Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-11-27
2002-04-16
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S464000, C424S443000, C514S290000, C514S322000, C514S212010
Reexamination Certificate
active
06372197
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of treating asthma, inflammation, and allergic conditions. In another aspect, this invention relates to the use of antihistamines and leukotriene inhibitors, and compositions containing them.
2. BACKGROUND OF THE INVENTION
Astemizole is an antagonist of the H-1 histamine receptor protein, which mediates the response antagonized by conventional antihistamines. Astemizole is well absorbed but is extensively metabolized. See Uchiyama et al.,
Pharmarcometrics,
40:7793 (1990). Three main metabolites have been identified, all of which are reported to have some antihistaminic activity. See Kamei et al.,
Arzneimittel
-
Forschung/Drug Research,
41:932-36 (1991).
Weintraub et al.,
Hosp. Formul.,
22:918-27 (1987) describes clinical efficacy of astemizole in the treatment of both seasonal and perennial allergies. It has also been suggested that astemizole would be useful for the treatment of asthma.
Astemizole is sold commercially as a prescription antihistamine (HISMANAL®), however, the use of astemizole is believed to have a potential for serious cardiotoxicity in certain patients. Norastemizole, one of the metabolites of astemizole, is said to have the beneficial effects of astemizole while having a reduced risk of cardiotoxicity. The preparation of norastemizole is described, e.g.; in WO 94/07495, published Apr. 14, 1994.
Leukotrienes augment neutrophil and eosinopil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increase capillary permeability, and smooth muscle
35
contraction, all of which contribute to inflammation, edema, mucus secretion, and bronchoconstriction. For example, zileuton, sold commercially as ZYFLO®, is a specific inhibitor of 5-lipoxygenase having 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 the astemizole and norastemizole, as well as the leukotriene inhibitor, technology presently available.
This invention relates to novel pharmaceutical compositions containing (a) norastemizole, or a pharmaceutically acceptable salt thereof, and (b) a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, and optionally (c) a decongestant, and a pharmaceutically acceptable carrier or excipient.
The compositions of the invention employing norastemizole and a leukotriene inhibitor, and optionally a decongestant, possess potent antihistaminic activity and are useful in treating, preventing, or managing asthma, asthma symptoms, inflammation, allergic rhinitis, and other allergic disorders, as well as dermatitis. The compositions employing norastemizole and a leukotriene inhibitor provide an improved overall therapy relative to either norastemizole or the leukotriene inhibitor alone. Additionally, the novel pharmaceutical compositions of the invention are useful in treating, preventing, or managing motion sickness, vertigo, diabetic retinopathy, small vessel complications due to diabetes and such other conditions as may be related to the activity of the norastemizole as an antagonist of the H-1 histamine receptor. The compositions of the invention are also useful in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, and are useful for the treatment of cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, pain, fever, and general malaise associated therewith. The aforementioned combinations (e.g., norastemizole and a leukotriene inhibitor) may optionally include one or more other active components including a decongestant, cough suppressant/antitussive, or expectorant.
The compositions of the invention can be used to treat, prevent, or manage the disorders described herein while reducing or avoiding adverse effects associated with administration of other non-sedating antihistamines, such as astemizole.
In one embodiment, this invention provides a method of preventing or treating asthma or the symptoms of asthma in a human which comprises administering to a human a therapeutically effective amount of norastemizole, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.
The invention also provides a method of treating or preventing asthma or the symptoms of asthma in a human which comprises administering to a human a composition, said composition comprising (i) a therapeutically effective amount of norastemizole or a pharmaceutically acceptable salt thereof; (ii) a leukotriene inhibitor selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene receptor antagonists, or a pharmaceutically acceptable salt thereof; (iii) optionally a therapeutically effective amount of a decongestant; and a pharmaceutically acceptable carrier or excipient.
This invention also includes a method of preventing or treating asthma or the symptoms of asthma in a human which comprises administering to a human a therapeutically effective amount of norastemizole, or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a decongestant.
In a second embodiment, the invention also provides for a method of preventing or treating allergic rhinitis in a human which comprises administering to a human a therapeutically effective amount of norastemizole, or a pharmaceutically acceptable salt thereof, and either a leukotriene inhibitor or a decongestant, or both, such that all three active ingredients are used.
In a third embodiment, the invention also provides for a method of preventing or treating dermatitis in a human which comprises administering to a human a therapeutically effective amount of norastemizole, or a pharmaceutically acceptable salt thereof, and either a leukotriene inhibitor or a decongestant, or both, such that all three active ingredients are used.
In a fourth embodiment, the invention also provides for a method of preventing or treating inflammation in a human which comprises administering to a human a therapeutically effective amount of norastemizole, or a pharmaceutically acceptable salt thereof, and a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.
Dudash Diana
Haghighatian M.
Sepracor Inc.
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