BACKGROUND One of the most frequent reasons for visiting a health practitioner is to obtain relief from nasal congestion. It is estimated that over 100 million Americans suffer annually from symptoms of nasal congestion due to either allergic or non-allergic causes. The direct costs of decongestant treatments are estimated at over 8 billion dollars annually, including many non-prescription decongestant formulations.

Many different agents have been used in the treatment of nasal congestion including, sympathomimetics, antihistamines, and leukotriene antagonists. However, none are entirely effective, and they are often associated with undesirable side-effects, such as increases in blood pressure, cardiac arrhythmias, and insomnia. Therefore, there is still an existing need for novel therapies to treat nasal congestion DESCRIPTION OF THE DRAWINGS Fig. 1 shows the ability of L-DOPS to antagonize the nasal congestion effects of compound 48/80. The arrow indicates when the active agent was administered.

DESCRIPTION OF THE INVENTION The present invention relates to articles of manufacture, compositions, and methods for treating nasal congestion, and associated disorders and conditions, in a subject in need thereof. The methods involve administering effective amounts of a norepinephrine precursor. The norepinephrine precursor can be administered with other effective compounds, such as histamine H1 receptor antagonists and leukotriene antagonists, which in combination can be utilized to treat nasal congestion.

A norepinephrine precursor is administered in amounts that are effective to treat <BR> <BR> nasal congestion. The term"treating"is used conventionally, e. g. , the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, <BR> <BR> improving, etc., nasal congestion. The phrase"nasal congestion, "as explained in more detail below, refers to any condition in which the nose, nasal sinuses, and/or associated nasal passages, become obstructed or blocked. Treating with a norepinephrine precursor can reduce the frequency, severity, intensity, and/or duration of any of the symptoms associated with nasal congestion.

The nasal sinuses are small mucus-lined pockets within the facial bones surrounding the nose. The human body produces approximately one liter per day of mucous in the nasal sinuses. The mucous must then pass through small (2 mm) openings, called the ostia, for drainage through the nose and throat. When the sinuses are healthy, the mucous drains easily from them into the nose, and air also passes freely, both in and out through the nose.

Nasal congestion occurs when the ostia are constricted or blocked. Most commonly, the blockade occurs when the blood vessels within the membranes lining the nasal passages becoming dilated and/or inflamed. For example, viral infection of mucous membranes in the nose causes blood vessels to dilate, causing local swelling and ostia blockage. Mucous is thereby trapped in the sinuses, causing the subjective sensation of nasal congestion.

While not wishing to be bound to any theory or mechanism of action, a norepinephrine precursor can be used to treat nasal congestion by stimulating, <BR> <BR> producing, increasing, increasing, augmenting, enhancing, etc. , the contraction of nasal blood vessels, thereby relieving nasal congestion and its associated symptoms.

Accordingly, a reduction in the diameter of the nasal blood vessels, and/or the volume of nasal blood vessels, and/or the nasal blood flow, can be effective for treating nasal congestion. Any quantity or amount of reduction that is adequate to relieve the congestion can be included in the present invention. However, the present invention relates to the use of norepinephrine precursors, irrespective of the mechanism through which they act.

Compounds of the present invention can also be used to increase nasal patency as measured by acoustic rhinometry, a noninvasive technique to evaluate changes in <BR> <BR> the geometry of the nasal cavity. See, e. g. , Koss et al., J. Appl. Physiol., 92: 617-621, 2002. Nasal patency refers to the degree of openness of the nasal cavity. As shown in the examples below, a compound of the present invention was effective in increasing nasal patency, thereby treating nasal congestion.

Any norepinephrine precursor that is effective in treating nasal congestion can be used. A norepinephrine precursor comprises any compound that is converted into norepinephrine. These include, e. g. , a substrate of the enzyme dopa decarboxylase that can be converted to norepinephrine, such as threo-3- (3, 4-dihydroxyphenyl) serine (threo-DOPS), or a substrate of the enzyme dopamine beta-hydroxylase that can be converted to norepinephrine, such as dopamine. The norepinephrine precursor can be used for the synthesis of norepinephrine, and therefore can increase its levels in the appropriate tissues.

The present invention also relates to methods of treating nasal congestion in a subject in need thereof, comprising, administering to the subject an amount of threo-3- (3, 4-dihydroxyphenyl) serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, which is effective to treat nasal congestion.

The methods of the present invention can be utilized to treat nasal congestion, regardless of its cause. For example, nasal congestion is the most common and <BR> <BR> bothersome symptom of rhinitis (i. e. , an inflammatory response in the nose). There are two major subtypes of rhinitis: non-allergic (most frequently caused by cold and flu viral infections) and allergic. Non-allergic types of rhinitis include, but are not limited to, vasomotor rhinitis, irritative rhinitis, and drug-induced rhinitis. In addition, compositions of the present invention can be used for the symptomatic relief of nasal inflammation or congestion due to infection of the nasal mucosa, sinus inflammation or congestion and inflammation or congestion associated with the Eustachian tube and other associated nasal and passages and sinus cavities, sinusitis, etc.

Nasal congestion can also be caused by (or associated with) infection (e. g. <BR> <BR> common cold and flu), environmental stimuli (e. g. , cigarette smoke, strong odors and fumes including perfume, hair spray, other cosmetics, laundry detergents, cleaning solutions, pool chlorine, car exhaust and other air pollution), hormonal changes (e. g., during pregnancy, hypothyroid states, puberty, and oral contraceptive use, conjugated estrogen use. ), and gustatory stimuli (e. g., following consumption of hot and spicy foods). Drug-induced nasal gestation includes"rebound congestion"which is produced by the excessive use of nasal sprays or nose drops administered in response to nasal obstruction. In addition, certain medications produce nasal congestion as an undesirable side-effect, such as prazosin, guanethidine, reserpine, cocaine, etc.

Nasal congestion can be associated with other conditions and disorders, including, but not limited to, sinus pain, impaired taste and/or smell, difficulty breathing, disturbed sleeping, impaired appetite, head pain, etc. The compositions and methods of the present invention can be utilized to treat one or more of the aforementioned conditions, as well any other that is associated with nasal congestion or nasal membrane dysfunction.

A norepinephrine precursor may be used as adjunct therapy with analgesics, antibiotics, antitussives, antihistamines or expectorants in treatment of respiratory tract disease. The norepinephrine precursor may be used alone or in combination with a histamine H1 receptor antagonist and/or a leukotriene antagonist. Examples of suitable H1 receptor antagonists include, but are not limited to, mepyramine, chlorpheniramine, diphenhydramine, terfenadine, astemizole, loratadine, cetirizine.

Examples of suitable leukotriene antagonists include, but are not limited to, montelukast and zafirlukast.

The specific dose level and frequency of dosage may vary, depending upon a variety of factors, including the activity of the specific active agent, its metabolic stability and length of action, rate of excretion, mode and time of administration, the age, body weight, health condition, gender, diet, etc. , of the subject, and the severity, intensity, and frequency of the symptoms associated with nasal congestion. A precursor in accordance with the present invention can be immediately effective in achieving therapeutic efficacy, or it can reach its maximal effect after multiple or regularly <BR> <BR> administered doses, e. g. , one or more doses a day for a week, two weeks, a month, etc.

Threo-3- (3, 4-dihydroxyphenyl) serine (also known as threo-DOPS or DOPS or droxidopa) is a synthetic amino acid precursor of NE (Freeman R., Clin. Neuropharm., 14,296-304, 1991). DOPS is directly converted to NE via L-aromatic amino acid decarboxylase (AADC), also known as dopa decarboxylase (DDC). It has four stereoisomers, L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS, and D-erythro-DOPS.

Of the four, L-threo-DOPS is preferred, but a racemate can also be used. Peak plasma levels of DOPS occur about 3 hours after oral ingestion, whereas peak NE levels occur about 5 hours after ingestion. Increased plasma levels of both molecules remain at least 12 hours after oral administration of DOPS (Suzuki et al., Eur. J. Clin. Pharmacol., 23 (5): 463-8,1982). Specific uptake of DOPS has also been demonstrated in microvessel preparations (Hardebo et al., Acta Physiol Scand. , 107 (2): 161-7,1979).

Although threo-3- (3, 4-dihydroxyphenyl) serine is known as a norepinephrine precursor,

the present invention includes any therapeutic effect for nasal congestion, regardless of its mechanism of action or how it is achieved.

DOPS has been used to treat motor or speech disturbances (e. g. , U. S. Pat. No.<BR> <P>5,656, 669), Parkinson's disease, cerebral ischemia (e. g. , EP 887 078), urinary<BR> incontinence (e. g. , U. S. Pat. No. 5,266, 596), orthostatic hypotension (Freeman, 1991), and pain (e. g., U. S. Pat. No. 5,616, 618; EP 681 838).

Any effective amount of threo-3- (3, 4-dihydroxyphenyl) serine can used, e. g. , from about 10 mg to about 1200 mg per day or per dosage unit, about 50 mg to about 600 mg per day or per dosage unit, about 100 mg to about 400 mg per day or per dosage unit, about 300 mg per day or per dosage unit, etc. Effective amounts can be determined routinely, and may vary depending upon the age, health, gender, and weight of a patient, as well as the severity, frequency, and duration of the nasal congestion. Amounts can be administered in a multiple doses over the course of the day, e. g. , in order to achieve a therapeutic effect.

Threo-3- (3, 4-dihydroxyphenyl) serine can be prepared according to any suitable <BR> <BR> method. These processes include those described in, e. g. , U. S. Pat. Nos. 4,480, 109, 4,562, 263 and 5,864, 041. It can be used as a racemic or optically active isomer, e. g., L-threo-DOPS.

Pharmaceutically-acceptable salts of threo-3- (3, 4-dihydroxyphenyl) serine can <BR> <BR> also be used, including addition salts, e. g. , inorganic acids, such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids, such as fumaric acid, citric acid, tartaric acid, and succinic acid.

Any pharmacologically active derivative of threo-3- (3, 4-dihydroxyphenyl) serine can be used. These include, e. g., N-methyl-3- (3, 4-dihydroxyphenyl) serine alkyl esters, such as N-methyl-D, L-threo-3- (3, 4-dihydroxyphenyl) serine and N-methyt-L-threo-3- (3, 4 dihydroxyphenyl) serine, lower alkyl esters, methyl esters, ethyl esters, n-propyl esters, isopropyl esters, etc. , as described in U. S. Pat. No. 5,288, 898.

Precursors can be further combined with any other suitable additive or pharmaceutical acceptable carrier. Such additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington : The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of <BR> <BR> Industrial Pharmacy (Lachman et al., eds. , 3rd edition, Lippincott Williams & Wilkins,<BR> 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds. , 2nd edition, Marcel Dekker, 2002).

These are generally referred to herein as"pharmaceutically acceptable carriers" to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes. These include, but are not limited to, antioxidants, preservatives, dyes, tablet-coating compositions, plasticizers, inert carriers, excipients, polymers, coating materials, osmotic barriers, devices and agents which slow or retard solubility, etc.

The present invention also relates to combinations of at least two active agents, comprising a norepinephrine precursor, and, but not limited to, histamine H1 receptor antagonists, leukotriene antagonists, acetaminophen, sympathomimetics,

antihistamines, alpha1-and alpha2-adrenergic agonists, NSAIDS, non-NASAIDS, etc. <BR> <BR> <P>Compositions can also comprise additional agents, such as salicylic acids (e. g. , aspirin, salicylate, and diflunisal), acetic acids (e. g., diclofenac, indomethacin, sulindac, and tolmetin), propionic acids (e. g. , fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, naproxen, and pirprofen), anthranilic acids (e. g., flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid), pyrazolones (e. g., phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, and dipyrone), oxicams <BR> <BR> (e. g. , piroxicam), etc. These compounds can be combined in effective amounts, e. g., effective to treat pain and/or fever associated with nasal congestion and/or diseases/conditions associated with nasal congestion (e. g., influenza, colds, allergy, viral diseases, bacterial diseases, etc).

These combinations can comprise synergistic amounts of these agents. The <BR> <BR> combinations can be in any effective form, e. g. , as compositions where the two agents are present in the same dosage unit, as a"multi-pill"unit which contains separate dosage units of the norepinephrine precursor and the second active agent, etc.

The active agents can be in any suitable form, without limitation. Forms suitable for oral use, include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups and elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

Compositions comprising precursors can also be formulated for controlled release, where release of the active ingredient is regulated or modulated to achieve a desired rate of delivery into the systemic circulation. A controlled release formulation can be pulsed, delayed, extended, slow, steady, immediate, rapid, fast, etc. It can comprise one or more release formulations, e. g. extended-and immediate-release components.

The compositions can be delivered to a subject in need of treatment through any suitable delivery means. For example, for local delivery to the nasal passages, devices that introduce compositions into the naval cavity can be utilized, i. e. , a nasal delivery device. Nasal solutions can be aqueous solutions for administration by spray or drops.

The dose can be metered by the spray pump or could have been pre-metered during manufacture. A nasal spray unit can be designed for unit dosing or can discharge up to several hundred metered sprays of formulation containing the drug substance. Dry <BR> <BR> formulations can also be used. Nasal delivery devices include, e. g. , devices described in U. S. Pat. Nos. 6,644, 305,6, 065,471, 5,437, 267,5, 983,893, etc.

Any suitable dosing interval can be used in accordance with the present invention. Extended delivery systems can be utilized to achieve a dosing internal of once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, etc.

The dosage form/delivery system can be a tablet or a capsule suited for extended release, but a sustained release liquid or suspension can also be used. A controlled release pharmaceutical formulation can be produced which maintains the release of, and or peak blood plasma levels of, threo-3- (3, 4-dihydroxyphenyl) serine, derivative

thereof, or salt thereof, over a period of at least 6 hours, 12 hours, 18 hours, 24 hours, etc. With this type of formulation, the DOPS can be continuously released in such a way that it is available and effective for maintaining the nerve terminal pools of norepinephrine.

Norepinephrine precursors in accordance with the present invention can be administered in any form by any effective route, including, e. g., oral, parenteral, enteral, <BR> <BR> intraperitoneal, topical, transdermal (e. g. , using any standard patch), ophthalmic, nasal, local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient (s), active or inactive.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, can utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The entire disclosure of all patents and publications cited herein are hereby incorporated by reference in their entirety.

EXAMPLES Canine Model of Nasal Congestion The present experiments were undertaken to pharmacologically characterize the effects of L-DOPS in a noninvasive, chronic, experimental dog model of nasal <BR> <BR> congestion (Koss, M. C. , et al., J Appl Physiol 92 : 617-621,2002). Nasal patency was measured using acoustic rhinometry. Solubilized compound 48/80 (Sigma Chemical Co.; Koibuchi, Y. , et al., Eur. J. Pharmacol. 115,163-170, 1985; Bronner, C. , et al., Biochim. Biophys. Acta 920,301-305, 1987) was administered as an intranasal mist to a single naris, to elicit nasal congestion in six conscious beagle dogs. The effects of localized degranulation of mast cells on nasal cavity volume, with and without pretreatment with oral decongestant drugs, were measured before and after compound 48/80 administration. Compound 48/80 caused a decrease of nasal cavity volume (to about 50% of control). Maximal responses were seen at 90-120 min after 48/80 administration and were of similar magnitude when trials were repeated.

In this animal model, the oral administration of the adrenergic agonist, d- pseudoephedrine (3.0 mg/kg), significantly antagonized all of the nasal effects of compound 48/80. By contrast, oral administration of the histamine H1 receptor antagonist chlorpheniramine (10 mg/kg) appeared to reduce the increased nasal secretions but was without effect on the compound 48/80-induced nasal congestion <BR> <BR> (i. e., volume and cross sectional area). (Koss, M. C. , et al., Am J Rhinology 16: 49-55, 2002).

Oral administration of L-DOPS (1 and 3 mg/kg), like d-pseudoephedrine (3. 0 mg/kg), significantly antagonized the nasal congestion effects of compound 48/80 in the animal model of nasal congestion. The effect was most significant at the 4 and 5 hour time points (measured 2 and 3 hours after Compound 48/80) for both the 1 mg/kg and 3 mg/kg dose. However, unlike the results obtained with d-pseudoephedrine (3.0 mg/kg), neither dose of L-DOPS caused any increase in blood pressure or heart rate. See, Fig.

1.