Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-26
2004-09-14
Krass, Fredrick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S826000, C514S849000, C514S850000, C514S853000, C514S860000, C514S862000, C514S887000
Reexamination Certificate
active
06790849
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of prevention and treatment using, and pharmaceutical compositions containing, cetirizine and a leukotriene inhibitor.
2. BACKGROUND OF THE INVENTION
In its racemic form, cetirizine, chemically named 2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, is an orally active, potent, long acting peripheral histamine H
1
receptor antagonist. See, e.g., Juhlin, L., et al.
J. Allergy Clin. Immunol.
80:599-602 (1987); De Vos, C., et al.
Annal. Allergy
59:278-282 (1987); U.S. Pat. No. 4,525,358. Cetirizine is a second generation H
1
histamine receptor antagonist that generally offers some significant advantages beyond the first generation compounds. These advantages include: (1) less sedation, (2) little anticholinergic activity, and (3) longer duration of activity. The medicinal chemistry of cetirizine is described by Campoli-Richards et al.,
Drugs
40:762-781(1990), Snyder and Snowman,
Allergy
59II:4-8(1987), and Rihoux and DuPont,
Annals of Allergy
59:235-238(1987).
Cetirizine has been employed in the treatment of some symptoms of allergic reactions. For example, U.S. Pat. No. 5,419,898 to Ikejiri et al. discloses antiallergic compositions containing cetirizine for ophthalmic or nasal use. Its efficacy in the treatment of some other symptoms associated with asthma, however, is limited. Specifically, clinical studies conducted by Gong and coworkers revealed that the compound, when administered to patients in doses as large as 20 mg, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction (Gong, H., et al.
J. Allergy Clin. Immunol.
85:632-641 (1990)).
In only a few cases has cetirizine been combined with other drugs for the treatment of disease. For example, U.S. Pat. No. 4,829,064 to Sunshine et al. discloses compositions useful for treating cold symptoms comprising cetirizine and an analgesic. Published European Patent Application No. 433766 A1 to York et al. discloses compositions of cetirizine and an antiallergic compound useful for treating ophthalmic allergic responses.
Although the stereoselectivity of some drugs is well known (see, e.g., Ariens, E. J. Schweiz. Med. Wocheuschr. 120:131-134 (1994)), disclosures directed to the combination of cetirizine with other drugs have taught away from combinations comprising optically pure enantiomers of cetirizine. Recently, however, some advantages of treating certain diseases with an optically pure enantiomer of cetirizine alone has been recognized.
U.S. Pat. No. 5,627,183 discloses methods of treating urticaria using optically pure (+) cetirizine. U.S. Pat. No. 5,698,558 discloses methods of treating certain allergic disorders using (−) cetirizine. Both patents disclose that the administration of optically pure enantiomers of cetirizine can reduce or avoid adverse side effects associated with the use of racemic cetirizine. These side effects include sedation and somnolence, headache, gastrointestinal disturbance, dizziness, nausea, cardiac arrhythmias, and other cardiovascular effects. Such adverse effects are common to non-sedating antihistamines.
It has been suggested that the moderate effectiveness of some H
1
-antihistamines is due in part to their additional activity against leukotrienes, particularly leukotriene D
4
(LTD
4
). Leukotrienes augment neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increase capillary permeability, and smooth muscle contraction, all of which contribute to inflammation, edema, mucus secretion, and bronchoconstriction.
In one study of guinea pigs, the increase in airway resistance caused by LTD
4
was suppressed by the antihistamine terfenadine. See Akagi et al.,
Oyo Yakuri,
35: 361-371 (1988). In another study, twenty H
1
-antihistamines with diverse chemical structures were tested for activity against LTD
4
-induced contraction in isolated guinea-pig ileum and displacement of [
3
H]LTD
4
from guinea-pig lung membrane proteins (M. Zhang et al.,
Inflamm. res.
46:Supp. I S93-S94 (1997)). The results indicated the drugs were weakly active in inhibiting LTD
4
-induced contraction of guinea pig ileum.
A number of drugs have been designed specifically to inhibit leukotriene formation. One of these, zileuton, is a specific inhibitor of 5-lipoxygenase. Commercially available as ZYFLO®, it has the chemical name (±)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known to inhibit leukotriene (LTH
4
, LTC
4
, LTD
4
, and LTE
4
) formation in vitro. Zileuton is an inhibitor ex vivo of LTB
4
formation in several species and inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. One study of 373 patients indicated that 600 mg of zileuton four times daily were required to provide efficacy, while 400 mg failed to do so. In some patients, zileuton was reported to cause headache, pain, asthenia, dyspepsia, nausea, and myalgia (
Physician's Desk Reference,
52 ed., Medical Economics Co., Inc., 474-76 (1998)).
Zafirlukast, sold commercially as ACCOLATE®, is another type of leukotriene inhibitor. This leukotriene inhibitor is a leukotriene receptor antagonist (LTRA) of leukotriene D
4
and E
4
, and has the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma. In vitro studies indicated that zafirlukast antagonized the contractile activity of three leukotrienes in conducting airway smooth muscle from laboratory animals and humans; prevented intradermal LTD
4
-induced increases in cutaneous vascular permeability; and inhibited inhaled LTD
4
-induced influx of eosinophils into animal lungs. In some patients, zafirlukast has been reported to cause headache, infection, nausea, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, and dyspepsia (
Physician's Desk Reference,
52 ed., Medical Economics Co., Inc., 3148-49 (1998)).
3. SUMMARY OF THE INVENTION
The present invention represents an improvement over both the cetirizine and the leukotriene inhibitor technology presently available.
This invention relates to novel pharmaceutical compositions comprising: (a) an optically pure enantiomer of cetirizine, a racemic mixture of cetirizine, or a pharmaceutically acceptable salt thereof; and (b) a leukotriene inhibitor. These compositions may optionally contain an additional ingredient, such as a decongestant.
The compositions of the present invention are believed to improve upon, and are superior to, those of the prior art used to treat or prevent asthma, asthma symptoms, inflammation, allergic disorders such as allergic rhinitis, and dermatitis. Unexpectedly, it is believed that there is a synergistic effect when cetirizine, or an enantiomer or salt thereof, is used in combination with one or more leukotriene inhibitors. Both racemic and optically pure enantiomers of cetirizine may be used to achieve this synergistic effect. Furthermore, the compositions and methods of this invention avoid or reduce certain adverse side effects associated with second generation H
1
histamine receptor antagonists.
The compositions of this invention possess potent antihistaminic activity. They are useful for treating and preventing the occurrence of asthma or asthma symptoms. They are also useful for the treatment and prevention of dermatitis, inflammation, and allergic disorders such as allergic rhinitis. The compositions of this invention may also be used to threat the symptoms of allergic asthma, allergic rhinitis, and other allergic disorders, as well as dermatitis. In addition, the compositions of the invention reduce or avoid adverse effects generally associated with administration of non-sedating antihistamines, such as racemic cetirizine or an enantiomer of cetirizine. Adverse effects include, but are not limited to, cardiac arrh
Jones Day
Krass Fredrick
Ostrup Clinton
Sepracor Inc.
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