Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-15
2002-08-20
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06436924
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions which contain a nonsedating antihistamine and a substance influencing leukotriene action to improve the local therapy of allergic and/or vasomotor rhinitis and of allergic conjunctivitis.
BACKGROUND
The number of allergic disorders is greatly increasing worldwide. Studies have shown that on average worldwide 7.5% of all children and adolescents suffer from rhinoconjunctivitis which is hay fever combined with an ocular symptomatology (Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC, Lancet, 351, 1225-1332, 1998). In West European countries, the prevalence, at about 14%, is markedly higher (Annesi-Maesano, I. and Oryszczyn, M. P.: Rhinitis in adolescents, Results of the ISAAC survey, Revue Francaise d'Allergologie et d'Immunologie Clinique, 38, 283-289, 1998; Norrman, E., L. Nystrom, E. Jonsson and N. Stjernberg: Prevalence and incidence of asthma and rhinoconjunctivitis in Swedish teenagers, European Journal of Allergy and Clinical Immunology, 53, 28-35, 1998).
Intensive research activities of recent years have led to the recognition that allergic rhinoconjunctivitis is an inflammatory process in the sense of a persistent inflammatory reaction. While histamine is still regarded as the most important mediator of the early phase and as the most important trigger of the symptoms such as reddening, sneezing, itching and hypersecretion (rhinorrhea and lacrimation), further mediators such as the leukotrienes are involved in the nasal obstruction, secretion and in the progression of the inflammation (e.g. attraction of the proinflammatory cells, promotion of cellular infiltration, etc.). Accordingly, the aims of the therapy have been shifted from symptomatic therapy to an additional antiinflammatory therapy with influencing of the inflammation underlying the allergic disorders. Both histamine and leukotrienes (LTs) are released in the allergic early phase and late phase.
The acute symptoms (itching, reddening, swelling, rhinorrhea and lacrimation) of rhinoconjunctivitis can be readily controlled, inter alia, with the aid of classical antihistamines of the first and second generations. However, they hardly have a therapeutically relevant influence on the inflammation which underlies the disorder and is always progressive. Often, the allergic rhinitis (rhinoconjunctivitis) is regarded both by patients and by the physician as a trivial disorder and accordingly is only inadequately treated. As a result, however, a so-called change of stage can occur, i.e. bronchial asthma, which is to be taken very seriously, develops from the relatively harmless rhinitis. For this reason, it is indispensable to treat even allergic rhinoconjunctivitis adequately and intensively. Only then can the patients live symptom-free and only then can a change of stage, which under certain circumstances is life-threatening, be prevented.
Numerous animal experimental and clinical studies indicate that both histamine and LTs can be detected in nasal secretion (Yamasaki, U., T. Matsumoto, S. Fukuda, T. Natayama, H. Nagaya, Y. Ashida. Involvement of thromboxane A
2
and histamine in experimental allergic rhinitis of guinea pigs. J. Pharmacol. Exp. Ther. 82:1046, 1997; Pipkorn, U, G Karlsson, L Enerbeck. Cellular response of the human allergic nasal mucosa to natural allergen exposure. J. Allergy Clin. Immunol. 35:234, 1988; Volovitz, B., S. L. Osur, M. Berstein, P. L. Ogra. Leukotriene C
4
release in upper respiratory mucosa during natural exposure to ragweed-sensitive children. J. Allergy Clin. Immunol. 82:414, 1988). Owing to the blockade of the histamine H
1
receptors, certain symptoms such as sneezing, reddening, itching and nasal or ocular hypersecretion (rhinorrhea, lacrimation) are significantly reduced (Simons, F. E. R., K. J. Simons. Second generation H
1
-receptor antagonists. Ann. Allergy 66:5, 1991). In the acute phase of any allergic reaction—independently of the location—degranulation and the emptying of the intracellular stores of the mast cells or of the basophilic granulocytes are prominent. This is a process which is controlled by the extra- or intracellular calcium.
Histamine, however, does not only act as a mediator which induces allergic symptoms, it also acts on the allergic inflammation by influencing the release of cytokines. In a study on human conjunctival epithelial cells (eye), it was shown that histamine greatly increases the secretion of II-8 and GM-CSF (granulocyte macrophage colony stimulating factor). This release can be prevented by histamine H
1
receptor antagonists, i.e. this action is mediated via H
1
receptors (Weimer, L. K., D. A. Gamache, J. M. Yanni. Histamine-stimulated cytokine secretion from human conjunctival epithelial cells: inhibition by histamine H
1
-antagonist emedastine. Int. Arch. Allergy Immunol. 115:288, 1998). In addition, we know that allergic stimulation not only releases the intracellularly stored histamine from the mast cells and basophilic granulocytes, but also brings about the de novo synthesis of other mediators such as leukotrienes.
Leukotrienes are mediators which belong to the group of eicosanoids. They are derivatives of arachidonic acid, a fatty acid which is a constituent of membrane phospholipids. The leukotrienes are formed from arachidonic acid via 5-lipoxygenase (5-LOX). At the present time, only the pathogenetically relevant role of the so-called cysteinyl-leukotrienes, to which LTC
4
, LTD
4
and LTE
4
belong, has been confirmed. The action of the leukotrienes can take place due to occupation of their receptors or by inhibition of their synthesis. In addition to the inhibition of 5-lipoxygenase, the inhibition of a 5-lipoxygenase-activating protein (hereinafter also referred to as “FLAP”) can also lead to decreased synthesis of leukotrienes.
Among the numerous LT antagonists, a few, such as zafirlukast, montelukast, pranlukast, etc. are employed therapeutically in bronchial asthma.
Zileuton is on the market of the 5-LOX inhibitors. The so-called FLAP inhibitors include, for example, MK-591, Bay 1005, which are still in the clinical testing phase.
Numerous investigations confirm the importance of the leukotrienes in allergic disorders. Thus after allergen provocation a marked increase in the LT concentration in the nasal lavage fluid of patients with allergic rhinitis was detected both in the early phase and in the late phase (Creticos, P. S., S. P. Peters, N. F. Adkinson. Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N. Eng. J. Med. 310:1626, 1984). Cysteinyl-LTs can induce hypersecretion (rhinorrhea or lacrimation), but the leukotrienes appear to be far more important for nasal obstruction.
The nasal obstruction induced by histamine is present in the early phase of the allergic reaction and lasts only minutes, while the obstruction due to leukotrienes can be observed up to the late phase, which lasts 6-8 hours after the allergic provocation. In contrast to histamine, sneezing and itching do not occur after LT provocation (Okuda, M., T. Watase, A. Mazewa, C. M. Liu. The role of leukotrine D
4
in allergic rhinitis. Ann. Allergy 60:537, 1988). After provocation with LTD
4
, however, there is a long-lasting infiltration of eosinophilic granulocytes, which for the greatest part are responsible for the allergic inflammation (Fujika, M. et al. see above).
These so-called late-phase reactions (e.g. nasal obstruction) can be improved by LT antagonists such as zafirlukast (Donnelly, A. L., M. Glass, M. C. Minkwitz, T. B. Casale. The leukotriene D
4
-receptor antagonist ICI 204219 relieves symptoms of acute seasonal allergic rhinitis. Am. J. Resp. Crit. Care Med. 151:1734, 1995) (ICI 204219=Zafirlukast). The 5-LOX inhibitors are also able markedly to reduce allergic reactions not only in animal experiments, but also in human therapy (Liu, M. C., L. M. Dube, J. Lancaster, and the zileuton study group. Acute and chronic effects of a 5-lipoxygenase in
Engel Jürgen
Poppe Hildegard
Szelényi István
ASTA Medica AG
Goodwin & Procter LLP
Reamer James H.
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