, Volume 27, Issue 3, pp 210-231
Date: 12 Oct 2012

Oxatomide

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Summary

Synopsis: Oxatomide1 is an orally active H1-histamine receptor antagonist which, as appears to occur with some other antihistamines, also inhibits mast cell degranulation. Oxatomide has demonstrated response rates similar to those with other more established members of its drug class in a few studies of chronic urticaria and allergic rhinitis. Interestingly, some patients responding to oxatomide were said to be unresponsive to previously administered antihistamines. The effect of oxatomide was little different from placebo in clinical trials of bronchial asthma in adults. While somewhat more encouraging results have been reported in children with bronchial asthma when higher than presently recommended dosages were employed, and in follicular conjunctivitis, atopic dermatitis and food allergy, reports to date are largely preliminary in nature and additional well-controlled studies are needed to clarify the efficacy of oxatomide in such conditions. The drug has been generally well tolerated, but shares some of the familiar H1-histamine receptor antagonist side effects. As with other similarly acting drugs, the 2 primary side effects with oxatomide are drowsiness and weight gain. Thus, on the basis of present evidence, a trial with oxatomide seems a potentially useful alternative in patients with conditions known or thought to be allergic in nature, in whom more established treatments were ineffective or poorly tolerated.

Pharmacodynamic Studies: Oxatomide, an H1-histamine receptor antagonist chemically related to cinnarizine, has demonstrated potent antihistamine activity, some anti-serotonin and anticholinergic activity, and possibly anti-SRS-A activity in several in vitro and in vivo models. Additionally, oxatomide has shown an inhibitory effect on the antigen and chemically mediated release of histamine from rat peritoneal mast cells, human lung tissue, and human basophilic leucocytes, and has attenuated the characteristic mast cell morphology changes associated with anaphylaxis in guinea-pigs and rats. However, the relative contribution of the inhibition of mediator release, versus the antagonism of mediators, to the drug’s observed antiallergic activity in vitro and in vivo (including exercise provocation studies in asthmatic patients) and to its clinical activity is unknown. Additionally, the mechanism by which oxatomide affects the histamine flux from mast cells is also unclear. However, it does not appear to be similar to the mechanism of action of sodium cromoglycate (cromolyn sodium), and probably more closely resembles the mechanism by which some other lipophilic H1-histamine receptor antagonists affect histamine flux in in vitro models of human mast cells. H1-histamine receptors are probably not involved, but there is some evidence to suggest that adsorption of oxatomide into the mast cell cellular membrane and a disruption of calcium movement into the cell are part of the process.

Pharmacokinetics: Peak plasma concentrations occur within 4 hours of administration of an oral oxatomide dose of 60 or 120mg. With long term administration of 30mg twice daily, the mean plasma concentrations increased gradually for about a week and then varied little with continued therapy. Mean monthly plasma concentrations, associated with long term administration of 60mg 3 times daily, remained constant for treatment periods of up to 6 months. A clear correlation was not demonstrated between oxatomide dose and plasma concentration — possibly a reflection of variations in absorption or, more likely, problems with current assay methods.

Oxatomide is highly bound to plasma proteins in human blood (91%). In experimental animals the drug is widely distributed, with highest drug concentrations occurring in the liver, lung and pancreas. Oxatomide also entered the breast milk in lactating beagle dogs, reaching peak milk concentrations of about one-half the peak concentrations in serum.

An elimination half-life of approximately 14 hours was observed following a single 120mg dose of oxatomide in healthy subjects. The drug is extensively metabolised via aromatic hydroxylation and oxidative-N-dealkylation in man, with approximately 40% and 54% of an administered dose excreted as urinary and faecal metabolites, respectively. Less than 0.1% of a dose is excreted in the urine as unchanged drug.

Therapeutic Trials: In placebo-controlled trials in patients with chronic urticaria, oxatomide therapy decreased symptom severity and supplemental antihistamine use, and improved global assessments. Comparative studies demonstrated that oxatomide was as effective as chlorpheniramine and clemastine, and somewhat more efficacious than the phenothiazine antihistamine mequitazine.

In placebo-controlled trials in allergic rhinitis, oxatomide improved symptoms and decreased supplemental antihistamine use. Oxatomide has been shown to be at least as effective as chlorpheniramine, diphenhydramine or the combination of cinnarizine and phenylpropanolamine. Thus, oxatomide is an additional option in patients with allergic rhinitis who do not respond to, or tolerate poorly, these more established antihistamines.

In placebo-controlled trials in adults having bronchial asthma, the activity of oxatomide was little different from that of placebo. A few unpublished studies have reported more encouraging results in children than those in adults when dosages higher than those presently recommended were employed, but further study is needed to clarify whether oxatomide offers a useful alternative in childhood asthma.

Encouraging preliminary results have also been obtained in follicular conjunctivitis, atopic dermatitis and food allergy.

Side Effects: Oxatomide has been generally well tolerated. In common with other H1-histamine receptor antagonists, drowsiness is the most frequent complaint. Weight gain, headache, gastrointestinal complaints, rash and dry mouth have also been reported. In the limited clinical experience reported to date only a few patients have discontinued therapy due to side effects.

Dosage and Administration: The recommended oral dosage is 30mg taken after breakfast and the evening meal. In children, correct dosage is more easily achieved with use of the oral drops in a dosage of 0.5 mg/kg twice daily (which can be doubled if there is insufficient response within a week).

Various sections of the manuscript reviewed by: P. Borum, University Ear, Nose and Throat Department, Rigshospitalet, Copenhagen, Denmark; J.H. Darbyshire, MRC Tuberculosis and Chest Diseases Unit, Brompton Hospital, London, England; J. De Cree, Clinical Research Unit, St. Bartholomeus Hospital, Antwerp, Belgium; R.T. Jackson, Laboratory of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia, USA; E.F. Juniper, Firestone Regional Chest and Allergy Unit, McMaster University, Ontario, Canada; C. Möller, Department of Pediatrics, University of Umea, Umea, Sweden; N. Mygind, University Ear, Nose and Throat Department, Rigshospitalet, Copenhagen, Denmark; H. Verhaegen, Clinical Research Unit, St. Bartholomeus Hospital, Antwerp, Belgium; J.D. Wilson, Department of Immunology, University of Auckland, Auckland, New Zealand; S. Wood, Department of General Practice, University of Glasgow, Glasgow, Scotland.
‘Tinset’ (Janssen).