WO2016120787A1

WO2016120787A1 - Oral n-acetylcysteine in the treatment of upper respiratory tract infections and symptoms

Info

Publication number: WO2016120787A1
Application number: PCT/IB2016/050381
Authority: WO
Inventors: Ian M. MARKS; Jacob Zijlstra
Original assignee: Novartis Consumer Health S.A.
Priority date: 2015-01-26
Filing date: 2016-01-26
Publication date: 2016-08-04

Abstract

A method, treatment course, treatment regimen, and/or course of therapy, for: (1) treatment of an upper respiratory tract infection (URTI); (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a subject having the URTI, in a subject in need thereof, comprising orally administering to the subject in need thereof a therapeutically effective amount of N-acetyl-L-cysteine (NAC), or a pharmaceutically acceptable salt, solvate, prodrug, or derivative thereof, and a pharmaceutically acceptable carrier; as well as a kit therefor.

Description

ORAL N-ACETYLCYSTEINE IN THE TREATMENT OF UPPER RESPIRATORY TRACT INFECTIONS AND SYMPTOMS FIELD OF THE INVENTION

The described invention relates to symptoms, treatment, treatment of symptoms, etc. of upper respiratory tract infections (URTI). BACKGROUND

Upper respiratory tract infections (URTIs) (also known as the "common cold") are part of life. Most adults have on average between 2 and 3 URTIs infections per year, and children having a much higher incidence per year. Over 200 antigenically-different viruses from five virus families can infect the upper airways and cause symptoms, although the majority of colds are believed to be caused by rhinovirus. Acute cough caused by URTIs is the most common reason patients seek medical attention. Acute cough disrupts everyday life, is often associated with absence from work and school and lost productivity, and significantly impacts on physical and psychosocial health leading to impairment in quality of life (QOL).

Current treatments options for URTIs, if they are to be treated, include over-the-counter (OTC) medication options such as nonsteroidal anti-inflammatory drugs, antitussives, decongestants, mucolytics, and expectorants. While these OTC medications can sometimes be effective in alleviating some of the symptoms of URTIs, additional and more effective treatments of URTIs and associated symptoms are strongly desired.

The described invention provides a treatment of URTIs using pharmaceutical compositions comprising N-acetylcysteine (NAC). The described compositions are safe, well-tolerated and efficacious pharmaceutical compositions comprising a therapeutic amount of NAC for this use.

SUMMARY

According to certain aspects, the present invention provides methods and/or treatment courses/regimens for:

(1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate of coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a person having an URTI.

In one embodiment, the methods and/or treatment courses/regimens include the steps of: (a) providing a pharmaceutical composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I:

Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and

(b) orally administering the pharmaceutical composition to the subject having an URTI and/or otherwise in need of such administration, wherein the therapeutic amount is effective to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

In alternative embodiments, the methods and/or treatment courses/regimens include:

(a) providing a pharmaceutical composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and

(b) orally administering the pharmaceutical composition to a subject having an URTI and/or otherwise in need of such administration, wherein the therapeutic amount is effective to provide a plasma concentration of NAC, glutathione, L-cysteine, or any combination thereof, in an amount effective to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

In another embodiment, the present invention provides kits for treating an URTI in a subject in need thereof, comprising:

(a) a first packaging material containing a composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and (b) a means for administering the composition. Optionally the kit further comprises (c) instructions for administration of NAC for treatment of an URTI.

DETAILED DESCRIPTION

The invention relates to methods and/or treatment courses for: (1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate of coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (11) improvement in the quality of life of a person having an URTI.

The methods and treatment courses comprise oral administration of a pharmaceutical composition comprising a therapeutic amount of N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof, to a subject in need of such administration. The methods and treatment courses further preferably comprise daily oral administration of NAC in the amounts herein described, every day over the course of therapy which last for at least 1 day, for at least 2 days, for at least 3 days, for at least 4 days, for at least 5 days, for at least 6 days, or more. In one embodiment, and without being bound by a particular mechanism of action, oral administration of the therapeutic amount of NAC, results in a plasma concentration of NAC which provides a therapeutic effect to: (1) treat the URTI; (2) treat symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce of cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI. In some embodiments the plasma concentration of NAC sufficient to provide the therapeutic effect is greater than 200 nanograms/ml; equal to or greater than 220 nanograms/ml; equal to or greater than 240 nanograms/ml; equal to or greater than 260 nanograms/ml; equal to or greater than 280 nanograms/ml equal to or greater than 300 nanograms/ml equal to or greater than 320 nanograms/ml equal to or greater than 340 nanograms/ml equal to or greater than 360 nanograms/ml equal to or greater than 380 nanograms/ml equal to or greater than 400 nanograms/ml equal to or greater than 420 nanograms/ml equal to or greater than 440 nanograms/ml equal to or greater than 460 nanograms/ml equal to or greater than 480 nanograms/ml equal to or greater than 500 nanograms/ml equal to or greater than 520 nanograms/ml equal to or greater than 540 nanograms/ml equal to or greater than 560 nanograms/ml equal to or greater than 580 nanograms/ml equal to or greater than 600 nanograms/ml equal to or greater than 620 nanograms/ml equal to or greater than 640 nanograms/ml equal to or greater than 660 nanograms/ml equal to or greater than 680 nanograms/ml equal to or greater than 700 nanograms/ml equal to or greater than 720 nanograms/ml equal to or greater than 740 nanograms/ml equal to or greater than 760 nanograms/ml equal to or greater than 780 nanograms/ml equal to or greater than 800 nanograms/ml equal to or greater than 820 nanograms/ml equal to or greater than 840 nanograms/ml equal to or greater than 860 nanograms/ml equal to or greater than 880 nanograms/ml equal to or greater than 900 nanograms/ml equal to or greater than 1020 nanograms/ml; equal to or greater than 1040 nanograms/ml; equal to or greater than 1040 nanograms/ml; equal to or greater than 1060 nanograms/ml; equal to or greater than 1080 nanograms/ml; or equal to or greater than 1100. In some preferred embodiments, the plasma concentration of NAC sufficient to provide the therapeutic effect is equal to or between 200 nanograms/ml and 800 nanograms/ml; equal to or between 250 nanograms/ml and 750 nanograms/ml; equal to or between 300 nanograms/ml and 700 nanograms/ml; equal to or between 350 nanograms/ml and 650 nanograms/ml; equal to or between 400 nanograms/ml and 600 nanograms/ml; or equal to or between 450

nanograms/ml and 550 nanograms/ml. In one embodiment, and without being bound by a particular mechanism of action, oral administration of the therapeutic amount of NAC, results in a plasma concentration of L- cysteine which provides a therapeutic effect to: (1) treat the URTI; (2) treat symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

In one embodiment, and without being bound by a particular mechanism of action, oral administration of the therapeutic amount of NAC, results in a plasma concentration of glutathione which provides a therapeutic effect to: (1) treat the URTI; (2) treat symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

In one embodiment, and without being bound by a particular mechanism of action, oral administration of the therapeutic amount of NAC, results in a plasma concentration of NAC, glutathione, L-cysteine, or any combination thereof, which provides a therapeutic effect to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

In other embodiments the plasma concentrations of NAC, glutathione, L-cysteine, or any combination thereof described above are minimum/floor plasma concentration levels which are sufficient to provide the therapeutic effect(s) described above and which are sustained in the subject over a period of time greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 24 hours, greater than or equal to 36 hours, greater than or equal to 48 hours, greater than or equal to 56 hours, greater than or equal to 72 hours, greater than or equal to 84 hours, greater than or equal to 96 hours, greater than or equal to 108 hours, greater than or equal to 120 hours, or more. Sustained plasma concentrations of NAC, glutathione, L-cysteine, or any combination thereof can be achieved by selecting an extended and/or delayed release dosage form for NAC or by dividing the total daily dose of NAC into individual doses taken throughout the day and over the course of a treatment regimen (e.g. multiple doses taken throughout the day, such as twice in one day, three times in one day, four times in one day, or more). Without being bound by a particular mechanism of operation, providing a sustained plasma concentration minimum/floor levels via a sustained or delayed release profile or by dividing the total daily dose into separate doses taken throughout the course of the day are believed to be sufficient in minimizing times between peak and trough plasma concentrations, while providing a minimum/floor plasma concentration level which still provides a therapeutic effect. The treatment course will preferably begin with a first administration of NAC within less than 72 hours of onset of URTI symptoms (e.g. nasal congestion, productive/wet cough with sputum production, sneezing). NAC will then be preferably orally administered in immediate release dosage forms several times a day (e.g. morning, noon, and night, or morning and night) or in the alternative orally administered as a delayed or extended dosage forms once a day. The treatment course will preferably extend for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. Preferably the treatment course will extend for the duration of the URTI and/or presence of related symptoms and/or until the related symptoms have been ameliorated.

According to some embodiments, the therapeutic amount of N-acetyl-L-cysteine (NAC) is from greater than 600 mg/day to about 8000 mg/day. According to one embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 8000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 7800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 7600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 7400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 7200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 7000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 6800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 6600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 6400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 6200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 6000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 5800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 5600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 5400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 5200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 5000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 4800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 4600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 4400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 4200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 4000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 3800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 3600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 3400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 3200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 3000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 2800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 2600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 2400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 2200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 2000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 1800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 1600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 1400 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 1200 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 1000 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 900 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 800 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is about 700 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is greater than 600 mg/day. According to another embodiment, the therapeutic amount of N-acetyl-L-cysteine (NAC) is greater than 1000 mg/day to less than 4000 mg/day, for example between 1500 mg/day and 3500 mg/day, for example between 2000 and 3000 mg/day.

According to some embodiments, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 6 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl- L-cysteine (NAC) is about 8 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 10 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 12 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L- cysteine (NAC) is about 14 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 16 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 18 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 20 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 22 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 24 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 26 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 28 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 30 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 32 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 34 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 36 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 38 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 40 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 42 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 44 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 46 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 48 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine

(NAC) is about 50 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 52 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 54 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 56 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 58 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 60 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 62 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 64 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 66 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 68 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 70 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 72 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 74 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 76 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 78 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 80 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 82 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 84 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 86 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 88 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 90 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 92 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 94 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 96 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine

(NAC) is about 98 mg/kg body weight. According to another embodiment, the daily adult dose of N-acetyl-L-cysteine (NAC) is about 100 mg/kg body weight.

According to some embodiments, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is from about 0.1 mg/kg body weight to about 11 mg/kg body weight. According to one embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 0.1 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 0.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 0.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 0.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 0.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 1.0 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 1.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 1.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 1.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 1.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 2.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 2.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 2.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 2.6 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 2.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 3.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 3.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 3.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 3.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 3.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 4.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 4.2 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 4.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 4.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 4.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 5.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 5.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 5.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 5.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 5.8 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 6.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 6.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 6.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 6.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 6.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 7.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 7.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 7.4 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 7.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 7.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 8.0 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 8.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 8.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 8.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 8.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.0 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.5 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.7 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 9.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl- L-cysteine (NAC) is about 9.9 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.1 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.2 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.3 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L- cysteine (NAC) is about 10.4 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.5 mg/kg body weight.

According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.6 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.7 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 10.8 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L- cysteine (NAC) is about 10.9 mg/kg body weight. According to another embodiment, the daily pediatric dose of N-acetyl-L-cysteine (NAC) is about 11 mg/kg body weight.

In other embodiments, NAC can be present in the pharmaceutical composition as both a reduced species of NAC and an oxidised species of NAC. Without being bound by a particular mechanism it is believed that, inter alia, first pass metabolism of NAC into degradation products and/or bioavailability of NAC and/or subsequent plasma

concentrations of NAC, glutathione, L-cysteine or any combination thereof, and/or the therapeutic effectiveness of these components can be modulated by adjusting the ratio of oxidised/reduced forms of NAC in the pharmaceutical composition. In some embodiments the pharmaceutical composition contains a NAC formulation comprising: 10% by weight of a reduced NAC species and 90% by weight of an oxidised NAC species; 20% by weight of a reduced NAC species and 80% by weight of an oxidised NAC species; 30% by weight of a reduced NAC species and 70% by weight of an oxidised NAC species; 40% by weight of a reduced NAC species and 60% by weight of an oxidised NAC species; 50% by weight of a reduced NAC species and 50% by weight of an oxidised NAC species; 60% by weight of a reduced NAC species and 40% by weight of an oxidised NAC species; 70% by weight of a reduced NAC species and 30% by weight of an oxidised NAC species; 80% by weight of a reduced NAC species and 20% by weight of an oxidised NAC species; or 90% by weight of a reduced NAC species and 10% by weight of an oxidised NAC species. In the alternative, the pharmaceutical composition contains a NAC formulation comprising 100% by weight of a reduced NAC species and 0% by weight of an oxidised NAC species; or 0% by weight of a reduced NAC species and 100% by weight of an oxidised NAC species. The determination of reduced and oxidized species present in a sample may be determined by various methods known in the art, for example, with capillary electrophoresis, HPLC, etc. as described by Chassaing et al., J. Chromatogr. B Biomed. Sci. Appl. 735(2): 219-227 (1999), the entire disclosure of which is incorporated herein by reference.

According to another embodiment, the therapeutic amount of the N-acetyl-L-cysteine (NAC) is effective to reduce upper respiratory tract infection (URTI) activity in the subject compared to an untreated control. According to another embodiment, the URTI activity is measured by the presence, duration, and intensity of symptoms including cough duration, cough intensity, cough count, sputum production, duration of these symptoms, quality of life of the subject, etc. According to another embodiment, the systemic URTI activity is reduced compared to an untreated control after at least 1 day of administration, after at least 2 days of administration, after at least 3 days of administration, after at least 4 days of administration, after at least 5 days of administration, or after at least 6 days of administration.

According to some such embodiments, URTI activity is measured by using an objective cough monitor, a validated Quality of Life (QOL) questionnaire (Birring et al., 2003); the Leicester Cough Questionnaire (Birring et al., 2003) modified for acute cough (LCQ-acute); the ATS approved short form of the Wisconsin Upper Respiratory Symptom Survey

(WURSS-11) questionnaire, frequency of sputum production recorded on an ordinal scale and frequency of nocturnal awakenings recorded on an ordinal scale, WURSS-11. According to some such embodiments, the therapeutic amount of N-acetyl-L-cysteine (NAC) is effective to reduce URTI activity as measured by any of these methods of determination by 10% or greater, 20% or greater, 30% or greater, 40% or great, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, or more as compared to an untreated control after at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or more of the administration.

According to another embodiment, the compositions of the present invention can further comprise one or more additional compatible active ingredients. "Compatible" as used herein means that the components of such a composition are capable of being combined with each other in a manner such that there is no interaction that would substantially reduce the efficacy of the composition under ordinary use conditions. According to another embodiment, the composition further comprises at least one additional therapeutic agent. According to another embodiment, the additional therapeutic agent is of a therapeutic amount effective to exert an additive effect in treating or alleviating one or more symptoms of the URTI. According to another embodiment, the additional therapeutic agent is of a therapeutic amount effective to exert a synergistic effect in treating or alleviating one or more symptoms of the URTI.

According to some embodiments, the additional therapeutic agent is selected from a group consisting of analgesics (e.g. acetaminophen, ibuprofen, ketoprofen, aspirin), antitussives (dextromethorphan, barbiturates), decongestants (pseudoephedrine, phenylephrine), mucolytics (guaifenesin), and expectorants (guaifenesin). Additional therapeutic agents used for treatment of URTIs are well known in the art and not particularly limited herein.

According to some embodiments, the administering step (b) comprises administering the NAC containing formulation orally. According to some embodiments, the composition is in the form of a tablet, a pill, a gel, a troche, a lozenge, an aqueous suspension, a thin film, an oily suspension, a dispersible powder, a granule, a bead, an emulsion, a capsule, a syrup, or a liquid filled gel capsule. Kits Comprising N-Acetyl Cysteine

According to another aspect, the described invention provides kits for treating an URTI in a subject in need thereof, comprising:

(a) a first packaging material containing a composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and (b) a means for administering the composition.

Optionally the kit further comprises (c) instructions for administration of NAC for treatment of an URTI. According to some embodiments, the kit further comprises a second packaging material containing at least one additional therapeutic agent. According to another embodiment, the additional therapeutic agent is of a therapeutic amount effective to exert an additive effect in treating or alleviating one or more symptoms of the URTI condition. According to another embodiment, the additional therapeutic agent is of a therapeutic amount effective to exert a synergistic effect in treating or alleviating one or more symptoms of the URTI condition.

According to some embodiments, the means for administering the composition is a syringe, a dropper, a tablet, a pill, a gel, a troche, a lozenge, an aqueous suspension, an oily suspension, a capsule, a syrup, an emulsion, a granule, or combination thereof.

According to some embodiments, the kit further comprises instructions for use. According to some embodiments, the kit further comprises packaging materials. According to some embodiments, the first or second packaging material is selected from the group consisting of a box, a pouch, a vial, a bottle, a tube, a blister pack, or a combination thereof. Definitions:

Unless expressly or inherently indicated to the contrary, the following definitions apply. The singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise.

The term "bioavailability" refers to the rate and extent to which NAC is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control. According to some studies the oral bioavailability of NAC is between about 3% and about 20% and the drug half life in humans is between about 3 and about 10 hours. According to Drugbank.com, the oral bioavailability of NAC is about 6 to about 10% and the half life is about 5.6 hours in adults and about 11 hours in neonates. The term "carrier" and "pharmaceutically acceptable carrier" etc. are used interchangeably herein and describe a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound of the composition of the described invention. Carriers must be of sufficiently high purity and of sufficiently low toxicity to render them suitable for administration to the mammal being treated. The carrier can be inert, or it can possess pharmaceutical benefits, cosmetic benefits or both. The terms "excipient", "carrier", or "vehicle" are used interchangeably to refer to carrier materials suitable for formulation and administration of pharmaceutically acceptable compositions described herein. Carriers and vehicles useful herein include any such materials know in the art which are nontoxic and do not interact with other components.

The term "delayed release" is used herein in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be "sustained release."

The term "derivative" as used herein refers to a compound that may be produced from another compound of similar structure in one or more steps. A "derivative" or "derivatives" of a compound retains at least a degree of the desired function of the compound.

Accordingly, an alternate term for "derivative" may be "functional derivative." A derivative of N-acetylcysteine has the same biological activity as does N-acetylcysteine. The derivatives of N-acetylcysteine, for example, contain one or more functional groups (e.g., aliphatic, aromatic, heterocyclic radicals, epoxides, and/or arene oxides) incorporated into N-acetylcysteine. According to another embodiment, the derivatives of N- acetylcysteine disclosed herein also comprise "prodrugs" of N-acetylcysteine, which are either active in the prodrug form or are cleaved in vivo to the parent active compound. According to another embodiment, the derivatives of N-acetylcysteine also include any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound, which, upon administration to the recipient, is capable of providing (directly or indirectly) N- acetylcysteine. The terms "dose" and "dosage" are used interchangeably and mean the quantity of a drug or other remedy to be taken or applied all at one time or in fractional amounts within a given period.

As used herein, the terms "oral" or "orally" refer to the introduction into the body by mouth whereby absorption occurs in one or more of the following areas of the body: the mouth, stomach, small intestine, and the small blood vessels of the oral mucosa.

The term "pharmaceutically acceptable salt" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, P. H. Stahl, et al. describe pharmaceutically acceptable salts in detail in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley VCH, Zurich, Switzerland: 2002).

The term "reduce" or "reducing" as used herein refers to a diminution, a decrease, an attenuation, limitation or abatement of the degree, intensity, extent, size, amount, density, number or occurrence of an URTI or its related symptoms (e.g. cough) in individuals having an URTI.

The terms "subject" or "individual" or "patient" are used interchangeably to refer to a member of an animal species of mammalian origin that may benefit from the administration of a drug composition or method of the described invention. Examples of subjects include humans, and other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. The term "subject in need thereof as used herein refers to a subject showing signs and symptoms of an upper respiratory tract infection (URTI).

The term "sustained release" (also referred to as "extended release") is used herein in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.

The term "symptom" as used herein refers to a phenomenon that arises from and

accompanies an URTI.

The terms "therapeutic amount", "therapeutic effective amount" or an "amount effective" of one or more of the therapeutic agents is an amount that is sufficient to provide the intended benefit of treatment. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and preferred mode of administration, an effective prophylactic or therapeutic treatment regimen may be planned which does not cause substantial toxicity and yet is effective to treat the particular subject. A therapeutic effective amount of the therapeutic agents that can be employed ranges from generally 0.1 mg/kg body weight and about 50 mg/kg body weight. A therapeutic effective amount for any particular application may vary depending on such factors as the disease or condition being treated, the particular therapeutic agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may determine empirically the effective amount of a particular inhibitor and/or other therapeutic agent without necessitating undue experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to some medical judgment. However, dosage levels are based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular therapeutic agent employed. Thus the dosage regimen may vary widely, but can be determined routinely by a surgeon using standard methods. "Dose" and "dosage" are used interchangeably herein. The term "therapeutic effect" as used herein refers to a consequence of treatment, the results of which are judged to be desirable and beneficial. A therapeutic effect may include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation. A therapeutic effect also may include, directly or indirectly, the arrest reduction or elimination of the progression of a disease manifestation.

The term "therapeutically effective amount" or an "amount effective" of one or more active agent(s) is an amount that is sufficient to provide the intended benefit of treatment. Dosage levels are based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular active agent employed. Thus the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods.

The term "treat" or "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting recurrence of symptoms in patients that were previously asymptomatic for the disorder(s). Reference throughout the specification to "one embodiment," "another embodiment," "an embodiment," "some embodiments," "aspects" and so forth, means that a particular element (e.g., feature, structure, property, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described element(s) may be combined in any suitable manner in the various embodiments.

Contemplated Mechanisms of Action:

Without being bound by specific mechanisms of action, the following is noted:

It is believed that the methods, treatment regimens, and kits of the present invention are effective in a subject having an URTI to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

The therapeutic amount of NAC orally administered to the subject is believed to result in a therapeutic plasma concentration of NAC, glutathione, L-cysteine, or any combination thereof to have the above recited therapeutic effects.

In particular, the presently recited oral doses of NAC are believed to result in a therapeutic amount of NAC, glutathione, l-cysteine, or any combination thereof in blood plasma which provides one or more of the following actions on mucous: First, NAC is believed to be effective as a mucolytic when it is in direct contact with mucous. When in direct contact with mucous NAC is believed to break/open disulfide bonds within the mucous, thereby decreasing viscosity of mucous and allowing for easier expulsion from the lungs.

Secondly, blood plasma concentration of NAC, glutathione, L-cysteine, other unidentified NAC degradation products or metabolites, or other metabolic products produced by unidentified metabolic pathway(s) which employ any of these components, is/are believed to have biologic activity within the goblet cells (e.g. mucous-producing cells) in the respiratory system (e.g. lungs). Such biologic activity is believed to reduce the viscosity of newly produced mucous within these goblet cells. This newly-produced reduced-viscosity mucous is more easily expelled from the lungs, as compared to mucous produced without said biologic activity. Thirdly, blood plasma concentration of NAC, glutathione, L-cysteine, other unidentified NAC degradation products or metabolites, or other metabolic products produced by unidentified metabolic pathway(s) which employ any of these components, is/are believed to have biologic activity with respect to glutathione transferase and its related thiol transfer metabolic pathway. Such biologic activity is believed to inhibit thiol transfer and thickening of mucous or production of thickened mucous in the goblet cells or after excretion from goblet cells. Prevention of thickening of mucous and/or prevention of building viscosity of mucous allows the mucous to be more easily expelled from the lungs as compared to mucous produced without said biologic activity. Since the present invention comprises methods, treatment regimens/protocols/courses, and kits all comprising NAC for "oral" administration, direct contact of NAC with mucous already excreted from the goblet cells can be reduced and/or minimized (minimally reduced, severally reduced, or completely eliminated) as compared to other treatment regimens which locally deliver NAC into direct contact with mucous (e.g. NAC administration via inhalation). Hence, oral administration of NAC according to certain embodiments herein described can result in reduction of mucous viscosity and any of the other recited therapeutic effects in the absence of substantial direct interaction of NAC with mucous which has already been excreted from the goblet cells in the respiratory tract.

Furthermore, since other treatments locally deliver NAC into direct contact with mucous (e.g. NAC administration via inhalation) (e.g., not orally) adsorption of NAC into the blood stream and systemic distribution of NAC can be limited/minimized (e.g. severely limited or completely prevented dependent upon several factors including mucous thickness). Hence in these local NAC delivery models (e.g. via inhalation), administration of NAC does not reach significant or the herein described systemic circulation or blood plasma

concentrations, and hence can provide limited, minimal, or no related circulating metabolic products and can provide limited, minimal, or no related metabolic activity within the goblet cells or with respect to glutathione transferase .

Next, L-cysteine is a metabolic byproduct of NAC which is produced by first pass metabolism of NAC. L-cysteine in turn is a metabolic precursor of glutathione. NAC, L- cysteine, and glutathione are believed to posses individually, or in combination, antioxidant and anti-inflammatory properties/activity. Hence, in certain contemplated mechanisms of action, oral administration of NAC at the described dosage levels, is contemplated to achieve some of the herein described therapeutic benefits/effects as related to viral URTI. In these embodiments, the therapeutic effective amount of NAC is sufficient to result in a blood plasma concentration of NAC, L-cysteine, glutathione, or any combination thereof in an amount effective to exhibit anti-inflammatory and/or antioxidant properties and/or responses within the subject. In certain embodiments the methods, treatment courses, treatment regimens, courses of therapy, and/or kits herein described are used for and/or suitable for use of acute viral URTIs. In certain embodiments the methods, treatment courses, treatment regimens, courses of therapy, and or kits herein described are not used and/or are not suitable in the treatment of chronic respiratory conditions and/or their symptoms. Such chronic conditions may include: COPD, cystic fibrosis, chronic bronchitis, asthma, etc. It is understood that, in the herein described embodiments including the described methods and kits, N-acetylcysteine is used, provided, present and/or administered in its (L) isomer form (e.g. N-acetyl-L-cysteine), in its (D) isomer form (e.g. N-acetyl-D-cysteine), and/or in a mixture of both (L) isomer form (e.g. N-acetyl-L-cysteine) and (D) isomer form (e.g. N- acetyl-D-cysteine) in any ratio including racemic mixtures. In certain embodiments the (L) isomer is preferred. In other embodiments the (D) isomer is preferred. Oral administration of any of the isomer forms of N-acetylcysteine in the amounts herein described is believed to provide plasma concentrations of N-acetylcysteine and/or its metabolic products, including cysteine and glutathione, which provide the herein recited therapeutic effects. The term "NAC" as used herein may refer to the L form, the D form, or mixtures thereof, but preferably refers to the L form.

In view of the above-made description, the present invention can be seen as providing the benefits described in the following numbered Paragraphs:

1. A method, treatment course, treatment regimen, and/or course of therapy, for:

(1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate of coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a subject having an URTI, the method, treatment course, treatment regimen, and/or course of therapy, including and/or comprising, the steps of: (a) providing a pharmaceutical composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and (b) orally administering the pharmaceutical composition to a subject having an URTI and/or otherwise being in need of such administration, wherein the therapeutic amount of NAC is effective to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of the subject having the URTI.

2. A method, treatment course, treatment regimen, and/or course of therapy, for:

(1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate of coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a person having an URTI, the method, treatment course, treatment regimen, and/or course of therapy, including and/or comprising, the steps of: (a) providing a pharmaceutical composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier; and

(b) orally administering the pharmaceutical composition to a subject having an URTI and/or otherwise being in need of such administration, wherein the therapeutic amount of NAC is effective to provide a plasma concentration of NAC, glutathione, L-cysteine, or any combination thereof, in an amount effective to: (1) treat the URTI; (2) treat the symptoms of the URTI; (3) reduce cough associated with the URTI; (4) reduce cough count associated with the URTI; (5) reduce the severity of cough associated with the URTI; (6) reduce cough duration associated with the URTI; (7) reduce acute cough associated with the URTI; (8) reduce the duration of cough symptoms associated with the URTI; (9) reduce the rate of coughing associated with the URTI; (10) reduce the duration of the URTI; (11) treat common cold or symptoms thereof associated with productive cough; (12) treat viral URTI or symptoms thereof associated with productive cough; and/or (13) improve the quality of life of a subject having the URTI.

3 a. The method, treatment course, treatment regimen, and/or course of therapy according to paragraph 2, wherein the therapeutic amount of NAC is effective to provide a plasma concentration of NAC equal to or between 200 nanograms/ml and 800 nanograms/ml; equal to or between 250 nanograms/ml and 750 nanograms/ml; equal to or between 300 nanograms/ml and 700 nanograms/ml; equal to or between 350 nanograms/ml and 650 nanograms/ml; equal to or between 400 nanograms/ml and 600 nanograms/ml; or equal to or between 450 nanograms/ml and 550 nanograms/ml.

3b. The method, treatment course, treatment regimen, and/or course of therapy according to paragraphs 1 or 2, wherein the therapeutic amount of N-acetyl-L-cysteine (NAC) for an adult is a daily dose of greater than 600 mg/day to about 8000 mg/day, for example 1000 mg/day to about 5000 mg/day, for example 2000 mg/day to about 3000 mg/day, e.g. about 2200 mg/day to about 2600 mg/day, e.g. about 2400 mg/day. 4. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 3b, wherein effectiveness of the administered therapeutic amount of NAC is measured against a control subject having an URTI who is not administered NAC. 5. The method, treatment course, treatment regimen, and/or course of therapy according to paragraph 4, wherein effectiveness of the administered therapeutic amount of NAC is measured using an objective cough monitor.

6. The method, treatment course, treatment regimen, and/or course of therapy according to paragraph 5, wherein effectiveness of the administered therapeutic amount of NAC is measured 1 day after the first administration of NAC, 2 days after the first administration of NAC, 3 days after the first administration of NAC, 4 days after the first administration of NAC, 5 days after the first administration of NAC, 6 days after of the first administration of NAC, and/or 7 days after the first administration of NAC.

7. The method, treatment course, treatment regimen, and/or course of therapy of paragraph

7. wherein the therapeutic amount of N-acetyl-L-cysteine (NAC) is effective to reduce URTI activity by 10% or greater, 20% or greater, 30% or greater, 40% or great, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, or more as compared to an untreated control after at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or more of daily NAC administration.

8. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 7, wherein the pharmaceutical composition further comprises at least one additional therapeutic agents selected from the group consisting of anti-inflammatory agents, analgesics, antitussive, decongestants, mucolytics, and expectorants.

9. The method, treatment course, treatment regimen, and/or course of therapy according paragraph 8, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin, arthopan, celecoxib, diclofenac, etodolac, fenprofen, flurbiprofen, ibuprofen, ketoprofen, meclofamate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, rofecoxib, sulindac, tolmetin, acetaminophen, or a combination thereof. 10. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 9, wherein the pharmaceutical composition is in form of a tablet, a pill, a gel, a troche, a lozenge, an aqueous suspension, an oily suspension, a capsule, or a syrup.

11. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 10, wherein the therapeutic amount of NAC is administered daily for a course of treatment extending 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or more.

12. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 11, wherein the daily therapeutic amount of NAC is divided into equal amounts to be administered at various times during the respective treatment day (e.g. 2 times in one day or 3 times in one day) in order to maintain a minimum/floor blood plasma concentration of NAC, glutathione, and/or L-cysteine and/or to minimize time between peak and trough blood plasma concentrations of these components.

13. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 11, wherein the daily therapeutic amount of NAC is provided in an extended or delayed release form which is administered once during the respective treatment day.

14. The method, treatment course, treatment regimen, and/or course of therapy according to any of paragraphs 1 to 11, wherein the pharmaceutical composition contains a NAC formulation comprising a reduced NAC species and an oxidised NAC species.

20. A kit for: (1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate of coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a person having an URTI, in a subject in need thereof, the kit comprising:

(a) a first packaging material containing a pharmaceutical composition comprising a therapeutic amount of a compound N-acetyl-L-cysteine (NAC) of Formula I or a

pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a

pharmaceutically acceptable carrier; (b) a means for administering the composition; and optionally the kit further comprises (c) instructions for administration of NAC for treatment of an URTI.

21. The kit according to paragraph 20, wherein the therapeutic amount of N-acetyl-L- cysteine (NAC) is a daily dose of greater than 600 mg/day to about 8000 mg/day, for example 1000 mg/day to about 5000 mg/day, for example 2000 mg/day to about 3000 mg/day, e.g. about 2200 mg/day to about 2600 mg/day, e.g. about 2400 mg/day, and wherein the kit comprises 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days worth NAC.

21. The kit according to any of paragraphs 20 to 21, wherein the kit further comprises a second packaging material containing at least one additional therapeutic agent selected from the group consisting of non-steroidal anti-inflammatory agents, analgesics, antitussive, decongestants, mucolytics, and expectorants

22. The kit according to paragraph 21, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin, arthopan, celecoxib, diclofenac, etodolac, fenprofen, flurbiprofen, ibuprofen, ketoprofen, meclofamate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, rofecoxib, sulindac, tolmetin, acetaminophen, or a combination thereof. 23. The kit according to any of paragraphs 21 to 22, wherein at least one of the first or second packaging material is selected from the group consisting of a box, a pouch, a vial, a bottle, a tube, a blister pack, or a combination thereof. 24. The kit according to any of paragraphs 20 to 23, wherein the kit further comprises instructions for use. 25. The kit according to any of paragraphs 20 to 25, wherein the kit comprises a

pharmaceutical composition which contains a NAC formulation comprising a reduced NAC species and an oxidised NAC species.

Example Clinical Trial Protocol: A Randomized, Parallel-Group, Double-Blind, Placebo-Controlled, Multiple-Dose, Pilot Study to Evaluate the Efficacy of N-acetylcysteine Capsules in the Treatment of the Common Cold (viral URTI) Associated with Productive Cough in an Adult Population.

Purpose and rationale for study:

To demonstrate the pharmacological effects of N-acetyl-L-cysteine (NAC) on cold and cough symptoms in adults over 7 days.

To demonstrate the ability to monitor subject improvements using an objective cough monitor, a validated QOL questionnaire (Birring et al, 2003), the Leicester Cough Questionnaire (Birring et al, 2003) modified for acute cough (LCQ-acute), the ATS approved short form of the WURSS-11 questionnaire, frequency of sputum production recorded on an ordinal scale and frequency of nocturnal awakenings recorded on an ordinal scale.

This study assesses NAC (2400 mg daily given orally in three divided doses of 800 mg per dose) for the treatment of productive cough and other cold symptoms in adults who are suffering from a viral URTI which has induced the production of sputum in the lower airways. PK sampling is used to assess response versus drug systemic availability. Sputum is collected to allow an assessment of inflammatory status and response to drug. Objectives: Primary Objective:

The primary objective of the study is to evaluate the efficacy of NAC 2400 mg daily dose (administered orally as 800 mg three times daily, TDD) for the treatment of cough and cold symptoms due to a viral URTI in adults.

The primary efficacy endpoint is the total cough count evaluated from the time of the first dose until the same time in the morning of Day 4, i.e. for a period of 72 hours.

Secondary Objectives:

• To assess the change in cough and cold symptoms as measured by validated

questionnaires, LCQ-acute and WURSS-11.

• To assess the safety of NAC 2400 mg daily in three divided doses (18 doses given over 7 days).

• To assess 24 hour cough frequency.

• To assess maintenance of benefit by monitoring cough continuously for the 7 day period.

• To assess sputum production frequency.

• To assess the time to cessation of sputum production.

• To assess the frequency of nocturnal awakenings due to cough.

Population: 70 subjects are randomized in order to yield at least 58 evaluable subjects (approximately 29 subjects in each treatment group). Subjects' randomization is stratified by sex as women are known to cough more frequently with the common cold than men.

The study population consists of a group of male and female subjects 18 to 65 years of age who are experiencing productive cough and cold symptoms associated with a viral URTI, and who are otherwise maintained in good health. Inclusion/Exclusion criteria: Inclusion criteria:

Subjects eligible for inclusion in this study must fulfill all of the following inclusion criteria:

Exclusion criteria:

Subjects are not eligible for participation in this study if any of the following exclusion criteria are noted:

Table 2.

1. Subject has an acute cough other than due to a cold/URTI, or a subchronic, or chronic cough (cough duration >2 months) due to any condition other than a cold/URTI as established by the investigator, in accordance with the American College of Chest Physician (ACCP) Guidelines for Diagnosis and Management of Cough (Irwin, 2006).

2. Diagnosed as suffering from any pulmonary conditions associated with cough, e.g., COPD, acute or chronic bronchitis, asthma, cystic fibrosis.

3. Suffering from any other conditions or taking any medications known to induce cough e.g., ACE inhibitors, statins, beta-blockers, cholinergic agonists, sitagliptin, inhaled drugs (especially dry powder formulations), vindestine, histamine liberators and acetylsalicylic acid.

4. Fever of greater than 39°C (102°F) orally, or, if, in the judgment of the investigator, the subject is too ill to participate in the study.

5. Subjects diagnosed as suffering from any respiratory allergic condition at the time of entry into the study which could interfere with the interpretation of changes in cold symptoms.

6. Subject exhibits clinical features of a complication of the common cold during the physical

examination at Screening (e.g., otitis media, severe sinusitis, or pneumonia).

7. Any clinically significant findings, other than those consistent with a typical URTI, deemed from full physical examination and vital sign recordings, or any condition, medical history, or medication history that the investigator believes would interfere with the evaluation of the study, pose a safety risk, or confound the interpretation of the study results.

8. History of or known hypersensitivity to any of the study drugs, excipients, or to drugs of similar chemical classes.

9. Subjects with allowed comorbidities that require modification of their treatment regimens during the course of the study.

10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urine dipstick.

11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are:

-women whose career, lifestyle or sexual orientation precludes intercourse with a male partner, at the judgment of the investigator.

-women who have been surgically sterilized or whose partners have been sterilized by vasectomy or other means.

-using a highly effective method of birth control (i.e., one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not an acceptable means of contraception.

A woman who is postmenopausal must have a negative urine pregnancy test at Screening but will not need to comply with an acceptable method of contraception. Women are considered postmenopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with reported serum follicle stimulating hormone (FSH) levels >40 mlU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.

12. Use of other investigational drugs within 30 days or 10 half -lives before enrollment, whichever is longer.

13. Unwilling or unable to discontinue any antibiotics, prescribed or OTC cough/cold medications and herbal cold treatments from screening onwards.

14. Taken a medication that is sedating within the past 24 hours prior to screening (e.g., sedatives, hypnotics, tranquilizers, anticonvulsants, benzodiazepines, and clonidine).

15. History of smoking tobacco-containing products within 6 months before entry into the study or current smoker. (Note: Smoking is defined as 3 or more cigarettes per week.)

16. History of alcoholism within 1 year prior to screening or current alcohol abuse (i.e., consuming at least 3 alcoholic drinks/day on a regular basis. Note: One "drink" of alcohol is 1½ ounces of 80 proof alcohol, 6 oz. Wine, or 12 oz. beer).

17. History of illicit drug abuse or investigator suspects current drug abuse with drug classes that include but are not limited to barbiturates, amphetamines, benzodiazepines, cocaine, opiates, cannabis or any other illicit drugs (verified by urine drug screen).

18. Previously enrolled in the current study.

19. Difficulty in swallowing tablets or capsules.

20. Persons directly or indirectly involved in the execution of this protocol, including employees of the Contract Research Organization (CRO) and persons related to them.

21. Is a first-degree relative of a study investigator, or is employed at the clinical study site.

Investigational and reference therapy: Capsules containing N-acetylcysteine 400 mg and matched placebo capsules. Study design: This is a randomized, parallel-group, double-blind, placebo-controlled, multiple-dose, pilot study evaluating the efficacy of N-acetylcysteine capsules in the treatment of the common cold (viral URTI) associated with productive cough in an adult population.

Treatment arms

Subjects are assigned to one of the following two treatment arms in a ratio of 1 : 1 :

• Arm A: NAC 400 mg capsules, 2 capsules to be taken TID with water for the duration of the study

• Arm B: Matching placebo capsules, 2 capsules to be taken TID with water for the duration of the study

For a subject to be eligible to participate he/she must be randomized within 4 days of the onset of symptoms as reported to the investigator including prodrome, e.g., 'scratchy throat.' He/she must also have a productive cough which has been present for no more than 3 days prior to randomization. If a subject qualifies during the pre-screening, he/she is asked to attend the site in the morning that day if possible or in the morning of the following day at the latest.

The first visit to the site (Visit 1) is on Day 1 during which the subject undergoes full eligibility screening. Eligibility screening includes a review of demographics, medical history, vital signs assessments (e.g., measurements of blood pressure, pulse rate, respiratory rate and body temperature), physical examination (including oropharyngeal examination), height, weight, and inclusion/exclusion criteria.

Subjects who qualify to the first set of inclusion and exclusion criteria are asked to remain at the site for the first hour and personally record the number of coughs they experience during that time. Subjects are randomized only if the 1 hour cough count is greater than 10. The subject is not be informed of the success criteria. Subjects must demonstrate sputum production during the 1 hour cough counting period. If that does not occur they undergo sputum induction using the 'Lung Flute' device. The subject is not informed of the success criteria. Subjects only qualify if they produce sputum, a sample of which is retained for possible analyses of inflammatory markers.

On achieving these eligibility endpoints the subject completes the baseline evaluations of cough and cold symptoms and is fitted with an objective cough monitor which records coughs 24 hours a day throughout the 7 days of the study duration. Subjects are instructed in its use and are provided with written instructions.

Eligible subjects are then randomized in a 1 : 1 ratio stratified by sex into one of the two treatment groups: NAC (800 mg TID) or matching placebo (TID). The study site dispenses blinded study medication (i.e., 18 doses) with instructions regarding self-administration of 2 capsules three times daily. Subjects are instructed not to take any further cough/cold medications. They are instructed to take their first dose of study medication on site under the site supervision and the second dose in the evening before retiring on Day 1. On subsequent days they take their medication in the morning on awakening, at lunchtime and in the evening before retiring every day until the final dose is taken the morning of Day 7. The study period is selected to be 7 days as the common cold symptoms are expected to be significantly attenuated after 7 days of treatment (Lee et al, 2013). Thirty (30) minutes after taking the first dose of study medication a blood sample is taken.

The study site provides subjects with instructions on how to complete the diary each day while on the study. Following dispensing of the assigned study medication, the subjects are instructed to return to the study site on Day 4 (Visit 2) and Day 7 (Final Visit). In the evening of each study day, subjects complete the Leicester Cough Questionnaire modified for acute cough (LCQ-acute) and the short form of WURSS-l 1. At the same time they also record the frequency with which their coughing produced sputum. Each morning the subject records the number of nocturnal awakening due to cough and if any sputum was produced during these episodes. When the subjects return to the study site on Day 4 (Visit 2) and Day 7 (Final Visit) they undergo a physical examination (including oropharyngeal examination) and a vital signs assessment (including body temperature, blood pressure, pulse, and respirations). A blood sample is taken on both days. The time of each drug administration is recorded in the subject diaries. The time of PK blood sample draw is recorded in the

Electronic Case Report/Record Form.

Adverse events and the use of concomitant medications are assessed throughout the study.

Study personnel monitor subjects at the return visits, Visit 2 (Day 4) and Final Visit (Day 7) to ensure they are or have been taking the study drug as instructed, completing their diaries and complying with study procedures. Information on adverse events and the use of concomitant medications are assessed throughout the study.

Subjects are instructed to complete the course of capsules irrespective of symptom resolution to avoid inappropriate discontinuation due to misinterpretation of reduced symptomatology attendant on the fluctuation of symptoms that occurs with a common cold. Additionally, the protective effect of anti-inflammatory activity should help to maintain any improvement as the inflammatory response continues even after symptoms appear to have resolved. If a subject reports stopping dosing prior to Day 7 he/she is instructed to return to the site as soon as possible but no more than 2 days later to undergo all final visit assessments, and then be discharged from the study.

Effi cacy as ses sments/ measurements : Cough symptoms

• Cough frequency is measured by a 24-hour ambulatory cough monitoring system.

This cough monitor device is worn every day for the duration of the study. Cough counting starts as soon as the cough monitor is fitted and continues for 24 hours throughout the 7 days of the study duration. The cough monitor provided on Visit 1 is replaced with a new one on Visit 2.

• Sputum production frequency is measured by the response to the following question, "How often when you cough does sputum get into your mouth or get coughed out?" The answer is on a five point scale, "never, not very often, about half the time I cough, more than half the times I cough, and every time I cough." The responses are recorded prior to the 1^st dose on Day 1, in the evenings of Days 1 through 6 and upon returning to the site on Day 7. Cessation of productive cough is defined as no sputum produced for 24 hours. · In addition, nocturnal awakenings due to cough, a major concern for patients with a common cold, are recorded in response to the simple question, "How many times during the night did cough wake you?" The answer is on a five point scale, "none, once, twice, three times, and 4 times or more." The responses are recorded in the mornings on Days 2 through 7. Cold symptoms

The subject completes the WURSS-l 1 and the Leicester Cough Questionnaire (LCQ-acute) quality of life assessment at the site prior to the randomization on Day 1, at home in the evenings of Days 1 through 6 and upon returning to the site on Day 7.

Claims

What is claimed is: 1. A method for:

(1) treatment of an upper respiratory tract infection (URTI); (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity of cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a subject having the URTI, in a subject in need thereof, comprising orally administering to the subject in need thereof a therapeutically effective amount of N-acetyl-L-cysteine ( AC) of Formula I

Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof,

pharmaceutically acceptable carrier.

2. The method according to claim 1 for the treatment of for the treatment of viral URTI or symptoms thereof associated with productive cough.

3. The method according to claims 1 or 2 which results in reduction in cough frequency, sputum production, and/or nocturnal awakenings due to cough.

4. The method according to clams 1 or 2 wherein said therapeutically effective amount of NAC is effective to provide a therapeutically effective blood plasma concentration of NAC, glutathione, L-cysteine, or any combination thereof.

5. The method according to claim 4 wherein said therapeutically effective blood plasma concentration of NAC, glutathione, L-cysteine, or combinations thereof is an amount sufficient to reduce the viscosity of newly produced mucous within the goblet cells in the respiratory system.

6. The method according to claim 4 wherein said therapeutically effective blood plasma concentration of NAC, glutathione, L-cysteine, or combinations thereof is an amount sufficient to act in the glutathione transferase pathway to inhibit thiol transfer and thereby inhibit thickening of mucous in the goblet cells in the respiratory system.

7. The method according to claims 1 or 2 wherein the therapeutically effective amount of NAC is effective to provide a plasma concentration of NAC equal to or between 200 nanograms/ml and 800 nanograms/ml.

8. The method according to claim 7 wherein the therapeutically effective amount of N- acetyl-L-cysteine (NAC) for an adult is a daily dose of from about 600 mg/day to about 8000 mg/day.

9. The method according to claim 8 wherein the therapeutically effective amount of N- acetyl-L-cysteine (NAC) is a daily dose of 2400 mg/day.

10. The method according to claim 8 wherein the first day of administration is less than 72 hours after onset of URTI symptoms.

11. The method according to claim 10 wherein the N-acetyl-L-cysteine (NAC) is administered daily for a period of from 1 day to 7 days.

12. The method according to claim 7 wherein the therapeutically effective amount of N- acetyl-L-cysteine (NAC) is effective to reduce URTI activity by 10% or greater, as compared to an untreated control after at least 1 day of administration.

13. The method according to claims 1 or 2 wherein the pharmaceutical composition further comprises at least one additional therapeutic agent selected from the group consisting of anti-inflammatory agents, analgesics, antitussive, decongestants, mucolytics, and expectorants.

14. The method according to claim 7 wherein the daily therapeutic amount of N-acetyl-L- cysteine (NAC) is divided into equal amounts to be administered at various times during the respective treatment day in order to maintain a minimum/floor blood plasma concentration of NAC, glutathione, and/or L-cysteine and/or to minimize time between peak and trough blood plasma concentrations thereof.

15. The method according to claim 14 wherein the daily therapeutic amount of NAC is provided in an extended or delayed release form which is administered once during the respective treatment day.

16. The method according to claims 1 or 2, wherein the N-acetyl-L-cysteine (NAC) is present as a reduced species and as an oxidised species.

17. A method for the treatment of viral URTI or symptoms thereof associated with productive cough comprising orally administering to a subject in need thereof a

therapeutically effective amount of N-acetyl-L-cysteine (NAC) of Formula I

Formula I or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof, and a pharmaceutically acceptable carrier, whereby cough frequency, sputum production, and/or nocturnal awakenings due to cough are reduced, said therapeutically effective amount being an amount sufficient effective to provide a plasma concentration of NAC equal to or between 200 nanograms/ml and 800 nanograms/ml.

18. A kit for:

(1) treatment of an URTI; (2) treatment of symptoms of an URTI; (3) reduction of cough associated with an URTI; (4) reduction of cough count associated with an URTI; (5) reduction of severity cough associated with an URTI; (6) reduction of cough duration associated with an URTI; (7) reduction of acute cough associated with an URTI; (8) reduction of duration of cough symptoms associated with an URTI; (9) reduction of the rate coughing associated with an URTI; (10) reduction of duration of an URTI; (11) treatment of common cold or symptoms thereof associated with productive cough; (12) treatment of viral URTI or symptoms thereof associated with productive cough; and/or (13) improvement in the quality of life of a person having an URTI, in a subject in need thereof, said kit comprising: (a) a first packaging material containing a pharmaceutical composition comprising a therapeutically effective amount of N-acetyl-L-cysteine (NAC), or a pharmaceutically acceptable salt, solvate, prodrug, or a derivative thereof; and a pharmaceutically acceptable carrier,

(b) a means for administering the composition, and

(c) optionally, instructions for administration of the NAC.

19. The kit according to claim 18, wherein the pharmaceutical composition comprises an amount of NAC sufficient to provide a daily dose of from about 600 mg/day to about 8000 mg/day, for a period of 1 or more days.

20. The kit according to claim 18 further comprising a second packaging material containing at least one additional therapeutic agent selected from the group consisting of anti-inflammatory agents, analgesics, antitussive, decongestants, mucolytics, and expectorants

21. The kit according to claim 18 which comprises (c) instructions for administration of NAC.