FIELD OF THE DISCLOSURE

[0001] The present disclosure pertains to combination drug products and methods of use thereof for reducing a risk of drug diversion and/or medication related adverse effects, including injury and undesirable behaviors associated with consumption of alcohol in conjunction with stimulant medications.

BACKGROUND

[0002] Stimulants are a broad class of drugs that include prescription medications and illicit drugs that increase the activity of the central nervous system (CNS).

Stimulants may affect brain activity of a user such that the user may feel more energized, alert, and focused. Prescription stimulants, such as amphetamine (Adderall™), methylphenidate (Ritalin™), and lisdexamfetamine (Vyvanse™) can treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (chronic sleep disorder). These medications are commonly misused, often by young adults who use them in efforts to improve academic performance. Stimulant medications are also misused for recreational purposes by individuals attempting to remain awake through their habitual sleep period. Stimulants are also known to speed up metabolism, and as a result can be misused by individuals who are trying to lose weight. Illicit stimulants may include, without limitation, cocaine, methamphetamine, and MDMA.

[0003] It is not uncommon for individuals who misuse stimulants to combine them with other centrally acting substances that enhance inhibitory GABA-ergic neurotransmission, also known as CNS depressants (e.g., alcohol). Concurrent consumption of stimulant drugs with CNS depressants, such as alcohol, may cause numerous potential interactions. For example, alcohol can negate or decrease the medicinal effects of stimulant drugs when stimulants are taken together with alcohol, thereby requiring more of the stimulant to experience its effects. Likewise, stimulants may reduce the effects that are commonly associated with drinking alcohol, when ingested together, and thus, the user may potentially consume more alcohol without feeling intoxicated. Therefore, the combination of alcohol and stimulant drugs may lead to potentially dangerous consequences, including the risk of stimulant overdose and/or alcohol poisoning. Furthermore, it can lead to an increased risk of cardiovascular toxicity, damage to the brain/cognitive function, and may lead to behavioral health consequences. Although it is routinely advised to avoid consumption of CNS depressants in conjunction with stimulant drugs, large portions of stimulant users continue to use CNS depressant(s) (e.g., alcohol) on a regular basis while taking stimulants.

SUMMARY

[0004] Disclosed is a method of reducing improper use of stimulants associated with inappropriate consumption of alcohol concurrent with the taking of a CNS stimulant. In embodiments, the method includes administering a combination drug product (e.g., combination medication) to a subject, the combination product including at least an effective amount of one or more stimulants and an effective amount of one or more aldehyde dehydrogenase inhibitors (ALDIs). The combination product may be in the form of a pill or other formulation (e.g., capsule, sublingual film, oral spray) that resists (e.g., makes extremely challenging) or entirely prevents separation of the one or more stimulants from the one or more ALDIs. The combination product may thus provide the desired effects (e.g., alertness, increased metabolism, increased energy, reduced daytime drowsiness, and the like) of the stimulant(s) while reducing improper use of the stimulants concurrent with the ingestion of alcohol.

[0005] Also disclosed is a combination medication that includes an effective amount of one or more stimulants, an effective amount of one or more ALDIs, and optionally, a pharmaceutically acceptable carrier.

[0006] In embodiments, the ALDI includes one or more of disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs NPI-1 and API-1 , CVT-10216, DEAB, gossypol, kynurenine tryptophan metabolites, molinate, nitroglycerin, pargyline, and active metabolites, analogs, or pharmaceutically acceptable salts thereof. In specific examples, the ALDI comprises, consists essentially of, or consists of disulfiram, active disulfiram metabolites and/or pharmaceutically acceptable salts thereof. In embodiments, the ALDI consists essentially of disulfiram, active metabolites and/or pharmaceutically acceptable salts thereof.

[0007] In embodiments, the one or more stimulants include one or more of amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, cathine, mixtures of any of the foregoing, salts of any of the foregoing, and the like.

[0008] In one aspect, the present disclosure provides a method of reducing concurrent use of a stimulant medication and alcohol, comprising administering a single composition to a subject in need of the stimulant medication, the single composition comprising an effective amount of one or more stimulant medications for the management of a condition or disorder; and an effective amount of one or more aldehyde dehydrogenase inhibitors (ALDIs) sufficient to prevent alcohol consumption. The one or more ALDIs may be selected from disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs, (benzoyloxy)[4-chlorophenyl)sulfonyl]carbamic acid 1 ,1 dimethyl ester (NPI-1 ), 4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamid (API-1 ), 3-(((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)o xy)methyl) benzoic acid (CVT-10216), N,N-diethylaminobenzaldehyde (DEAB), gossypol, molinate, nitroglycerin, pargyline, or pharmaceutically acceptable salts thereof, enabling provision of the effects of the one or more stimulant medications in a manner which prevents concomitant alcohol consumption.

[0009] In some embodiments, the condition or disorder is attention deficit disorder or attention deficit-hyperactivity disorder, a sleep-wake disorder (e.g., narcolepsy, idiopathic hypersomnia), obesity, or an eating disorder (e.g., binge eating, hedonic hunger). [0010] In some embodiments, the ALDI is disulfiram, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the one or more stimulant medications is one or more prescription stimulant medications.

[0012] In some embodiments, the one or more stimulant medications comprises one or more of amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, and cathine. For example, in an embodiment the one or more stimulant medications is amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the one or more stimulant medications consists essentially of amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the stimulant medication is amphetamine. [0013] In some embodiments, the subject is prescribed one or more stimulant medications for the management of a sleep-wake disorder.

[0014] In some embodiments, the subject is prescribed one or more stimulant medications for the management of attention deficit disorder or attention deficithyperactivity disorder.

[0015] In some embodiments, the subject is prescribed one or more stimulant medications for the management of obesity or an eating disorder.

[0016] In one aspect, the present disclosure provides a method of reducing concurrent use of a stimulant medication and alcohol, comprising administering to a subject in need of the stimulant medication a single combination medication, comprising an effective amount of one or more stimulant medications for the management of a condition or disorder, wherein the one or more stimulant medications is selected from amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, or cathine; and an effective amount of one or more aldehyde dehydrogenase inhibitors (ALDIs) selected from disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs, (benzoyloxy)[4- chlorophenyl)sulfonyl]carbamic acid 1 ,1 dimethyl ester (NPI-1 ), 4-chloro-N-ethyl-N- [(propylamino)carbonyl]benzenesulfonamid (API-1 ), 3-(((3-(4- (methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl) benzoic acid (CVT- 10216), N,N-diethylaminobenzaldehyde (DEAB), gossypol, molinate, nitroglycerin, pargyline, or pharmaceutically acceptable salts thereof, enabling provision of the effects of the one or more stimulant medications in a manner which prevents concomitant alcohol consumption.

[0017] In some embodiments, the condition or disorder is attention deficit disorder, attention deficit-hyperactivity disorder, a sleep-wake disorder, obesity, or an eating disorder.

[0018] In some embodiments, the ALDI is disulfiram, or a pharmaceutically acceptable salt thereof. In some embodiments the ALDI consists essentially of disulfiram, or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the one or more stimulant medications comprises amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the one or more stimulant medications consists essentially of one or more of amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the one or more stimulant medications is amphetamine.

[0020] In some embodiments, the subject is prescribed one or more stimulants for the management of a sleep-wake disorder.

[0021] In some embodiments, the subject is prescribed one or more stimulants for the management of attention deficit disorder or attention deficit hyperactivity disorder.

[0022] In some embodiments, the subject is prescribed one or more stimulants for the management of obesity or an eating disorder.

[0023] In one aspect, the present disclosure provides a combination medication, comprising an effective amount of one or more CNS stimulants; and an effective amount of one or more aldehyde dehydrogenase inhibitors (ALDIs) and a pharmaceutically acceptable carrier, wherein the one or more ALDIs is selected from one or more of disulfiram, calcium carbimide, coprine, cyanamide, 1 - aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs (benzoyloxy)[4-chlorophenyl)sulfonyl]carbamic acid 1 ,1- dimethylethyl ester (NPI-1 ) and 4-chloro-N-ethyl-N- [(propylamino)carbonyl]benzenesulfonamid (API-1 ), 3-(((3-(4- (methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl) benzoic acid (CVT- 10216), N,N-diethylaminobenzaldehyde (DEAB), gossypol, kynurenine tryptophan metabolites, molinate, nitroglycerin, pargyline, S-methyl N,N-diethyldithiocarbamate, S- methyl N,N-diethyldithiocarbamate sulfoxide, and S-methyl N,N-diethylthiocarbamate sulfoxide, HNO, 1 -aminocyclopropanol (ACP), thioampal, 2- mercaptobenzothiazole (MBT), molinate sulfoxide, molinate sulfone, NO3, propiolaldehyde, or pharmaceutically acceptable salts thereof.

[0024] In some embodiments, the ALDI is disulfiram, or a pharmaceutically acceptable salt thereof. In some embodiments, the ALDI consists essentially of disulfiram, or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the one or more CNS stimulants is one or more prescription CNS stimulants.

[0026] In some embodiments, the one or more CNS stimulants is one or more of amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, and cathine. In some embodiments, the one or more CNS stimulants is amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the one or more CNS stimulants consists essentially of one or more of amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the CNS stimulant is amphetamine. [0027] In any of the various embodiments of the methods of combination medications discussed above or herein, the combination medication (or single composition) may comprise from 1 mg to 1000 mg of the one or more CNS stimulants (or stimulant medications). In some cases, the combination medication (or composition) comprises from 1 mg to 60 mg of the one or more CNS stimulants. In some cases, the combination medication (or composition) comprises from 1 mg to 20 mg of the one or more CNS stimulants. In any of the embodiments of the methods of combination medications, the combination medication (or composition) may comprise from 25 mg to 500 mg of the one or more ALDIs (e.g., disulfiram). In some cases, the combination medication (or composition) may comprise from 50 mg to 250 mg of the one or more ALDIs (e.g., disulfiram). In some cases, the combination medication (or composition) may comprises from 100 mg to 250 mg of the one or more ALDIs (e.g. , disulfiram).

[0028] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.

DETAILED DESCRIPTION

[0029] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed subject matter belongs. Definitions of common terms in chemistry terms may be found in The McGraw-Hill Dictionary of Chemical Terms, 1985, and The Condensed Chemical Dictionary, 1981.

[0030] As used herein, the singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Also, as used herein, the term "comprises" means "includes." Hence "comprising A or B" means including A, B, or A and B. Except as otherwise noted, any quantitative values are approximate whether the word "about" or "approximately" or the like are stated or not. The materials, methods, and examples described herein are illustrative only and not intended to be limiting. Any molecular weight or molecular mass values are approximate and are provided only for description.

[0031] Except as otherwise noted, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361 , 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-lnterscience, 2001 ; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978.

[0032] In case of conflict, the present specification, including explanations of terms, will control.

[0033] To facilitate review of the various embodiments of this disclosure, the following explanations of specific terms are provided:

[0034] Administration: To provide or give a subject a composition, such as a pharmaceutical composition including an ALDI and a stimulant medication formulated as a combination drug product, by any effective route. Exemplary routes of administration include, but are not limited to, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal (ip), and intravenous (iv)), oral, sublingual, transdermal, and inhalation routes.

[0035] Aldehyde dehydrogenases: Enzymes of enzyme class (EC) 1 2 1 3 that catalyze the oxidation of aldehyde. Aldehyde dehydrogenases comprise the primary enzymes involved in alcohol metabolism.

[0036] Aldehyde dehydrogenase inhibitor (ALDI): An inhibitor of the enzymatic activity of an aldehyde dehydrogenase. Examples of aldehyde dehydrogenase inhibitors include: disulfiram ([1 -diethylthiocarbamoyldisulfanyl-N,N-diethylmethanethioamide] ) and active metabolites thereof, such as S-methyl N,N-diethyldithiocarbamate, S-methyl N,N-diethyldithiocarbamate sulfoxide, and S-methyl N,N-diethylthiocarbamate sulfoxide; calcium carbimide, sold as the citrate salt under the trade name Temposil®; coprine and active metabolites thereof, such as 1 -amino cyclopropanol; cyanamide and active metabolites thereof, such as HNO; 1 -aminocyclopropanol and active metabolites thereof, such as ACP; daidzin; cephalosporins; antidiabetic sulfonyl ureas; metronidazole; ampal and active metabolites thereof, such as thioampal; benomyl (methyl [1-[(butylamino)carbonyl]-1 H-benzimidazol-2-yl]carbamate) and active metabolites thereof, such as MBT; citral and active isomers thereof, such as neral and geranial; chloral hydrate; chlorpropamide analogs NPI-1 and API-1 ; CVT-10216; DEAB; gossypol, kynurenine tryptophan metabolites KA, 3-HK, and 3-HAA; molinate and active metabolites thereof, such as molinate sulfoxide and molinate sulfone; nitroglycerin and active metabolites thereof, such as NO3; pargyline and active metabolites thereof, such as propiolaldehyde; and any other metabolites or analogs exhibiting aldehyde dehydrogenase inhibiting activity.

[0037] Combination product(s): As discussed herein pertain to pharmaceutical preparations that include at least a first agent and a second agent prepared in such a way as to prevent or resist separation of the active pharmaceutical agents into their individual counterparts. In examples, the first agent and the second agent may be included in a single tablet or other oral or sublingual formulation (e.g., tamper-resistant matrix formulation, oral spray, and the like) thereby preventing or resisting separation of the individual active pharmaceutical agents. As discussed herein, a combination product may be referred to as a combination drug, combination drug product, combination medication, or fixed-dose combination (FDC).

[0038] Contacting: Placement in direct physical association including both in solid or liquid form. Contacting can occur in vivo, for example by administering an agent (e.g., combination drug product) to a subject.

[0039] Effective amount: An amount of therapeutic agent that is sufficient to generate a desired response, such as reducing or inhibiting one or more signs or symptoms associated with a condition/disorder or disease. When administered to a subject, a dosage will generally be used that will achieve target tissue/cell concentrations. In some examples, an “effective amount” is one that reduces diversion or prevents improper use of a stimulant medication in conjunction with consumption of a substance (e.g., CNS depressant such as alcohol). [0040] In particular examples, it is an amount of an agent capable of inhibiting one or more aldehyde dehydrogenase(s) from catalyzing the oxidation of acetaldehyde, for example following consumption of alcohol. In the absence of alcohol metabolism, a subject consuming alcohol may experience unpleasant effects (e.g., nausea, headache, dizziness, abdominal discomfort, etc.) that may deter concurrent alcohol consumption. In some examples, it is an amount of an agent that prevents or reduces a subject’s desire for and/or consumption of a substance (e.g., CNS depressant such as alcohol) that, when otherwise combined with a stimulant medication, can increase a risk of stimulant overdose and/or alcohol poisoning.

[0041] In examples, signs and/or symptoms of unpleasant effects (e.g., nausea, headache, dizziness, abdominal discomfort, etc.) do not have to be produced completely for the pharmaceutical preparation to be effective. For example, a pharmaceutical preparation (e.g., an ALDI) may produce signs or symptoms of unpleasant effects during concomitant consumption of a stimulant medication and an agent that enhances inhibitory GABAergic neurotransmission (e.g., CNS depressant such as alcohol) by a desired amount, for example by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or even at least 100% as compared to signs or symptoms in the absence of the pharmaceutical preparation.

[0042] In examples, an effective amount is an amount of a stimulant medication sufficient to elicit a desired effect, such as a desired degree of wakefulness, alertness and/or a desired degree of anti-narcoleptic effects.

[0043] Inhibiting or treating a disease or a condition: As discussed herein pertains to inhibiting the full development of a disease or condition, for example, in a subject who is in need of a stimulant medication, such as a subject suffering from ADD, ADHD and/or narcolepsy (chronic sleep-wake disorder) and/or obesity or an eating disorder. For example, treatment with a stimulant medication may prevent the full development of, or reduce the symptoms of ADD, ADHD, narcolepsy, and/or an eating disorder (e.g., obesity) in the subject.

[0044] "Treatment" refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. For example, treatment with a stimulant medication may ameliorate one or more signs or symptoms of ADD, ADHD, narcolepsy, obesity, and/or an eating disorder. As another example, treatment with an ALDI may ameliorate one or more signs or symptoms of alcohol use or overconsumption (e.g., alcohol abuse). The term "ameliorating," with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. For example, a stimulant medication may be used to ameliorate one or more signs or symptoms associated with sleep disorders. As another example, an ALDI may be used to ameliorate one or more signs or symptoms associated with alcohol consumption (e.g., overconsumption, or any level of consumption that may increase a risk of a medically related adverse event, organ damage (e.g., liver damage), and the like). The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease/condition in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, such as sleep disturbances, a slower progression of the disease/condition, an improvement in the overall health or well-being of the subject, or by other clinical or physiological parameters associated with a particular disease/condition. In examples, a combination drug product comprising one or more ALDIs and one or more stimulants may be used to ameliorate one or more signs or symptoms associated with alcohol consumption, while also ameliorating one or more signs or symptoms associated with, e.g., sleep irregularities and/or ADD or ADHD. A "prophylactic" treatment as discussed herein may pertain to a treatment administered to a subject who may exhibit signs of a particular condition (e.g., ADD, ADHD, obesity or narcolepsy) and who may also be at risk of misusing a stimulant in conjunction with a CNS depressant if the treatment (e.g., combination of an ALDI with a stimulant) is not provided. For example, a person with a history of alcohol abuse may be given a stimulant medication as a combination drug product that also includes one or more ALDIs in order to reduce diversion or improper use of the stimulant concomitant with alcohol consumption while taking the stimulant for the desired purpose.

[0045] Inhibit: To reduce to a measurable extent. For example, to reduce the full development of a disease or condition (e.g., ADD, ADHD, obesity or narcolepsy). As another example, to reduce diversion or misuse of a stimulant concomitant with consumption of alcohol. [0046] Reducing drug diversion or misuse: As discussed herein, drug diversion” or “diversion” refers to an illegal sale or transfer of a drug or medication from a patient to whom it is prescribed to someone else. In the context of the present disclosure, by combining an effective amount of a stimulant medication with an effective amount of an ALDI in the form of a combination drug product, diversion of the stimulant medication may be reduced. In exemplary aspects, the anti-diversion characteristics of the combination drug product relate to a reduced “street value” or illicit demand for the product. Such reduced demand results from the combination product because diverted stimulant medications are frequently used for recreational purposes in which alcohol is involved. Since the combination drug products, disclosed herein, prevent concurrent alcohol consumption, the combination drug products will be much less appealing to such recreational users.

[0047] Unpleasant effects: As discussed herein, pertains to an unpleasant effect that is precipitated by combining a therapeutic agent with another agent that causes an interaction in the body of a subject leading to the unpleasant effect. In examples, the therapeutic agent is a combination drug product of an ALDI and a stimulant, and the other agent is alcohol (or other CNS depressant). In examples, during concomitant consumption of the combination drug product and alcohol, the ALDI of the combination drug product can interfere with alcohol metabolism in the body of a subject leading to unpleasant effects. Unpleasant effects, as discussed herein, comprise effects that would occur with reduced detrimental consequences and/or severity to the subject in the presence of the other agent such as alcohol. Unpleasant effects may include but are not limited to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, general hangover-like symptoms, and the like. In examples disclosed herein, an improper use of a stimulant (e.g., in a non-medical context) may be reduced or avoided by combining one therapeutic agent (e.g., CNS stimulant) with another therapeutic agent (e.g., ALDI), for example in the form of a combination product, thereby reducing the likelihood of diversion to an improper use.

[0048] Central nervous system stimulants: Drugs used for treatment of various physical and mental health disorders including but not limited to ADHD, obesity, narcolepsy or other sleep disorders, and the like. Prescription stimulants, such as amphetamines or methylphenidate, are an option for treating ADHD. Other stimulants, such as modafinil, are preferred for sleep disorders, including narcolepsy, shift work disorder, and obstructive sleep apnea. Phentermine has stimulant effects and is used as an appetite suppressant for treating obesity.

[0049] Without intending to be bound by any specific mechanism of action, CNS stimulants generally work by increasing catecholamine levels in the brain.

Catecholamines are a group of neurotransmitters that include norepinephrine and dopamine. CNS stimulants work by blocking the reuptake of norepinephrine and dopamine in the brain. They may also directly increase the release of these neurotransmitters in the brain. Norepinephrine and dopamine are believed to be involved with different physical and mental processes like attention, mood, and motivation. CNS stimulants, such as dextroamphetamine and methylphenidate, can help stimulate increased activity in the brain. However, they can also have other effects in the body. Catecholamines are involved with the body’s fight-or-flight response during stressful situations. CNS stimulants can increase norepinephrine levels, which can lead to increased blood pressure, increased heart rate, and narrowed blood vessels.

[0050] CNS stimulants are also controlled substances that can have addictive properties. While prescribed stimulants are safe and effective, they do carry a risk of misuse, abuse, and dependence. Some CNS stimulants, such as cocaine, ecstasy, and MDMA (methylenedioxymethamphetamine), are not prescribed, because they have a high potential for abuse. Misuse of the stimulant medications, especially in conjunction with a CNS depressant (e.g., alcohol) can increase the risk of overdose and other complications. Additionally, long-term CNS stimulant use may also result in tolerance, abuse, and dependence.

[0051] Examples of stimulants include, but are not limited to, amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, cathine, mixtures of any of the foregoing, salts of any of the foregoing, and the like. [0052] Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington's Pharmaceutical Sciences, by E.W. Martin, Mack Publishing Co., Easton, PA, 19th Edition, 1995, describes compositions and formulations suitable for pharmaceutical delivery of the compositions disclosed herein. [0053] In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (such as powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

[0054] Subject: The term "subject" includes both human and veterinary subjects, for example, humans, non-human primates, dogs, cats, horses, rats, mice, and cows. Similarly, the term mammal includes both human and non-human mammals. In some embodiments, a subject is a patient, such as patient prescribed one or more stimulant medications.

[0055] Therapeutic agent or Pharmaceutical agent: A chemical compound, small molecule, or other composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject, for example reducing misuse of a stimulant in combination with alcohol consumption.

[0056] Therapeutically effective amount or Effective amount: The amount of agent, such as an ALDI and a stimulant medication, that is sufficient to prevent, treat, reduce and/or ameliorate the symptoms and/or underlying causes of any of a disorder, condition, or disease. For example, a combination drug product comprising an ALDI and a stimulant may be used to prevent and/or reduce improper use of a stimulant concomitant with alcohol consumption. A therapeutically effective amount of a stimulant may be an amount that induces a desired effect, such as a desired level of alertness and/or desired level of anti-narcoleptic effects, in a subject suffering from such conditions. A therapeutically effective amount of an ALDI may be an amount that substantially reduces or entirely prevents a subject from imbibing alcohol.

[0057] Suitable methods and materials for the practice or testing of this disclosure are described below. Such methods and materials are illustrative only and are not intended to be limiting. Other methods and materials similar or equivalent to those described herein can be used. For example, conventional methods well known in the art to which this disclosure pertains are described in various general and more specific references. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0058] Overview

[0059] Stimulant medications are commonly prescribed to treat ADHD, obesity, narcolepsy or other sleep disorders, with potentially low risk of side effects. The mechanism of action of stimulants is to increase catecholamine (e.g., norepinephrine and dopamine) levels in the brain by blocking their reuptake and/or directly increasing the release of these neurotransmitters in the brain. This promotes stimulatory effects, such as alertness, focus, increased energy, and the like. These drugs can help stimulate the activity of the central nervous system, thereby increasing brain activity in a subject.

[0060] Stimulant medications are effective, but are known to have habit-forming potential or addictive properties. These medications carry a risk of misuse, abuse, and dependence. One commonly known misuse of stimulant medications is taking them in conjunction with a CNS depressant (e.g., alcohol). As alcohol and a stimulant medication can mask or negate each other’s effects in the body of a subject during concurrent consumption, this may lead to an increased risk of stimulant overdose, alcohol poisoning, or both, and/or other complications.

[0061] Combining stimulant medications with other substances can potentiate numerous risks in general. One particularly relevant example described herein is the combination of stimulants with alcohol. As described above, alcohol can decrease or completely mask central nervous system effects of stimulants such as alertness, focus, and increased energy, and can further exacerbate impairments in thinking, judgement, memory and/or reflexes. Despite these known risks, patients exhibit high rates of nonadherence with medical recommendations to avoid alcohol consumption when taking stimulant medications. Such risks are particularly relevant among the younger population, for whom abusing stimulant medications in conjunction with drinking alcohol is very prominent and for whom the combination of stimulant medications with alcohol can lead to increased risks of overdose and other complications. Given the high prevalence of stimulant abuse among the younger population (reported to be as high as ~42%), it is not surprising that the concurrent use of alcohol may contribute to the risks of stimulant overdose and/or alcohol poisoning, or behaviors that can lead to serious injury or death.

[0062] Thus, the current standard of care for preventing the combination of alcohol with stimulant medications, which is essentially limited to patient counseling, is ineffective. Accordingly, an improved solution is needed for preventing or substantially reducing the combining of alcohol and stimulant medication, to enhance the safety of use of the stimulant medications.

[0063] Methods of Treatment

[0064] Disclosed herein is a method of reducing improper use of a stimulant medication concomitant with alcohol consumption. The disclosed method involves combining an ALDI (e.g., disulfiram [1 -diethylthiocarbamoyldisulfanyl-N,N- diethylmethanethioamide]) into a combination drug product, such as a 'poly-pill', with a CNS stimulant (e.g., prescribed stimulant medication), for example with one or more of amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, and the like, and administering the combination to a subject, such as a subject for whom the stimulant has been prescribed. Administration of such a combination enables delivery of the stimulant(s) in a manner that prevents co-consumption of alcohol, thereby in turn reducing a risk of the subject from misusing or abusing the stimulant medication. [0065] Existing pharmacotherapies for treating alcoholism include administration of agents that inhibit the enzyme aldehyde dehydrogenase (ALDH), which is involved in the removal of acetaldehyde, a toxic metabolite of alcohol. Although multiple forms of ALDH exist, ALDH-I and ALDH-II are the major enzymes responsible for the oxidation of acetaldehyde. While not being bound by theory, ALDH-I has a higher affinity for acetaldehyde than ALDH-II, and is believed to be the primary enzyme involved in alcohol detoxification. The combination, such as in a poly-pill, of the ALDI with a prescribed stimulant will prevent the co-consum ption of alcohol with prescribed stimulant medications, because disulfiram and other ALDIs prevent the metabolism of alcohol. Therefore, once a stimulant-ALDI combination medication is administered, the stimulant will induce its typical profile of intended effects (e.g., alertness, increased energy, and the like), but any subsequent co-consumption of alcohol will result in a strong noxious physiologic reaction to the alcohol or unpleasant effects (e.g., nausea, dizziness, headache, and the like). Therefore, it prevents the subject from consuming alcohol to the point where an unpleasant effect may occur stemming from the synergistic effects of alcohol and the combination medication.

[0066] The disclosed method includes providing and/or administering to a subject a pharmaceutical preparation (e.g., combination drug product) that includes an effective amount of one or more stimulants and an effective amount of one or more ALDIs. In this way, a risk that a subject will consume alcohol while taking a stimulant medication may be reduced. Examples of ALDIs include, e.g., disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs NPI-1 and API-1 , CVT-10216, DEAB, gossypol, kynurenine tryptophan metabolites, molinate, nitroglycerin, pargyline and any active metabolites or analogs exhibiting aldehyde dehydrogenase inhibiting activity.

[0067] Patients who consume such inhibitors of ALDH experience mild to severe discomfort if they ingest alcohol. Disulfiram, the best known ALDI and sold under the tradenames Cronetai™, Abstenil™, Stopetyl™, Contrain™, Antadix™, Anietanol™, Exhoran™, Antabuse™, Etabuse™, Abstinyl™, Thiuranide™, Esperal™, Tetradine™, Noxal™, Tetraeti™, is a potent irreversible inhibitor of ALDH-II that slightly inhibits ALDH-I. Ingestion of alcohol while taking disulfiram and other aldehyde dehydrogenase inhibitors results in the accumulation of aldehydes, which causes tachycardia, flushing, diaphoresis, dyspnea, nausea and vomiting (also known collectively as the disulfiram or disulfiram-ethanol reaction). Disulfiram consumption produces sensitivity to alcohol which results in a highly unpleasant reaction or effects when the subject ingests even small amounts of alcohol. Thus, in specific embodiments, the dehydrogenase inhibitor comprises, consists essentially of, or consists of disulfiram.

[0068] In specific embodiments, the method includes the administration of one or more of disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs NPI-1 and API-1 , CVT-10216, DEAB, gossypol, kynurenine tryptophan metabolites, molinate, nitroglycerin, pargyline, and/or any active metabolites or analogs exhibiting aldehyde dehydrogenase inhibiting activity. In specific embodiments, the method includes the administration of one or more of disulfiram and/or active metabolites thereof, such as S- methyl N,N-diethyldithiocarbamate, S-methyl N,N-diethyldithiocarbamate sulfoxide, and S-methyl N,N-diethylthiocarbamate sulfoxide.

[0069] As disclosed herein, the method includes the administration of a stimulant medication, such as one or more prescription stimulants. Stimulant medications within the present disclosure include, but are not limited to, amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, mixtures of any of the foregoing, and/or salts of any of the foregoing. Thus, in embodiments, a subject is administered a therapeutically effective amount of one or more of amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, cathine, salts thereof, and/or combinations thereof. In specific embodiments, the one or more stimulants comprises, consists essentially of, or consists of amphetamine, methylphenidate, or lisdexamfetamine. In some embodiments, the stimulant medication is, or comprises, or consists of amphetamine. [0070] In embodiments, the subject is prescribed one or more stimulant medications for the management of an ADHD and/or a sleep disorder (e.g., narcolepsy, and the like). Additionally or alternatively, the subject is prescribed one or more stimulant medications for the management of obesity or another eating disorder. Additionally or alternatively, the subject is prescribed one or more stimulant medications for other neurological disorders. Other reasons why a particular subject may be prescribed a stimulant medication are within the scope of this disclosure.

[0071] Therapeutic formulations

[0072] Aspects of the present disclosure further concern a combination medication that includes an ALDI and a stimulant medication.

[0073] In embodiments, the combination medication includes an effective amount of one or more ALDIs. In embodiments, the one or more ALDIs is selected from one or more of disulfiram, calcium carbimide, coprine, cyanamide, 1 -aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole, ampal, benomyl, citral and active isomers thereof, chloral hydrate, chlorpropamide analogs NPI-1 and API-1 , CVT-10216, DEAB, gossypol, kynurenine tryptophan metabolites, molinate, nitroglycerin, pargyline and any active metabolites or analogs exhibiting aldehyde dehydrogenase inhibiting activity. In specific embodiments, the ALDI comprises, consists essentially of, or consists of one or more of disulfiram and/or active metabolites thereof, such as S-methyl N,N-diethyldithiocarbamate, S-methyl N,N- diethyldithiocarbamate sulfoxide, and S-methyl N,N-diethylthiocarbamate sulfoxide. In specific embodiments, the aldehyde dehydrogenase inhibitor comprises, consists essentially of, or consists of disulfiram.

[0074] In embodiments, the one or more stimulant medications included in the combination medication is selected from amphetamine, dextroamphetamine, levoamphetamine, methylphenidate, dexmethylphenidate, lisdexamfetamine, methamphetamine, atomoxetine, modafinil, armodafinil, pitolisant, solriamfetol, oxybate, methylenedioxymethamphetamine, benzoylmethylecgonine, piracetam, phenylpiracetam, picrotoxin, phentermine, phendimetrazine, amfepramone, benzphetamine, cathinone, cathine, mixtures of any of the foregoing, salts of any of the foregoing, and the like. In specific embodiments, the one or more stimulants comprises, consists essentially of, or consists of amphetamine, methylphenidate, or lisdexamfetamine.

[0075] The method of treatment and pharmaceutical formulations of the present disclosure may further include one or more drugs in addition to the stimulant medication and the ALDI, which additional drug(s) may or may not act synergistically therewith. Thus, in certain embodiments, a combination of two or more stimulants may be included in the formulation, in addition to the ALDI (or ALDIs). For example, the dosage form may include stimulants having different properties, such as half-life, solubility, potency, mechanism of action, and a combination of any of the foregoing. In yet further embodiments, one or more stimulants and one or more ALDIs are included, and a further non-stimulant drug is also included, in addition to the stimulant medication. In certain embodiments, such non-stimulant drugs could preferably provide additional analgesia, as sleep disorders are often associated with pain (e.g., chronic pain) or muscle spasticity. Accordingly, such non-stimulant drugs may include but are not limited to baclofen, aspirin; acetaminophen; non-sterioidal antiinflammatory drugs (“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine; cycooxygenase-ll inhibitors (“COX-II inhibitors”); and/or glycine receptor antagonists. [0076] Suitable non-steroidal anti-inflammatory agents include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zido-metacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. Useful dosages of these drugs are well known to those skilled in the art.

[0077] N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art, and encompass, for example, morphinans such as dextromethorphan or dextrorphan, ketamine, d-methadone or pharmaceutically acceptable salts thereof. For purposes of the present disclosure, the term “NMDA antagonist” is also deemed to encompass drugs that block a major intracellular consequence of NMDA-receptor activation, e.g. a ganglioside such as GMi or GTw a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6-aminothexyl)-5-chloro-1 - naphthalenesulfonamide. These drugs can be used to inhibit the development of tolerance to and/or dependence on addictive drugs, and/or to treat pain.

[0078] The treatment of chronic pain via the use of glycine receptor antagonists and the identification of such drugs is described in U.S. Pat. No. 5,514,680. COX-2 inhibitors have been reported in the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601 ; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521 ,213;

5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311. Certain preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966, nabumetone (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.

[0079] The dosage form of a disclosed pharmaceutical composition will be determined by the mode of administration chosen. For example, in addition to injectable fluids, oral dosage forms may be employed. Oral formulations may be liquid such as syrups, solutions or suspensions (e.g., oral sprays) or solid such as powders, pills, tablets, or capsules. Methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.

[0080] In embodiments the combination medication is an oral dosage. The oral dosage forms of the disclosure comprise a therapeutically effective amount of a stimulant medication, together with an ALDI, in a therapeutically effective amount that provides a negative, “aversive” physical experience when alcohol is taken in conjunction with the oral dosage form.

[0081] The combination of the stimulant medication, together with an ALDI can be employed in admixtures with conventional excipients, i.e. , pharmaceutically acceptable organic or inorganic carrier substances suitable for oral administration, known to the art. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They can also be combined where desired with other active agents, for example other anti-narcoleptic and/or analgesic agents. For oral administration, particularly suitable are tablets, dragees, liquids, drops, capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. In tablet form, the tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0082] Aqueous suspensions containing the above-identified combinations typically include one or more excipients suitable as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums. Oily suspensions may be formulated by suspending the above-identified combinations in a vegetable oil or mineral oil. The oily suspensions may contain a thickening agent such as beeswax or cetyl alcohol. A syrup, elixir, or the like can be used wherein a sweetened vehicle is employed. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. [0083] An oral dosage form according to the disclosure may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as “multiparticulates”). An amount of the multiparticulates which is effective to provide the desired dose of stimulant over time may be placed in a capsule or may be incorporated in any other suitable oral solid form. Alternatively, the oral dosage form may be in the form of a tablet.

[0084] Certain embodiments of the pharmaceutical compositions comprising a stimulant medication (e.g., one or more stimulants) and an ALDI (e.g., one or more ALDIs) may be formulated in unit dosage form suitable for individual administration of precise dosages. The amount of active ingredient such as a stimulant medication and an ALDI administered will depend on the subject being treated, the severity of the disorder, and the manner of administration, and is known to those skilled in the art. Within these bounds, the formulation to be administered will contain a quantity of the stimulant medication and the ALDI in an amount effective to achieve the desired effect in the subject being treated.

[0085] In particular examples, for oral administration the compositions are provided in the form of a tablet or capsule containing from about 5 mg to about 1000 mg, or about 25 mg to 500 mg of the ALDI (e.g., disulfiram), particularly about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 250 mg, or about 500 mg of the active ingredient, in combination with the dose of the selected stimulant medication necessary to provide the desired effect (e.g., desired level of alertness, reduction of narcolepsy, etc.). In some embodiments, the composition comprises the ALDI (e.g., disulfiram) in an amount of from 25 mg to 250 mg, from 25 mg to 200 mg, from 50 mg to 200 mg, from 75 mg to 200 mg, from 100 mg to 200 mg, from 50 mg to 250 mg, from 75 mg to 250 mg, or from 100 mg to 250 mg. These range of doses of disulfiram were selected to facilitate achieving a total daily dose of disulfiram between 50 mg and 500 mg, between 50 mg and 250 mg, between 50 mg and 200 mg, between 100 mg and 250 mg, between 100 mg and 200 mg, or between 250 mg and 500 mg and to allow for wide variability in the frequency of the stimulant medication dosing schedules (e.g., the stimulant medication can be taken one time daily, or more than one time in some examples, such as two times or even three times. In other examples, the stimulant medication need not be taken every day). In one exemplary oral dosage regimen, a tablet containing about 100 mg to about 500 mg, for example 250 mg, of disulfiram in combination with 1 -1000 mg of a stimulant medication is administered once per day, thereby providing a typical total daily dose of disulfiram between 100 mg and 500 mg, for example 250 mg. Typical dosage forms of the most common stimulant medications (e.g., amphetamine, methylphenidate, lisdexamfetamine) are formulated as about 1 -500 mg. Thus, combinations of stimulant medication with various doses of disulfiram, for example between 25 mg and 500 mg to allow flexibility with regard to the frequency of stimulant dosing, are contemplated. Thus, for example, in the patient who occasionally takes a single stimulant tablet on an as-needed basis or who takes a single long-acting stimulant tablet (e.g., on a daily basis), that stimulant medication would be combined with either 125 mg, 250 mg or 500 mg disulfiram. It is also contemplated herein, that in some examples a patient could take a stimulant medication at a greater frequency (e.g., more than one time per day), and in such an example the stimulant medication may be combined with disulfiram at a dose that results in a daily dose of disulfiram between 125 mg and 500 mg. Disulfiram suits this need for flexibility in treating a range of patients with sleep disturbances because it can be administered in a once-daily or a multiple-times daily manner and still be effective for the entire day. Thus, in embodiments, the disulfiram dose is selected which, when the stimulant medication is taken in the prescribed manner, results in the delivery of a total daily dose of 125 - 500 mg disulfiram. Any of the doses or ranges of doses of the ALDi (e.g. disulfiram) can be combined with any of the doses or ranges of doses of stimulant medication mentioned below or herein in the compositions of the present disclosure.

[0086] In particular examples, for oral administration the compositions are provided in the form of a tablet or capsule containing from about 1 .0 mg to about 20 mg (or even higher, such as 30 mg or 60 mg) of the stimulant medication, particularly about 1 .0 mg, about 2.0 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 60 mg of the stimulant medication (depending on the potency of the particular stimulant selected), which accounts for the symptomatic adjustment of the dosage to the subject being treated. In one exemplary oral dosage regimen, a tablet containing from about 1 mg to about 60 mg stimulant medication is administered one (or in some examples more and in some examples less) time(s) a day. In other embodiments, the combination product may contain from about 1 mg to about 1000 mg of the stimulant medication, e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. Any of the doses or ranges of doses of the stimulant medication can be combined with any of the doses or ranges of doses of the ALDI (e.g., disulfiram) mentioned above or herein in the compositions of the present disclosure.

[0087] Single or multiple administrations of the composition comprising the stimulant medication, together with an ALDI, can be carried out with dose levels and pattern being selected by the treating physician. Generally, single doses are administered in the case of a stimulant used for treatment of narcolepsy. In particular examples, the composition is administered once per day (or in some examples more, such as twice per day or three times per day), every other day, twice a week, weekly, monthly, or as desired. Treatment will typically continue for some period of time (e.g., one week, one month, etc.), and may in rare circumstances even continue indefinitely, i.e. , chronically. Repeat courses of treatment are also possible.

[0088] Routes of administration useful in the disclosed methods include but are not limited to oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, and transdermal. Pharmaceutical compositions comprising a combination drug product that includes a stimulant medication and an ALDI can be administered to subjects by a variety of routes. These include oral, nasal (such as intranasal), ocular, buccal, enteral, intravitreal, or other mucosal (such as rectal or vaginal) or topical administration. Alternatively, administration will be by orthotopic, intradermal subcutaneous, intramuscular, parenteral intraperitoneal, or intravenous injection routes. Such pharmaceutical compositions are usually administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers, or other excipients. [0089] An effective amount of a stimulant medication (e.g., one or more stimulants) and an ALDI (e.g., one or more ALDIs) will depend, at least, on the particular method of use, and the manner of administration of the therapeutic composition. A "therapeutically effective amount" of a composition is a quantity of a specified compound sufficient to achieve a desired effect in a subject being treated. Ideally, a therapeutically effective amount of an ALDI is an amount sufficient to cause a subject to forgo alcohol without a substantial side effect in the subject. For example, a therapeutically effective amount of an ALDI may be an amount sufficient to cause a subject to stop consumption of alcohol (or significantly reduce consumption). Similarly, a therapeutically effective amount of a stimulant medication is an amount sufficient to cause the desired effect, such as a desired level of alertness or desired anti-narcoleptic effects, without a substantial side effect in the subject.

[0090] The specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, and diet of the subject, mode and time of administration, rate of excretion, drug combination, and severity of the condition of the subject undergoing therapy.

[0091] Typically, preparation of a pharmaceutical composition (for example, for use as a medicament or in the manufacture of a medicament) entails preparing a pharmaceutical composition that is essentially free of pyrogens, as well as any other impurities that could be harmful to humans or animals. The stimulant medication and an ALDI may be included in pharmaceutical compositions (including therapeutic and prophylactic formulations), which are typically combined together with one or more pharmaceutically acceptable vehicles or carriers and, optionally, other therapeutic ingredients.

[0092] To formulate the pharmaceutical compositions, the stimulant medication and the ALDI can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound. Desired additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like. In addition, local anesthetics (for example, benzyl alcohol), isotonizing agents (for example, sodium chloride, mannitol, sorbitol), adsorption inhibitors (for example, Tween 80), solubility enhancing agents (for example, cyclodextrins and derivatives thereof), stabilizers (for example, serum albumin), and reducing agents (for example, glutathione) can be included. When the composition is a liquid, the tonicity of the formulation, as measured with reference to the tonicity of 0.9% (w/v) physiological saline solution taken as unity, is typically adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration. Generally, the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1 .7.

[0093] The stimulant medication and the ALDI can be dispersed in a base or vehicle, which can include a hydrophilic compound having a capacity to disperse the compound, and any desired additives. The base can be selected from a wide range of suitable compounds, including but not limited to, copolymers of poly carboxy lie acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like, and natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof. Often, a biodegradable polymer is selected as a base or vehicle, for example, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly (hydroxybutyric acid-glycolic acid) copolymer and mixtures thereof. Alternatively or additionally, synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters and the like can be employed as vehicles. Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by partial crystallization, ionic bonding, cross-linking and the like. The vehicle can be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, and microspheres.

[0094] The stimulant medication and the ALDI can be combined with the base or vehicle according to a variety of methods, and release of the compound can be by diffusion, disintegration of the vehicle, or associated formation of water channels. In some circumstances, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from a suitable polymer, for example, isobutyl 2- cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol. 43: 1-5, 1991 ), and dispersed in a biocompatible dispersing medium, which yields sustained delivery and biological activity over a protracted time.

[0095] The stimulant medication and ALDI combination drug products can alternatively contain as pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. [0096] Pharmaceutical compositions for administering the stimulant medication and the ALDI can be also be formulated as a solution, microemulsion, or other ordered structure suitable for high concentration of active ingredients. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity for solutions can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants. In many cases, it will be desirable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol and sorbitol, or sodium chloride in the composition. Prolonged absorption of the compound can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

[0097] For prophylactic and therapeutic purposes, the pharmaceutical compositions can be administered to the subject in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily, or weekly, repeated administration protocol). The therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein.

[0098] Therapeutic compositions that include a stimulant medication and an ALDI can be delivered by way of a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 , 1987; Buchwald et al, Surgery 88:507, 1980; Saudek et al, N. Engl. J.

Med. 321 :574, 1989) or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution can also be employed. One factor in selecting an appropriate dose is the result obtained, as measured by the methods disclosed here, as are deemed appropriate by the practitioner. Other controlled release systems are discussed in Langer (Science 249: 1527-33, 1990).

[0099] In one example, a pump is implanted (for example see U.S. Patent Nos. 6,436,091 ; 5,939,380; and 5,993,414). Implantable drug infusion devices are used to provide patients with a constant and long-term dosage or infusion of a therapeutic agent. Such device can be categorized as either active or passive.

[00100] Active drug or programmable infusion devices feature a pump or a metering system to deliver the agent into the patient's system. An example of such an active infusion device currently available is the Medtronic SYNCHRO MED™ programmable pump. Passive infusion devices, in contrast, do not feature a pump, but rather rely upon a pressurized drug reservoir to deliver the agent of interest. An example of such a device includes the Medtronic ISOMED™.

[00101] In particular examples, therapeutic compositions are administered by sustained-release systems. Suitable examples of sustained-release systems include suitable polymeric materials (such as, semi-permeable polymer matrices in the form of shaped articles, for example films, or mirocapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt). Sustained-release compositions can be administered orally, parenterally, intracistemally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), or as an oral or nasal spray. Sustained-release matrices include polylactides (U.S. Patent No. 3,773,919, EP 58,481 ), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al, Biopolymers 22:547-556, 1983, poly(2-hydroxyethyl methacrylate));

(Langer et al., J. Biomed. Mater. Res.15: 167-277, 1981 ; Langer, Chem. Tech. 12:98- 105, 1982), ethylene vinyl acetate (Langer et al., Id.)y, or poly-D-(-)-3-hydroxybutyric acid (EP 133,988).

[00102] Polymers can be used for ion-controlled release. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art. In specific examples, the stimulant medication and the ALDI are contained in a time released and/or tamper proof pill and/or capsule. Example or such capsule formulations are well known in the art and include those formulations sold under the tradename OxyContin® and the like. Examples of such time release formulations can be found for example in U.S. Pat. Nos. 5478577; 5681585,5672360; 5958459; 6103261 ; 6143332; 5965161 ; 5958452, 5968551 , 5681585, 5811126, 5843480, 5681585, 5811126, 5843480, 5849240, 5866164, 5879705, 5891471 , 5914131 , 5965163, 5968551 , 6103261 , 6143322, 6245357, 6261599, 6294195, 6419960, 6696066, 7514100, 7514100, 7829120, 7846476, 7988998, 8071119, 8075872, 8114383, 8114384, 8153149, 8153152, 8153661 , 8168217, 8192722, 8231898, 8309060, 8323889, 8354124, 8361499, 8362029, 8372432, 8414919, 8415401 , 8420056, 8420120, 8445018, 8486448, 8486449, 8487002, 8529948, 8551520, 8597681 , 8609683, 8647667, 8653066, 8658631 , 8668929,8685447, 8691270, 8715721 , 8722086, 8728522, 8741885, 8753665, 8765178, 8795723, 8808740, 8808745, 8815289, 8821929, 8834925, 8846072, 8846086, 8858963, 8871265, 8877241 , 8894987, 8894988, 8911719, 8920833, 8920834, 8927013, 8927014, 8927025, 8937097, 8945614, 8951555, 8951556, 8956644, 8962019, 8974821 , 8980291 , 8987291 , 8999961 ,, 9023394, 9023401 , 9034376, 9040084, 9044402, 9050335, 9056052, 9056107, 9060940, 9060976, 9084816, 9095614, 9095615, 9101661 , 9132096 , 9149533, 9161917, 9198861 , 9198863, 9198867, 9205055, 9205056, 9216176, 9226901 , 9226907, 9233073, 9233160, 9278074, 9278083, 9289391 , 9308170, 9308171 , 9320717, 9387174, 9387177, 9393206 , 9393207, 9399022, 9402813, 9427407, 9433582, 9433625, 9439866, 9452163, 9456985, 9468636, 9486412, 9486413, 9486451 , 9492389, 9492390, 9492391 , 9492392, 9492393, 9498444, 9498456, 9504681 , 9517207, 9517236, 9517271 , 9526704, 9526724, 9539328, 9545380, 9545448, 9555113, 9572779, 9572803, 9572804, 9572805, 9572885, 9579285, 9579389, 9592204, 9616030, 9616055, 9629807, 9629837, 9636303, 9642809, 9655853, 9655861 , 9655893, 9655894, 9655971 , 9662326, 9662399, 9669022, 9669023, 9669024, 9675581 , 9675610, 9675611 , 9682077, 9693961 , 9694080, 9707179, 9707180, 9707224, 9713611 , 9730885, 9737490, 9744136 , 9744151 , 9750701 , 9750703 , 9750736, 9757341 , 9757371 , 9763886, 9763933, 9770416, 9770417, 9775808, 9775809, 9775810, 9775811 , 9775812, 9775837, 9789104, and 9789105.

[00103] The subject matter of the present disclosure is further illustrated by the following non-limiting Examples.

[00104] Examples

[00105] This example describes exemplary methodology (clinical trial) for testing the efficacy of the disclosed stimulant-ALDI combination drug product.

[00106] A clinical trial is instituted to demonstrate that the combination therapy 1 ) remains effective as with regard to the desired purpose (e.g., ADHD, narcolepsy medication, etc.) and 2) effectively prevents co-administration of alcohol while the patient is using a stimulant medication (for example, within 12 - 24 hours following administration of the last dose of the combination medication).

[00107] The following represents one of the possible clinical trials that may be instituted to determine efficacy of the combination medication and methods of treatment disclosed herein.

1. Eligibility Assessment and Enrollment a. Inclusion Criteria i. An individual with a relevant condition (e.g., ADHD, narcolepsy) treated with a stimulant medication. ii. The individual has a prior history of alcohol abuse or is suspected of non-adherence with recommendations to avoid concomitant alcohol consumption while taking a stimulant medication. iii. Age greater than 18 years. iv. Adults must be able to understand and sign the informed consent document. v. Patients must have an ECOG performance score of 0-2. vi. Patients must have laboratory and physical examination parameters within acceptable limits by standard of practice guidelines. b. Exclusion criteria

Comorbid alcohol dependency (active, not in remission), or stimulant use disorder (active, not in remission). c. Patient registration

Patients will be registered on the trial by the principal investigator or their designee using a protocol specific registration form after signing the appropriate informed consent or agreeing by assent. Study Implementation

This is a prospective study of the efficacy of the combination of an aldehyde dehydrogenase inhibitor (ALDI), such as disulfiram, and a stimulant medication. As both classes of drugs have proven individual efficacy at achieving the desired clinical outcome when administered individually, toxicity studies would be unnecessary. In an example, the study would include 3 groups plus a control: traditional stimulant, traditional disulfiram, and a comparable stimulant-disulfiram combination. Pharmacokinetics would also be performed, as there may need to be some adjustment (for example lowering) in the dosing of certain stimulants because their metabolism may be slowed by the disulfiram. Patients are asked to complete a wellness rating (e.g., rating related to quality of life, level of energy and alertness during the day, etc.) daily or multiple times per day and are advised/counseled on the importance of alcohol avoidance when taking the stimulant medication. They are selected/notified randomly at multiple intervals throughout the trial (1 - 3x/wk) that they must provide a urine or blood sample, and complete surveys regarding their consumption of alcohol during the trial. The groups are then compared for safety and efficacy (in terms of both stimulant effects and prevention of alcohol co-consumption), side effect profile, and the like. Study Evaluation

Patients will undergo the following evaluations which may be performed within 4 weeks of enrollment:

Detailed History and Physical Examination including, vital signs, ECOG status, demographic information and family history.

Laboratory evaluations: CBC with differential; Chem 20 [Sodium (Na), Potassium (K), Chloride (Cl), Total C02 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid] ;

PT/PTT.; Blood alcohol concentration; Urine drug screen (with quantitative and qualitative stimulant analyses). Follow-up Examinations

Patients following evaluations: a. physical exam to include vital signs and ECOG status; b. laboratory evaluations: pharmacokinetic analysis of aldehyde dehydrogenase inhibitor and stimulant medication. c. Patients are asked to complete a wellness rating daily or multiple times per day. d. Patients are advised/counseled on the importance of alcohol avoidance when taking the stimulant medication. e. Patients are required to provide urine samples and/or other samples needed to determine blood-alcohol levels at random intervals. f. Patients complete a survey/questionnaire about their recent level of alcohol consumption at multiple points over the course of the study. g. Patients agree to inform study investigators if they experience a complication associated with stimulant use at any point over the course of the study.

5. Data Collection

Data prior to and during the course of the patient's participation will be collected in order to monitor patient eligibility, and will include review of medical and family history records, blood work, and urinary studies. a. Toxicity Criteria: This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 4 for toxicity and adverse event reporting. CTCAE version 4 is available on the World Wide Web at ctep.info.nih.gov. All appropriate treatment areas should have access to a copy of the CTCAE version 4. b. Statistical Considerations: A primary objective of this study is to determine the efficacy of the combination medication to provide the desired stimulant effect while reducing the incidence of co-consum ption with alcohol.

6. Rationale for subject selection

Subjects will be selected for this protocol based on relevant condition (e.g., narcolepsy, ADHD) managed with stimulants and alcohol abuse or non-adherence with recommendations to avoid alcohol consumption while taking stimulant medication.

7. Data Reporting a. Routine Data Reporting: All details of patient evaluation, management and treatment will be documented in the patient medical record. The following information may be captured on the CRFs: detailed demographic information including family history; and laboratory results). b. Serious Adverse Event Reporting Requirements: The following events will be reported: all deaths with the exception of those due to progressive disease; all events that are not listed in the consent form and that are possibly, probably, or definitely related to the research; all serious adverse events (SAEs) that are not listed in the consent form, but are possibly, probably, or definitely related to the research (with the exception of death due to progressive disease). An SAE is defined as an untoward medical occurrence that: resulted in death; was life-threatening; required or prolonged hospitalization; caused persistent or significant disability/incapacity; resulted in congenital anomalies or birth defects; or required intervention to prevent permanent impairment or death. c. Adverse Event Reporting in the Continuing Review Report: The following events will be presented to provide the information necessary to clearly identify risks to participants and to make a risk: benefit determination: all Grade 2 events that are not in the consent form, but are possibly, probably or definitely related to the research; all Grade 3 and 4 events that are possibly, probably or definitely related to the research; all Grade 5 events regardless of attribution; and all Serious Events regardless of attribution.

[00108] Although certain embodiments have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that a wide variety of alternate and/or equivalent embodiments or implementations calculated to achieve the same purposes may be substituted for the embodiments shown and described without departing from the scope. Those with skill in the art will readily appreciate that embodiments may be implemented in a very wide variety of ways. This application is intended to cover any adaptations or variations of the embodiments discussed herein. Therefore, it is manifestly intended that embodiments be limited only by the claims and the equivalents thereof.