, was the mainconcern leading to this choice [1].

Pharmacodynamic properties

Bronchodilating effects

The pharmacological action of theophylline ismainly bronchodilation. Other therapeutic prop-erties include decreasing lung vascular resistance,modulating respiratory tract mucociliary clear-ance, suppressing chemical mediator release andinhibiting vascular permeability caused by chem-ical mediator release [4]. Moreover, it has beenshown to improve respiratory muscle fatigue,especially that of the diaphragm [6].

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306 Expert Rev. Resp. Med.2(3), (2008)

Drug Profile Nuhoglu & Nuhoglu

The mechanism by which theophylline exerts its pharmaco-logical activity is not precisely known. Alterations in intracellu-lar calcium mobilization [7], stimulation of endogenous cate-cholamine release [8], adenosine receptor antagonism [9],phosphodiesterase 4 inhibition [10], increasing histone deacety-lase activity [11] and inhibiting phosphatidylinositol 3-kinaseactivity [12]are mechanisms that have been proposed.

Phosphodiesterase inhibition [4]and promotion of binding ofcAMP to soluble protein [6]are the main mechanisms underly-ing the bronchodilator effect of theophylline. As a result, cAMPconcentration in the cell is maintained at a suitable level [4].

Another main mechanism is adenosine receptor antagonism [13].The upregulation of adenosine A1 receptors following allergicsensitization has been shown to take place after theophyllineadministration in experimental animal studies [14]. Asthmatic sub-

jects airways contract in response to inhaled adenosine throughan adenosine A1 receptor-dependent mechanism [15]. Theophyl-line has been shown to block the sensitivity of asthmatic subjectsto inhaled adenosine [16,17].

Theophylline also has actions in the CNS and cardiovascularsystem, in addition to hepatic, digestive and metabolic effects [18].

Serum concentrations higher than the therapeutic level causeside effects in these systems [4].

Immunomodulatory & anti-inflammatory effects

Inflammation is known to be the main problem in the lungsof asthmatic patients [19]. It is now recognized thatT lymphocytes play a central role in the pathogenesis of theallergic inflammation. Theophylline inhibits allergen-inducedrecruitment of T lymphocytes into the airways [20] andincreases the number of suppressor CD8 cells in peripheralblood [21,22]. Furthermore, it has been shown that asthmasymptoms worsen in patients in whom theophylline had been

withdrawn and that this result was associa ted with an increasein T lymphocytes in the airways [3]. This is an immunomodu-latory effect that occurs at plasma levels below 10 g/ml [23].In addition, the number of inflammatory cells expressing IL-4in the airways is shown to decrease after regular treatment

with theophylline [24].IL-5-mediated prolongation of eosinophil survival has been

shown to be inhibited in vitroby theophylline, together withthe acceleration of apoptosis at concentrations below10 g/ml [25]. Eosinophil activation has been shown to beattenuated in vitro by theophylline [26]. IL-10 productionfrom peripheral mononuclear cells of asthmatics has also been

reported to be induced after treatment with theophylline [27].IL-10 is known to shorten eosinophil survival [28]and induceT-cell tolerance [29].

Pharmacokinetic propertiesDistribution

Aminophylline (theophyllineethylenediamine) dissociates rap-idly to theophylline in biological fluids. Theophylline reachesthe peripheral tissues very rapidly. Theophylline crosses the pla-centa and passes into breast milk. In total, 4060% of theo-phylline combines with protein [4]. The mean volume of distri-bution of the drug is 0.450.50 l/kg [19]. The volume ofdistribution increases in liver cirrhosis and premature infantsand decreases in obese patients [4].

Metabolism & clearance

Theophylline is metabolized mainly by the liver (approximately90%). The remainder is excreted from the kidney unchanged.The clearance rate of theophylline is approximately 0.4 l/kg/h inhealthy nonsmoking patients with asthma. Clearance is affectedby factors that influence the activity of the hepatic enzymes thatmetabolize the drug. Two cytochromes, cytochrome P450(CYP) and CYP1A2 are mainly involved in the metabolism [19].

Smoking, age and drug interactions affect theophylline metab-olism [3032]. In neonates, metabolism is not fully developed;thus, approximately 50% of the dose is excreted in urine asunchanged theophylline [4]. In children who are 3 or 4 monthsold, elimination half-life becomes almost the same as that ofhealthy adults. Theophylline clearance is fastest at 19 years of

age, at that time, the half-life is approximately 34 h [33,34]. Theclearance rate decreases gradually after this age and falls to nearadult values in adolescence [33,34]. In elderly patients, theophyl-line elimination decreases owing to reduced clearance, variousunderlying diseases and multiple coadministered drugs [35].Recently, Edginton et al.demonstrated that elimination half-life of theophylline is longer in young neonates; yet, there is noage-dependent bias for term neonates to 18 years of age [36].

Smoking increases serum clearance by approximately4060%. The mechanism underlying this effect is nicotine andother benzoic hydrocarbons ability to induce the cytochromeenzymes in the liver [3739].

Theophylline clearance decreases in patients with noncom-pensatory liver cirrhosis [4]. Liver disease selectively modulatesCYP-mediated metabolism, which is one of the main metabolicpathways of theophylline [40]. Besides, many of these patientsusually have high serum bilirubin concentrations andhypoalbuminemia; therefore, theophyllines protein bindingcapacity decreases and volume of distribution increases. A sig-nificant correlation was reported between theophylline clear-ance and serum bile acid and bilirubin concentrations [41].Therefore, decrease of theophylline clearance in liver cirrhosis isdeclared to be the result of the metabolism impairment due tothe reduction of blood flow to injured hepatocytes.

Figure 1. Theophylline.

NH

NN

N

O

CH3

O

CH3

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Aminophylline for treating asthma & COPD Drug Profile

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Furthermore, cardiac heart failure patients have beenreported to show low theophylline clearance [42]. The clearancerate in congestive heart failure is 0.0160.001 l/h/kg, thisdecrease is again due to impairment of hepatocytes. Stasis in theliver bloodstream results in hypoxia of the hepatocytes [43].

Viral infections also affect the clearance of theophylline [44].It has been reported that its elimination half-life was prolongedin asthmatic children who had viral upper respiratory tractinfection. This effect is explained by suppression of theophyl-line metabolism in the liver by interferon [4]. Theophyllinekinetics change during an asthma attack [45]. During an asthmaattack, dehydration, change of arterial blood pH, humoral fac-tors, hypoxemia or acidosis occur in various degrees. Thedecrease in theophylline clearance during an asthma attack isbelieved to depend on hypoxemia. During the hypoxemicstage, oxidative drug metabolism in the liver is suppressed [46].Theophylline metabolism is also affected by the concomitantuse of some drugs. The drugs that increase the clearance rateand the ones that decrease the clearance rate are listed in BOXES1& 2, respectively.

Clinical efficacy of aminophylline in acute

asthma attacks

Theophylline produces bronchodilation in a linear fashionwith logarithmic increases in serum concentration [47].Although the optimal serum level for adequate bronchodila-tion is declared to be between 10 and 20 g/ml, serum levelsless than 10 g/ml are also reported to be able to achieve remis-sion or improvement of asthmatic condition due to possible

actions of theophylline, such as anti-inflammatory and immu-nomodulatory effects, and strengthening of diaphragmaticcontractions [48].

Dosage

A loading dose is needed to achieve the serum target level rapidly.The intravenous loading dose should not be administered in lessthan 1530 min in order to avoid severe cardiac arrhythmia. The

loading dose is 610 mg/kg, followed by a maintenance infusionof 1.0 mg/kg/h for children under 10 years of age and0.8 mg/kg/h if older than 10 years of age.

Efficacy of aminophylline in acute asthma

Efficacy in children

The Cochrane Collaboration presented a meta-analysis thatevaluates the role of aminophylline in the management of acutesevere asthma in children [49]. Seven published randomized,controlled trials comparing intravenous aminophylline withplacebo studying over 400 children met the inclusion criteria ofthe meta-analysis. Five were from the USA, one from Australiaand one from Turkey. The methodological quality, which isdescribed by Jadad, is scored out of 5 [50]. The mean qualityscore for the trials was 4.7. The trials scored as follows: Bien: 5;Carter: 5; DiGuilio: 4; Needleman: 5; Nuhoglu: 5; Strauss: 4;

and Yung: 5 [49].The trials focus predominantly on school-aged children. All

of the studies had been conducted on children with acute severeasthma who required hospital admission despite nebulized salb-utamol. Failure to respond to two or three successive nebuliza-tions of salbutamol was an inclusion criterion for all studies,except Strauss. In two studies, the ability to perform spirometry

was an inclusion criterion. The mean predicted forced expira-tory volume in 1 s (FEV1) at baseline was 41% in Cartersstudy, and mean peak expiratory flow at baseline was 37.5% inStrausss study. The mean age of the children was between 5and 9 years in all studies, except for Strauss, where the mean

age was 11.5 years for the aminophylline group and 10.5 yearsfor the placebo group. Children who had already been treated

with theophylline were excluded from all studies.All trials used clinical assessment scoring systems in order to

indicate baseline asthma severity. A baseline pulmonary indexscore was used to assess severity in four studies [51]. Pulmonaryindex scores between 5 and 7 were reported by Bien [52],Carter [53], Di Guiolio [54] and Nuhoglu [55]. The trial con-ducted by Strauss [56] reported a baseline WoodDownes [57]score of over 3 and Yung [58]reported a Bishop score [59]greaterthan 6. Needleman et al. reported a clinical score of 7 [60]. In allof these studies, intravenous aminophylline was applied as an

Box 1. Drugs that decrease the plasmatheophylline clearance rate.

Antimicrobials

Erythromycin Roxithromycin

Troleandomycin

Norfloxacin

Ofloxacin

Pefloxacin

-adrenoceptor blockers

Propranonol

Calcium channel blockers

Diltiazem

Nifedipine

Verapamil

Box 2. Drugs that increase the plasma theophyllineclearance rate.

Antimicrobials

Rifampicin

Isoniazid

Antiepileptic and sedative drugs

Phenytoin

Phenobarbital

Histamine H2 receptor antagonists

Cimetidine

Sympathomimetic drugs

Isoproterenol

Terbutaline

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initial bolus, followed by a continuous infusion. Four studies;Bien, Carter, Needleman and Strauss, aimed at therapeutic levelsbetween 1020 g/ml; in three studies, the aimed therapeuticlevels were slightly different. In all trials, systemic glucocorticoids

were administered to children together with regular nebulized

therapy [49]. The details of each study are given in TABLE1.No significant reduction in the number of nebulizers

needed was reported in the aminophylline-treated groups inany of the studies [49]. There was no significant effect withrespect to hospital stay. However, a statistically significantimprovement in FEV1was reported in children receiving ami-nophylline in the study by Yung, the largest trial. Theimprovement was 910% in the predicted value of FEV1,

which was detected between 6 and 24 h. A similar improve-ment of 1015% in the predicted peak expiratory flow (PEF)values was also reported [58]. A significant reduction in theclinical Bishop score occurred in the aminophylline group at6 h in the trial by Yung. No differences were found at anyother time with respect to clinical scoring. None of theremaining studies report significant differences in clinicalasthma scores [58].

A significant improvement in oxygen saturation and a signif-icant reduction in length of oxygen requirements werereported in the aminophylline group by Yung et al. Intubation

was also an outcome measure in this study. It was reportedthat 11 children out of 81 needed mechanical ventilation inthe placebo group, while only three children out of 82 neededmechanical ventilation in the aminophylline-treated group.The children treated with aminophylline had a statisticallysignificant reduction in the intubation rate [58].

The trials report vomiting as the most common side effect inthe aminophylline groups when compared with placebo. There

were no significant differences between aminophylline andplacebo groups with respect to the incidence of headache,tremor, seizures or arrhythmias at the aimed therapeutic levels,

which vary between 10 and 20 g/ml in all studies [49].As a result, we see that, in children with severe acute asthma

exacerbations unresponsive to bronchodilating treatment andsystemic steroids, the addition of intravenous aminophyllinemay improve lung function within 68 h and reduce the riskof intubation. However, it seems that no significant reductionin the number of bronchodilating nebulizations and thelength of hospital stay can be expected.

The latest Expert Panel Report-3 (2007) does not suggestusing intravenous methylxantines in the hospital managementof acute asthma [101]. Yet it notes that, in the study by Yunget al . [58], aminophylline decreases the need for intensive-careunit admission and intubation.

Efficacy in adults

Recently, a meta-analysis reviewing trials that examined theeffect of aminophylline additional to the standard care ofacute asthma exacerbations in adults was reported by theCochrane Collaboration [61]. Studies involving adult patients(>16 years of age) with acute asthma attending emergencydepartments were included. Patients with chronic obstruc-tive pulmonary disease (COPD) were excluded; studiesinvolving patients requiring mechanical ventilation at pres-entation were also excluded. Studies comparing intravenousaminophylline plus standard care versus placebo plus stand-ard care were included. The standard therapy included neb-ulized -agonists with or without corticosteroids. Trials

comparing aminophylline with 2-agonists were notincluded. There were six double-blind, placebo-controlled

Table 1. Controlled clinical trials (with a methodological quality score of at least 4) on children reported ina meta-analysis.

Trial Methodologicalquality score

(out of 5*)

Children(n)

Theurapeuticlevels (g/ml)

Mean age(years)

Severityat

baseline

Results Ref.

Carter et al. (1993) 5 21 1020 1112 57* No additional benefit [53]

DiGuilio et al. (1993) 4 29 1220 6.97.5 57* No additional benefit [54]

Bien et al. (1995) 5 44 1020 4.15.7 57

*

No additional benefit[52]

Needleman et al. (1995) 5 42 1020 78.5 >7 No additional benefit [60]

Strauss et al. (1994) 4 26 1020 10.711.5 >3 No additional benefit [56]

Nuhoglu et al. (1998) 5 38 10.514.3 5.25.9 57* No additional benefit [55]

Yung et al. (1998) 5 159 1520 6.26.3 >6 Additional benefit to

standard therapy

[58]

*Pulmonary index score from [51].Clinical asthma score from [60].From [57].From [59].Data from [49].

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trials that were accepted as adequate (Jadad quality score 4 or5) methodologically by the Cochrane analysis: Siegel [62],Emerman [63], Wrenn [64], Huang [65], Murphy [66] and Col-eridge [67]. The overall age range was 1560 years in the trials.The study population was composed of previously diagnosed

asthma patients who had come to the emergency departmentwith asthma exacerbation. The details of the studies are listedin TABLE2.

No statistically significant effect was reported with respect topulmonary function and hospital admission rate by the additionof aminophylline to -agonists in any of the trials. In addition,side effects, such as arrhythmia and vomiting, were observed tobe significantly higher in the aminophylline-treated groups [61].

In conclusion, most of the outcomes in these studies showthat there is no outstanding difference that aminophyllineadds to standard therapy in adult acute asthma. The narrowtherapeutic range and unfavorable safety profile relegate it to alast-line agent or no use at all.

Similarly, in the Expert Panel Report 3, aminophylline is notrecommended as part of the acute asthma treatment plan inadults [101].

Efficacy of aminophylline in COPD

Intravenous aminophylline has been used in the treatment ofchronic obstructive airway disease (COPD) exacerbations, yet,current evidence supporting its usage in this respect is rather

weak. The National Institute for Clinical Excellence suggests thatit should only be used when there is inadequate response to neb-ulized bronchodilators (grade D evidence) in the National

Clinical Guideline on Management of COPD in Adults in Pri-mary and Secondary Care [68]. In addition, The Thoracic Societyof Australia and New Zealand Guidelines for the Managementof COPD state that, The routine use of aminophylline is notrecommended for acute exacerbations (grade D evidence) [69].

A meta-analysis was reported by Barr et al. in 2003 withregards to this treatment. Four clinical trials have beenincluded, comprising a total of 169 subjects. No benefit interms of lung function, symptom scores or length of hospitalstay has been reported. Significant side effects, such as nausea

and vomiting, have also been noted [70].Recently, Duffy et al. investigated the efficacy of intravenous

aminophylline in 80 matched subjects with nonacidotic COPDexacerbations in a randomized, double-blind, placebo-control-led trial. No significant difference in spirometry, symptomscores or length of hospital stay was reported [71].

Another aspect in the use of aminophylline in COPD is theuse of oral aminophylline as a controlling agent. Aminophyl-line is absorbed rapidly after oral administration. Peak serumlevels occur in 1.52 h. A controlled trial by Chen et al. com-pared the efficacy of long-acting aminophylline (225 mg twicedaily for 8 weeks) in patients with COPD with different agegroups [72]. In one of the groups, the age range was5574 years; in the other it was 7590 years. The investigatorsdetected no significant difference with respect to FEV1 andforced vital capacity. Yet, in the o lder group, a symptom reliefin chest tightness had been reported.

Tolerability

Adverse reactions at theophylline serum concentrations of lessthan 20 mg/l are generally mild, such as nausea, vomiting,headache and insomnia. However, at dosages resulting inserum concentrations of more than 20 mg/l, potentially fataladverse events, including persistent vomiting, cardiac arrhyth-

mias and intractable seizures, can be seen. At therapeuticserum concentrations between 10 and 20 mg/l, adverse reac-tions, such as diarrhea, irritability, restlessness, fine tremorsand transient diuresis, can occur [19].

Recent advances

An intravenously administered theophyl-line (IAT) was developed recently in

Japan in 2000. Theophyll ine is not com-bined with ethylenediamine. Recently,Inoue et al . investigated the efficacy and

safety of IAT [73]. In total, 16 asthmaticpatients with mild acute exacerbations ofbronchial asthma were included in thestudy. The investigators administeredIAT (200 mg theophylline with 200 mlsaline) intravenously for 2 h. After thetreatment, significant increases in PEFand FEF in 1 s were reported. Clinicalseverity of asthma was also reported toimprove significantly. The study suggeststhat IAT is useful for patients with acuteexacerbations of bronchial asthma.

Table 2. Controlled clinical trials (with a methodological quality scoreof at least 4) in adults reported in a meta-analysis.

Trial Methodologicalquality score

(out of 5*)

Age(years)

Outcomemeasures

Result Ref.

Siegel et al. (1985) 4 1845 FEV1 Not effective [62]

Emerman et al. (1986) 45 1845 PEFR Not effective [63]

Wrenn et al. (1991) 4 >16 FEV1and

PEFR

Not effective [64]

Huang et al. (1993) 5 1850 FEV1 Not effective [65]

Murphy et al. (1993) 45 1845 PEFR Not effective [66]

Coleridge et al. (1993) 5 1555 PEFR Not effective [67]

*Methodological quality score from [50].FEV1: Forced expiratory volume in 1 s; PEFR: Peak expiratory flow rate.Data from [61].

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Similarly, in 2005, Yamauchi et al. reported a study investi-gating the efficacy of IAT in asthmatic subjects with mildexacerbations [74]. The study was randomized and placebocontrolled. The study group had received IAT 200 mg in200 ml of saline. The subjects were assessed with respect to

pulmonary functions and clinical asthma severity; the investi-gators reported a significant improvement both in pulmonaryfunction and clinical asthma severity score.

Conclusion

The Cochrane Collaboration has reported two large meta-analyses, one in adults [61] and one in children [49], whichinclude trials examining the efficacy of aminophylline inacute asthma attacks with appropriate methodological quality.

A statistically significant improvement in FEV1was reportedin children receiving aminophylline in the study by Yunget al.[57], which is the largest trial included in the meta-analy-ses. The improvement was 910% in the predicted value ofFEV1, which was detected between 6 and 24 h. A similarimprovement of 1015% in the predicted values of PEF wasalso reported. Yung et al.reported a significant improvementin oxygen saturation and reduction in length of oxygenrequirements with aminophylline. Intubation was also anoutcome measure. The children treated with aminophyllinehad a statistically significant reduction in the intubation rate.The remaining trials in children do not report a significantadditional benefit. The result of the adult trials that meet themethodological quality criteria reveal that aminophyllineadds no significant benefit to standard therapy. The answer to

why we see only a limited additional bronchodilating effectwith aminophyll ine, while it seems to be quite ef fective in thepast, might be:

The use of higher doses of-agonists (150 g/kg)

The higher level of specificity of the -agonists in thebeginning

The early administration of corticosteroids

In high serum theophylline concentrations, systemic sideeffects, such as seizures and cardiac arrhythmias, may also causeserious problems in these patients.

Expert commentary

The role of aminophylline in the treatment of acute asthmaexacerbations is still debated among physicians. In light of thecurrent data, we see that aminophylline should not be a part of

the acute asthma treatment plan in adults, due to the sideeffects and lack of additional benefit over standard therapy. Yet

we all know that it is not very easy to treat asthmatic attacks,especially in young children, in whom the respiratory musclesand diaphragm are not fully developed. The need for intensivecare and mechanical ventilation can arise very easily, even wheninhaled bronchodilators and intravenously administered ster-oids are used. In view of recent data regarding the efficacy ofaminophylline in the treatment of asthma attacks in children,

we as pediatricians think that aminophylline may be an alter-native to intravenous infusion of -agonists, heliox or magne-sium sulfate administration in children when respiratoryfatigue begins to develop and intensive-care unit admission andmechanical ventilation seems to be next treatment in line.

Five-year view

Aminophyll ine (theophyllineethylenediamine), which is anintravenous form of theophylline, seems set to remain in themarket for the next 5 years, especially for young children whohave severe asthma attacks unresponsive to standard therapies,in order to prevent mechanical ventilation. The efficacy andsafety of IAT (IAT without ethylenediamine) in the treatmentof acute asthma attacks need further research. However, currentdata show that this form of theophylline may find a place in the

future. Aminophylline in its oral form should be the subject offuture studies as a controller agent for elderly COPD patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript. This

includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

Aminophylline (theophyllineethylene diamine) is the intravenous form of theophylline.

Theophylline is a xanthine derivative. Its main pharmacological action is direct relaxation of bronchial smooth muscle,

relieving bronchospasm.

Although it has been used in the treatment of acute asthma for more than 50 years, its use started to decline owing to

safety concerns.

Most of the current data in children show that aminophylline does not have any additional benefit to standard therapy. However, one

large trial with high methodological quality reported improved pulmonary function and reduced intubation rate.

Aminophylline is not recommended for use in adults owing to safety concerns and the lack of additional benefit over

standard treatment.

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References

Papers of special note have been highlighted as:

of interest

of considerable interest

1Weinberger M, Hendeles L. Theophyllinein asthma. N. Engl. J. Med. 334 (21),

13801388 (1996).

2 Ward AJ, McKenniff M, Evans JM,

Page CP, Costello JF. Theophylline: an

immunomodulatory role in asthma?Am. Rev. Respir. Dis. 147(3), 518523

(1993).

3 Kidney J, Dominguez M, Taylor PM,

Rose M, Chung KF, Barnes PJ.

Immunomodulation by theophylline in

asthma demonstration by withdrawal oftherapy.Am. J. Respir. Crit. Care Med.

151(6), 19071914 (1995).

4 Kawai M, Kato M. Theophylline for the

treatment of bronchial asthma: present

status.Methods Find. Exp. Clin. Pharmacol.

22(5), 309320 (2000).

5 Herrmann G, Aynesworth MB, Martin J.

Successful treatment of persistent extremedyspnea status asthmaticus: use of

theophylline ethylenediamine intravenously.

J. Lab. Clin. Med.23, 135148 (1937).

6 Aubier M, De Troyer A, Sampson M,

Macklem PT, Roussos C. Aminophylline

improves diaphragmatic contractility.N. Engl. J. Med. 305(5), 249252 (1981).

7 Kolbeck RC, Speir WA Jr, Carrier GO,Bransome ED Jr. Apparent irrelevance of

cyclic nucleotides to the relaxation of

tracheal smooth muscle induced by

theophylline. Lung156(3), 173183(1979).

8 Higbee MD, Kumar M, Galant SP.Stimulation of the endogenous

cathecolamine release by theophylline: a

proposed additional mechanism of action

for theophylline effects.J. Allergy Clin.Immunol. 70(5), 377382 (1982).

9 Horrobin DF, Manku MS, Franks DJ,

Hamet P. Methyl xanthinephosphodiesterase inhibitors behave as

prostoglandin antagonists in a perfused rat

mesenteric artery preparation. Prostoglandins13(1), 3340 (1977).

10 Nicholson CD, Shahid M. Inhibitors ofcyclic nucleotide phosphodiesterase

isoenzymes-their potential utility in the

therapy of asthma. Pulm. Pharmacol.7(1),

117 (1994).

11 Ito K, Lim S, Caramori G, Cosio B, Chung

KF, Adcock IM, Barnes PJ. A molecularmechanism of action of theophylline:

induction of histone deacetylase activity todecrease inflammatory gene expression.

Proc. Natl Acad. Sci. USA99(13),

89218926 (2002).

12 Foukas LC, Daniele N, Ktori C et al.

Direct effects of caffeine and theophylline

on the p110d and otherphosphoinositiode 3 kinases; differential

effects on lipid kinase and protein kinase

activities.J. Biol. Chem. 277(40),

3712437130 (2002).

13 Fredholm BB. Theophylline actions on

adenosine receptors. Eur. J. Respir. Dis.Suppl.109, 2936 (1980).

14 El-Hashim A, DAgostino B, Matera MG,Page C. Characterization of adenosine

receptors involved in adenosine-induced

bronchoconstriction in allergic rabbits.

Br. J. Pharmacol.119(6), 12621268

(1996).15 Bjorck T, Gustaffsson LE, Dahlen SE.

Isolated bronchi from asthmatics are

hyperresponsive to adenosine, which

apparently acts indirectly by liberation of

leukotriens and histamine.Am. Rev.Respir. Dis. 145(5), 10871091 (1992).

16 Cushley MJ, Tattersfield AE, Holgate ST.Adenosine-induced bronchoconstricition

in asthma. Antagonism by inhaled

theophylline.Am. Rev. Respir. Dis. 129(3),

380384 (1984).

17 Mann JS, Holgate ST. Specific

antagonism of adenosine-inducedbronchoconstriciton in a sthma by oral

theophylline. Br. J. Clin. Pharmacol.

19(5), 685692 (1985).

18 Schudt C, Tenor H, Hatzelmann A.

PDE isoenzymes as targets for anti-asthma

drugs. Eur. Respir. J. 8(7), 11791183(1995).

19 Markham A, Faulds D. Theophylline: areview of its potential steroid sparing

effects in asthma. Drugs56(6),

10811091 (1998).

20 Jaffar Z, Sull ivan PJ, Page CP, Costel lo JF.

Low dose theophylline therapy modulates

T-lymphocyte activity in subjects withatopic asthma. Eur. Resp. J. 9(3), 456463

(1996).

21 Shohat B, Volovitz B, Varsano I.

Induction of suppressor T cells in

asthmatic children by theophylline

treatment. Clin. Allergy 13(5), 487493(1983).

22 Fink G, Mittelman M, Sholat B, SpitzerSA. Theophylline-induced alterations in

cellular immunity in asthmatic patients.

Clin. Allergy 17(4), 313316 (1987).

23 Page CP. Recent advances in ourunderstanding of the use of theophylline

in the treatment of asthma.J. Clin.

Pharmacol. 39(3), 237240 (1999).

24 Finnerty JP, Lee C, Wilson S, Madden J,

Djukanovic R, Holgate ST. Effects of

theophylline on inflammatory cells andcytokines in asthmatic subjects: a placebo

controlled parallel group study. Eur. Respir. J.

9(8), 16721677 (1996).

25 Ohta K, Sawamoto S, Nakajima M et al. The

prolonged survival of human eosinophils

with interleukin-5 and its inhibition bytheophylline via apoptosis. Clin. Exp. Allergy

26(Suppl. 2), 1015 (1996).

26 Spoelstra FM, Berends C, Dijkhuizen B,

de Monchy JG, Kauffman HF. Effect of

theophylline on CD11b and L-selectin

expression and density of eosinophils and

neutrophils in vitro. Eur. Respir. J. 12(3),585591 (1998).

27 Mascali JJ, Cvietusa P, Negri J, Borish L.

Antiinflammatory effects of theophylline:

modulation of cytokine production.Ann.

Allergy Asthma Immunol. 77(1), 3438(1996).

28 Punnonen J, de Wall Malefty R,van Vlasselaer P. IL-10 and viral IL-10

prevent IL-4 induced IgE synthesis by

inhibiting the accessory cell function of

monocytes.J. Immunol. 151(3), 12801289(1993).

29 Enk AH, Angeloni VL, Udey MC, Katz SI.Inhibition of Langerhans cell antigen-

presenting function by IL-10: a role for

IL-10 in induction tolerance.J. Immunol.

151(5), 23902398 (1993).

30 Kroon LA. Drug interactions with smoking.

Am. J. Health Syst. Pharm.64(18),19171921 (2007).

31 Mcelnay JC, Smith GD, Helling DK.A practical guide to interactions involving

theophylline kinetics. Drug Intell. Clin.

Pharm. 16(78), 533542 (1982).

32 Lu C, Miwa GT, Prakash SR, Gan LS,

Balani SK. A novel model for the prediction

of drug-drug interactions in humans basedon in vitrocytochrome p450 phenotypic

data. Drug Metab. Dispos.35(1), 7985

(2007).

33 Weinberger MW, Matthay RA, Ginchansky

EJ, Chidsey CA, Petty TL. Intravenous

aminophylline dosage: use of serumtheophylline measurement for guidance.

JAMA 235(19), 21102113 (1976).

34 Zaske DE, Miller KW, Strem EL, Austrian S,

Johnson PB. Oral aminophylline therapy:

increased dosage requirements in children.

JAMA 237(14), 14531455 (1977).

8/12/2019 2E305

8/9



35 Ohnishi A, Kato M, Kojima J, Ushiama H,Yoneko M, Kawai H. Differential

pharmacokinetics of theophylline in elderly

patients. Drugs Aging20(1), 7184 (2003).

36 Edginton AN, Schmitt W, Willmann S.

Development and evaluation of a generic

physiologically based pharmacokineticmodel for children. Clin. Pharmacokinet.

45(10), 10131034 (2006).

37 Cusack B, Kelly JG, Lavan J, Noel J,

OMalley K. Theophylline kinetics in

relation to age: the importance of smoking.

Br. J. Clin. Pharmacol. 10(2), 109114(1980).

38 Jusko WJ, Schentag JJ, Clark JH,Gardner M, Yurchak AM. Enhanced

biotransformation of theophylline in

marihuana and tobacco smokers. Clin.

Pharmacol. Ther. 24(4), 405410 (1978).

39 Grygiel JJ, Birkett DJ. Cigarette smokingand theophylline clearence and metabolism.Clin. Pharmacol. Ther. 30(4), 491496

(1981).

40 Frye RF, Zgheib NK, Matzke GR et al.Liver

disease selectively modulated cytochrome P-

450-mediated metabolism. Clin. Pharmacol.

Ther.80(3), 235245 (2006).

41 Mangione A, Imhoff TE, Lee RV, Shum LY,

Jusko WJ. Pharmacokinetics of theophyllinein hepatic disease. Chest 73(5), 616622

(1978).

42 Self TH, Chafin CC, Soberman JE. Effect of

disease states on theophylline serumconcentrations: are we still vigilant?Am. J.

Med. Sci.319(3), 177182 (2000).

43 Vozeh S, Powell JR, Riegelman S, Costello

JF, Sheiner LB, Hopewell PC. Changes intheophylline clearance during acute illness.

JAMA 240(17), 18821884 (1978).

44 Itazawa T, Adachi Y, Nakabayashi M,

Fuchizawa T, Murakami G, Miyawaki T.

Theophylline metabolism in acute asthma

with MxA-indicated viral infection. Pediatr.Int. 48, 5457 (2006).

45 Odajima Y. Examination of theophylline

pharmacokinetics during an attack ofbronchial asthma in children.Arerugi 41(1),

2228 (1992).

46 Resar RK, Walson PD, Fritz WL, Perry DF,

Barbee RA. Kinetics of theophylline

variability and effect of arterial pH inchronic obstructive lung disease. Chest76(1),

1116 (1979).

47 Ohnishi A. A review of clinical use of

theophylline in acute asthma: factors

influencing kinetic disposition and drug

interactions.Methods Find. Exp. Clin.Pharmacol.22(4), 253258 (2000).

48 Thomson NC. Asthma therapy:theophylline. Can. Respir. J.5(Suppl. A),

A60A63 (1998).

49 Mitra A, Bassler D, Goodman K, Lasserson

TJ, Ducharme FM. Intravenous

aminophylline for acute severe asthma in

children over two years receiving inhaledbronchodilators. Cochrane Database Syst. Rev.

(2), CD001276 (2005).

Meta-analysis examining trials on the

efficacy of aminophylline in the treatment of

acute asthma attacks in children.

50 Jadad AR, Moore RA, Carroll D et al.Assessing the quality of randomized

controlled trials: is blinding necessary?

Control. Clin. Trials17(1), 112 (1996).

51 Becker AB, Nelson NA, Simons ER.

The pulmonary index assessment of a clinical

score for asthma.Am. J. Dis. Child.138(6),

574576 (1984).

52 Bien JP, Bloom MD, Evans RL, Specker B,OBrien KP. Intravenous theophylline in

pediatric status asthmaticus. A prospective,

randomized, double-blind, placebo-

controlled trial. Clin. Pediatr.(Phila.)34(9),475481 (1995).

53 Carter E, Cruz M, Chesrown S, Shieh G,Reilly K, Hendeles L. Efficacy of

intravenously administered theophylline in

children hospitalised with severe asthma.

J. Pediatr.122(3), 470476 (1993).

54 DiGiulio GA, Kercsmar CM, Krug SE,

Alpert SE, Marx CM. Hospital treatment ofasthma: lack of benefit from theophylline

given in addition to nebulized albuterol and

intravenously administered corticosteroid.J.

Pediatr.122(3), 464469 (1993).

55 Nuhoglu Y, Dai A, Barlan IB, Baaran MM.

Efficacy of aminophylline in the treatment ofacute asthma exacerbation in children.Ann.

Allergy Asthma Immunol.80(5), 395398

(1998).

56 Strauss RE, Wertheim DL, Bonagura VR,

Valacer DJ. Aminophylline therapy does not

improve outcome and increases adverse events

in children hospitalized with acute asthmaticexacerbations. Pediatrics93(2), 205210

(1994).

57 Wood DW, Downes JJ, Leeks HI. A clinical

scoring system for the diagnosis of respiratory

failure.Am. J. Dis. Child.123(3), 227228(1972).

58 Yung M, South M. Randomized controlledtrial of aminophylline for severe acute asthma.

Arch. Dis. Child. 79(5), 405410 (1998).

Largest trial in the meta-analysis by Mitra et

al. that reports benefit with the use of

aminophylline in children.

59 Bishop J, Carlin J, Nolan T. Evaluation ofthe properties and reliability of a clinical

severity scale for acute asthma in children.

J. Clin. Epidemiol. 45(1), 7176 (1992).

60 Needleman JP, Kaifer MC, Nold JT,

Shuster PE, Redding MM, Gladstein J.

Theophylline does not shorten hospitalstay for children admitted for asthma.

Arch. Pediatr. Adolesc. Med.149(2),

206209 (1995).

61 Parameswaran K, Belda J, Rowe BH.

Addition of intravenous aminophylline to

-2 agonists in adults with acute asthma.Cochrane Database Syst. Rev. (4),

CD002742 (2000).

Meta-analysis examining trials on the

efficacy of aminophylline in the

treatment of acute asthma attacks

in adults.

62 Siegel D, Sheppard D, Gelb A, Weinberg

PF. Aminophylline increases the toxicitybut not the efficacy of an inhaled-adrenergic agonist in the treatment of

acute asthma exacerbations.Am. Rev.

Respir. Dis. 132 (2), 283286 (1985).

63 Emerman CL, Crafford WA, Vrobel TR.

Ventricular arrhythmias during treatmentfor acute asthma.Ann. Emerg. Med. 15(6),

699702 (1986).

64 Wrenn K, Slovis CM, Murphy F,

Greenberg RS. Aminophylline therapy for

acute bronchospastic disease in the

emergency room.Ann. Int. Med. 115(4),241247 (1991).

65 Huang D, OBrien RG, Harman E et al.Does aminophylline benefit adults

admitted to the hospital for an acute

exacerbation of asthma?Ann. Int. Med.

119(12), 11551160 (1993).

66 Murphy DG, McDermott MF, Rydman

RJ, Sloan EP, Zalenski RJ. Aminophyllinein the treatment of acute asthma when -2

adrenergics and steroids are provided.

Arch. Int. Med. 153(15), 17841788

(1993).

67 Coleridge J, Cameron P, Epstein J,Teichtahl H. Intravenous aminophyllineconfers no benefit in acute asthma treated

with intravenous steroids and inhaled

bronchodilators.Aust. NZ J . Med. 23(4),

348354 (1993).

68 National Collaborating Centre for

Chronic Conditions. Chronic obstructivepulmonary disease. National clinical

guideline on management of chronic

obstructive pulmonary disease in adults in

primary and secondary care. Thorax59(Suppl. 1), 1232 (2004).

8/12/2019 2E305

9/9



69 McKenzie DK, Frith PA, Burdon JG,Town GI; Australian Lung Foundation;

Thoracic Society of Australia and New

Zealand. The COPDX plan: Australian

and New Zealand guidelines for themanagement of COPD 2003.Med. J.

Aust. 178(Suppl.), S7S39 (2003).70 Barr RG, Rowe BH, Camargo CA Jr.

Methylxanthines for exacerbations of

chronic obstructive pulmonary disease:

meta-analysis of randomised trials. BMJ327(7416), 643648 (2003).

71 Duffy N, Walker P, Diamantea F, CalverleyPM, Davies L. Intravenous aminophylline

in patients admitted to hospital with non-

acidotic exacerbations of chronic

obstructive pulmonary disease: aprospective randomised controlled trial.

Thorax60(9), 713717 (2005).

72 Chen CY, Yang KY, Lee YC, Perng PP.Effect of oral aminophylline on pulmonary

function improvement and tolerability in

different age groups of COPD patients.Chest 128(4), 20882092 (2005).

73 Inoue H, Yamauchi K, Kobayashi H,Tanifuji Y. The efficacy of intravenous

theophylline injection for treatment of

acute exacerbations of bronchial asthma.

Arerugi51(4), 379382 (2002).

74 Yamauchi K, Kobayashi H, Tanifuji Y,

Yoshida T, Pian HD, Inoue H. Efficacy andsafety of intravenous theophylline

administration for treatment of mild acute

exacerbation of bronchial asthma.

Respirology 10(4), 491496 (2005).

Website

101 National Asthma Education and Prevention

Program: Expert Panel Report III:Guidelines for the Diagnosis and

Management of Asthma. National Heart,

Lung, and Blood Institute, Bethesda, MD,

USA (2007)

www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Latest guideline that has suggestions with

respect to aminophylline use in acute

asthma attacks.

Affiliations

Yonca NuhogluProfessor of Pediatric Allergy, Istanbul

Bilim University, Faculty of Medicine,

Department of Pediatrics, Istanbul, Turkey

Tel.: +90 216 363 4273

Fax: +90 216 369 [email protected]

Cagatay NuhogluGeneral Pediatrician, Haydarpasa Numune

Training and Research Hospital,

Department of Pediatrics, Istanbul, Turkey

Tel.: +90 216 363 4273Fax: +90 216 369 3235

[email protected]

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