Thursday, July 1, 2010

DOXOPHYLLINE +TERBUTALINE

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 β2-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

B-6/151, SECTOR-3, NEAR JAIPURE GOLDEN HOSPITAL, DELHI-85

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

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