Compositions comprising cytisine in treatment and / or prevention of addiction in subjects in need thereof

Abstract

To provide methods of treatment of addiction and / or dependence, methods of promoting cessation of various addictions, such as smoking and / or vaping, and methods of promoting a reduction in various addictions, such as smoking and / or vaping.SOLUTION: Uses of cytisine as an addiction cessation treatment, and dosage regimens for the foregoing are provided.SELECTED DRAWING: None

Description

[Background technology]

[0001] Claiming priority This application is a joint venture with U.S. Provisional Application No. 62 / 988,890, filed March 12, 2020. and priority to U.S. Provisional Application No. 62 / 899,637, filed September 12, 2019. No. 6,399,433, the entire contents of each of which are incorporated by reference herein and relied upon.

[0002] Nicotine is an addictive substance that is rapidly absorbed during tobacco smoking. , neuronal nicotinic acetylcholine receptors (nACh) in the central nervous system (CNS) R) and nicotine addiction is thought to be due, at least in part, to this interaction. Many smokers attempt to quit smoking but do so without pharmacological supportive therapy. Very few succeed.

[0003] Tobacco smoking is responsible for approximately 7 million premature deaths worldwide each year. Smoking is highly addictive. More than 95% of unassisted quit attempts do not last six months. It is estimated that for every year that a person delays smoking, they lose three months of life expectancy. The World Health Organization Framework Convention on Smoking Cessation identifies evidence-based approaches to promote smoking cessation. These include mass media campaigns, increased tobacco taxes, and support for smokers who want to quit. Can be enjoyed.

[0004] Pharmacotherapy currently available in the United States and Western Europe to help smokers quit includes Cognitive replacement therapy (NRT) and bupropion (Zyban®, Glaxo-S mithKline) and varenicline (Chantix® / Champi Two non-nicotine-containing drugs, including x (registered trademark), Pfizer), are included. NRT And bupropion are thought to have approximately the same efficacy. Varenicline is a single NRT And is more effective than bupropion, but the combined NRT is comparable in efficacy.

[0005] (-)-Cytisine (cytisinicline, generally simply called cyt isine) is a plant-based alkaloid isolated from the seeds of Cytisus laburnum L (Golden chai n). References to cytisine in this specification refer to (-)-cytisine, cytisinicline.

[0006] The mechanism of action of cytisine has helped basic pharmacologists understand the complex pharmacology of various subtypes of nicotinic acetylcholine receptors. These studies have shown that both nicotine and cyt isine strongly and preferentially bind to the alpha4, beta2 (α β 4 β 2 ) receptors that mediate dopamine release in the shell of the nucleus accumbens and other locations. This receptor subtype is involved in the onset and maintenance of nicotine dependence and was the main target of the drug varenicline mentioned above.

[0007] Tabex (registered trademark), which contains the active ingredient cytisine, has been licensed and sold in Central and Eastern Europe by Sopharma PLC ( Sophia, Bulgaria) for decades.

[0008] Is cheaper, more effective, has an improved safety profile, and / or Treats individuals who have failed to quit nicotine using known treatments better There is a need for a patient-friendly regimen for treating nicotine addiction that can be achieved.

Summary of the Invention

[0009] In one aspect, the present specification provides a method for treating nicotine addiction in a subject , which method comprises administering cytisine to a subject in need thereof two times a day (「bid」 or 「B ID」) or three times a day (「tid」 or 「TID」) in equal dosage amounts .

[0010] In another aspect, the present specification provides a method for treating nicotine addiction, promoting smoking cessation, and / or promoting a reduction in smoking in a subject in need thereof, the method comprising administering cytisine provided in unit dosages of 3.0 mg or 1.5 mg of cytisine to the subject three times a day.

[0011] In yet another aspect, the present specification provides a method for treating nicotine addiction in a subject , which method comprises administering cytisine in either a dosage of 1.5 mg or 3.0 mg of cytisine to a subject in need thereof three times a day .

[0012] In yet another aspect, the present specification provides a method for treating nicotine dependence in a subject , which method comprises administering cytisine in either a dosage of 1.5 mg or 3.0 mg of cytisine to a subject in need thereof three times a day .

[0013] In yet another aspect, the present specification provides a method for treating nicotine addiction in a subject , which method comprises administering cytisine to a subject in need thereof, wherein the subject has one or more The patient is refractory and has failed treatment for nicotine addiction.

[0014] In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering to the subject cytisine in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, three times a day. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks. In some embodiments, cytisine is administered to the subject in need thereof 1-6 times a day. In some embodiments, cytisine is administered to the subject in need thereof 1-6 times a day. In some embodiments, cytisine is administered to the subject in need thereof 1-6 times a day.

[0015] In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping. In yet another aspect, the present specification provides a method for a subject in need of preventing relapse of smoking, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment with one or more smoking cessation treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes (e-cigarettes), and vaping.

[0016] In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks. In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks. In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks. In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks. In one embodiment, each of the three daily administrations is performed in the morning, at noon, and in the evening, or at approximately 4-5 hour intervals. In one embodiment, the administration is performed for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In another embodiment, the administration is performed for a period of at least about 6 weeks or at least about 12 weeks, or is repeated indefinitely for 6-12 weeks.

[0017] In some embodiments, cytisine is administered to the subject in need thereof 1-6 times a day. is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytosine. In some embodiments cytosine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytosine, 3 to 6 times a day to a subject in need thereof. In some embodiments, cytosine is provided in a unit dose of 1.5 mg of cytosine, 3 times a day to a subject in need thereof . In some embodiments, cytosine is provided in a unit dose of 1.5 mg of cytosine, 6 times a day to a subject in need thereof . In some embodiments, cytosine is provided in a unit dose of 3.0 mg of cytosine, 3 times a day to a subject in need thereof . In some embodiments, cytosine is provided in a unit dose of 3.0 mg of cytosine, 6 times a day to a subject in need thereof .

[0018] In some embodiments, cytosine is administered in one or more unit doses. In some embodiments, each unit dose of cytosine (e.g., a tablet or capsule) contains 1. 0 mg of cytosine. In some embodiments, each unit dose of cytosine (e.g , a tablet or capsule) contains 1.5 mg of cytosine. In some embodiments , the unit dose of cytosine contains 3.0 mg of cytosine. In some embodiments, each unit dose is a tablet, e.g., a compressed and film-coated tablet

[0019] In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction therapies . In some embodiments, the subject is a refractory patient who has failed treatment with two or more nicotine addiction therapies. In some embodiments, the ​Cotinine addiction treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject smoked 10 or more cigarettes per day prior to the administration of cytisine.

[0020] In some embodiments, the subject had an exhaled carbon monoxide (CO) concentration of about 10 parts per million (ppm) or more prior to the administration of cytisine. In some embodiments, the subject smoked 10 or more cigarettes per day prior to the administration of cytisine. In some embodiments, the subject had an exhaled carbon monoxide (CO) concentration of about 10 parts per million (ppm) or more prior to the administration of cytisine. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) was a combination of (a) and (b). In some embodiments, the subject had an exhaled carbon monoxide (CO) concentration of about 10 ppm or more prior to the administration of cytisine. In some embodiments, the subject (a) smoked 10 or more cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) was a combination of (a) and (b).

[0021] In some embodiments, the subject did not experience adverse events after receiving cytisine treatment. In some embodiments, the adverse events are selected from the group consisting of upper respiratory tract infections (URTIs), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the adverse events are selected from the group consisting of upper respiratory tract infections (URTIs), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0022] In some embodiments, the method further comprises providing behavioral support to the subject. In some embodiments, the method further comprises providing behavioral support to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

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BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Although the present disclosure can be embodied in various forms, the following description should be regarded as illustrative of the present disclosure and is not intended to limit the present invention to the specific embodiments shown. The headings are provided for convenience only and should not be construed as limiting the present invention in any way. The embodiments shown under any heading can be combined with the embodiments shown under any other heading. Under the understanding that the present disclosure should be regarded as an exemplification of the present invention and is not intended to limit the present invention to the specific embodiments shown. The headings are provided for convenience only and should not be construed as limiting the present invention in any way. The embodiments shown under any heading can be combined with the embodiments shown under any other heading. It is to be understood that the use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. It is to be understood that the use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. It is to be understood that the use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. It is to be understood that the use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range.

[0057] The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. The use of numerical values in the various quantitative values specified in this application is described as an approximation as if the word "about" were prefixed to both the minimum and maximum values within the specified range, unless otherwise explicitly specified. Although not always explicitly stated, it is to be understood that the term "about" precedes all numerical representations. Such a range format is used for convenience and brevity and should be understood flexibly to include the numerical values explicitly specified as limitations of the range, as if each numerical value and subrange were explicitly specified, and all individual numerical values or subranges included within that range. It should also be understood to include. For example, a percentage in the range of about 1 to about 200 includes the explicitly recited limitations of about 1 and about 200, but also includes individual percentages such as about 2, about 3, and about 4, as well as sub-ranges such as about 10 to about 50, about 20 to about 100, etc. Although not always explicitly stated, the reagents described herein are merely exemplary, and it should also be understood that such equivalents are known in the art. When used herein, the term "about" when referring to a measurable value such as an amount or concentration means an inclusion of a variation of 20%, 10%, 5%, 1%, 0.5%, or 0.1% of the specified amount. Also, the disclosure of a range is intended as a continuous range that includes any value between the recited minimum and maximum values, and any range that can be formed by such values. Also, any and all ratios (and ranges of any such ratios) that can be formed by dividing the disclosed numerical values by any other disclosed numerical value are also disclosed herein. Thus, one of ordinary skill in the art will clearly be able to obtain many such ratios, ranges, and ranges of ratios from the numerical values presented herein, and in all cases, will understand that such ratios, ranges, and ranges of ratios represent various embodiments of the present disclosure. When used herein, the phrase "statistical significance" refers to the results from data generated by a test or experiment, which are unlikely to occur randomly or by chance, but rather are highly likely to be due to a specific cause. Statistical significance is when the p-value is the average of the data sample

[0058]

[0059]

[0060] ​ and is a function of the standard deviation, and is evaluated from the calculated probability (p-value) that indicates the probability that the statistical result occurred by chance or sampling error. If the p-value is 0.05 or less, the result is considered statistically significant and corresponds to a 95% confidence level.

[0061] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements but do not exclude others. "Consisting essentially of" is meant to exclude any other elements that are essential to the combination for the stated purpose when used to define compositions and methods. Thus, a composition consisting essentially of elements as defined in the specification does not exclude other materials or steps that do not substantially affect the basic and novel characteristics of the claimed invention. "Consisting of" is meant to exclude elements in excess of trace amounts of other components and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of the present invention.

[0062] As used herein, the term "control subject" refers to any subject used as a basis for comparison with a test subject. A control subject may include, but is not limited to, any subject that has not been administered a composition, has been administered a composition other than the test composition (e.g., 1.5 mg of cytisine three times a day or 3.0 mg of cytisine three times a day), or has been administered a placebo. (e.g., 1.5 mg of cytisine three times a day or 3.0 mg of cytisine three times a day), or has been administered a placebo.

[0063] The term "treatment" related to a given disease or disorder inhibits the disease or disorder ​​​​​​​​​​​​​such as, for example, halting the progression of a disease or disorder, alleviating a disease or disorder such as, for example, causing regression of a disease or disorder, or alleviating a condition caused by or resulting from a disease or disorder, such as, for example, alleviating or treating the symptoms of a disease or disorder, including, but not limited to, these. The term "prevention" as related to a given disease or disorder means preventing the onset of disease progression when nothing is occurring, preventing the occurrence of a disease or disorder in a subject who may be prone to, but has not yet been diagnosed as having, the disorder or disease, and / or preventing further disease / disorder progression if a disease or disorder is already present.

[0064] "Vaping" refers to the act of a subject inhaling vapor produced by a device from a solution carried in a cartridge or chamber. In some embodiments, the device is electronic and mimics smoking. Vaping devices include, but are not limited to, a power source, an atomizer, and a cartridge or chamber. In some embodiments, vaping refers to the consumption of e-juice or vaping activity, such as taking in or, if not, consuming the vapor exhaled from a vaping device, performing a vaping activity with a vaping device, or, if not, ingesting vapor using a vaping device. In another embodiment, vaping refers to the consumption of e-juice. In an alternative embodiment, vaping refers to the consumption of e-juice, or taking in the vapor exhaled from a vaping device, or, if not, otherwise consuming the vapor from a vaping device. refers to consumption if so desired. In yet another embodiment, vaping refers to vaping activity. In other embodiments, vaping refers to taking in or otherwise consuming the vapor exhale from a vaping device, performing vaping activity with a vaping device, or otherwise ingesting vapor using a vaping device. In a further embodiment, vaping refers to taking in or otherwise consuming the vapor exhale from a vaping device, or otherwise ingesting vapor using a vaping device. In yet another embodiment, vaping refers to ingesting vapor using a vaping device. As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. In yet another embodiment, vaping refers to ingesting vapor using a vaping device. As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year.

[0065] As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year. As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. As used herein, the terms “decrease in vaping,” “decreased vaping,” and “decreasing vaping” refer to decreasing the amount of e-liquid consumed, decreasing the number or frequency of vapor exhales taken in or otherwise consumed from a vaping device, decreasing the number or frequency of vaping activities performed with a vaping device, or decreasing the use of a vaping device to ingest vapor, such as decreasing the frequency or amount of vaping per hour, per day, per week, per month, or per year. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition.

[0066] As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. As used herein, the term “adverse event” (AE) refers to any untoward medical occurrence in a subject administered a composition, which is not necessarily related to the treatment. Thus, an AE may or may not be considered related to the composition. , unfavorable and unintended signs (including abnormal test findings ), symptoms, or diseases that may be temporarily associated with the use of the composition.

[0067] As used herein, the term "adverse drug reaction" refers to any unfavorable and unintended response to the administered composition. The term "response to the composition" means that the attribution has at least a reasonable possibility (i.e., the relationship cannot be excluded and is determined by the investigator in charge of the clinical trial as at least possible) (see the following definition). The term "response to the composition" means that the attribution has at least a reasonable possibility (i.e., the relationship cannot be excluded and is determined by the investigator in charge of the clinical trial as at least possible) (see the following definition). belongs to have at least a reasonable possibility (i.e., it is not possible to exclude the relationship and is determined by the investigator in charge of the clinical trial as at least possible) (see the following definition). (see the following definition). ).

[0068] The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, life-threatening, requires hospitalization or prolongs the subject's current hospitalization, results in persistent or serious disability or incapacity, congenital anomaly or congenital defect, or is an important medical event that requires medical intervention to prevent any of the aforementioned outcomes. The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, life-threatening, requires hospitalization or prolongs the subject's current hospitalization, results in persistent or serious disability or incapacity, congenital anomaly or congenital defect, or is an important medical event that requires medical intervention to prevent any of the aforementioned outcomes. The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, life-threatening, requires hospitalization or prolongs the subject's current hospitalization, results in persistent or serious disability or incapacity, congenital anomaly or congenital defect, or is an important medical event that requires medical intervention to prevent any of the aforementioned outcomes. The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, life-threatening, requires hospitalization or prolongs the subject's current hospitalization, results in persistent or serious disability or incapacity, congenital anomaly or congenital defect, or is an important medical event that requires medical intervention to prevent any of the aforementioned outcomes. The terms "serious adverse event" (SAE) and "serious adverse reaction" (SAR) refer to an AE that results in at least one of the following AEs: death, life-threatening, requires hospitalization or prolongs the subject's current hospitalization, results in persistent or serious disability or incapacity, congenital anomaly or congenital defect, or is an important medical event that requires medical intervention to prevent any of the aforementioned outcomes. .

[0069] As used herein, the term "suspected unexpected serious adverse reaction" (SUSAR) refers to a serious and unexpected AE for which there is at least a reasonable possibility of attribution between the event and the composition. An important medical event may not immediately threaten life but may pose a risk to the subject and may require intervention to prevent one of the other serious outcomes listed above. Examples of such events include allergic bronchospasm that does not result in hospitalization, or blood dyscrasia, or emergency room or home treatment for convulsions ). bronchospasm, or blood dyscrasia, or emergency room or home treatment for convulsions This is intensive treatment. The term "life-threatening" refers to an event where the subject had a risk of death at the time of the event, and by assumption, an event that could have caused death if it had been more severe. It does not refer to an event that could have caused death if it had been more severe. For example, drug-induced hepatitis that resolves without evidence of liver failure is not considered life-threatening, even if drug-induced hepatitis could be fatal. Admission or extension of the current hospitalization means that the hospitalization and / or extension of the hospitalization of the in-patient was required for the treatment of the AE or occurred as a result of the event. It does not refer to a pre-planned elective hospitalization for the treatment of an existing condition that has not deteriorated significantly or a diagnostic procedure. The terms "cytisine treatment group", "active group", "treatment group", "active treatment group", and "investigation group" are used interchangeably throughout and refer to the subjects to whom the composition containing cytisine is administered. List of abbreviations: ADR, adverse drug reaction; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; Cmax, maximum observed plasma concentration; CrCl, creatinine clearance; CRF, case report form; DSM, data safety monitor; ECG, electrocardiogram; GCP, clinical trial implementation standard; ICH, International Conference on Harmonization of Pharmaceutical Regulations; IMP, investigational medicinal product (in this protocol, it refers to cytisine 3.0 mg film-coated tablets); MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event; SAR, serious adverse reaction; SmPC, summary of product characteristics; SOC, MedDRA organ class; SUSAR, suspected unexpected serious

[0070]

[0071] Major adverse reaction; Tmax, time to the observed maximum concentration; UADR, unexpected adverse drug reaction; UAE, unexpected adverse event; ULN, upper limit of normal.

[0072] Composition The composition for use in the methods of the present disclosure comprises cytosine or a pharmaceutically acceptable derivative, conjugate, or salt thereof, or a mixture of any of the foregoing, and are collectively referred to herein as "cytosine". The term "pharmaceutically acceptable" as used in this context means that the substance is not toxic to the subject or causes an interaction with other components of the composition. Cytosine, (-)-cytosine, and cytisine are referred to interchangeably.

[0073] Any suitable cytosine pharmaceutical composition or formulation can be used in the methods described herein. In some embodiments, cytosine can be formulated in tablet form, e.g., as a compressed film-coated tablet for oral administration.

[0074] The composition for use in accordance with the present disclosure can be formulated as one or more dosage units. The terms "dosage unit" and "administration unit" as used herein refer to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units can be administered once to multiple times per day (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 times), or as many times as necessary to induce a therapeutic response.

[0075] A unit dose can include a single tablet, such as a tablet containing 3.0 mg of cytosine, and the like. or it may be two tablets containing together a unit dose (e.g., 3.0 mg of cytisine). For example, a 3.0 mg unit dose may contain two Tabex ( The tablet may contain two tablets, each containing 1.5 mg of cytisine, such as a cytisine tablet. Each Tabex® tablet typically contains a number of tablet-forming excipients, including calcium sulfate. cellulose powder, colloidal silica, magnesium stearate) in a single Each tablet contains 1.5 mg of cytisine and is free of polyvinyl alcohol, titanium dioxide, and Compressed film coated with a pigmented film coating containing iron oxide As another example, a 3.0 mg unit dose may be formulated as a coated tablet. Three tablets, each of which was formulated similarly to the Tabex® tablet, were included, each weighing 1.0 ml. It can contain three tablets containing 100 g of cytisine.

[0076] Alternatively, cytisine may be formulated into a capsule or another vehicle for oral administration. and can be delivered orally or formulated into compositions for nasal or topical administration. As used herein, the term "orally deliverable" or "oral administration" refers to the administration of a therapeutic agent to a subject. The present invention includes any form of delivery of the agent or composition thereof, whether or not the agent or composition is swallowed. Regardless of whether the agent or composition is administered orally, it is placed in the mouth of the subject. " includes buccal and sublingual, as well as esophageal administration.

[0077] The tablets and other dosage forms (hereinafter all referred to as "compositions") may be prepared in any manner known in the art. The composition may contain one or more excipients such as: It includes, for example, fillers, disintegrants, preservatives, lubricants, and wetting agents.

[0078] Examples of fillers that can be used include lactose (e.g., either anhydrous or monohydrate), cellulose, starch (e.g., corn and / or wheat starch), calcium phosphate, calcium sulfate, and mannitol.

[0079] Preservatives prevent bacterial or fungal contamination of the formulation and include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid.

[0080] Suitable lubricants include stearic acid and its salts. An example of a lubricant for use in the compositions of the present disclosure is magnesium stearate.

[0081] The pharmaceutical composition can further include a sweetening agent, a flavoring agent, or a coloring agent.

[0082] In some embodiments, the placebo is a tablet containing the same, substantially the same, similar, or substantially similar inactive (e.g., citicin) components as the test composition. In these embodiments, the placebo includes excipients, fillers, preservatives, lubricants, sweetening agents, flavoring agents, and / or coloring agents, and at least one inactive component, such as cellulose, that are the same as, substantially the same as, similar to, or substantially similar to those of the test composition. In some embodiments, the placebo tablets and the test composition tablets are of the same or substantially the same weight, size, shape, color, and / or are contained in the same or substantially the same packaging.

[0083] ​One of ordinary skill in the art will be familiar with suitable fillers, preservatives, and lubricants other than those specifically mentioned above, as well as suitable sweeteners, flavorants, colorants, and other additives. The pharmaceutical composition of cytisine useful in the methods of the present disclosure can include a coating, for example, a film coating, and can be coated according to any method known in the art, for example, using collidon, shellac, gum arabic, talc, titanium dioxide, or sugar. The pharmaceutical composition containing cytisine can be prepared by any suitable method. For example, capsules can be prepared by mixing cytisine with one or more inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Tablets can be made by known compression methods.

[0084] In one embodiment, the compositions of the present disclosure are stored in a sealed container maintained at room temperature, refrigerated (e.g., about 5 to about -10 °C), or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months and exhibit at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient initially present therein.

[0085] The present disclosure provides a method of treating nicotine addiction or nicotine dependence in a subject in need thereof, the method comprising administering to the subject an effective amount of cytisine. In some embodiments, the method of treating nicotine addiction or nicotine dependence further comprises preventing relapse of smoking in a subject in need thereof and / or

[0086] Method ​ or promoting smoking cessation or reduction.

[0087] In some embodiments, the present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the present disclosure relates to a method for preventing smoking relapse in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In another embodiment, the present disclosure provides a method for promoting smoking cessation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the present disclosure provides a method for promoting reduction of smoking in a subject in need thereof, comprising administering to the subject an effective amount of cytisine. In some embodiments, the present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the present disclosure provides a method for treating nicotine addiction or nicotine dependence in a subject in need thereof, wherein the nicotine addiction or nicotine dependence is in the form of tobacco, smokeless tobacco, snus, electronic cigarettes ( e-cig), vaping using a vaping device, and / or water glycerel, etc. In some embodiments, the vaping device contains a liquid containing nicotine, such as nicotine from about 1 mg / ml to about 12 mg / ml, or nicotine exceeding about 13 mg / ml. Any patient having nicotine addiction or nicotine dependence can be treated by the methods disclosed herein.

[0088] In additional embodiments, the disclosure provides a method of treating and / or preventing addiction or dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. Without intending to be bound by any particular theory, cytisine interacts with the dopamine neurotransmitter release cycle as a partial agonist of nicotinic acetylcholine receptors (nAChRs) and is useful for doing so in a subject in need of treating and / or preventing a plurality of addictions or dependencies. Non-limiting examples of addictions and dependencies that are thought to be treatable and / or preventable by administration of cytisine include addictions and / or dependencies to substances, compounds, and / or behaviors that can involve the dopamine neurotransmitter release cycle. Exemplary substances, compounds, and / or behaviors include, but are not limited to, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), alcohol, opioids and other analgesics, cocaine, eating, gambling, sexual activity, heroin, benzodiazepines, barbiturates, stimulants, and inhalants. In further embodiments, the disclosure provides a method of facilitating cessation of an addiction or dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the disclosure provides a method for facilitating a reduction in a subject's addiction and / or dependence, comprising administering to the subject an effective amount of cytisine. The compositions and methods described herein in connection with smoking, vaping, and nicotine are applicable to any subject having an addiction or dependence involving the dopamine neurotransmitter release cycle. In a subject in need of treating and / or preventing addiction or dependence, a method of treating and / or preventing addiction or dependence is provided, comprising administering to the subject a therapeutically effective amount of cytisine. Without intending to be bound by any particular theory, cytisine interacts with the dopamine neurotransmitter release cycle as a partial agonist of nicotinic acetylcholine receptors (nAChRs) and is useful for doing so in a subject in need of treating and / or preventing a plurality of addictions or dependencies. In a subject in need thereof, it is useful for treating and / or preventing a plurality of addictions or dependencies. Addiction and dependence are thought to be treatable and / or preventable by administration of cytisine. Non-limiting examples of addictions and dependencies that are thought to be treatable and / or preventable by administration of cytisine include addictions and / or dependencies to substances, compounds, and / or behaviors that can involve the dopamine neurotransmitter release cycle. Exemplary substances, compounds, and / or behaviors include, but are not limited to, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), alcohol, opioids and other analgesics, cocaine, eating, gambling, sexual activity, heroin, benzodiazepines, barbiturates, stimulants, and inhalants. In a further embodiment, the disclosure provides a method of facilitating cessation of an addiction or dependence in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the disclosure provides a method for facilitating a reduction in a subject's addiction and / or dependence, comprising administering to the subject an effective amount of cytisine. The compositions and methods described herein in connection with smoking, vaping, and nicotine are applicable to any subject having an addiction or dependence involving the dopamine neurotransmitter release cycle. In a subject in need of facilitating cessation of an addiction or dependence, a method of facilitating cessation of an addiction or dependence is provided, comprising administering to the subject a therapeutically effective amount of cytisine. In some embodiments, the disclosure provides a method for facilitating a reduction in a subject's addiction and / or dependence, comprising administering to the subject an effective amount of cytisine. The compositions and methods described herein in connection with smoking, vaping, and nicotine are applicable to any subject having an addiction or dependence involving the dopamine neurotransmitter release cycle, such as in a subject in need of treating, preventing, and / or reducing a craving or dependence that can be used to treat, prevent, and / or reduce a craving or dependence .

[0089] In further embodiments, a method of treating nicotine craving or nicotine dependence includes performing it in a subject in need of preventing relapse of vaping and / or facilitating cessation or reduction of vaping. In some embodiments, the present disclosure relates to a method for preventing relapse of vaping in a subject in need thereof, and includes administering to the subject a therapeutically effective amount of cytisine . In another embodiment, the present disclosure provides a method for facilitating cessation of vaping in a subject in need thereof, and includes administering to the subject a therapeutically effective amount of cytisine . In some embodiments, the present disclosure provides a method for facilitating reduction of vaping in a subject in need thereof, and includes administering to the subject a therapeutically effective amount of cytisine . . In some embodiments, provided herein is a method of treating nicotine craving or nicotine dependence in a subject, and includes administering cytisine to the subject in need thereof two times a day (''bid'' or ''BID'') or three times a day (''tid'' or ''TID'') in equal doses. In one embodiment, each of the twice-daily administrations is performed in the morning and evening, respectively. In another embodiment, each of the twice-daily administrations is such that...

[0090] In some embodiments, provided herein is a method of treating nicotine craving or nicotine dependence in a subject, and includes administering cytisine to the subject in need thereof two times a day (''bid'' or ''BID'') or three times a day (''tid'' or ''TID'') in equal doses. In one embodiment, each of the twice-daily administrations is performed two times a day (''bid'' or ''BID'') or three times a day (''tid'' or ''TID'') in equal doses. In one embodiment, each of the twice-daily administrations is performed in the morning and evening, respectively. In another embodiment, each of the twice-daily administrations is ​​It is carried out at intervals of 10 to 12 hours. In yet another embodiment, each of the three administrations per day is carried out in the morning, afternoon, and evening. In another embodiment, each of the three administrations per day is carried out at intervals of approximately 4 to 5 hours. In yet another embodiment, each of the three administrations per day is carried out at intervals of approximately 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more than that. In one embodiment, the administration is carried out for at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, or an indefinite period. In this embodiment , the administration can include BID or TID on any day or week during the administration. For example, in these embodiments, the entire period of administration can be BID or TID. As another example, in these embodiments, at least a part of the administration, for example, at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 12 weeks, etc. can be BID or TID. As yet another example, in these embodiments, BID or TID administration can be carried out on the 1st day during the administration period as BID or TID, on the 2nd day as BID or TID, on the 3rd day as BID or TID, etc., in any order. In some embodiments, the administration is carried out regardless of whether the subject is in a fed state or a fasting state. For example, the administration can be carried out simultaneously with food, with food, at any time before the subject ingests food, or at any time after the subject ingests food. Without intending to be limited by any particular theory, food (or the fed state or fasting state has no impact on the administration).

[0091] In some embodiments, the administration is carried out regardless of whether the subject is in a fed state or a fasting state. For example, the administration can be carried out simultaneously with food, with food, at any time before the subject ingests food, or at any time after the subject ingests food. Without intending to be limited by any particular theory, food (or the fed state or fasting state has no impact on the administration). is not intended to be limited by any particular theory, food (or the fed state or fasting state ) can be determined by the systemic absorption of cytosine in the subject, the bioavailability of cytosine nor is it considered likely to affect the overall bioavailability of cytosine.

[0092] In some embodiments, the TID dose is 1 mg, 1.5 mg, 2 mg, 2.5 m g, or 3.0 mg of cytosine. In some embodiments, the TID dose is 1 mg, regardless of how that dose is divided. For example, each TID dose can be two 0.5 mg strength tablets administered three times a day, or one 1 mg tablet administered three times a day, or any other possibility. In some embodiments the TID dose is 1.0 mg, regardless of how the dose is divided among the dosing units. In some embodiments the TID dose is 1.5 mg, regardless of how the dose is divided among the dosing units. In some embodiments the TID dose is 2 mg, regardless of how the dose is divided among the dosing units. In yet another embodiment the TID dose is 2.5 mg, regardless of how the dose is divided among the dosing units. In some embodiments the TID dose is 3.0 mg, regardless of how the dose is divided among the dosing units. In some embodiments, the TID dose is 3.0 mg, regardless of how the dose is divided among the dosing units.

[0093] In some embodiments, the subject does not experience adverse events associated with cytosine treatment. Adverse events can be mild (e.g., no interference with activity), moderate (some interference with activity, but no or minimal medical intervention required), or severe (hindering daily activities and requiring medical intervention). Non-limiting examples of adverse events include upper respiratory tract infections (UR (TI) include abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In other embodiments the subject experiences nausea, abnormal dreams, insomnia, headache associated with cytosine treatment, and / or about 0% to about 10% of URTI, such as about 0%, about 1%, about 2%, about 3 %, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% increase, etc., and experiences two or fewer adverse events. In some embodiments, the subject does not experience adverse events compared to subjects administered nicotine replacement therapy (NRT), bupropion, varenicline, electronic cigarettes, vaping, and / or combinations thereof.

[0094] In some embodiments, the subject experiences nicotine addiction or nicotine dependence by smoking tobacco such as daily nicotine unit consumption per day, consuming smokeless tobacco and / or snus, using electronic cigarettes (e-cig g) and / or vaping, and / or using water glycerel. In some embodiments, a subject having nicotine addiction or nicotine dependence consumes about 0 to about 100 units of nicotine per day. For example, just one cigarette can be a unit of nicotine, and a subject having nicotine addiction or nicotine dependence consumes about 0 cigarettes per day to about 100 cigarettes per day, about 5 cigarettes per day to about 75 cigarettes per day, about 5 cigarettes per day to about 50 cigarettes per day, about 5 cigarettes per day to about 25 cigarettes per day, about 10 cigarettes per day to about 50 cigarettes per day, about 20 cigarettes per day to about 50 cigarettes per day, about 25 cigarettes per day to about 50 cigarettes per day, etc. ​​​from about 75 cigarettes, from about 25 cigarettes per day to about 50 cigarettes per day, for example from about 0 cigarettes per day, from about 1 cigarette per day, from about 2 cigarettes per day from about 3 cigarettes per day, from about 4 cigarettes per day, from about 5 cigarettes per day, from about 6 cigarettes per day, from about 7 cigarettes per day, from about 8 cigarettes per day, 1 from about 9 cigarettes per day, from about 10 cigarettes per day, from about 11 cigarettes per day, from about 12 cigarettes per day, from about 13 cigarettes per day, from about 14 cigarettes per day to about 15 cigarettes per day, from about 16 cigarettes per day, from about 17 cigarettes per day to about 18 cigarettes per day, from about 19 cigarettes per day, from about 20 cigarettes per day to about 25 cigarettes per day, from about 30 cigarettes per day, from about 35 cigarettes per day, from about 40 cigarettes per day, from about 45 cigarettes per day, from about 50 cigarettes per day, from about 55 cigarettes per day, from about 60 cigarettes per day, from about 65 cigarettes per day, 1 day from about 70 cigarettes per day, from about 75 cigarettes per day, from about 80 cigarettes per day, from about 85 cigarettes per day, from about 90 cigarettes per day, or from about 100 cigarettes per day. In other examples, the nicotine unit also includes the intake of smokeless tobacco and / or snus, the use of electronic cigarettes (e-cigs) and / or vaping (e.g., vaping), and / or the use of water gels instead of or in combination with tobacco on a daily basis. In some embodiments, the administration of cytisine is, such as the number of cigarettes a subject smokes per day, or the use of water gels instead of or in combination with tobacco on a daily basis.

[0095] In some embodiments, the administration of cytisine is, such as the number of cigarettes a subject smokes per day, Reduce the number of nicotine units ingested by the subject per day. In some embodiments, the method of the present technology reduces the proportion of tobacco absorbed by the subject by at least about 60%, at least about 65% compared to a control subject, a placebo control, and / or a baseline, after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine, by at least about 70%, at least about 75%, at least about 80%, at least about 85%

[0096] In some embodiments, the administration of cytisine increases smoking cessation in subjects after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine. In these embodiments, the subject has an increase in smoking cessation of about 5% to about 30%, such as about 5% to about 15%, about 5% to about 10 %, about 5% to about <10%, about 10% to about 25%, about 15% to about 20%, about 20% to about 30 %, or about 25% to about <30%, about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 25% to about 75%, about 25% to about 50%, about 30% to about 50%, about 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100%, for example, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55% compared to smoking cessation achieved without cytisine treatment. In some embodiments, smoking cessation is about 2-week smoking cessation, about 3-week smoking cessation, about 4-week smoking cessation, about 5-week smoking cessation, about 6-week smoking cessation, about 7-week smoking cessation, about 8-week smoking cessation, about 9-week smoking cessation, about 10-week smoking cessation, about 11-week smoking cessation, about 12-week smoking cessation, about 13-week smoking cessation, about 6-week smoking cessation, about 7-week smoking cessation, about 8-week smoking cessation, about 12-week smoking cessation, about 16-week smoking cessation, about 20-week smoking cessation, about 2 4-week smoking cessation, about 28-week smoking cessation, or about 32-week smoking cessation, etc. are the smoking cessation periods. In certain embodiments the smoking cessation period is about 1 day to about 4 weeks, about 1 week to about 8 weeks, about 2 weeks to about 12 weeks, about 4 weeks to about 24 weeks, or about 8 weeks to about 32 weeks.

[0097] In some embodiments, the administration of cytosine increases the smoking cessation rate in the subject after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytosine. In these embodiments, the subject, after cytosine treatment, after 4 weeks of smoking cessation, or during continuous smoking cessation for 5 to 8 weeks, has a smoking cessation rate of about 5% to about 30%, for example, about 5% to about 15%, about 5% to about 10%, about 5% to about <10%, about 10% to about 25%, about 15% to about 20%, about 20% to about 30%, or about 25% to about <30%, about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 25% to about 75%, about 25% to about 50%, about 30% to about 50%, about 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or from about 30% to about 100%, for example at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55%. In some embodiments, the smoking cessation rate is for about 1-day smoking cessation, about 3-day smoking cessation, about 7-day smoking cessation, about 1 0-day smoking cessation, about 2-week smoking cessation, about 3-week smoking cessation, about 4-week smoking cessation, about 5-week smoking cessation, about 6-week smoking cessation, about 7-week smoking cessation, about 8-week smoking cessation, about 9-week smoking cessation, about 10-week smoking cessation, about 11-week smoking cessation, about 12-week smoking cessation, about 16-week smoking cessation, The smoking cessation period, such as smoking cessation at about 20 weeks, about 24 weeks, about 28 weeks, or about 32 weeks, etc. is determined later. In certain embodiments, the smoking cessation period is from about 1 day to about 4 weeks, from about 1 week to about 8 weeks, from about 1 week to about 2 weeks, from about 3 weeks to about 6 weeks, from about 2 weeks to about 12 weeks, from about 9 weeks to about 12 weeks, from about 4 weeks to about 24 weeks, or from about 8 weeks to about 32 weeks.

[0098] In some embodiments, the subject has an exhaled CO level of from about 0 ppm to about 50 ppm, for example, from about 10 ppm to about 40 ppm, from about 10 ppm to about 30 ppm, from about 10 p pm to about <20 ppm, from about 20 ppm to about 30 ppm, from about 20 ppm to about 40 ppm, from about 20 ppm to about <50 ppm, or from about 20 ppm to about 50 ppm, for example, about 0 ppm , about 2 ppm, about 4 ppm, about 6 ppm, about 8 ppm, about 10 ppm, about 12 ppm, about 14 ppm, about 16 ppm, about 18 ppm, about 20 ppm, about 22 ppm, about 24 ppm , about 26 ppm, about 28 ppm, about 30 ppm, about 32 ppm, about 34 ppm, about 36 p pm, about 38 ppm, about 40 ppm, about 42 ppm, about 44 ppm, about 46 ppm, about 4 8 ppm, or about 50 ppm before treatment with cytosine. In some embodiments, the administration of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytosine, or the treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytosine reduces the exhaled CO level of the subject by at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% compared to the control subject, placebo control, and / or baseline. Reduce by about 90%, at least about 95%, or at least about 100%. In some embodiments, after treatment with cytisine, the subject has an exhaled CO level of about 0 ppm to about 30 ppm, such as, about 10 ppm to about 25 ppm, about 10 ppm to about 20 ppm, about 10 ppm to about <20p pm, about 5 ppm to about 15 ppm, about 5 ppm to about 10 ppm, about 1 ppm to about <10p pm, or about 10 ppm to about 5 ppm, such as, about 0 ppm, about 2 ppm, about 4 ppm , about 6 ppm, about 8 ppm, about 10 ppm, about 12 ppm, about 14 ppm, about 16 ppm , about 18 ppm, or about 20 ppm.

[0099] In some embodiments, before treatment with cytisine, the subject has a level of about 5 ng / mL to about 500 ng / mL, about 25 ng / mL to about 400 ng / mL, about 25 ng / mL to about 40 0 ng / mL, about 25 ng / mL to about 300 ng / mL, about 50 ng / mL to about 200 n g / mL, about 75 ng / mL to about 150 ng / mL, about 85 ng / mL to about 100 ng / mL, about 100 ng / mL to about 400 ng / mL, about 100 ng / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 300 ng / mL, about 200 ng / mL to about 400 ng / mL, about 200 ng / mL to about <500 ng / mL, about 200 ng / mL to about 500 ng / mL, such as, about 10 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / m L, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 275 ng / mL, about 300 ng / mL, about 325 ng / mL, about 350 ng / mL, about 375 ng / mL, about 400 ng / mL, about 425 ng / mL, about 450 ng / mL, about 475 ng / mL, or about 500 ng / mL of serum and / or plasma cotinine levels. In some embodiments, administering 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine, or treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine reduces serum and / or plasma cotinine levels in the subject by at least 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% decrease compared to a control subject, a placebo control, and / or baseline. In some embodiments, the subject has, after treatment with cytisine, about 0.1 ng / mL to about 20 ng / mL, about 0.1 ng / mL to about 15 ng / mL, about 0.5 ng / mL to about 10 ng / mL, about 1 ng / mL to about 10 ng / mL, about 0.5 ng / mL to about 5 ng / mL, or about 0.5 ng / mL to about 1 ng / mL, e.g., about 0.1 ng / mL, about 0.5 ng / mL, about 1 ng / mL, about 1.5 ng / mL, about 3 ng / mL, about 5 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 15 ng / mL, or about 20 ng / mL of serum and / or plasma cotinine levels has.

[0100] In some embodiments, the administration of cytosine increases the odds ratio in subjects at 4 weeks, 8 weeks, and 4 weeks after the end of treatment, following 4 weeks of treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytosine. In these embodiments, the subject has an odds ratio of about 1. 1 to about 20, about 1.1 to about 15, about 1.1 to about 10, about 1.1 to about 5, about 5 to about 10, about 5 to about 15, about 10 to about 15, about 10 to about <20, or about 10 to about 20, compared to a control subject, placebo control, and / or baseline. 1 to about 20, about 1.1 to about 15, about 1.1 to about 10, about 1.1 to about 5, about 5 to about 10, about 5 to about 15, about 10 to about 15, about 10 to about <20, or about 10 to about 20. has.

[0101] In some embodiments, the subject's vital signs, hematology and chemistry levels, as well as ECG are measured before and / or after administration of cytosine. In some embodiments, the subject does not show a clinically significant change in vital signs, hematology and chemistry levels, as well as ECG after administration of cytosine.

[0102] In some embodiments, the subject is a heavy, moderate, or light nicotine user, such as a smoker or vaper who uses nicotine, and can be classified as a "heavy smoker" or "heavy vaper", "moderate smoker" or "moderate vaper", "light smoker" or "light vaper". For example, a "heavy smoker" as provided herein refers to a subject who reports consuming 20 or more cigarettes per day. A "moderate smoker" as provided herein refers to a subject who reports consuming 11 - 19 cigarettes per day. A "light smoker" as provided herein refers to a subject who reports consuming 1 - 10 cigarettes per day. A "moderate smoker" as provided herein refers to a subject who reports consuming 1 - 10 cigarettes per day. Refers to the subject to be informed. As another example, the "heavy vaper" provided in this specification conducts vaping activities more than 20 times a day, reports consuming the exhalation from a vaping device more than 20 times a day, or otherwise refers to the subject who reports using a vaping device more than 20 times a day. The "moderate vaper" provided in this specification conducts vaping activities 11 - 19 times a day, reports consuming the exhalation from a vaping device 11 - 19 times a day, or otherwise refers to the subject who reports using a vaping device 11 - 19 times a day. The "light vaper" provided in this specification conducts vaping activities 1 - 10 times a day, reports consuming the exhalation from a vaping device 1 - 10 times a day, or otherwise refers to the subject who reports using a vaping device 1 - 10 times a day. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as heavy smokers or heavy vapers. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as moderate smokers or moderate vapers. In yet another embodiment, the administration of cytisine reduces the cotinine level in subjects identified as light smokers or light vapers. or conducts vaping activities more than 20 times a day, reports consuming the exhalation from a vaping device more than 20 times a day, or otherwise reports using a vaping device more than 20 times a day. The "moderate vaper" provided in this specification conducts vaping activities 11 - 19 times a day, reports consuming the exhalation from a vaping device 11 - 19 times a day, or otherwise reports using a vaping device 11 - 19 times a day. reports consuming the exhalation from a vaping device 11 - 19 times a day, or otherwise reports using a vaping device 11 - 19 times a day. The "light vaper" provided in this specification conducts vaping activities 1 - 10 times a day, reports consuming the exhalation from a vaping device 1 - 10 times a day, or otherwise reports using a vaping device 1 - 10 times a day. or reports consuming the exhalation from a vaping device 11 - 19 times a day, or otherwise reports using a vaping device 11 - 19 times a day. The "light vaper" provided in this specification conducts vaping activities 1 - 10 times a day, reports consuming the exhalation from a vaping device 1 - 10 times a day, or otherwise reports using a vaping device 1 - 10 times a day. or reports consuming the exhalation from a vaping device 1 - 10 times a day, or otherwise reports using a vaping device 1 - 10 times a day. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as heavy smokers or heavy vapers. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as moderate smokers or moderate vapers. In yet another embodiment, the administration of cytisine reduces the cotinine level in subjects identified as light smokers or light vapers. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as heavy smokers or heavy vapers. In some embodiments, the administration of cytisine reduces the cotinine level in subjects identified as moderate smokers or moderate vapers. In yet another embodiment, the administration of cytisine reduces the cotinine level in subjects identified as light smokers or light vapers. In some embodiments, the subject has been, prior to the administration of cytisine, at least about 1 year, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 55 years, at least about 60 years, at least about 65 years, at least about 70 years, at least about 75 years, at least about 80 years, at least about 85 years, at least about 90 years, at least about 95 years, or at least about 100 years a smoker or vaper.

[0103] In some embodiments, the subject has been, prior to the administration of cytisine, at least about 1 year, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 55 years, at least about 60 years, at least about 65 years, at least about 70 years, at least about 75 years, at least about 80 years, at least about 85 years, at least about 90 years, at least about 95 years, or at least about 100 years a smoker or vaper. Has smoked or vaped for about 45 years, at least about 50 years, or more.

[0104] In some embodiments, the subject started smoking or vaping during adolescence. In some embodiments, the subject started smoking or vaping between 10 and 19 years of age. In some embodiments, the subject started smoking or vaping during adolescence and has smoked or vaped for at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, or more prior to administration of cytisine. In some embodiments, the length of administration is up to about 26 weeks. In certain embodiments, the length of administration is from about 6 weeks to about 12 weeks, and in some embodiments, cytisine is administered for about 6 weeks as described above. Compared to a commercially available 25-day dosing schedule with a unit dose of 1.5 mg of cytisine, the percentage of smokers with continuous smoking cessation is surprisingly high in patients treated according to the methods disclosed herein, as shown, for example, in FIG. 7. In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine.

[0105] In some embodiments, the subject is a refractory patient. As used herein, In some embodiments, the length of administration is up to about 26 weeks. In certain embodiments, the length of administration is from about 6 weeks to about 12 weeks, and in some embodiments, cytisine is administered for about 6 weeks as described above. In some embodiments, the length of administration is up to about 26 weeks. In certain embodiments, the length of administration is from about 6 weeks to about 12 weeks, and in some embodiments, cytisine is administered for about 6 weeks as described above.

[0106] Compared to a commercially available 25-day dosing schedule with a unit dose of 1.5 mg of cytisine, the percentage of smokers with continuous smoking cessation is surprisingly high in patients treated according to the methods disclosed herein, as shown, for example, in FIG. 7. In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine. In some embodiments, the subject is a refractory patient. As used herein,

[0107] In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine. In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine. In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine. In some embodiments, the subject is a smoker who smokes, for example, more than about 3 cigarettes per day. In some embodiments, the subject is a smoker who smokes more than about 5 or more than about 10 cigarettes per day. In some embodiments, the subject has a measurable exhaled CO concentration of more than about 10 ppm prior to administration of cytisine.

[0108] In some embodiments, the subject is a refractory patient. As used herein, "Refractory patients" or "refractory subjects" are subjects who have failed treatment for one or more nicotine addictions or nicotine dependencies. In some embodiments, treatment for nicotine addiction or nicotine dependence includes treatments approved by regulatory authorities, as well as both smoking cessation methods such as vaping and behavioral support. Non-limiting examples of behavioral support include behavioral support useful for reducing, preventing, or otherwise treating anxiety, depression, and / or withdrawal symptoms. In certain embodiments, behavioral support includes counseling, diaries, wearable devices, apps, web-based smoking cessation programs, text message interventions, and combinations thereof. In further embodiments, behavioral support is provided to non-refractory patients such as control patients (e.g., baseline, placebo administration, smoking without cytisine, vaping, or administration of nicotine cessation pharmaceuticals). In some embodiments, treatment for nicotine addiction or nicotine dependence includes first-line smoking cessation pharmaceuticals approved by the FDA such as NRT, bupropion, and varenicline. Nicotine replacement therapy can be in the form of patches, gums, lozenges, sprays, and inhalers. In some embodiments, the subject is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies. For example, the subject has failed treatment two or more times, three or more times, four or more times, five or more times, six or more times, seven or more times, eight or more times, nine or more times, or ten or more times. In some embodiments, the subject has received NRT, administration of bupropion, administration of varenicline, e-cigarettes, including treatments approved by regulatory authorities, as well as both smoking cessation methods such as vaping and behavioral support. Non-limiting examples of behavioral support include behavioral support useful for reducing, preventing, or otherwise treating anxiety, depression, and / or withdrawal symptoms. In certain embodiments, behavioral support includes counseling, diaries, wearable devices, apps, web-based smoking cessation programs, text message interventions, and combinations thereof. In further embodiments, behavioral support is provided to non-refractory patients such as control patients (e.g., baseline, placebo administration, smoking without cytisine, vaping, or administration of nicotine cessation pharmaceuticals). In some embodiments, treatment for nicotine addiction or nicotine dependence includes first-line smoking cessation pharmaceuticals approved by the FDA such as NRT, bupropion, and varenicline. Nicotine replacement therapy can be in the form of patches, gums, lozenges, sprays, and inhalers. including treatments approved by regulatory authorities, as well as both smoking cessation methods such as vaping and behavioral support. Non-limiting examples of behavioral support include behavioral support useful for reducing, preventing, or otherwise treating anxiety, depression, and / or withdrawal symptoms. In certain embodiments, behavioral support includes counseling, diaries, wearable devices, apps, web-based smoking cessation programs, text message interventions, and combinations thereof. In further embodiments, behavioral support is provided to non-refractory patients such as control patients (e.g., baseline, placebo administration, smoking without cytisine, vaping, or administration of nicotine cessation pharmaceuticals). In some embodiments, treatment for nicotine addiction or nicotine dependence includes first-line smoking cessation pharmaceuticals approved by the FDA such as NRT, bupropion, and varenicline.

[0109] In some embodiments, the subject is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies. For example, the subject has failed treatment two or more times, three or more times, four or more times, five or more times, six or more times, seven or more times, eight or more times, nine or more times, or ten or more times. In some embodiments, the subject has received NRT, administration of bupropion, administration of varenicline, e-cigarettes, including treatments approved by regulatory authorities, as well as both smoking cessation methods such as vaping and behavioral support. In some embodiments, the subject is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies. For example, the subject has failed treatment two or more times, three or more times, four or more times, five or more times, six or more times, seven or more times, eight or more times, nine or more times, or ten or more times. In some embodiments, the subject has received NRT, administration of bupropion, administration of varenicline, e-cigarettes, for the treatment of nicotine addiction or nicotine dependence, including vaping or combinations thereof is a refractory patient who has failed treatment

[0110] In some embodiments, the subject has attempted to stop smoking or vaping at least once, at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least ten times, or more than that, in the past before the administration of cytisine

[0111] In some embodiments, the refractory subject has received nicotine addiction and / or nicotine dependence treatment for at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks, in the past before the administration of cytisine

[0112] In one aspect, the method includes administering cytisine to a subject, and the cytisine is provided in a unit dose of about 1 .0 mg to about 5.0 mg. In certain embodiments, the unit dose of cytisine is about 1.0 mg. In certain embodiments, the unit dose of cytisine is about 1.5 mg. In certain embodiments, the unit dose of cytisine is about 3.0 mg . In some embodiments, the unit dose of cytisine is administered to the subject 3 to 6 times a day . In some embodiments, the unit dose of cytisine is administered to the subject 3 times a day . In some embodiments of the methods disclosed herein, the unit dose is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks ​​, for about 12 weeks, about 4 months, about 1 year, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, or for more than about 2 years, is either about 1.0 mg administered three times a day, about 1.5 mg administered three times a day, or about 3.0 mg administered three times a day. In certain embodiments , the unit dose of cytosine is administered for up to about 2 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 6 weeks, or about 9 weeks to about 12 weeks. In some embodiments, the recurrence rate is lower in subjects administered the unit dose of cytosine for at least about 4 weeks compared to subjects administered the unit dose of cytosine for at least about 2 weeks. In other embodiments, the recurrence rate is lower in subjects administered the unit dose of cytosine for at least about 6 weeks compared to subjects administered the unit dose of cytosine for at least about 4 weeks. In further embodiments , the recurrence rate is lower in subjects administered the unit dose of cytosine for at least about 8 weeks compared to subjects administered the unit dose of cytosine for at least about 4 weeks. In still further embodiments , the recurrence rate is lower in subjects administered the unit dose of cytosine for at least about 12 weeks compared to subjects administered the unit dose of cytosine for at least about 4 weeks.

[0113] In some embodiments, the administration of cytosine to the subject results in a significantly superior nicotine cessation rate (smoking cessation rate or vaping continuation rate) compared to subjects administered commercially available 1.5 mg per unit dose schedule. In some embodiments, a unit dose of 3.0 mg of cytosine is administered three times a day for 6 weeks (e.g., the first 6 weeks), followed by placebo administered for 6 weeks (e.g., the next 6 weeks). In certain embodiments, the behavior ​Support is provided during at least a portion of the first six weeks, at least a portion of the next six weeks, prior to at least a portion of the first six weeks, after at least a portion of the next six weeks, or in combination thereof. In some embodiments, a unit dose of 3.0 mg of cytosine is administered three times a day for 12 weeks. In certain embodiments, behavioral support is provided to the subject during at least a portion of the 12 weeks, prior to the 12 weeks, after the 12 weeks, or in combination thereof. Thereafter, in some embodiments, the subject shows (a) a decrease in the units of nicotine used per day, such as tobacco smoked per day or vaping per day, compared to a subject receiving NRT, a control subject, a placebo control, and / or a baseline line; (b) a decrease in exhaled CO levels compared to a subject receiving NRT, a control subject, a placebo control, and / or a baseline

[0114] line; (c) a decrease in the serum and / or plasma cotinine levels of the subject compared to a subject receiving NRT, a control subject, a placebo control, and / or a baseline line; (d) an increase in the smoking cessation rate compared to a subject receiving NRT, a control subject, a placebo control, and / or a baseline line; and (e) no change, no increase, or a decrease in adverse events compared to a subject receiving NRT, a control subject, a placebo control, and / or a baseline

[0115] line.

[0116]

[0117]

[0118]

[0119] (f) An increase in the odds ratio of the subject compared to the subject receiving NRT, the control subject, the placebo control, and / or the base line and / or a decrease in the severity of nicotine withdrawal symptoms,

[0120] (g) An increase in smoking cessation in the subject receiving NRT compared to the control subject, the placebo control, and / or the base line and / or a decrease in nicotine craving and / or tobacco craving,

[0121] (h) A decrease in the severity of nicotine withdrawal symptoms in the subject receiving NRT compared to the control subject, the placebo control, and / or the base line and / or a decrease in the severity of anxiety, and / or

[0122] (i) A decrease in the severity of nicotine withdrawal symptoms in the subject receiving NRT compared to the control subject, the placebo control, and / or the base line and / or a decrease in the severity of depression, among one or more of the following:

[0123] (j) A decrease in the severity of anxiety in the subject receiving NRT compared to the control subject, the placebo control, and / or the base line, and / or and / or a decrease in the severity of depression, among one or more of the following:

[0124] (k) A decrease in the severity of depression in the subject receiving NRT compared to the control subject, the placebo control, and / or the base line, among one or more of the following: In one embodiment, the method of the present disclosure includes measuring the baseline level of one or more markers shown in (a) to (k) above before administering to the subject or group of subjects.

[0125] In one embodiment, the method of the present disclosure includes measuring the baseline level of one or more markers shown in (a) to (k) above before administering to the subject or group of subjects. In another embodiment, the method includes administering the composition disclosed herein to the subject after the baseline level of one or more markers shown in (a) to (k) has been determined, and subsequently performing additional measurements of the one or more markers. In another embodiment, in the treatment with the composition of the present disclosure, the subject shows one or more of the following: (a) an increase in the odds ratio of the subject compared to the subject receiving NRT, the control subject, the placebo control, and / or the base line

[0126] (a) Compared with the subject administered with NRT, control subject, placebo control, and / or baseline a decrease of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or more in the units of nicotine used per day, such as the tobacco smoked per day or vaping per day

[0127] (b) A decrease in exhaled CO level of about 5% to about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, 30%, about 35%, compared with the baseline, control, or placebo level, such as in the subject administered with NRT, control subject, placebo control, and / or baseline about 40%, about 45%, about 50%, or more

[0128] (c) Compared with the subject administered with NRT, control subject, placebo control, and / or baseline a decrease in serum and / or plasma cotinine level of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more

[0129] (d) An increase in the smoking cessation rate of about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 25% to about 75%, about 25% to about 50%, 30% to about 50%, about 30% to about 75%, about 30% to about <100%, or about 30% to about 100%, compared with the subject administered with NRT, control subject, placebo control, and / or baseline

[0130] ​​​​​​​(e) No change, no increase, or a decrease of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more in adverse events, compared to the subjects receiving NRT, control subjects, placebo controls, and / or the base line.

[0131] (f) An increase in the odds ratio of subjects of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more, compared to the subjects receiving NRT, control subjects, placebo controls, and / or the base line.

[0132] (g) An increase in smoking cessation of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more, compared to the subjects receiving NRT, control subjects, placebo controls, and / or the base line.

[0133] (h) A decrease in tobacco craving of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more, compared to the subjects receiving NRT, control subjects, placebo controls, and / or the base line.

[0134] (i) A decrease in the severity of nicotine withdrawal symptoms of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more, compared to the subjects receiving NRT, control subjects, placebo controls, and / or the base line.

[0135] (j)A reduction in the severity of anxiety of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, and / or a reduction in the severity of depression of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, as compared to a subject, control subject, placebo control, and / or base line receiving NRT. compared to a subject, control subject, placebo control, and / or base line receiving NRT, a reduction in the severity of anxiety of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30 %, about 35%, about 40%, about 45%, about 50% or more, and / or and / or

[0136] (k)A reduction in the severity of anxiety of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, and / or a reduction in the severity of depression of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, as compared to a subject, control subject, placebo control, and / or base line receiving NRT. compared to a subject, control subject, placebo control, and / or base line receiving NRT, a reduction in the severity of anxiety of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30 %, about 35%, about 40%, about 45%, about 50% or more, and / or a reduction in the severity of depression of about 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, as shown by one or more of the following. One or more of the following are shown.

[0137] In some embodiments, the methods of the disclosure include performing the methods in a subject in need thereof for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, and the methods include administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one administering cytisine to the subject three times a day at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine. In certain embodiments, the subject does not experience an adverse event after receiving cytisine treatment. In some embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) one A single tablet containing either 0.5 mg or 3.0 mg of cytisine, or (c ) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments the subject is a refractory patient who has failed treatment for one or more nicotine addictions, nicotine dependencies, or smoking cessation treatment . In some embodiments, the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes , vaping, and combinations thereof. In some embodiments the subject has smoked 10 or more cigarettes per day or used 10 or more vapes before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments the method further comprises providing behavioral support to the subject. In some embodiments, the method of the present disclosure treats nicotine addiction, nicotine dependence , promotes cessation of smoking and / or vaping, and / or promotes reduction of smoking

[0138] and / or vaping in a subject in need thereof, and the method comprises administering cytisine provided in unit doses of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine to the subject three times a day, and the subject does not experience adverse events after receiving cytisine treatment . In some embodiments, the adverse events are selected from the group consisting of URT I, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. . In some embodiments, the method of the present disclosure treats nicotine addiction, nicotine dependence and does not experience adverse events after receiving cytisine treatment. In some embodiments, the adverse events are selected from the group consisting of URT I, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0139] In some embodiments, the method of the present disclosure treats nicotine addiction, nicotine dependence performing, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, in a subject in need thereof, the method comprising administering cytisine at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine three times a day to a subject, wherein the subject does not experience nausea after receiving cytisine.

[0140] In some embodiments, the method of the disclosure comprises treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, in a subject in need thereof, the method comprising administering cytisine at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine three times a day to a subject for about 6 weeks or 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0141] In some embodiments, the method of the disclosure comprises treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, in a subject in need thereof, the method comprising administering cytisine at a unit dose of 3.0 mg, administering cytidine provided in a dosage three times a day to a subject, the subject being one or more nicotine addicts, nicotine dependents, or refractory patients who have failed in smoking cessation treatment. In some embodiments, the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof.

[0142] In some embodiments, the method of the present disclosure treats nicotine addiction and nicotine dependence, promotes cessation of smoking and / or vaping, and / or promotes reduction of smoking and / or vaping in a subject in need thereof, and includes doing so by administering cytidine provided in a unit dosage of 3.0 mg, 1.5 mg, or 1.0 mg of cytidine to the subject three times a day, the subject being (a) one who smoked 10 or more cigarettes per day prior to administration of cytidine, (b) one having an exhaled CO concentration of about 10 ppm or more prior to administration of cytidine, or (c) a combination of (a) and (b).

[0143] In some embodiments, the method of the present disclosure treats nicotine addiction and nicotine dependence, promotes cessation of smoking and / or vaping, and / or promotes reduction of smoking and / or vaping in a subject in need thereof, and includes doing so by administering cytidine provided in a unit dosage of 3.0 mg, 1.5 mg, or 1.0 mg of cytidine to the subject three times a day, and providing behavioral support to the subject.

[0144] ​​​​​The methods of the disclosure include administering nicotine to a subject in need of treatment for nicotine addiction or nicotine dependence. The method further includes treating nicotine addiction or nicotine dependence by administering cytisine to the subject. and administering to the subject a nicotine addiction or nicotine dependence treatment that has resulted in treatment failure. In certain embodiments, the patient is a refractory patient suffering from nicotine addiction or nicotine dependence. Treatment options include NRT, bupropion, varenicline, e-cigarettes, vaping, or or combinations thereof. In some embodiments, cytisine is The drug is administered in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to subjects with In certain embodiments, cytisine is administered three times a day to a subject in need thereof. In some embodiments, the unit dose is provided in a 3.0 mg unit dose of cytisine. The amount of cytisine is: (a) each tablet contains either 1.5 mg or 3.0 mg of cytisine; (b) two tablets containing either 1.5 mg or 3.0 mg of cytisine; or (c) three tablets, each containing 1.0 mg of cytisine. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject experiences an adverse event after receiving cytisine treatment. In certain embodiments, the adverse events are URTIs, abnormal dreams, nausea, insomnia. In some embodiments, the symptoms are selected from the group consisting of headache, fatigue, and constipation. The elephants were randomly assigned to either (a) smoke 10 or more cigarettes per day before cytisine administration or (b) smoke 10 or more cigarettes per day before cytisine administration. (c) have a CO concentration of about 10 ppm or more before administration of the drug; or ) is a combination of

[0145] The method of the present disclosure further requires preventing relapse of smoking and / or vaping and provides a method for preventing relapse of smoking and / or vaping in a subject in need thereof. The method comprises administering to the subject cytosine in a unit dose of (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine, three times a day. In some embodiments, cytosine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytosine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject is (a) a heavy smoker who smoked 10 or more cigarettes per day before cytosine administration, (b) had an exhaled CO concentration of about 10 ppm or more before cytosine administration, or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapies include NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or combinations thereof.

[0146] The method of the present disclosure further includes preventing relapse of smoking and / or vaping in a subject in need thereof, and the method comprises administering cytosine to the subject, and the subject has received NRT, bupropion administration, varenicline Selected from the group consisting of phosphorus administration, e-cigarettes, vaping, or combinations thereof is a refractory patient who has failed treatment with one or more smoking cessation treatments. In some embodiments , the subject has smoked (a) more than 10 cigarettes per day prior to administration of cytisine, , (b) has an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, , (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, and is included three times a day for the subject , and cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments , the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia , headache, fatigue, and constipation after receiving cytisine treatment.

[0147] The present disclosure also provides a pharmaceutical product, such as a pharmaceutical product containing a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine, for use in treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, in a subject in need thereof, the pharmaceutical product being for oral administration three times a day to the subject. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation . is selected. In certain embodiments, the subject experiences nausea after receiving cytosine treatment and does not. In some embodiments, cytosine is administered for about 6 weeks or about 12 weeks . In some embodiments, the unit dose of cytosine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each tablet containing 1 .0 mg of cytosine. In some embodiments, the subject is a refractory patient who has failed treatment for one or more nicotine addictions, nicotine dependencies, or smoking cessation treatments . In certain embodiments, the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytosine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytosine, or (c) a combination of (a) and (b) . In some embodiments, the method further comprises providing behavioral support to the subject .

[0148] The present disclosure also provides a pharmaceutical such as a pharmaceutical comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytosine for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in a subject in need thereof, the pharmaceutical being for oral administration to the subject three times a day, and the subject has received cytosine treatment Does not experience an adverse event. In certain embodiments, the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment.

[0149] The present disclosure further provides a pharmaceutical such as a pharmaceutical comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for use in a subject in need of treating nicotine addiction, treating nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, wherein the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0150] In some embodiments, the present disclosure further provides a pharmaceutical comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for use in a subject in need of treating nicotine addiction, treating nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or smoking cessation therapies. In certain embodiments, the nicotine addiction or smoking cessation therapy is NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. ​​​​​​​​​​ selected from

[0151] In some embodiments, the present disclosure further provides a pharmaceutical comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for treating nicotine addiction, nicotine dependence, promoting smoking and / or vaping cessation, and / or reducing smoking and / or vaping in a subject in need thereof, wherein the subject is (a) smoking 10 or more cigarettes per day prior to administration of cytisine, (b) having an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b). The present disclosure further provides a pharmaceutical, such as a pharmaceutical comprising cytisine, for treating nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments, the pharmaceutical being for oral administration to the patient three times a day. In some embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times a day to a subject in need thereof. In certain embodiments, cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) containing either 1.5 mg or 3.0 mg of cytisine or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b).

[0152] The present disclosure further provides a pharmaceutical for treating nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. The pharmaceutical is for oral administration to the patient three times a day. In some embodiments, the nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times a day to a subject in need thereof. In certain embodiments, cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) containing either 1.5 mg or 3.0 mg of cytisine or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). or (c) a combination of (a) and (b). 、 a single tablet, or (c) three tablets, each containing 1.0 mg of cytisine, are included. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks . In some embodiments, the subject does not experience adverse events after receiving cytisine treatment . In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache , fatigue, and constipation. In some embodiments, the subject is (a) smoked more than 10 cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine , or (c) a combination of (a) and (b).

[0153] In some embodiments, the pharmaceutical composition is used to prevent relapse of smoking and / or vaping in a subject in need thereof, and for this purpose, a unit dose of cytisine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytisine , (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each containing 1.0 mg of cytisine, and the pharmaceutical composition is for oral administration to the subject three times a day . In certain embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue , and constipation. In some embodiments, the subject is (a) smoked more than 10 cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine , or (c) a combination of (a) and (b). . In certain embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue , and constipation. In some embodiments, the subject is (a) smoked more than 10 cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine . In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue , and constipation. In some embodiments, the subject is (a) smoked more than 10 cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine , or (c) a combination of (a) and (b). before administration of cytisine,​ has an exhaled CO concentration of about 10 ppm or more, or is a combination of (c)(a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, or combinations thereof. .

[0154] The present disclosure further provides a pharmaceutical product such as a pharmaceutical product containing cytidine to prevent relapse of smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addictions or nicotine dependence treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, electronic cigarettes, or vaping, and the pharmaceutical product is for oral administration three times a day to the subject. In some embodiments, the subject has ( a) smoked 10 or more cigarettes per day before administration of cytidine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytidine, or (c) a combination of (a) and (b). In some embodiments, the unit dose of cytidine includes (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1 .5 mg or 3.0 mg of cytidine, or (c ) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytidine treatment.

[0155] ​​​​​​​​​ In some embodiments, the present disclosure treats nicotine addiction, nicotine dependence , promotes cessation of smoking and / or vaping, and / or promotes reduction of smoking and / or vaping in a subject in need thereof, and provides for the use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for that purpose, wherein the cytisine is for oral administration to the subject three times a day. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In certain embodiments, the subject does not experience nausea after receiving cytisine treatment. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction, nicotine dependence, or smoking cessation treatments. In certain embodiments, the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion Have an exhaled CO concentration of about 10 ppm or more before administration of the agent, or (c) (a) and (b) And combinations thereof. In some embodiments, use further comprises providing behavioral support to a subject Thereof.

[0156] The present disclosure further provides for the treatment of nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments Thus, the use of cytisine is provided, and cytisine is for oral administration to the patient three times a day There is. In certain embodiments, the nicotine addiction or nicotine dependence treatment is NRT, bup Lopion administration, varenicline administration, e-cigarettes, vaping, or combinations thereof Including. In some embodiments, cytisine is provided in unit doses of about 1.0 mg to about 6.0 mg of cytisine three to six times a day to a subject in need thereof. In certain embodiments In some embodiments, cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof. In certain embodiments, the unit dose of cytisine is (a) two tablets, each tablet Containing either 1.5 mg or 3.0 mg of cytisine, (b A single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) Three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments The adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation In some embodiments, the subject is (a) administered cytisine In some embodiments, the subject is (a) administered cytisine In some embodiments, the subject is (a) administered cytisine In some embodiments, the subject is (a) administered cytisine Have smoked more than 10 cigarettes per day previously, (b) have an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) be a combination of (a) and (b). or (c) is a combination of (a) and (b).

[0157] In some embodiments, the use of a unit dose of cytisine in the form of (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, includes preventing relapse of smoking in a subject in need thereof, and the cytisine is for oral administration three times a day to the subject. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. or (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine or (c) three tablets, each tablet containing 1.0 mg of cytisine, includes preventing relapse of smoking in a subject in need thereof, and the cytisine is for oral administration three times a day to the subject. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. or (c) three tablets, each tablet containing 1.0 mg of cytisine, includes preventing relapse of smoking in a subject in need thereof, and the cytisine is for oral administration three times a day to the subject. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. and the cytisine is for oral administration three times a day to the subject. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. and the cytisine is for oral administration three times a day to the subject. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, the cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In certain embodiments, the adverse events are selected from the group consisting of URI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, the subject has (a) smoked more than 10 cigarettes per day prior to the administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. or (c) is a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. In certain embodiments, the smoking cessation therapy includes NRT, bupropion administration, varenicline administration, e-cigarette, vaping, or a combination thereof. or a combination thereof.

[0158] In some embodiments, NRT, bupropion administration, varenicline administration, e-cigarette, vaping The use of cytidine for preventing relapse of smoking in a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies selected from the group consisting of vaping or smoking and is for oral administration to the subject three times a day. In some embodiments, the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytidine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytidine, or (c) a combination of (a) and (b). In certain embodiments, the unit dose of cytidine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytidine, or (c) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytidine treatment. and is for oral administration to the subject three times a day. In some embodiments, the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytidine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytidine, or (c) a combination of (a) and (b). and is for oral administration to the subject three times a day. In some embodiments, the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytidine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytidine, or (c) a combination of (a) and (b). In certain embodiments, the unit dose of cytidine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytidine, or (c) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In certain embodiments, the unit dose of cytidine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytidine, or (c) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In certain embodiments, the unit dose of cytidine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytidine, or (c) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In certain embodiments, the unit dose of cytidine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytidine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytidine, or (c) three tablets, each tablet containing 1.0 mg of cytidine, and the cytidine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytidine treatment. In some embodiments, the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytidine treatment.

[0159] The present disclosure further provides tablets containing about 1.0 mg or 1.5 mg of cytidine for oral administration to a subject three times a day for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in the subject. In some embodiments, the subject does not experience adverse events after receiving cytidine treatment. In certain embodiments, the adverse events are URTI, abnormal dreams, nausea The present disclosure further provides tablets containing about 1.0 mg or 1.5 mg of cytidine for oral administration to a subject three times a day for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in the subject. In some embodiments, the subject does not experience adverse events after receiving cytidine treatment. In certain embodiments, the adverse events are URTI, abnormal dreams, nausea The present disclosure further provides tablets containing about 1.0 mg or 1.5 mg of cytidine for oral administration to a subject three times a day for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in the subject. In some embodiments, the subject does not experience adverse events after receiving cytidine treatment. In certain embodiments, the adverse events are URTI, abnormal dreams, nausea It is selected from the group consisting of qi, insomnia, headache, fatigue, and constipation. In certain embodiments , the subject does not experience nausea after receiving cytisine treatment. In some embodiments , cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the unit dose of cytisine is (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, the subject is a refractory patient who has failed treatment for one or more nicotine addictions, nicotine dependencies, or smoking cessation treatments. In certain embodiments the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject is (a) smoking more than 10 cigarettes per day before administration of cytisine, (b) having an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments the use further includes providing behavioral support to the subject. In some embodiments, the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for the oral administration three times a day of about 3.0 mg of cytisine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies for treating nicotine addiction or nicotine dependence in the subject. In certain embodiments the nicotine addiction, nicotine dependence, or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, and combinations thereof. In some embodiments, the subject is (a) smoking more than 10 cigarettes per day before administration of cytisine, (b) having an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments the use further includes providing behavioral support to the subject. In some embodiments, the subject is (a) smoking more than 10 cigarettes per day before administration of cytisine, (b) having an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and (b). In some embodiments the use further includes providing behavioral support to the subject. In some embodiments, the use further includes providing behavioral support to the subject. In some embodiments, the use further includes providing behavioral support to the subject.

[0160] In some embodiments, the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for the oral administration three times a day of about 3.0 mg of cytisine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies for treating nicotine addiction or nicotine dependence in the subject. In certain embodiments the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for the oral administration three times a day of about 3.0 mg of cytisine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies for treating nicotine addiction or nicotine dependence in the subject. In certain embodiments the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for the oral administration three times a day of about 3.0 mg of cytisine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies for treating nicotine addiction or nicotine dependence in the subject. In certain embodiments the use of tablets containing about 1.0 mg or 1.5 mg of cytisine is for the oral administration three times a day of about 3.0 mg of cytisine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions or nicotine dependencies for treating nicotine addiction or nicotine dependence in the subject. In certain embodiments Currently, nicotine addiction or nicotine dependence treatment includes NRT, bupropion administration, varenicline administration, e-cigarettes, vaping, or combinations thereof. In some embodiments, cytisine is provided in unit doses of about 1.0 mg to about 6.0 mg of cytisine, 3 to 6 times a day, to a subject in need thereof. In certain embodiments, cytisine is provided in a unit dose of 3.0 mg of cytisine, 3 times a day, to a subject in need thereof. In some embodiments, the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine. In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience adverse events after receiving cytisine treatment. In certain embodiments, the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b). In some embodiments, the use of tablets containing about 1.0 mg or about 1.5 mg of cytisine is for oral administration of about 3.0 mg of cytisine, 3 times a day, to a subject to prevent relapse of smoking and / or vaping in the subject. In certain embodiments,

[0161] In some embodiments, tablets containing about 1.0 mg or about 1.5 mg of cytisine are for oral administration of about 3.0 mg of cytisine, 3 times a day, to a subject to prevent relapse of smoking and / or vaping in the subject. In certain embodiments, In some embodiments, cytisine is administered for about 6 weeks or about 12 weeks. In certain embodiments, the subject does not experience any adverse events after receiving cytisine treatment. Adverse events included URTIs, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. In some embodiments, the subject is selected from the group consisting of: (a) prior to administration of cytisine; (b) smoked 10 or more cigarettes per day or (c) consumed approximately 10 ppm or more of cytisine before administration or (c) a combination of (a) and (b). In some embodiments, the subject is a refractory patient who has failed treatment with one or more smoking cessation therapies. In certain embodiments, the smoking cessation treatment includes NRT, bupropion administration, varenicline, These include nicotine dosing, e-cigarettes, vaping, or a combination thereof.

[0162] In some embodiments, a tablet containing about 1.0 mg or about 1.5 mg of cytisine. The use of NRT, bupropion, and balanol to prevent relapse in subjects. One or more of the following are selected from the group consisting of nicotine administration, e-cigarettes, or vaping: Approximately 3.0 mg of citrate is administered to subjects with nicotine addiction or who have failed nicotine dependence treatment. In some embodiments, the subject is administered orally three times a day. (a) smoking 10 or more cigarettes per day before cytisine administration; (b) or (c) a combination of (a) and (b) and In some embodiments, the unit dose of cytisine is a combination of: (a) each tablet Two tablets containing either 1.5 mg or 3.0 mg of cytisine (b )Either a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each tablet containing 1.0 mg of cytosine, wherein the cytosine is administered for about 6 weeks or about 12 weeks. In some embodiments, the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytosine treatment.

[0163] Thus, in yet another aspect, provided herein is a method of treating nicotine addiction or nicotine dependence in a subject, comprising administering cytosine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction or nicotine dependence treatments. Suitable unit doses include doses of about 1.0 mg to about 6 mg that can be administered 3 to 6 times a day, for example, at substantially equal intervals. For example, in some embodiments, the method comprises administering cytosine provided as a unit dose of 3.0 mg of cytosine to a refractory patient 3 times a day. Any suitable administration period can be used in the methods disclosed herein, for example, about 26 weeks, about 12 weeks, or about 6 weeks. In some embodiments, the treatment is administered for about 6 weeks. In some embodiments, the method disclosed herein can further comprise providing behavioral support to a subject, such as a refractory patient. Behavioral support includes, as topics, smoking cessation, past smoking cessation experiences, prediction of motivation or challenges in future attempts, alcohol use, proximity and frequency of approaching other nicotine users (e.g., smokers), recognition of risky situations, and

[0164] In some embodiments, the method disclosed herein can further comprise providing behavioral support to a subject, such as a refractory patient. Behavioral support includes, as topics, smoking cessation, past smoking cessation experiences, prediction of motivation or challenges in future attempts, alcohol use, proximity and frequency of approaching other nicotine users (e.g., smokers), recognition of risky situations, and Counseling can be included, including but not limited to, further including the ability to handle stress. .

[0165] In some embodiments, the methods disclosed herein can further include providing one or more questionnaires to a subject. Non-limiting examples of one or more questionnaires can include electronic Tobacco Dependence Scale Questionnaire, Marijuana Craving Questionnaire - Short Form, Fagerstrom Test for Nicotine Dependence, Smoking Self-Efficacy Questionnaire (SEQ-12), Brief Questionnaire for Smoking Urge (Q SU-Brief) Questionnaire, Minnesota Nicotine Withdrawal Scale (MNWS) Questionnaire, "Since the Last Visit" C-SSRS Questionnaire, and HADS Questionnaire. In certain embodiments, the questionnaire can be provided to the subject at any time during administration of the composition, before administration of the composition, or after administration of the composition. In some embodiments, one or more questionnaires are provided to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 times, or 30 times.

[0166] The patents, patent applications, and scientific literature referred to herein are incorporated herein by reference in their entirety as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. Any conflict between the reference literature cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Similarly, any conflict between the definition of a word or phrase as understood in the art and the definition of a word or phrase specifically taught herein shall be resolved in favor of the latter.

[0167] As can be understood from the above disclosure, the present invention has a wide variety of applications. The present invention is hereinafter is further illustrated by the examples, which are merely illustrative and are not intended to limit the definition and scope of the present invention in any way.

[0168] Example 1: Effect of Cytisine in the Treatment of Nicotine Addiction This was a six-group, multi-site, double-blind, randomized, placebo-controlled trial conducted in adult men and women aged ≧18 years who smoked ≧10 cigarettes per day and intended to set a quit date 5 - 7 days after randomization. This trial was designed to evaluate the efficacy of 1.5 mg of cytisine versus placebo using the commercially approved dosing schedule in Central and Eastern Europe. In this trial, the efficacy of a simplified TID dosing schedule of 1.5 mg and an increased dose of 3.0 mg (using both the commercial dosing setting (COM) and the simplified TID dosing schedule) was also evaluated. The overall goal of this trial was to obtain estimates of effect sizes for efficacy and safety endpoints that would be used to inform the design of future Phase 3 trials.

[0169] The dosing schedule of the trial is shown in Figure 1. The trial was double-blinded with respect to dose rather than dosing schedule, and the study groups are shown in Figure 2. As shown in Figure 3, the study treatment was initiated on the day after randomization so that the study treatment would start before the quit date.

[0170] The primary efficacy endpoint in this trial was the rate of decrease in the number of cigarettes smoked during treatment and was calculated as follows:

Number

[0171] The secondary efficacy endpoint was the smoking cessation rate (confirmed with CO < 10 ppm), including analysis at week 4 (i.e., the end of treatment), and sustained (for 4 weeks) smoking cessation from week 5 to week 8 (i.e., after treatment). That is, the end of treatment), and sustained (for 4 weeks) smoking cessation from week 5 to week 8 (i.e., after treatment). Included.

[0172] The subject attributes are summarized in Figure 4. The cigarettes smoked by the subjects before and after treatment are shown in Figure 5. Shown.

[0173] 1.1 Results Table 1 summarizes the subject attributes. A total of 254 adult men or women aged ≥ 18 years who smoked ≥ 10 cigarettes per day and had the intention to set a stop date after 5 - 7 days of randomization were assigned to the trial. Attributes and baseline characteristics were well balanced across both schedules and treatment groups. That is, the end of treatment), and sustained (for 4 weeks) smoking cessation from week 5 to week 8 (i.e., after treatment). Shown. Across both schedules and treatment groups.

Table 1

[0174] Of the trial population, 53% were women and 47% were men. 79% of the trial population were white, 18% were black, and 3% were of another race. Smoking diary compliance, on which the primary analysis was partly based, was high across all treatment groups. Trial drug compliance was > 94% across all treatment groups and was slightly higher (> 98%) with the TID schedule. The mean treatment duration was 23.4 days, and 96.6% of the subjects received the mean dose of cytisine. That is, the end of treatment), and sustained (for 4 weeks) smoking cessation from week 5 to week 8 (i.e., after treatment). Across all treatment groups. With the TID schedule. Received the mean dose of cytisine.

[0175] Table 2 summarizes the smoking history of the subjects in all treatment groups. Overall, the trial population represents highly addicted smokers who were on average 48.4 years old and had smoked for 32 years, which means that most of them started smoking in adolescence. Furthermore, they had previously tried to quit smoking an average of 4.5 times, and the last attempt to quit was about 3.7 years before entering the trial. Currently, they smoked an average of 1 pack of cigarettes per day. Among previous attempts to quit smoking, 35% of the subjects had been administered varenicline in the past, 16% of the subjects had received bupropion, and 48% of the subjects had received NRT .

Table 2

[0176] Overall, trial drug compliance was high in all treatment groups, and the TID schedule (98.18% ) was better than the commercial schedule (94.90%). More specifically, Table 3 summarizes the trial drug compliance in all treatment groups. The trial drug compliance ranged from 96.7% to 99.5% in the TID group, but the trial drug compliance ranged from 94.2% to 96.4% in the COM group .

Table 3

[0177] The reduction in cigarettes smoked in all treatment groups is shown in Figure 6 and summarized in Table 4. The primary analysis The results from both COM groups showed a significant decrease in the predicted percentage of cigarettes smoked (cigarette score). Pooling the placebo groups, the cigarette score significantly decreased in both COM groups and the 1.5 mg TID group, and significantly approached that in the 3.0 mg TID group. Using the COM schedule, subjects treated with 1.5 mg or 3.0 mg of cytisine smoked approximately 14% - 16% less cigarettes than predicted compared to the placebo. On the TID schedule, subjects treated with 1.5 mg or 3.0 mg of cytisine smoked approximately 9% - 12% less cigarettes than predicted compared to the placebo group.

Table 4

[0178] The decrease on the TID schedule was not as high as that shown on the COM schedule, but it should be noted that subjects in the TID schedule placebo group reported a higher decrease in cigarettes smoked than those in the COM schedule placebo group. TID placebo subjects smoked only one-third of the normal amount of cigarettes (LS mean: 35.30%), while COM placebo subjects smoked half of the cigarettes (LS mean: 47.10%), so the cytisine treatment on the TID schedule may have been masked.

[0179] Exhaled CO levels were also measured during this trial period as an objective biochemical marker of smoking reduction. The decrease in CO in all treatment groups is shown in Figure 6 and summarized in Table 4. In all cytisine treatment groups, the decrease in CO (a 55% - 62% decrease) was consistent with the reported decrease in cigarettes smoked (for example, a range of 25% - 32% as the cigarette score corresponded to a reduction in smoking). ​​​​​​​​​​​A 75% to 68% reduction in smoke (is represented). Conversely, in the placebo treatment group, the reported decrease in the number of cigarettes smoked (e.g., representing a 59% decrease in the cigarettes smoked, a tobacco score of 4 1%) was not paralleled by only a 29% decrease in the corresponding CO. A similar pattern in plasma cotinine levels was observed by a much greater decrease in the cotinine levels in the cytisine group compared to the placebo group.

[0180] These changes in the objective markers generally suggest that subjects receiving placebo treatment over-reported the decrease in the cigarettes smoked. Also, the true difference in the tobacco scores between the subjects treated with cytisine and those treated with placebo was also suggested to be greater than what was actually observed.

[0181] The smoking cessation rates of the TID schedule group versus placebo are shown in Figures 7 and 8 and summarized in Table 5 . The results of the initial smoking cessation rates at week 4 showed that both groups on the TID schedule had a high odds of success in smoking cessation compared to placebo, and the subjects in the 3.0 mg cytisine group had the highest odds of success in smoking cessation with an OR: 6.31 (95% CI: 2.28, 18.45). The OR of the 1.5 mg cytisine group on the T ID schedule was 5.81 (95% CI: 2.12 16.87). In the COM schedule, the ORs of the 1.5 and 3.0 mg cytisine groups were 5.59 (95% CI: 2.03, 16.29) and 5.38 (9 5% CI: 1.95, 15.72), respectively.

Table 5

[0182] Referring to FIGS. 7 and 8 and Table 5, long-term smoking cessation from 5 weeks to 8-week endpoint In the TID schedule, both groups had a high odds of success in smoking cessation compared to placebo Subjects in the 3.0 mg cytisine group had the highest odds of success in smoking cessation from 5 weeks to 8 weeks with an OR of 5.04 (95% CI: 1.42, 22.32). The OR of the 1.5 mg cytisine group in the T ID schedule was 4.33 (95% CI: 1.21 , 19.30). In the COM schedule, the ORs in the 1.5 mg cytisine and 3.0 m g groups were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI: 0.55, 10.82), respectively.

[0183] Table 6 summarizes the comparison of exhaled CO levels and the reduction in smoking cessation rate at week 4 and weeks 5 - 8 between the 3.0 mg cytisine group and placebo [Table 6]

[0184] Subjects in the cytisine group in the TID schedule also had high odds of smoking cessation at weeks 6, 7, and 8 compared to subjects in the corresponding group in the COM schedule compared to placebo, as indicated by the high ORs at each time point

[0185] 1.2 Objectives and General Methods of Sensitivity The primary outcome (tobacco score) and the primary secondary smoking cessation outcome were subjected to sensitivity analysis. The primary secondary smoking cessation outcome was the initial smoking cessation rate at week 4 and continuous 4-week smoking cessation from week 5 to week 8 and was designed as Cess / W5 - 8 / CO success, confirmed by exhaled CO < 10 ppm ​​​was recognized. The objective was to evaluate the robustness of the results from the clinical trial and determine whether the observed results could be confirmed, or to perform any alternative analysis that could challenge the conclusion of the trial.

[0186] Other outcomes related to objective biochemical evaluations were also analyzed. The relationships between these biochemical evaluations are particularly important when used as part of the definition of smoking cessation and abstinence, and are important because there is no evaluation subjectivity.

[0187] The focus of these sensitivity analyses in this report is on the comparison between the 3.0 mg cytosine TID group and the pooled placebo (0 mg cytosine) group. Some analyses show other comparisons for contrast.

[0188] Effect of modified analysis methodology A common method for evaluating the robustness, consistency, and meaning of results from a clinical trial is to perform an effect modification analysis (EMA). The goal of EMA is to evaluate the degree to which the estimated effects of groups differ for discrete values of baseline attributes. For example, the EMA for gender estimates the effects of gender-specific groups and evaluates whether these estimates differ. When the baseline attributes evaluated using EMA are not discrete, the attributes are discretized by specifying cut points based on external criteria, or by using percentiles (median, tertiles, or quartiles) calculated from the pooled data. For example, the baseline CO level is divided into less than 10 ppm or not, or using the pooled quartiles.

[0189] EMA fits a statistical model to the data. The EMA model includes discrete factors It has interaction terms to detect the existence of differences in group effects across values. Heterogeneity of effect estimation is detected when the interaction term significantly improves the model fit beyond a model without the interaction term. The improvement in fit by the interaction term is measured by the interaction P-value, and a small P-value, usually less than 0.10, indicates an improvement in fit.

[0190] There are two types of interactions: qualitative and quantitative. A quantitative interaction exists when the direction of the group effect estimate is the same for all discrete values of the factor. A qualitative interaction exists when the direction of the effect is mixed across the values of the factor.

[0191] The results from multiple EMAs conducted in this study are presented compactly as a forest plot, showing for each factor value the subset-related frequency (distribution between groups), the estimate of the effect, and the applicable confidence interval. The graph of the EMA forest provides a gestalt regarding the stability of the overall effect estimate for the factors included in the graph. The complete EMA forest plot also shows, for each factor, a quantitative assessment of heterogeneity from the EMA model, e.g., the interaction P-value. Also, the estimates of the group effects and the confidence intervals at each value of the factor are presented in the forest plot. (Such a forest plot will be shown later.)

[0192] Justification in the pooled control group The comparison between groups was a pairwise comparison of each active group with the pooled placebo group. The justification for comparing with the pooled placebo was that · two placebo groups had P-values of 0.1197 each in a stratified comparison of control groups for the tobacco score, success of initial smoking cessation at week 4, and Cess / W5-8 / CO success outcome. ​​​​​​​​​​​​ having 0.9963 and 0.9996 and being different for primary or two secondary regressions and having no evidence · Randomization between placebo groups has no evidence of being different for any of the baseline attributes presented later, including clinical facilities, and is used as a factor of the EMA Based on this, it was done.

[0193] For the purpose of sensitivity evaluation, the lack of evidence of differences in the placebo group is considered as a justification for pooling, which has the advantage of increasing statistical sensitivity.

[0194] Descriptive graph of the average number of cigarettes reported daily The longitudinal graph regarding the average number of cigarettes reported in the diary for each test treatment day (days 1 to 25 after randomization) is shown below. Each group and the pooled placebo group are displayed in different colors or in solid line vs. dashed line. Figure 5 shows that the subject attempted to quit smoking until the planned smoking cessation interval (days 5 to 7) until the 8th day and reduced the number of cigarettes smoked per day.

[0195] 1.3 Biochemical verification analysis The following are two longitudinal graphs of the mean visits and 95% confidence intervals of CO and cotinine, respectively, for the pooled placebo group and the cytisine treatment group.

[0196] The CO level (ppm) was evaluated weekly during the test period, at screening, at baseline, at the end of the test treatment intervention (4th week), and until the 8th week (Figure 9). The mean CO at screening and at baseline visits was approximately the same in all groups. At the 4th week, regardless of the schedule, there was a significant decrease in the CO level in all subjects treated with the cytisine treatment group. A decrease was observed. During the follow-up period from week 4 to week 8 (with only behavioral support), the mean CO of the pooled placebo group was almost constant, but was somewhat lower than the mean before the start of the test treatment intervention. The mean of the active treatment group remained clearly lower compared to the pooled placebo group for all follow-up visits, but the mean showed a slight upward trend.

[0197] Serum cotinine levels were exploratory and were evaluated only at screening, week 4, and week 8. Results reported with < 10 ng / mL of cotinine were converted to 0 ng / mL before statistical analysis. The cotinine graph in Figure 10 showed the same pattern as that observed with CO. All subjects in the cytisine treatment group had a significant decrease in cotinine levels at week 4 and showed a slight upward trend until week 8.

[0198] 1.4 Tobacco Score Analysis Primary Model Stratification and Covariate Assumptions The primary model for the tobacco score included covariates for BMI stratification (3 levels) and the average number of cigarettes reported in the screening diary. The validity of the conclusions from the primary model results depended on there being no interaction between each of these covariates and the group variable. If one or both of these interactions were essential in the statistical model, the magnitude of the estimated group effect would be a function of the BMI class and / or the average number of cigarettes reported in the screening diary.

[0199] Planned statistical analyses of the primary endpoints were performed, and as part of those analyses, each of the cytisine treatment groups was compared to the pooled placebo on the primary efficacy endpoint (tobacco score). ​​​​​​​​​​​​were compared with the group. These analyses were performed using a variable model with a fixed effect for the treatment group, as well as the covariates of BMI (18.5 to <25 kg / m 2 , 25 to <30 kg / m 2 , 30 to <35 kg / m 2 ), and the number of baseline cigarettes. In the analysis, a BMI variable derived from the subject's actual BMI was used, and one subject (104 - 144) was excluded because the subject's BMI (39.9 kg / m ) was higher than the upper limit of the upper BMI classification (30 to <35 kg / 2 m m 2 ).

[0200] Two variables in this analysis were performed as part of a sensitivity analysis. These were the following models . · A model using a BMI variable derived from the subject's actual BMI, but with all 254 subjects included in the overall randomization set. The BMI classifications used in this analysis were 18.5 to <25 kg / m , 25 to <30 kg / m 2 , 30 to <35 kg / m2, and ≥35 k 2 g / m g / m 2 . · A model using a BMI stratification variable at the time of randomization. Subjects 104 - 144 were within the BMI stratum (30 to <35 kg / m ) reported for that subject at randomization and were included in this 2 analysis. As a result, this analysis included all 254 subjects in the overall randomization set. The BMI classifications used in this analysis were 18.5 to <25 kg / m , 25 to < 30 kg / m 2 , and 30 to <35 kg / m 30 kg / m 2 , and 30 to <35 kg / m 2 .

[0201] Figures 11A - 11B show the comparison between the homogeneity of each group (COM 0 mg and TID 0 mg, and between TID 0 mg and TID 3.0) as a factor of the predicted percentage of cigarettes smoked ( cigarette score).

[0202] Figures 16 and 17 are additional evaluations regarding the interaction number between BMI and the baseline mean of cigarettes in the 3.0 mg TID group, especially compared with the pooled placebo group .

[0203] Regarding BMI, this evaluation of the existence of an interaction with the group was evaluated as an EMA using BMI as a factor, and the size of the interaction P indicates the information of the existence of this interaction (Figure 16 ). The EMA interaction P value for BMI is 0.1303, which is not small enough to raise concerns , but based on the estimation of the layer - specific effect size, it was suggested that patients with high BMI may be more effective compared to those with low BMI .

[0204] Evidence of an interaction between the group and the baseline mean of cigarettes (model covariate) was evaluated by the parallelism between groups of the linear correlation between the cigarette score and the baseline mean of cigarettes . The P value for this evaluation of parallelism shown in the scatter plot (Figure 17) is 0.2754 , providing evidence of no parallelism

[0205] Alternative cigarette score analysis The primary outcome was based on the number of cigarettes smoked daily from the diary. The cigarette score used the diary data for the planned 25 - day period during the test treatment . A sensitivity analysis for the comparison between the 3.0 mg TID group and the pooled placebo group regarding the changes related to the cigarette score in the primary analysis of the cigarette score is shown . An alternative definition of the cigarette score is after a planned washout period between 5 - 7 days, that is​ It is characterized by the tobacco recorded in the diary after the 8th day rather than after the 1st day.

[0206] Another alternative analysis is based on the re - analysis of the primary tobacco score and the above - mentioned alternative tobacco scores and involves weighting related to the standard error of the average number of tobacco estimated from diary entries The weight used for each subject is 1 / (SE) 2 where SE is the standard error of the average estimate. This type of weighting is called inverse - variance weighting and is commonly used. This weighting gives a larger weight to the average estimated with a smaller SE. However, it was necessary to slightly modify the definition of this weighting. When calculating 1 / (SE) specific rules were used when SE = 0, especially when all diary entry values were equal. In these cases, SE was calculated as if only one of the recorded values was greater than 1. When this correction is made to the data, SE = 1 / N can be shown, 2 where N is the number of subject registrations per day. Table 7 shows the P - values and effect estimates in the 95% confidence intervals for the four analyses described for the comparison between the 3.0mg TID group and the pooled placebo group. When the start of the diary data was the 8th day instead of the 1st day, the effect estimates were somewhat better (for the primary tobacco score, - 11.8 vs - 9.5 respectively), but that is because the smoking data before the planned stop date was excluded.

[0207] For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that For the analysis, when weighting was applied to the primary tobacco score, the effect - estimated P - value was 0.0466 compared to 0.0675 in the unweighted analysis of the primary tobacco score. This is because the diary data before the planned stop date (before the 8th day) and that Subsequent smoking cessation led to a large SE, resulting in a decrease in the weight of smokers. This decrease in weight was redefined using diary data starting from the 8th day and not applied to the redefined tobacco score, so the weighted effect size of the redefined tobacco score was clearly beneficial compared to the unweighted primary tobacco score starting from the 1st day (-15.0 vs -9.5 respectively).

Table 7

[0208] An analysis of whether there is evidence of heterogeneity of effects across eight clinical facilities (sources of subjects) was performed as an EMA where the interaction P-value provides a measure of heterogeneity of effects. This analysis was performed for both the primary outcome variable of the tobacco score and Cess / W5-8 / CO success. For the tobacco score, the EMA model has additional covariates for BMI stratification and the mean number of cigarettes reported by the screening diary. For Cess / W5-8 / CO success, covariates were not added to the EMA model because there is a possibility of empty cells in the cross-classification across binary outcomes, groups, and discrete variables of clinical facilities. For example, there were situations where a particular

[0209] clinical facility had no subjects who were successful in one or both groups. Figures 18 to 25 provide the EMA analysis results for each of the four comparisons of active cytisine against the pooled placebo group and for both outcome variables. Evidence of heterogeneity of effects due to clinical facilities was not observed

[0210] 1.5 Comparison of Smoking Cessation Rates between Varenicline and Chantix (registered trademark) Figures 12 and Table 8 show the test design for comparing varenicline (Chicixin) and Chantix (registered trademark). The treatment period of Chantix (registered trademark) (12 weeks) was approximately 3.5 times longer than that of varenicline (25 days). The sustained smoking cessation time point of Chantix ( registered trademark) (week 12, measured beyond the last 4 weeks of treatment) was longer than that of varenicline (week 8, measured beyond 4 weeks after the end of treatment). Table 8 includes additional details regarding the clinical trials using varenicline and Chantix (registered trademark).

Table 8

[0211] Figure 13 shows the smoking cessation rates confirmed by CO between 3.0 mg of varenicline and 3.0 mg of Chantix (registered trademark) at week 4 and week 12 of treatment. The Chantix ( registered trademark) data are the 7-day point smoking cessation rates, while varenicline is the 1-day point smoking cessation rate . The smoking cessation rate at the end of treatment confirmed by CO in the subjects treated with 3.0 mg of varenicline exceeded that of the subjects treated with 3.0 mg of Chantix (registered trademark) at both week 4 and week 12 (the end of Chantix ( registered trademark) treatment). Varenicline had higher efficacy compared to Chantix (registered trademark).

[0212] Figures 14 and Tables 9 - 11 show the odds ratios of varenicline and Chantix (registered trademark) at the end of week 4 of treatment and 4 weeks after the end of treatment. Varenicline and Cha ntix (registered trademark) NTix (registered trademark) has similar odds ratios and efficacy. The 95% CIs of both treatments overlap, but the odds ratio for cytisine treatment is consistently superior to that of Chantix (registered trademark).

Table 9

Table 10

Table 11

[0213] Table 12 shows the latest EAGLES trial published in 2018 that compares the smoking cessation rates in the United States with those in non-US regions. This trial shows a significantly lower smoking cessation rate in the United States compared to non-US regions. The overall smoking cessation rate of 22% at 24 weeks for subjects treated with Chantix (registered trademark) was only 16% in US patients (N = 1065). The smoking cessation rate was significantly lower than that in previous trials with Chantix (registered trademark) based on the entire United States. The 24-week smoking cessation rate in the EAGLES trial was lower than the 52-week smoking cessation rate in the main trial. The outcomes of smoking cessation related to the first smoking at a young age and being born in the United States were poor.

Table 12

[0214] Figure 15 shows the odds ratios of cytisine at week 4, at the end of treatment, and 4 weeks after the end of treatment compared to the current product. The 94% CIs of the treatment slightly overlap, but the odds ratio for cytisine treatment is consistently superior to those of NRT, Zyban (registered trademark), and Chantix (registered trademark). ​​​​​​

[0215] 1.6 Analysis of baseline attributes and smoking status Effect modification analysis of baseline patient attributes A summary of baseline attributes including age, race, sex, smoking duration, and number of quit attempts was analyzed for both the tobacco score primary outcome variable and Cess / W5 - 8 / CO success (Figures 26 and 27). Only the comparison between the cytisine 3.0 mg TID group and the pooled placebo group is shown. The same EMA model as that used to analyze the clinical sites was used. The forest plots for these analyses are as follows. (Note: In these forest plots, the final (M), (T), or (Q) in the factor display indicates that the pooled data was divided by the median, tertile, or quartile, respectively. Hx indicates "history".) The only interaction P - value of note was for the duration of smoking history divided by quartile of the tobacco score ( "smoking Hx duration ( years)(Q)"), which had P = 0.0800

[0216] Other smoking history duration variables did not have significant P - values (P≥0.2566), so this result was considered not important. None of the other factors raised concerns about heterogeneity of effect. Effect modification analysis of history regarding anti - smoking interventions

[0217] Previous anti - smoking intervention factors were analyzed for the tobacco score primary outcome variable and Cess / W5 - 8 / CO success in comparison to the pooled placebo group with the cytisine 3.0 mg TID group (Figures 28 and 29). The factors analyzed were whether there were more than two attempts at anti - smoking interventions and whether Chantix®, Zyban®, vaping, or ​​​​ Includes whether ever or recently treated with any nicotine replacement therapy. Clinical Performed the same EMA model that was used to analyze the clinical forest graphs are as follows.

[0218] The only interaction P-value of note was for the history of past use of Chantix® ("Chantix® Hx"), with P = 0.0508. However, the interaction P-value in the factor variable showing Chantix® as the most recent intervention ("Chantix® current") showed no concern (P = 0.3179). The interaction appeared to be quantitative, and since the results of recent use were inconsistent, the concern that Chantix® is an effect modifier was reduced.

[0219] Effect modification analysis of baseline test markers related to smoking The baseline test factors were analyzed for the nicotine score primary outcome variable and success of Cess / W5-8 / CO by comparing the placebo group pooling the cytisine 3.0 mg TID group (Figures 30 and 31). These factors included nicotine metabolic ratio (NMR), exhaled CO, and serum cotinine, and were analyzed by median, tertiles, and quartiles. Clinical Performed the same EMA model that was used to analyze the clinical facilities. The forest graphs of these analyses yield Figures 30 and 31. (Note: In these forest graphs, the last (M), (T), or (Q) in the factor display indicates that the pooled data were split by median, tertiles, or quartiles, respectively.)

[0220] In the tobacco score, only the interaction P-values of 0.0434 and 0.0652 for the median and tertile division of baseline cotinine respectively met the criteria suggesting effect modification. However, the interaction P-values in the secondary outcomes of sustained smoking cessation were 0.2925, 0.3738, and 0.9732 respectively in the median, tertile, and quartile divisions, showing no effect modification regarding the baseline cotinine level. Since the 4-week smoking cessation is planned to be the primary outcome of a future Phase 3 trial, the concern regarding baseline cotinine as an effect modifier is a lesser concern.

[0221] 1.7 Analysis of the switching point for 5 - 8 weeks of smoking cessation The switching point analysis was performed for Cess / W5 - 8 / CO success in comparison between the cytisine 3.0 mg TID group and the pooled placebo group, as shown in Figure 32. The purpose of the switching point analysis was to evaluate the extent to which reallocation of cases defined as failures due to insufficient evaluation data would affect the results. The evaluation of the switching point involved re - analyzing the data for all possible reversals where there was a possibility of re - allocating failures to success, with a graph showing which re - allocations met the statistical criteria. The horizontal axis represents the number of possible re - allocations to the control group, and the vertical axis represents the number of possible re - allocations to the experimental group. Each combination of re - allocations was re - analyzed to evaluate whether the statistical criteria were met. The bottom - left point represents the

[0222] cases with no re - allocation (i.e., the planned analysis). The area where re - allocation The most important result from F is that when there are 0 or 1 reassignments in the experimental group, if there are 3 or more reassignments in the control group, the statistical criteria are not met. Similarly, when there are 2 or 3 reassignments in the experimental group, if there are 5 or more reassignments in the control group, the statistical criteria are not met. Therefore, the continued smoking cessation secondary outcomes were robust against reassignments.

[0223] In summary, the results of the initial smoking cessation rates at week 4 for all cytosine treatment groups showed significantly increased initial rates (50% - 54%) compared to pooled placebo (16%), with ORs in the range of 5.38 - 6.31. The long-term smoking cessation from week 5 to week 8 (i.e., 4 weeks after treatment completion) also showed significantly increased long-term smoking cessation rates of 16 - 30% compared to 8% in pooled placebo in the cytosine treatment groups, with ORs of 3.23 - 5.04. Overall, the initial and long-term smoking cessation rates were highest in the 3.0 mg TID group at 54% and 30% respectively, with maximum ORs of 6.31 and 5.04 respectively.

[0224] Safety Analysis Overall, there were no safety concerns after administration on both schedules in either the 1.5 mg cytosine or 3.0 mg treatment groups, and no new or unexpected AEs were identified during the study period.

[0225] Table 13 summarizes the treatment-emergent adverse events (TEAEs). TEAEs were experienced by approximately half of the study population in all treatment groups. The TID dosing schedule had overall slightly fewer TEAEs. Across both schedules, no TEAE was ​​​​​​​​​​​​​​The SOCs with the highest incidence were infectious diseases and parasitism, mental disorders, and gastrointestinal disorders. The common TEAE were AEs that had already been reported in other trials or the investigational drug summaries. All TEAE were of mild or moderate severity on the commercial schedule, and all events except for two were mild or moderate on the TID schedule. One subject experienced a severe head injury and another subject experienced a severe influenza case. Neither event was considered related to the investigational drug.

Table 13

[0226] There were no related mean changes or shifts from baseline in the test parameters over time or in the 12-lead ECG results. The overall incidence of potential clinically significant changes in vital sign measurements was low, and the incidence was lowest on the TID schedule.

[0227] Table 14 summarizes the TEAE of cicinicline compared to Chantix (registered trademark) in the past 2016 trial. The TEAE were experienced by less than 30% of the test population treated with either cicinicline, Chantix (registered trademark), or placebo. Subjects treated with Chantix (registered trademark) experienced the highest incidence of TEAE compared to cicinicline and placebo. The incidence of most TEAEs with cicinicline treatment was only slightly higher than that of placebo.

Table 14

[0228] In summary, there were no serious or severe adverse events, and the overall incidence of adverse events was low. . The results from the trial showed no clinically significant changes in vital signs, routine hematology and / or chemistry, and no changes in the ECG. Overall, no new safety signals were observed during the conduct of this trial.

[0229] Conclusion The results from the trial showed that the benefits of cytisine occurred across all baseline characteristics and attributes. Specifically, the benefits of cytisine occurred across target attributes, baseline CO levels, and number of cigarettes smoked per day, and were based on smoking history. With respect to target attributes, the benefits were consistent across the target population regardless of race, sex, age, and BMI. Furthermore, with respect to smoking history, subjects showed the same benefits from cytisine administration regardless of duration of smoking, attempts to quit, and past history of quit medication use (e.g., Chantix®, Zyban®, NRT, bupropion). The results further demonstrated that subjects showed similar benefits from cytisine administration regardless of their ability to metabolize nicotine. In particular, the treatment relationship was not observed based on the subject's baseline nicotine metabolite ratio, and similar cytisine benefits were seen for both rapid and slow nicotine metabolites.

[0230] The results from the primary analysis showed a reduction in the predicted proportion of cigarettes smoked for both schedules compared to pooled placebo. The results at the early smoking cessation rate endpoint showed that both cytisine groups in the TID schedule had higher odds of success compared to placebo, 3.0 m

[0231] Subjects in the g cytisine group had the highest odds of success in quitting smoking at week 4.

[0232] For long-term smoking cessation from weeks 5 to 8, both TID schedule arms were significantly better than placebo. subjects in the 3.0 mg cytisine group had higher odds of success compared with the control group from weeks 5 to 8. had the highest odds of success in quitting smoking. This study showed a favorable adverse event profile for cytisine. It is an effective adjunct to smoking cessation with a history of smoking cessation, and the adverse events were demonstrated that it was more effective overall without an increase in

[0233] Overall, there were no significant differences in the 1.5 mg or 3.0 mg cytisine groups for either schedule. There were no safety concerns following administration of the drug.

[0234] Example 2: Effect of continued treatment with cytisine on smoking cessation This example was designed to evaluate the efficacy and safety of cytisine in adult smokers. This study describes a phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial conducted in a randomized, placebo-controlled setting. To determine whether continued treatment can improve efficacy outcomes and prevent early relapse to smoking The study was designed to: Treatment with cytisine (e.g., cytisiniculine) for 6 weeks (B); The study is designed to evaluate treatment across three arms of 12 weeks of treatment (C). Subjects will be randomized to one of three groups: A, B, or C. In group A, subjects In group B, subjects will be treated with placebo plus behavioral support for 12 weeks. 3.0 mg cytisine TID followed by 6 weeks of placebo plus behavioral support. In group C, the subjects are treated with behavioral support in addition to 3.0 mg of cytisine TID for 12 weeks. Cytisine treatment is evaluated in a 6 - or 12 - week study population, with a primary efficacy endpoint of continuous smoking abstinence at week 4 during treatment and a 6 - month follow - up period.

[0235] 2.1 Objectives of the study 2.1.1 Coprimary efficacy objectives The coprimary efficacy objectives of the study are such that the success of the study can be based on the success in either of two comparisons: · To evaluate whether subjects randomized to group B are more likely to abstain from smoking from week 3 to week 6 after randomization compared to subjects randomized to group A, and · To evaluate whether subjects randomized to group C are more likely to abstain from smoking from week 9 to week 12 after randomization compared to subjects randomized to group A.

[0236] 2.1.2 Secondary efficacy objectives If the corresponding primary comparison meets the statistical criteria, subsequent analyses for secondary objectives are then performed. The secondary efficacy objectives of this study are: · To evaluate whether subjects randomized to group B have a high likelihood of continuous smoking abstinence from week 6 to week 24 after randomization compared to subjects randomized to group A, and · To evaluate whether subjects randomized to group C have a high likelihood of continuous smoking abstinence from week 12 to week 24 after randomization compared to subjects randomized to group A.

[0237] If the coprimary comparison meets the statistical criteria, analyses for subsequent additional secondary objectives are then performed. The additional secondary efficacy objectives of this study are: ​​​​​​​​​· After administering 3.0 mg of cytisine for 6 weeks, continue with 3.0 mg of cytisine for 6 to 12 weeks (Group C), or switch to placebo from 6 to 12 weeks (Group B). Evaluate the reduction in the risk of relapse from 6 to 24 weeks in the subjects, which is as follows.

[0238] Subjects who have not quit smoking at week 6 are considered to have relapsed.

[0239] 2.1.3 Other Objectives Other objectives of this study are · From week 2 to week 12, and then at weeks 16, 20, and 24, compare the groups (Group B vs. Group A, Group C vs. Group A) with respect to the smoking cessation rate at 7-day time points per week; · Bi-weekly from week 2 to week 12, and then at weeks 16, 20, and 24, compare the groups (Group B vs. Group A, Group C vs. Group A) with respect to serum cotinine levels; · Weekly from week 2 to week 12, and then at weeks 16, 20, and 24, compare the groups (Group B vs. Group A, Group C vs. Group A) with respect to exhaled CO levels; · During the test treatment from week 2 to week 12 and the test follow-up period from week 16 to week 24, compare the groups (Group B vs. Group A, Group C vs. Group A) with respect to the use of any non-tobacco nicotine products including vaping; · Evaluate whether the subjects randomized to Group B have a higher probability of quitting smoking from week 9 to week 12 compared to the subjects randomized to Group A (placebo); · Evaluate whether the subjects randomized to Group B have a higher probability of · Subjects randomized to group C have a high and continuous probability of abstinence from the 9th week to the 24th week after randomization compared to subjects randomized to group A, or are evaluated among subsets of subjects who achieve abstinence from the 9th week to the 12th week, · Compare the period until failure to maintain abstinence until the 24th week between groups (group B vs. group A, group C vs. group A) among subjects who achieve abstinence from the 3rd week to the 6th week, · Explore the magnitude of the treatment effect between groups across various subgroups defined by attributes and baseline characteristics for primary and secondary outcomes, · Explore the possible relationships between outcomes reported by subjects (e.g., anxiety, depression, withdrawal symptoms, tobacco craving) and primary and secondary outcomes.

[0240] 2.1.4 Safety Objectives The safety objectives of the trial are · To evaluate the safety profile of 3.0 mg TID cytisine compared to placebo (e.g., group B vs. group A and group C vs. group A), · To compare the safety profiles of group B subjects vs. group C subjects with respect to adverse events occurring after the 6th week of the trial.

[0241] 2.2 Trial Design The population for this trial consists of adult men or women smokers who smoke daily, intend to quit smoking, and intend to set a quit date within 5 - 7 days of starting treatment. The trial treatment starts on the day after randomization. Subjects meet all requirements outlined in the inclusion and exclusion criteria. A total of approximately 750 subjects are randomly assigned with equal probability to one of three groups as shown in Figure 33.

[0242] ​​Administered (Group A, 12-week placebo: N = 250, Group B, 6-week cytisine and subsequent 6-week placebo: N = 250, Group C, 12-week cytisine: N = 25 0).

[0243] Each randomized subject receives 12 weeks of treatment using a TID dosing schedule . Smoking cessation assessment begins at Week 2 (Day 14 ± 1 after randomization) and continues with CO chemical verification and self-reporting of smoking status by the subjects weekly during the treatment period until the follow-up visits at Weeks 16 , 20, and 24. All subjects receive concurrent smoking cessation behavioral support during the test treatment period (Weeks 1 - 12). Additional behavioral support is provided during the follow-up period based on issues, concerns, and / or questions raised by the subjects

[0244] . Safety assessments at visits are performed on Days 2 and 7 of Week 1 and then weekly throughout the treatment period. Laboratory hematology and chemistry evaluations are performed on Day 7, Week 6, and Week 12 (End of Treatment "EOT"). Adverse events ongoing at Week 12 are followed until resolved or determined to be chronic. The end of the study is defined as the last follow-up visit of the last subject (visits up to Week 24).

[0245] 2.3 Treatment Period The treatment period begins the day after randomization. The test treatment is blinded, and subjects take one test reagent three times a day at approximately 5-hour intervals. Subjects randomly assigned to Group A take one placebo tablet per day per dose for 12 weeks. Subjects in Group B take each dose per day and Group C takes one cytisine tablet per day per dose

[0246] for 12 weeks. The test treatment is blinded, and subjects take one test reagent three times a day at approximately 5-hour intervals. Subjects randomly assigned to Group A take one placebo tablet per day per dose for 12 weeks. Subjects in Group B take each dose per day and Take one cytisine tablet for the first 6 weeks, and then take one placebo tablet per dose for the last 6 weeks. The subjects in Group C will take one cytisine tablet per dose for 12 weeks. The subjects in Group C will take one cytisine tablet per dose for 12 weeks.

[0247] 2.4. Inclusion Criteria Subjects who meet all of the following criteria are eligible to participate in the study. · Male or female subjects aged 18 years or older. · Current smokers who smoke at least 10 cigarettes per day on average (at the time of completing the 7-day screening smoking diary), and those who intend to quit smoking. · Expired CO ≥ 10 ppm. · Regardless of the availability of treatment support, they have failed at least one previous attempt to quit smoking. · They intend to start the study treatment on the day after randomization and set a stop date within 5 to 7 days of the start of treatment. · They are willing to actively participate in the smoking cessation behavioral support provided in the study throughout the study. · They fully understand the study requirements, are willing to participate, and are able to comply with the dosing schedule. · Sign the informed consent form.

[0248] 2.5. Exclusion Criteria Subjects will be excluded from participating in the study if any of the following criteria apply. · More than one study participant in the same household. · Previous cytisine treatment in past clinical trials or any other past use of cytisine. · Known hypersensitivity to cytisine or any of the excipients. · Positive result of a dependence drug urine screening determined within 28 days before the first dose of cytisine. ​· Clinically significantly abnormal serum chemistry or hematology values within 28 days of randomization (i.e., requiring treatment or monitoring). · Clinically significant abnormalities in a 12-lead electrocardiogram determined at least 5 minutes after supine position within 28 days of randomization (i.e., requiring treatment or further evaluation). · Having a low body weight (<18.5 kg / m2) according to the BMI classification or having obesity of class 2 or higher (≥35 kg / m2). · History of hospitalization due to acute myocardial infarction, unstable angina, stroke, cerebrovascular disorder, or congestive heart failure within the last 3 months. · Current untreated hypertension (blood pressure ≥160 / 100 mmHg). · Documented diagnosis of schizophrenia or bipolar disorder, current psychosis, suicidal ideation / risk (answering "yes" to question 4 or question 5, or answering "yes" to the suicidal behavior question of the C-SSRS), or current symptoms of moderate to severe depression (HADS score ≥11). · Renal dysfunction defined as creatinine clearance (CrCl) <60 mL / min (estimated by the Cockcroft-Gault formula). · Liver dysfunction defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN). · Women who are pregnant or breastfeeding. · Male or female subjects who do not consent to use an acceptable contraceptive method during the study treatment period and who are at risk of pregnancy. · Participation in a clinical trial using investigational drugs 4 weeks before randomization. · Treatment with other smoking cessation medications (bupropion, varenicline, nortriptyline, or any nicotine replacement therapy [NRT]) 4 weeks before randomization or planned use of these other smoking cessation medications during the study period.· Non - tobacco and / or non - combustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, water pipes, e - cigarettes / vaping) or marijuana smoking or vaping, use two weeks before randomization or planned use during the trial period. · Any other reason that the principal investigator of the clinical trial deems that the subject should not participate or will not be able to meet the requirements of the trial. · Use two weeks before randomization or planned use during the trial period of non - tobacco and / or non - combustible nicotine products (pipe tobacco, cigars, snuff, smokeless tobacco, water pipes, e - cigarettes / vaping) or marijuana smoking or vaping. · Any other reason that the principal investigator of the clinical trial deems that the subject should not participate or will not be able to meet the requirements of the trial. · Any other reason that the principal investigator of the clinical trial deems that the subject should not participate or will not be able to meet the requirements of the trial.

[0249] 2.6 Existing and concomitant medications All subjects continue to receive their existing prescribed medications. During the trial period, efforts are made to ensure that the regimen of the existing medications remains stable. At the discretion of the principal investigator of the clinical trial, if clinically indicated during the trial period, the use of medications other than the investigational drug (prescription drugs or over - the - counter drugs) may be given. All details of new medications are recorded in the subject's case report form (CRF).

[0250] All concomitant medications taken during the clinical trial, and changes (additions, deletions, dosage changes) are recorded in the CRF. All details of new medications are recorded in the subject's case report form (CRF). All concomitant medications taken during the clinical trial, and changes (additions, deletions, dosage changes) are recorded in the CRF.

[0251] All concomitant medications taken during the clinical trial, and changes (additions, deletions, dosage changes) are recorded in the CRF. All concomitant medications taken during the clinical trial, and changes (additions, deletions, dosage changes) are recorded in the CRF.

[0252] 2.7 Treatment compliance Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Treatment compliance is monitored during the 84 - day (12 - week) treatment period through review of dosing timing and investigational drug management. Subjects have a daily treatment diary in which they record the number of tablets taken and the time of taking. Subjects are instructed to bring their medicine pack (blister pack) to each clinic visit so that clinic staff can reconcile it with the treatment diary and record the number of tablets taken and the number of missed tablets. Additionally, an optional text messaging system is implemented to send reminders corresponding to the approximate time of dosing to each subject. Provide the text.

[0253] 2.8 Test Procedure After providing signed informed consent, all subjects participated in a 28-day screening study. Subjects who meet the inclusion criteria will be evaluated for inclusion in the study during the treatment-lean period. Provide a stop date that must be within 5-7 days of starting treatment and begin study treatment the day after randomization. Both the planned stop date and treatment start date must be agreed upon. Documentation will be provided to confirm enrollment. Once all eligibility criteria have been met, randomization will be Study day 1 is defined as the first day of treatment. , completed visits at 21, 28, 35, 42, 49, 56, 63, 70, 77, and 86 days. Follow-up visits will be scheduled at 16, 20, and 24 weeks.

[0254] 2.8.1 Procedure Schedule Table 15 provides a summary of the test assessments required. Screening assessments are The study will be conducted within 28 days between the start of the study and randomization. Start study treatment, so that study treatment is stopped 1 day before the stop date, or within 5-7 days after the 1st day The process begins within [Table 15] JPEG2025081331000017.jpg255170JPEG2025081331000018.jpg255170JPEG2025081331000019.jpg255170JPEG2025081331000020.jpg255170 [Table 16]

[0255] 2.8.2 Target Log The 7-day smoking log is collected during the screening period to obtain the number of cigarettes smoked daily for 7 consecutive days. This data is used to calculate the average number of cigarettes smoked per day to support the second item of the selection criteria.

[0256] Furthermore, the test treatment log is maintained by each subject to record the date and timing of the test drug administration during the treatment period. The log is structured into specific sections to support the above reports by the subject.

[0257] 2.9 Efficacy Criteria This test follows the general criteria applicable to past and current trials of smoking cessation aids. Participants have a predetermined target cessation date and have direct contact with the investigator or clinic staff. Endpoint analysis for smoking cessation (4-week smoking cessation recorded in the last 4 weeks of treatment) and continuous smoking cessation (recorded continuously until 24 weeks after randomization) includes the following criteria: · Self-report of smoking cessation after the last visit in each clinic evaluation. · Biochemical verification of smoking cessation by exhaled CO at each visit. · Use of the "intention to treat" approach where data from all randomized smokers are included in the analysis. · Subjects with unknown smoking status or who failed follow-up at the 6-week, 12-week, and 24-week evaluations are classified as having failed to quit. · During the follow-up period (12 weeks to 24 weeks) only, self-report of smoking cessation follows the Russell Standard. · During the collection of follow-up data up to 24 weeks, the treatment assignment remains continuously blinded.

[0258] 2.9.1 Safety Assessment​​​​​​​​​​​ All subjects start from screening (pre - test), with a phone call on Day 1, visits on Day 2 and Day 7 of Week 1, and then weekly throughout the treatment period (from Week 2 to Week 12 / EOT), and monthly during the follow - up period, and are monitored for adverse events (see Tables 15 and 16). The evaluation of tests (hematology and chemistry) is carried out using the central laboratory at the visits on Week 1, Week 6, and Week 12. Safety is evaluated considering all adverse events reported or elicited from the subjects, as well as abnormalities detected in hematology and serum chemistry tests. Worsening of other existing medical conditions

[0259] and any changes to co - administered medications / treatments are also considered in this evaluation.

[0260] 2.9.2 Laboratory Routine laboratory evaluations Routine laboratory safety samples are analyzed by the central laboratory for each subject at the screening and visits specified in Table 15. Whether results outside the reference range are clinically significant or not is determined by the principal investigator of the clinical trial, and the reports are annotated accordingly. Clinically significant abnormalities occurring during the trial are recorded on the AE page. The reference ranges for laboratory parameters are also entered into the database and filed in the principal investigator's facility file.

[0261] Hematology: Hemoglobin, red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets.

[0262] Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT (AST), alkaline phosphatase, glucose, sodium, potassium, calcium, chloride ​Nicotine and urea.

[0263] Exhaled CO Exhaled CO is obtained using a calibrated device (e.g., Bed font Micro+ Smokerlyzer (registered trademark)) provided and maintained by the clinical facility. Each clinical facility has documentation regarding the device in use and the current calibration. The CO value is reported in parts per million (ppm) weekly from week 2 to week 12, and at weeks 16, 20, and 24.

[0264] Serum cotinine level Serum samples are collected to determine cotinine levels at weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24. For the baseline cotinine test, frozen serum collected at the time of the first visit to SV1 is used for the randomized subjects. The cotinine levels are determined at a central laboratory.

[0265] 2.9.3 Vital signs Measurements of systolic / diastolic blood pressure, heart rate, and oral temperature are recorded in the sitting position. Weight is also recorded. Height is recorded at the first screening visit for BMI calculation.

[0266] 2.9.4 Physical examination The physical examination is performed by the investigator. The examination includes general appearance, head, ears, eyes, nose, throat , neck, skin, cardiovascular system, respiratory system, gastrointestinal system, central nervous system, lymph nodes, and musculoskeletal system. The investigator may, at his or her discretion, examine other body systems as needed.

[0267] 2.10 Primary outcome of the subjects The primary efficacy outcome in each subject (biochemically examined for the last 4 weeks of cytisine treatment) The proven smoking cessation is a binary of success or failure. Success is defined as reporting smoking cessation (no tobacco after the last visit) at each clinic evaluation from week 3 to week 6 (Group B) and from week 9 to week 12 (Group C) for the subjects, with biochemical verification at each evaluation. Biochemical verification is defined by an exhaled carbon monoxide concentration of less than 10 ppm. Similar time frames and analyses are performed for the Group A placebo subjects. verification is defined by an exhaled carbon monoxide concentration of less than 10 ppm. Similar time frames and analyses are performed for the Group A placebo subjects.

[0268] 2.11 Secondary Outcomes of Subjects The secondary efficacy outcomes 1 and 2 (sustained smoking cessation biochemically verified up to week 24) for each subject are a binary of success or failure. Success is defined as reporting smoking cessation after the last visit at each clinic evaluation from week 6 (Group B) or from week 12 to week 24 (Group C) for the subjects, with biochemical verification at each evaluation. Biochemical verification is defined by an exhaled carbon monoxide concentration of less than 10 ppm. During the follow-up smoking cessation evaluation period from week 12 to week 24, self-reporting of smoking cessation follows the Russell criteria.

[0269] The secondary efficacy outcome 3 is success regarding no relapse at week 24. The secondary efficacy outcome 3 ( reduction in the relapse risk from week 6 to week 24 for Group C compared to Group B) is evaluated for each subject (both Group C and Group B). Subjects who were not smoking at week 6 are considered to have relapsed.

[0270] 2.12 Safety Objectives The safety evaluation includes reported adverse events, clinical laboratory results, and vital signs. Safety variables are summarized for the safety analysis set (SAS) defined as all randomized subjects who received at least one dose of the investigational drug.

[0271] Adverse events are coded using the MedDRA dictionary. The coding includes System Organ Class (SOC) and Preferred Term (PT). All literal explanations and coded terms are listed for all AEs. Various embodiments of the present invention are shown in paragraphs 272-391 below of this specification.

[0272] A method of treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting reduction of smoking and / or vaping in a subject in need thereof, the method comprising administering to the subject cytisine at a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg three times a day. A method according to paragraph 272, wherein the subject does not experience an

[0273] adverse event after receiving cytisine treatment.

[0274] A method according to paragraphs 272 and 273, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia,

[0275] headache, fatigue, and constipation.

[0276] A method according to paragraphs 272-274, wherein the subject does not experience

[0277] nausea after receiving cytisine treatment. A method according to paragraphs 272-275, wherein cytisine is administered for about 6 weeks or about 12 weeks. The method of paragraphs 272-276, comprising three tablets.

[0278] The subject is a refractory patient who has failed treatment for one or more nicotine addictions or smoking cessation therapy. The method of paragraphs 272-277, wherein the subject is as defined above.

[0279] Nicotine addiction or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, and combinations thereof. The method of paragraphs 272-278. Nicotine addiction or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, and combinations thereof. The method of paragraphs 272-278. Method.

[0280] The subject has either (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b). The method of paragraphs 272-279. The subject has either (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b). The method of paragraphs 272-279. The method of paragraphs 272-279, wherein the subject is as defined above.

[0281] The method of paragraphs 272-280, further comprising providing behavioral support to the subject.

[0282] In a subject in need of treating nicotine addiction and / or nicotine dependence, a method of treating nicotine addiction and / or nicotine dependence, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addiction therapies. In a subject in need of treating nicotine addiction and / or nicotine dependence, a method of treating nicotine addiction and / or nicotine dependence, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addiction therapies. In a subject in need of treating nicotine addiction and / or nicotine dependence, a method of treating nicotine addiction and / or nicotine dependence, the method comprising administering cytisine to the subject, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addiction therapies. Method, wherein the subject is as defined above.

[0283] Nicotine addiction or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, and combinations thereof. The method of paragraph 282. Nicotine addiction or smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, and combinations thereof. The method of paragraph 282.

[0284] Cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine, 3 to 6 times a day, to a subject in need thereof. The method of paragraphs 282 and 283. Cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine, 3 to 6 times a day, to a subject in need thereof. The method of paragraphs 282 and 283.

[0285] A method according to paragraphs 282 - 284, wherein cytosine is provided to a subject in need thereof at a unit dose of 3.0 mg of cytosine three times a day. A method according to paragraphs 282 - 284, wherein the unit dose of cytosine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine.

[0286] A method according to paragraphs 282 - 285, wherein the unit dose of cytosine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine. A method according to paragraphs 282 - 285, wherein the unit dose of cytosine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine. A method according to paragraphs 282 - 285, wherein the unit dose of cytosine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine. A method according to paragraphs 282 - 285, wherein the unit dose of cytosine is provided in (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine.

[0287] A method according to paragraphs 282 - 286, wherein cytosine is administered for about 6 weeks or about 12 weeks.

[0288] A method according to paragraphs 282 - 287, wherein the subject does not experience an adverse event after receiving cytosine treatment. .

[0289] A method according to paragraphs 282 - 288, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. A method according to paragraphs 282 - 288, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0290] A method according to paragraphs 282 - 289, wherein the subject (a) smoked more than 10 cigarettes per day before administration of cytosine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) is a combination of (a) and (b). A method according to paragraphs 282 - 289, wherein the subject (a) smoked more than 10 cigarettes per day before administration of cytosine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) is a combination of (a) and (b). A method according to paragraphs 282 - 289, wherein the subject (a) smoked more than 10 cigarettes per day before administration of cytosine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) is a combination of (a) and (b).

[0291] A method for preventing relapse of smoking and / or vaping in a subject in need thereof, the method comprising (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) A method for preventing relapse of smoking and / or vaping in a subject in need thereof, the method comprising (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) .5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine. A single tablet containing either 5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, provided in a unit dose of cytisine administered to a subject three times a day.

[0292] The method of paragraph 291, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0293] The methods of paragraphs 291 and 292, wherein the subject does not experience an adverse event after receiving cytisine treatment. Method.

[0294] The methods of paragraphs 291 to 293, wherein the adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. Method.

[0295] The methods of paragraphs 291 to 294, wherein the subject has (a) smoked more than 10 cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b).

[0296] The methods of paragraphs 291 to 295, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addictions or smoking cessation therapy. Method.

[0297] The methods of paragraphs 291 to 296, wherein the smoking cessation therapy is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping and combinations thereof.

[0298] In a subject in need of preventing relapse of smoking and / or vaping, a method of preventing relapse of smoking and / or vaping, the method comprising administering cytisine to the subject, wherein the subject has NRT, bupropion administration, varenicline administration, e-cigarette administered, electronic cigarette who have failed treatment with one or more smoking cessation therapies selected from the group consisting of bupropion and vaping A method for refractory patients.

[0299] wherein the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b), the method of paragraph 298.

[0300] wherein the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, and the cytisine is administered for about 6 weeks or about 12 weeks, the method of paragraphs 298 - 299. (c) three tablets, each tablet containing 1.0 mg of cytisine, and the cytisine is administered for about 6 weeks or about 12 weeks, the method of paragraphs 298 - 299. 299.

[0301] wherein the subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue and constipation after receiving cytisine treatment, the method of paragraphs 298 - 300 .

[0302] A pharmaceutical composition comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for treating nicotine addiction, nicotine dependence, promoting cessation of smoking and / or vaping and / or promoting reduction of smoking and / or vaping, for use in a subject in need thereof, the pharmaceutical composition being for oral administration to the subject three times a day and / or promoting reduction of smoking and / or vaping, for use in a subject in need thereof, the pharmaceutical composition being for oral administration to the subject three times a day and / or promoting reduction of smoking and / or vaping, for use in a subject in need thereof, the pharmaceutical composition being for oral administration to the subject three times a day A pharmaceutical composition.

[0303] The pharmaceutical composition of paragraph 302, wherein the subject does not experience adverse events after receiving cytisine treatment.

[0304] The adverse events consist of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation The pharmaceutical products of paragraphs 302 and 303, selected from the group

[0305] The pharmaceutical products of paragraphs 302 to 304, wherein the subject does not experience nausea after receiving cytisine treatment products

[0306] The pharmaceutical products of paragraphs 302 to 305, wherein cytisine is administered for about 6 weeks or about 12 weeks

[0307] The pharmaceutical products of paragraphs 302 to 306, wherein the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine products

[0308] The pharmaceutical products of paragraphs 302 to 307, wherein the subject is a refractory patient who has failed treatment by one or more nicotine addictions or smoking cessation treatments products

[0309] The pharmaceutical products of paragraphs 302 to 308, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, and combinations thereof products products

[0310] The pharmaceutical products of paragraphs 302 to 309, wherein the subject has (a) smoked more than 10 cigarettes per day before cytisine administration, (b) had an exhaled CO concentration of about 10 ppm or more before cytisine administration, or (c) a combination of (a) and (b) products (b)

[0311] The pharmaceutical products of paragraphs 302 to 310, further comprising providing behavioral support to a subject.

[0312] In a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments A pharmaceutical product containing cytisine for treating nicotine addiction or nicotine dependence, the pharmaceutical product being for oral administration to a subject three times a day.

[0313] The pharmaceutical product of paragraph 312, wherein the nicotine addiction or nicotine dependence treatment comprises NRT, bupropion administration, varenicline administration, electronic cigarettes, vaping, or combinations thereof.

[0314] The pharmaceutical products of paragraphs 312 to 313, wherein cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times a day to a subject in need thereof.

[0315] The pharmaceutical products of paragraphs 312 to 314, wherein cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof. The pharmaceutical products of paragraphs 312 to 315, wherein the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0316] The pharmaceutical products of paragraphs 312 to 315, wherein cytisine is administered for about 6 weeks or about 12 weeks. The method of paragraphs 312 to 317, wherein the subject does not experience an adverse event after receiving cytisine treatment. The pharmaceutical products of paragraphs 312 to 316, wherein cytisine is administered for about 6 weeks or about 12 weeks. The pharmaceutical products of paragraphs 312 to 315, wherein the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine.

[0317] The pharmaceutical products of paragraphs 312 to 316, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0318] The method of paragraphs 312 to 317, wherein the subject does not experience an adverse event after receiving cytisine treatment. .

[0319] The adverse events consist of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation The pharmaceutical of paragraphs 312 - 318, selected from the group

[0320] where the subject has (a) smoked 10 or more cigarettes per day prior to the administration of cytisine, (b) has a breath CO concentration of about 10 ppm or more prior to the administration of cytisine, or (c) a combination of (a) and (b), the pharmaceutical of paragraphs 312 - 319

[0321] In a subject in need of preventing relapse of smoking and / or vaping, for preventing relapse of smoking and / or vaping, a pharmaceutical comprising a unit dose of cytisine in (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b ) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, wherein the pharmaceutical is for oral administration to the subject three times a day

[0322] The pharmaceutical of paragraph 321, wherein cytisine is administered for about 6 weeks or about 12 weeks

[0323] The pharmaceutical of paragraphs 321 and 322, wherein the subject does not experience adverse events after receiving cytisine treatment

[0324] The adverse events consist of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation The pharmaceutical of paragraphs 321 - 323, selected from the group

[0325] where the subject has (a) smoked 10 or more cigarettes per day prior to the administration of cytisine, (b) ​Having an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or a combination of (c)(a) and The pharmaceutical products of paragraphs 321 - 324, which is a combination of (b).

[0326] The subject is a refractory patient who has failed treatment for one or more nicotine addictions or smoking cessation treatment The pharmaceutical products of paragraphs 321 - 325.

[0327] Smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e - cigarettes, vaping The pharmaceutical products of paragraphs 321 - 326, which is a combination of them.

[0328] A pharmaceutical product containing cytisine to prevent relapse of smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e - cigarettes, vaping where the pharmaceutical product is for oral administration to the subject three times a day. The subject has smoked (a) 10 or more cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) a combination of (a) and The pharmaceutical products of paragraph 328, which is a combination of (b).

[0329] The pharmaceutical products of paragraph 328, which is a combination of (b). The pharmaceutical products of paragraph 328, which is a combination of (b).

[0330] The unit dose of cytisine includes (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, and cytisine is administered for about 6 weeks or about 12 weeks. The pharmaceutical products of paragraphs 328 - 329. The unit dose of cytisine includes (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, and cytisine is administered for about 6 weeks or about 12 weeks. The pharmaceutical products of paragraphs 328 - 329. The pharmaceutical products of paragraphs 328 - 329.

[0331] The subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue , and constipation after receiving cytisine treatment, the medicament of paragraphs 328 - 330.

[0332] Treatment of nicotine addiction, nicotine dependence, promotion of smoking and / or vaping cessation , and / or promotion of reduction of smoking and / or vaping, in a subject in need thereof, the use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine, wherein the cytisine is for oral administration to the subject three times a day.

[0333] The use of paragraph 332, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0334] The adverse event is selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, lethargy, and constipation, the use of paragraphs 332 and 333.

[0335] The use of paragraphs 332 - 334, wherein the subject does not experience nausea after receiving cytisine treatment.

[0336] The use of paragraphs 332 - 335, wherein the cytisine is administered for about 6 weeks or about 12 weeks.

[0337] The unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, the use of paragraphs 332 - 336.

[0338] ​​​​​​​Use in refractory patients who have failed treatment for one or more nicotine addictions or smoking cessation treatment Use according to paragraphs 332 - 337

[0339] Nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, electronic tobacco, vaping, and combinations thereof, use according to paragraphs 332 - 338 Use

[0340] The subject has (a) smoked more than 10 cigarettes per day before cytisine administration, (b) had an exhaled CO concentration of about 10 ppm or more before cytisine administration, or (c) a combination of (a) and (b), use according to paragraphs 332 - 339

[0341] Use according to paragraphs 332 - 340, further comprising providing behavioral support to the subject

[0342] Use of cytisine for treating nicotine addiction or nicotine dependence in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments wherein the cytisine is for oral administration to the subject three times a day, use

[0343] Nicotine addiction treatment includes NRT, bupropion administration, varenicline administration, electronic cigarette, be vaping, or combinations thereof, use according to paragraph 342

[0344] Cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times a day to a subject in need thereof, use according to paragraphs 342 and 343

[0345] Cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof use according to paragraphs 342 - 344

[0346] The use according to paragraphs 342 - 345, wherein the unit dose of cytosine comprises: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine. The use according to paragraphs 342 - 346, wherein cytosine is administered for about 6 weeks or about 12 weeks. The use according to paragraphs 342 - 347, wherein the subject does not experience adverse events after receiving cytosine treatment. The use according to paragraphs 342 - 348, wherein the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0347] The use according to paragraphs 342 - 346, wherein cytosine is administered for about 6 weeks or about 12 weeks.

[0348] The use according to paragraphs 342 - 347, wherein the subject does not experience adverse events after receiving cytosine treatment. .

[0349] The use according to paragraphs 342 - 348, wherein the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation. The use according to paragraphs 342 - 349, wherein the subject is: (a) a smoker of more than 10 cigarettes per day prior to cytosine administration; (b) has an exhaled CO concentration of about 10 ppm or more prior to cytosine administration; or (c) a combination of (a) and (b).

[0350] The use according to paragraphs 342 - 349, wherein the subject is: (a) a smoker of more than 10 cigarettes per day prior to cytosine administration; (b) has an exhaled CO concentration of about 10 ppm or more prior to cytosine administration; or (c) a combination of (a) and (b). The use according to paragraphs 342 - 349, wherein the subject is: (a) a smoker of more than 10 cigarettes per day prior to cytosine administration; (b) has an exhaled CO concentration of about 10 ppm or more prior to cytosine administration; or (c) a combination of (a) and (b). The use according to paragraphs 342 - 349, wherein the subject is: (a) a smoker of more than 10 cigarettes per day prior to cytosine administration; (b) has an exhaled CO concentration of about 10 ppm or more prior to cytosine administration; or (c) a combination of (a) and (b).

[0351] The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day. The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day. The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day. The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day. The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day. The use of a unit dose of cytosine in the form of: (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine; (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine; or (c) three tablets, each containing 1.0 mg of cytosine, for preventing relapse of smoking and / or vaping in a subject in need thereof, wherein cytosine is for oral administration to the subject three times a day.

[0352] The use of paragraph 351, wherein cytosine is administered for about 6 weeks or about 12 weeks.

[0353] The use of paragraphs 351 and 352, wherein the subject does not experience adverse events after receiving cytosine treatment. Use.

[0354] The adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation, the use of paragraphs 351 - 353. The use of paragraphs 351 - 353, wherein the adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0355] The use of paragraphs 351 - 354, wherein the subject is (a) one who smoked 10 or more cigarettes per day before administration of cytosine, (b) one who had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) a combination of (a) and (b). The use of paragraphs 351 - 354, wherein the subject is (a) one who smoked 10 or more cigarettes per day before administration of cytosine, (b) one who had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) a combination of (a) and (b). The use of paragraphs 351 - 354, wherein the subject is (a) one who smoked 10 or more cigarettes per day before administration of cytosine, (b) one who had an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or (c) a combination of (a) and (b).

[0356] The use of paragraphs 351 - 355, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addictions or smoking cessation treatment. Use.

[0357] The smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e - cigarettes, vaping, and combinations thereof, the use of paragraphs 351 - 356. The smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e - cigarettes, vaping, and combinations thereof, the use of paragraphs 351 - 356.

[0358] A pharmaceutical composition containing cytosine for preventing relapse of smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e - cigarettes, vaping A pharmaceutical composition containing cytosine for preventing relapse of smoking and / or vaping in a subject who is a refractory patient who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e - cigarettes, vaping wherein cytosine is for oral administration to the subject three times a day. Use.

[0359] The use of paragraphs 351 - 354, wherein the subject is (a) one who smoked 10 or more cigarettes per day before administration of cytosine, (b) Having an exhaled CO concentration of about 10 ppm or more before administration of cytosine, or the use of paragraph 358 that is a combination of (c)(a) and (b).

[0360] The unit dose of cytosine includes (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine, and the use of paragraphs 358 and 359 where cytosine is administered for about 6 weeks or about 12 weeks.

[0361] The subject does not experience adverse events selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation after receiving cytosine treatment, the use of paragraphs 358 - 360.

[0362] The use of tablets containing about 1.0 mg or 1.5 mg of cytosine for oral administration three times a day to a subject for treating nicotine addiction and nicotine dependence, wherein it promotes cessation of smoking and / or vaping in the subject and / or promotes a decrease in smoking and / or vaping.

[0363] The use of paragraph 362 where the subject does not experience adverse events after receiving cytosine treatment.

[0364] The adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, lethargy, and constipation, the use of paragraphs 362 and 363.

[0365] The use of paragraphs 362 - 364 where the subject does not experience nausea after receiving cytosine treatment.

[0366] Use according to paragraphs 362 - 365, wherein cytosine is administered for about 6 weeks or about 12 weeks.

[0367] Use according to paragraphs 362 - 366, wherein the unit dose of cytosine comprises (a) two tablets, each containing either 1.5 mg or 3.0 mg of cytosine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytosine, or (c) three tablets, each containing 1.0 mg of cytosine. Use according to paragraphs 362 - 367, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addictions or smoking cessation.

[0368] Use according to paragraphs 362 - 368, wherein the nicotine addiction or smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e - cigarettes, vaping, and combinations thereof.

[0369] Use according to paragraphs 362 - 369, wherein the subject (a) smoked more than 10 cigarettes per day prior to cytosine administration, (b) had an exhaled CO concentration of about 10 ppm or more prior to cytosine administration, or (c) is a combination of (a) and (b).

[0370]

[0371] Use according to paragraphs 362 - 370, further comprising providing behavioral support to the subject.

[0372] Use of a tablet containing about 1.0 mg or 1.5 mg of cytosine for oral administration three times a day at about 3.0 mg of cytosine to a subject who is a refractory patient who has failed treatment for one or more nicotine addictions, for treating nicotine addiction and / or nicotine dependence in the subject.

[0373] Nicotine addiction treatment, use of paragraph 372, including NRT, bupropion administration, varenicline administration, e-cigarettes, bupropion, or combinations thereof.

[0374] Cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine, three to six times a day, to a subject in need thereof, use of paragraphs 372 and 373.

[0375] Cytisine is provided in a unit dose of 3.0 mg of cytisine three times a day to a subject in need thereof, use of paragraphs 372 - 374.

[0376] Unit dose cytisine includes either (a) two tablets, each tablet containing 1.5 mg of cytisine, or (b) a single tablet containing 3.0 mg of cytisine, use of paragraphs 372 - 375.

[0377] Cytisine is administered for about 6 weeks or about 12 weeks, use of paragraphs 372 - 376.

[0378] A subject does not experience an adverse event after receiving cytisine treatment, use of paragraphs 372 - 377 .

[0379] Adverse events are selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue, and constipation, use of paragraphs 372 - 378.

[0380] A subject has either (a) smoked more than 10 cigarettes per day prior to cytisine administration, (b) had an exhaled CO concentration of about 10 ppm or more prior to cytisine administration, or (c) a combination of (a) and (b), use of paragraphs 372 - 379.

[0381] For preventing relapse of smoking and / or vaping in a subject, about 3. 0 mg of cytisine for three times daily oral administration of about 1.0 mg or about 1.5 mg of cytisine-containing tablets.

[0382] Use according to paragraph 381, wherein cytisine is administered for about 6 weeks or about 12 weeks.

[0383] Use according to paragraphs 381 and 382, wherein the subject does not experience an adverse event after receiving cytisine treatment.

[0384] Use according to paragraphs 381 to 383, wherein the adverse event is selected from the group consisting of upper respiratory tract infection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.

[0385] Use according to paragraphs 381 to 384, wherein the subject (a) smoked more than 10 cigarettes per day before administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more before administration of cytisine, or (c) was a combination of (a) and (b).

[0386] Use according to paragraphs 381 to 385, wherein the subject is a refractory patient who has failed treatment for one or more nicotine addictions or smoking cessation treatment.

[0387] Use according to paragraphs 381 to 386, wherein the smoking cessation treatment is selected from NRT, bupropion administration, varenicline administration, e-cigarettes, vaping , and combinations thereof.

[0388] For preventing relapse of smoking in a subject, for three times daily oral administration of about 3.0 mg of cytisine to a subject who has failed treatment with one or more nicotine addiction treatments selected from the group consisting of NRT, bupropion administration, varenicline administration, e-cigarettes, and vaping ​​​ Use of a tablet containing about 1.0 mg or about 1.5 mg of cytisine.

[0389] where the subject has (a) smoked 10 or more cigarettes per day prior to administration of cytisine, (b) had an exhaled CO concentration of about 10 ppm or more prior to administration of cytisine, or (c) a combination of (a) and (b), the use of paragraph 388.

[0390] where the unit dose of cytisine comprises (a) two tablets, each tablet containing either 1.5 mg or 3.0 mg of cytisine, (b) a single tablet containing either 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg of cytisine, and cytisine is administered for about 6 weeks or about 12 weeks, the use of paragraphs 388 and 389. Use of paragraphs 388 to 390, where the subject does not experience an adverse event selected from the group consisting of URTI, abnormal dreams, nausea, insomnia, headache, fatigue,

[0391] and constipation after receiving cytisine treatment. and constipation after receiving cytisine treatment. Use.

Claims

1. 1. A pharmaceutical composition comprising 1.5 mg of cytisine for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof who has been smoking for at least about 20 years, The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

2. 1. A pharmaceutical composition comprising 3.0 mg of cytisine for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping in a subject in need thereof who has been smoking for at least about 20 years, The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

3. 1. A pharmaceutical composition for use in preventing relapse to smoking and / or vaping in a subject in need thereof who has been smoking for at least about 20 years, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

4. 1. A pharmaceutical composition for use in preventing relapse to smoking and / or vaping in a subject in need thereof who has been smoking for at least about 20 years, comprising: The pharmaceutical composition, wherein the pharmaceutical composition is for oral administration to the subject three times daily for a period of at least three weeks.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the subject has been a smoker for at least about 25 years.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject has been a smoker for at least about 30 years.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the subject began smoking at age 10 to 19 years.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is a refractory patient who has previously undergone one or more smoking cessation therapies.

9. 9. The pharmaceutical composition of claim 8, wherein the one or more smoking cessation therapies are selected from the group consisting of nicotine replacement therapy, varenicline administration, and bupropion administration.

10. The object is (a) smoking 10 or more cigarettes per day prior to administration of cytisine; (b) having an exhaled CO concentration of about 10 ppm or greater prior to administration of said cytisine; or The pharmaceutical composition of any one of claims 1 to 9, which is a combination of (c) (a) and (b).

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the subject is provided with behavioral support.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein cytisine is administered for at least 6 weeks, or at least 12 weeks.

13. 1. A tablet comprising 1.5 mg of cytisine for oral administration three times daily to a subject for a period of at least three weeks for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping, wherein the subject has been smoking for at least about 20 years.

14. 1. A tablet comprising 3.0 mg of cytisine for oral administration three times daily to a subject for a period of at least three weeks for use in treating nicotine addiction and / or nicotine dependence, promoting cessation of smoking and / or vaping, and / or promoting a reduction in smoking and / or vaping, wherein the subject has been smoking for at least about 20 years.

15. 15. The tablet of claim 13 or 14, wherein the subject has been a smoker for at least about 25 years.

16. The tablet of any one of claims 13 to 15, wherein the subject has been a smoker for at least about 30 years.

17. The tablet according to any one of claims 13 to 16, wherein the subject started smoking at age 10 to 19 years.

18. The tablet according to any one of claims 13 to 17, wherein the subject is a refractory patient who has previously undergone one or more smoking cessation therapies.

19. 19. The tablet of claim 18, wherein the smoking cessation therapy is selected from the group consisting of nicotine replacement therapy, varenicline administration, and bupropion administration.

20. The object is (a) smoking 10 or more cigarettes per day prior to administration of cytisine; (b) having an exhaled CO concentration of about 10 ppm or greater prior to administration of said cytisine; or The tablet according to any one of claims 13 to 19, which is a combination of (c) (a) and (b).

21. The tablet of any one of claims 13 to 20, wherein the subject is provided with behavioral support.

22. The tablet of any one of claims 13 to 21, wherein cytisine is administered for at least 6 weeks, or at least 12 weeks.

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