DOXOPHYLLINE + TERBUTALINE

FIXED DOSE COMBINATION

JUSTIFICATION RATIONALE
In about 50% of children with asthma, the condition may become inactive in the
teenage years. The symptoms, however, may reoccur anytime in adulthood. You
have a 6% chance of having asthma if neither parent has the condition, a 30%
chance if one parent has it, and a 70% chance if both parents have it. Asthma is
not contagious. Swimming is an optimal exercise for those with asthma. On the
other hand, exercising in dry, cold air may be a trigger for asthma in some
people. There is no cure for asthma, but the disease can be controlled in most
patients with good medical care. The condition should be taken seriously, since
uncontrolled asthma may result in emergency hospitalization and possible death.

Methylexanthines are widely used in the treatment of asthma. Being one of the
new drugs that can be administered orally, these are especially helpful in
resource restricted settings. In 2006, revised global initiatives for asthma
guideline (GINA), methylexanthines have been included in the category of add on
controller drugs in step-3 and step-4 for children above 5 years of age.

The bronchodialatory effect of methylexanthines is due to their ability to inhibit

phosphodiasterase (PDE) and thus breakdown of cAMP (cyclic adenosine
monophosphate). Increase in cyclic AMP inhibits activation of inflammatory cells
in addition to bronchodialation.

Of the Methylexanthines, theophylline has been in use for several decades now.
In addition to bronchodiallation, it has immunomodulatory, anti-inflammatory and
bronchoprotective effects also. However, theophylline often results in wide range
of adverse effects, involving cardiac, GIT and CNS which accounts for the poor
compliance and high dropouts rate reported with its use. Moreover it has a
narrow therapeutic index thus warranting strict monitoring of its level in the blood.

A new methylxanthine derivative that possesses similar efficacy as theophylline,

but has significantly less side effects may immensely benefits the patients.
Doxophylline has emerged as one such wonderful drug, studied in animal as well
as human adults and children with obstructive airway disease have found it to be
effective and safe.

Successful treatment of acute, severe asthma with subcutaneous injections of

adrenaline started 100 years ago. Over the years, synthetic congeners of
adrenaline (i.e. terbutaline, ibuterol, bambuterol) have been produced and tested
for their pharmacological properties. Because of its relatively high metabolic
stability, terbutaline can be systemically administered, and its duration of action is
prolonged in comparison to the solely amine-substituted analogues of adrenaline.
Terbutaline stimulates b-adrenergic receptors of the sympathetic nervous system
and has little or no effect on a-adrenergic receptors3. Despite its low and
stereoselective bioavailability, terbutaline is widely used as a bronchodilator for
treatment of bronchial asthma, chronic bronchitis and emphysema. On the other
hand, terbutaline has not been approved and should not be used without
permission of the patient in preterm labor. Although terbutaline may produce a
wide range of adverse effects (e.g. nervousness, tremor, palpitation, tachycardia,
headache, nausea, sweating), all these reactions are transient in nature and
usually do not require treatment.

In vitro studies conducted in the Department of Clinical Pharmacology and Lung

Medicine, University of Göteborg, Fack, Sweden on human bronchial and
skeletal muscle indicate that combination of theophylline and adrenergic β2-
stimulants may give a potentiated therapeutic effect with fewer side-effects, such
as tremor, than treatment with β2-stimulants alone. In vivo studies in asthmatics
showed that pre-treatment with equipotent oral broncho-dilating doses of
theophylline and terbutaline potentiated the effect of terbutaline by inhalation to
the same degree, in contrast to pre-treatment with equipotent bronchodilating
doses of terbutaline given by inhalation. Moderate oral bronchodilating doses of
either theophylline or β2-adrenostimulant combined with β2-stimulants by aerosol,
therefore, seem to be an effective form of treatment. The choice of oral treatment
depends on the side-effects. In patients with tremor problems, theophylline would
appear to be preferable: combination of low oral doses of theophylline and β 2-
adreno-stimulants gave a better bronchodialation with lower degree of skeletal
muscle tremor than a higher dose β2-adrenostimulants by mouth alone.

It is very true the choice of oral treatment depends on the side-effects. Therefore,
FDC of doxophylline and terbutaline is a better alternative for the treatment of
acute and chronic asthma as efficacy and safety goes hand-in-hand. It is
noteworthy that doxophylline doesn’t affects CNS, GIT, heart and kidney unlike
other mehtylxanthines.

Reference

• Waldeck B. b-adrenoceptor agonists and asthma – 100 years of

development, Eur. J. Pharmacol., 445, 1-12, 2002.
• Rosenborg J. Clinical-pharmacokinetic aspects of prolonged effect
duration as illustrated by b2-agonists, Eur. J. Clin. Pharmacol. 58(4), 1-21,
2002.
• AHFS Drug Information. McEvoy GK (ed), American Society of Health-
System Pharmacists, 1313-13172002.
• Physicians Desk Reference, 56th ed., 2313-2315, 2002.

MEHER PHARMA INTERNATIONAL

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DR.MOHD SHAHBAZ ALAM-9818131498, shahbaz@meherpharma.com