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US20120302590A1 - Methods and compositions to prevent addiction - Google Patents

Methods and compositions to prevent addiction Download PDF

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US20120302590A1
US20120302590A1 US13/389,959 US201013389959A US2012302590A1 US 20120302590 A1 US20120302590 A1 US 20120302590A1 US 201013389959 A US201013389959 A US 201013389959A US 2012302590 A1 US2012302590 A1 US 2012302590A1
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mph
opioid receptor
administering
stimulant
naltrexone
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Pradeep G. Bhide
Jinmin Zhu
Thomas J. Spencer
Joseph Biederman
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General Hospital Corp
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Assigned to THE GENERAL HOSPITAL CORPORATION reassignment THE GENERAL HOSPITAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIEDERMAN, JOSEPH, SPENCER, THOMAS J., ZHU, JINMIN, BHIDE, PRADEEP G.
Assigned to THE GENERAL HOSPITAL CORPORATION reassignment THE GENERAL HOSPITAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIEDERMAN, JOSEPH, SPENCER, THOMAS J., ZHU, JINMIN, BHIDE, PRADEEP G.
Publication of US20120302590A1 publication Critical patent/US20120302590A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to the field of drug therapies and the prevention of addiction to drugs such as those that activate the dopamine receptor.
  • Methylphenidate is the most commonly prescribed stimulant compound for treatment of attention deficit hyperactivity disorder (ADHD) 1,2 . Although its therapeutic efficacy and safety is well documented in pediatric and adult patients 3 , serious concerns persist about its abuse potential upon long-term usage 4-9 . Moreover, recreational or street-use of stimulants and analeptics is on the rise further adding to the concerns about stimulant abuse 8,10,11 . In fact, non-human primates can self-administer MPH 12,13 —a hallmark of addiction. Prevailing notions of molecular mechanisms mediating MPH addiction rely on the central actions of MPH on dopamine and noradrenaline signaling mechanisms 14-17 . However, these neurotransmitter mechanisms alone are inadequate for fully explaining MPH addiction.
  • ADHD attention deficit hyperactivity disorder
  • One aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a central nervous system (CNS) stimulant and an opioid receptor antagonist.
  • the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof.
  • the CNS stimulant is selected from the group consisting of methylphenidate, amphetamine, modafinil, and combinations thereof.
  • the CNS stimulant is present in a therapeutic amount and the opioid receptor antagonist is present in an amount for preferred inhibition of the mu opioid receptor.
  • the composition is formulated for enteral administration. In one embodiment of the various pharmaceutical compositions described herein, the pharmaceutical composition is formulated for oral administration. In one embodiment of the various pharmaceutical compositions described herein, the pharmaceutical composition is formulated as a tablet or capsule. In one embodiment of the various pharmaceutical compositions described herein, the opioid receptor antagonist is formulated such that when ingested, the opioid receptor antagonist remains intact.
  • the various pharmaceutical compositions described herein are suitable for use in the methods described herein.
  • Another aspect of the invention relates to a method of reducing or preventing the development of aversion to a CNS stimulant in a subject comprising, administering a therapeutic amount of the neurological stimulant and administering an antagonist of the kappa opioid receptor, to thereby prevent the development of aversion to the CNS stimulant in the subject.
  • the method further comprises selecting a subject at risk for the development of aversion to the CNS stimulant, prior to the administering.
  • the subject is diagnosed with attention deficit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue syndrome, or depression.
  • ADHD attention deficit hyperactivity disorder
  • narcolepsy narcolepsy
  • chronic fatigue syndrome or depression.
  • Another aspect of the invention relates to a method to decrease the dysphoria associated with the use of therapeutic doses of a CNS stimulant comprising administering a therapeutic amount of the CNS stimulant and administering a kappa opioid receptor antagonist, to thereby decrease the dysphoria.
  • the method further comprises selecting a subject at risk for the development of dysphoria, prior to administering.
  • Another aspect of the invention relates to a method to decrease the euphoria associated with the use of therapeutic doses of a CNS stimulant comprising administering a therapeutic amount of the CNS stimulant and administering a mu opioid receptor antagonist, to thereby decrease the euphoria.
  • the method further comprises selecting a subject at risk for the development of euphoria, prior to administering.
  • Another aspect of the invention relates to a method of reducing or preventing the development of addiction to a CNS stimulant in a subject, comprising, administering the CNS stimulant and administering a mu opioid receptor antagonist to thereby reduce or prevent the development of addiction to the CNS stimulant in the subject.
  • the method further comprises selecting a subject at risk for the development of addiction to the CNS stimulant, prior to the administering.
  • Another aspect of the invention relates to a method of treating a subject for ADHD, comprising administering a therapeutically effective amount of methylphenidate and administering an opioid receptor antagonist to thereby treat the subject for ADHD.
  • the method further comprises selecting a subject at risk for the development of aversion or addiction to methylphenidate, prior to the administering.
  • the CNS stimulant is selected from the group consisting of methylphenidate, amphetamine, modafinil, and combinations thereof. In one embodiment of the various methods described above, the CNS stimulant results in activation of a dopamine receptor. In one embodiment, the dopamine receptor is selected from the group consisting of D1, D2, D3, D4, D5, and combinations thereof.
  • the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof.
  • the administering is oral.
  • the CNS stimulant and the opioid receptor antagonist are administered in the same pharmaceutical composition.
  • the CNS stimulant and the opioid receptor antagonist are administered sequentially.
  • the opioid receptor antagonist is administered in the dosage of from about 50 to about 100 mg.
  • reduce or reducing refers to a reduction or decrease in the dysphoric or euphoric effects experienced by the subject with administration of the drug.
  • a reduction is determined as a statistically significant, detectable, reproducible, decrease, as measured by one or more accepted methods of detection.
  • Dysphoric effects can include, without limitation, an abnormal mood state of feeling unwell, unhappy, uncomfortable, irritable, disliking and anxious.
  • Euphoria effects can include, without limitation, an abnormal mood state of feeling elation, abnormal happiness, severe excitement, abnormal joy not connected to objective circumstances.
  • Reduce or reducing refers to a decrease or lessening of the aversion or addiction. Such a decrease can be evidenced, for example, by preventing or delaying the onset of the development of symptoms of drug aversion or addiction.
  • aversion refers to avoidance of or failure to adhere to a prescribed regimen of a therapeutic composition, due to the negative effects (dysphoria) experienced therefrom.
  • an effective amount refers to an amount of a drug or agent that produced the desired result (e.g, partial or complete inhibition of one or more opioid receptors (mu or kappa).
  • an effective amount is an amount that preferentially inhibits one opioid receptor without substantially inhibiting another opioid receptor. For example, preferentially inhibiting the MOPR without substantially inhibiting the KOPR, or vice versa.
  • the terms subject and patient are used interchangeably, and refer to a recipient in need of the therapy described herein.
  • the subject is a human.
  • the human is mature (e.g., at least 18 years of age).
  • the human is immature (e.g., less than 18 years of age), also referred to herein as a child.
  • Subject further refers to mammals such as rats, mice, rabbits, sheep, cats, dogs, cows, pigs, horses and non-human primates.
  • FIG. 1A-1B are graphical representations of experimental results that indicate supratherapeutic doses of methylphenidate (MPH) induce conditioned place preference (CPP).
  • CPP conditioned place preference
  • CPP induced by intraperitoneal administration of saline (negative control), low dose (0.75 mg/kg) MPH, high dose (7.5 mg/kg) MPH and cocaine (10 mg/kg; positive control) was analyzed.
  • time spent in the drug-paired chamber during the pre-conditioning (PC) and test (Test) sessions was calculated and the difference between the two was compared for each drug treatment group. Mice exposed to cocaine or high-dose MPH and cocaine spent significantly longer period of time in the drug-paired chamber during the test sessions compared to the PC sessions (t-test; p ⁇ 0.05).
  • [ 35 S]GTP ⁇ S binding was increased by DAMGO in a concentration-dependent manner with an EC 50 of ⁇ 1 and 0.1 ⁇ M.
  • the maximal binding, which represented 1.75-fold of the basal level was reached at 10 ⁇ M concentration ( FIG. 2A ).
  • This concentration of DAMGO was used in the bindings assays from the 4 groups of mice shown in FIG. 2B .
  • agonist-stimulated MOPR activity was analyzed using the [ 35 S]GTP ⁇ S binding in membrane preparations of the caudate-putamen and nucleus accumbens from the saline alone, MPH (7.5 mg/kg) alone and MPH+naltrexone (10 mg/kg) groups of mice that had been used in the CPP assay.
  • FIG. 4A-4B are graphical representations of experimental results that indicate dopamine D1-receptor antagonist Schering 23390 but not the D2-receptor antagonist raclopride can block high dose (7.5 mg/kg) methylphenidate (MPH) induced conditioned place preference (CPP).
  • MPH methylphenidate
  • CPP induced conditioned place preference
  • FIG. 6A-6B are bar graphs of experimental results which indicate DAMGO-stimulated [ 35 S]GTP ⁇ S binding in corpus striatum ( FIG. 6A ) and nucleus accumbens ( FIG. 6B ) membrane preparations following intraperitoneal MPH (0.75 or 7.5 mg/kg) or cocaine (10 mg/kg) administration.
  • t-test Mean ⁇ SEM, **P ⁇ 0.01, *P ⁇ 0.05 vs. saline; ++P ⁇ 0.01, +P ⁇ 0.05 vs. MPH (0.75).
  • aspects of the present invention relate to methods for reducing or preventing dysphoria in a subject associated with administration of a therapeutic amount of a drug to the subject, by administering an effective amount of an agent that inhibits the kappa opioid receptor to the subject, to thereby reduce or prevent dysphoria in the subject.
  • the reduction of dysphoria is expected to reduce the development of aversion to the drug by the subject, and to therefore promote adhereance by the subject to a prescribed therapeutic regimen.
  • another aspect of the invention relates to a method of reducing or preventing the development of aversion to a drug in a subject. The method comprises administering a therapeutic amount of the drug and administering an effective amount of an agent that inhibits the kappa opioid receptor, to thereby reduce or prevent the development of aversion to the drug in the subject.
  • a subject is first identified or selected as a subject at risk for the development of dysphoria or aversion to the drug, prior to the administration of the drug and the agent.
  • aspects of the present invention relate to methods for reducing or preventing euphoria in a subject associated with administration of a therapeutic amount of a drug to the subject, by administering an effective amount of an agent that inhibits the mu opioid receptor to the subject, to thereby reduce or prevent euphoria in the subject.
  • the reduction of euphoria is expected to reduce the development of addiction to the drug by the subject.
  • another aspect of the invention relates to a method of reducing or preventing the development of addiction to a drug in a subject. The method comprises administering a therapeutic or supratherapeutic amount of the drug and administering an effective amount of an agent that inhibits the mu opioid receptor, to thereby reduce or prevent the development of addiction to the drug in the subject.
  • the subject is first identified or selected as a subject at risk for the development of euphoria or addiction to the drug, prior to the administration of the drug and the agent.
  • Another aspect of the present invention is a method of treating a subject for a disease or disorder typically treated with a drug discussed herein.
  • the method involves administering the drug to the subject and administering an agent that inhibits an opioid receptor (mu and/or kappa), to the subject, to thereby treat the subject for the disease or disorder.
  • the agent is administered in an amount effective to inhibit the mu and/or kappa opioid receptor.
  • the subject is diagnosed with the disease or disorder prior to treatment.
  • the subject is identified as at risk for the development of euphoria/addiction or dysphoria/aversion, prior to the administering of a mu or kappa opioid receptor inhibitor, respectively.
  • the disease or disorder is attention deficit hyperactivity disorder, narcolepsy, chronic fatigue syndrome, or depression
  • the drug is methylphenidate.
  • the agent is naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine or combinations thereof.
  • the disease or disorder is age-related memory decline, attention deficit disorder, depression, fatigue caused by high-pressure jobs requiring long hours, fatigue caused by chemotherapy treatment for cancer patients, fatigue experienced by persons suffering from diseases such as multiple sclerosis, fatigue experienced by people who need to be awake and alert for extended amounts of times such as soldiers, truckers or students cramming for finals, jet lag, memory problems associated with Alzheimer's disease, post-anesthesia grogginess, sleepiness caused by other prescription medications, or treatment for cocaine addiction, and the drug is modafinil.
  • Subjects who are at risk for the development of aversion or addiction can be identified by a variety of means known in the art.
  • Subjective drug experience, especially euphoria is thought to be an indicator of risk of abuse (Jasinski and Henningfield, 1989; Jasinski, 2000; Kollins et al., 2001) and dysphoria is thought to be a major determinant of tolerability and adherence with treatment regimen in clinical practice.
  • Subjective responses to oral MPH were reported in 18 (72%) of 25 studies that evaluated detection/likeability (Kollins et al., 2001).
  • the large extent of clinical trials literature documents the frequent occurrence of dysphoric effects in clinical populations that adversely impact tolerability and eventually compliance with stimulant treatment.
  • Subjects who are at risk for the development of aversion or addiction can be identified, for example, by assessment of the subjects dysphoric or euphoric response, respectively, to the drug by established methods.
  • Assessment of euphoria and dysphoria can be assessed in a subject, for example, by assessing the subjective response of euphoria (liking) and dysphoria (disliking) of acute oral therapeutic doses of the drug using the Drug Rating Questionnaire (DQRS), (Jasinski and Henningfield, 1989; Jasinski, 2000; Kollins et al., 2001).
  • DQRS Drug Rating Questionnaire
  • Constituent elements of the DQRS scale have been standardized by comparison to responses to known drugs of abuse and validated against observer ratings and physiologic changes (Jasinski and Henningfield, 1989). Subjects who experience dysphoria or euphoria in connection with a specific drug, are likely to have the same or even an enhanced experience, upon repeated exposure to the drug. As such, the assessment is also useful in identifying a subject at risk for ongoing dysphoria or euphoria associated with the drug.
  • assessment of euphoria and dysphoria to a drug similar (e.g., in mode of action) to the intended therapeutic prescribed drug will also yield useful information regarding a subject's likelihood of developing dysphoria and/or aversion, or euphoria and/or addiction.
  • Another method of identifying a subject at risk for aversion/dysphoria or addiction/euphoria is by analysis of the subject's history with other drugs. In one embodiment, a subject with a history or drug aversion/dysphoria, or drug addiction/euphoria, to other drugs, is identified as at risk.
  • Drugs for which the herein described methods are appropriate include, without limitation, CNS stimulants, drugs which activate one or more dopamine receptors, and analeptics.
  • the drug is methylphenidate, amphetamine, or modafinil.
  • Agents that inhibit the respective opioid receptors described herein include, without limitation, agents that work directly (e.g., antagonists of the receptors) and also agents that work indirectly (e.g., agents that inhibit signaling from the receptor or agents that inhibit expression of the receptors). Examples of such agents are described herein.
  • the agent is naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine or combinations thereof.
  • a pharmaceutical composition includes one or more active agents, formulated appropriately for the desired route of administration, and a pharmaceutically acceptable carrier(s) and/or excipient(s) suitable for the desired route of administration.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and anti fungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier can be suitable for intravenous injection or for oral administration.
  • Excipients include pharmaceutically acceptable stabilizers and disintegants.
  • the pharmaceutical composition of the present invention is formulated for enteral or oral administration.
  • the pharmaceutical composition is formulated as a tablet or capsule.
  • the drug is a CNS stimulant, a drug which actives one or more dopamine receptors, an analeptic, or combinations thereof.
  • the drug is methylphenidate, amphetamine, or modafinil.
  • the agent for inhibition of opioid receptor is naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine, or combinations thereof.
  • the drug e.g., CNS stimulant
  • the opioid receptor antagonist is present in an amount for preferred inhibition of a specific opioid receptor (e.g., MOPR).
  • a low dose as described herein can be included in the pharmaceutical composition with the drug (e.g, methylphenidate).
  • the exact amount of the opioid receptor inhibitor can be determined from the amount of the drug in the composition, since the amount of the drug will determine the amount and frequency of therapeutic administration of the pharmaceutical composition.
  • a drug formulated in combination with the mu opioid receptor inhibitor has the advantage that it will be “less-abusable” or “non-abusable”. That is to say, the euphoric effects experience are substantially reduced or eliminated.
  • the formulations described herein would be less attractive for illegal, non-therapeutic administration, and also far less likely to cause addition in a subject who was self-administering for non-therapeutic purposes.
  • Such effective formulations could theoretically avoid the requirement for classification as a Schedule II drug. This would make them more readily available and more easily obtained for therapeutic purposes.
  • the pharmaceutical composition comprises the drug (e.g., methylphenidate) and the opioid receptor inhibitor (e.g., naltrexone), formulated to prevent MPH abuse potential without affecting the development of dysphoria/aversion in a subject.
  • the drug e.g., methylphenidate
  • the opioid receptor inhibitor e.g., naltrexone
  • a recent technology is used in which an oral preparation (capsule or tablet) is prepared with naltrexone embedded in the core surrounded by MPH. When the capsules/tablets are ingested only MPH is released and the naltrexone core passes through the gut intact.
  • This technology is available commercially (AVERSION ⁇ , Acura Pharmaceuticals; Embeda®, King Pharmaceuticals). In such preparations, MPH exerts its actions without naltrexone interference. However, if the preparation is crushed for intra-nasal administration or other abuse purposes, naltrexone is released blocking MPH addiction. This approach will not help prevent
  • CNS stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both.
  • CNS stimulants include, but not limited to, caffeine, nicotine, cocaine, amphetamine, dextroamphetamine.
  • the CNS stimulants is an antidepressant.
  • Antidepressant drugs include the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs).
  • CNS stimulants include psychostimulants, agents for treatment of ADHD, or nootropics (cognitive enhancers). Examples of these types of CNS stimulants are shown in Table 2.
  • compositions described herein, as they relate to CNS stimulants can also be used to reduce the dysphoria and euphoria associated with administration of analeptics.
  • another aspect of the invention relates to the use of opioid receptor antagonists to reduce the dysphoria and euphoria associated with analeptic therapeutic and supratherapeutic administration.
  • Analeptics are drugs that principally act as or are used as a central nervous system stimulant. Some examples are, but not limited to, modafinil and d-amphetamine. In one embodiment, the analeptic activates one or more dopamine receptors.
  • Analeptics may also be respiratory analeptics (e.g., respiratory stimulants) such as picrotoxin, pentylenetetrazol, caffeine, theophylline, strychnine, ethamivan and doxapram. which activates other receptors, (e.g., chemoreceptors, GABAA receptor or glycine receptors in central nervous system).
  • compositions described herein are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • quantity to be administered and timing depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual.
  • compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired. Administration may be topical (including ophthalmic, vaginal, rectal, intranasal, epidermal, and transdermal), enteral (e.g., oral) or parenteral. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, pulmonary administration, e.g., by inhalation or insufflation, or intracranial, e.g., intrathecal or intraventricular, administration.
  • Administration may be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration may be through nasal sprays, for example, or using suppositories.
  • the compositions of the invention are formulated into conventional oral administration forms such as capsules, tablets and tonics.
  • Administration of the drug (e.g., methylphenidate) and the agent that inhibits opioid receptor can be at the same time (co-administration), or at different times (e.g., sequentially). Co-administration can be in the same therapeutic formulation, or in different formulations, by the same or different routes. In one embodiment, the drug is administered at different times, and at different rates of frequency than the opioid receptor inhibiting agent.
  • Suitable formulations for the compositions described herein are those appropriate for the desired route of administration.
  • compositions may take the form of, for example, liquids, beverages, tablets, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups, or elixirs.
  • 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 such as sweetening agents, flavoring agents, coloring agents, and preserving agents. They may also contain one or more additional ingredients such as vitamins and minerals, etc. Tablets may be manufactured to contain one or more active ingredients described herein, in admixture with non-toxic, pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be used.
  • Methylphenidate is available commercially in a variety of forms. Each version of methylphenidate is envisioned for use in the present invention. Methylphenidate comes as an immediate-release tablet, a chewable tablet, a solution (liquid), an intermediate-acting (extended-release) tablet, a long-acting (extended-release) capsule, and a long-acting (extended-release) tablet. The long-acting tablet and capsules supply some medication immediately and release the remaining amount as a steady dose of medication over a long time. All of these forms of methylphenidate are typcially administered orally for therapeutic purposes.
  • the dose regimen usually varies with commercially-packaged forms of methylphenidate.
  • the regular tablets, chewable tablets (Methylin), and solution (Methylin) are usually taken two to three times a day by adults and twice a day by children, preferably 35 to 40 minutes before meals.
  • Adults who are taking three doses should take the last dose should be taken before 6:00 pm, so that the medication will not cause difficulty in falling asleep or staying asleep.
  • the intermediate-acting extended release tablets (Ritalin SR, Metadate ER, Methylin ER) are usually taken once or twice a day, in the morning and sometimes in the early afternoon 30-45 minutes before a meal.
  • the long-acting extended release capsule (Metadate CD) is usually taken once a day before breakfast; the long-acting extended-release tablet (Concerta) and capsule (Ritalin LA) are usually taken once a day in the morning with or without food.
  • a therapeutic dose for ADHD treatment is typically in the range of about 0.05 mg/kg/day to about 2.0 mg/kg/day, for both children and adults. In one embodiment, about 0.075 mg/kg/day to about 0.3 mg/kg/day is administered. The average total dosage is about 20 to 30 mg daily. Some patients may require about 40 to 60 mg daily. In others, about 10 to 15 mg daily is adequate.
  • the initial recommended dosage is about 5 mg twice daily before breakfast and lunch, increased by about 5-10 mg per week to about 60 mg per day.
  • Methylphenidate is typically administered in divided dose 2 or 3 times daily, preferably 30 to 45 minutes before meals. For narcolepsy in adults, the recommended dose is about 5-20 mg two to three times a day, 30-45 minutes before meals.
  • the effective amount of an agent that inhibits a specific opioid receptor can be determined by the skilled practitioner, from the knowledge in the art and the guidance provided by the Examples section herein. The amount may depend upon the specific opioid receptor(s) to be inhibited. In one embodiment, the dosage is from about 50 to about 100 mg. In one embodiment, the opioid inhibitor is naltrexone.
  • Dosage may be optimized to result in increased/preferred inhibition of one receptor (e.g., MOPR) over one or more other opioid receptor types (e.g, KOPR and/or DOPR).
  • MOPR one receptor
  • other opioid receptor types e.g., KOPR and/or DOPR.
  • a low dose of an opioid receptor inhibitor that has a higher affinity for MOPR than for KOPR e.g., naloxone
  • a low dose of an opioid receptor inhibitor that has a higher affinity for KOPR than for MOPR is given to a patient to produce an increased inhibition of KOPR, with little to no inhibition of MOPR.
  • the term “low dose” refers to dosages given to a patient that are less than about 1.5 ⁇ g/kg (drug weight drug/patient weight). In one embodiment, the low dose is about 0.1 ng/kg to about 100 ⁇ g/kg. In one embodiment the low dose is between about 0.01 ng/kg and about 1.5 ⁇ g/kg, (e.g., between about 0.01 ng/kg and about 150 ng/kg). These dosages may administered one time per day, or 2 to 3 times daily. In some embodiments, one or both of the dosages are administered at night. Other dosing schedules are envisioned. For example, the dosages may be administered less frequently in extended release or controlled delivery formulations. In one embodiment, naltrexone or naloxone is administered in a low dose.
  • Methylphenidate is a central nervous system (CNS) stimulant and also an analeptic. Methylphenidate increases dopamine level in the brain by blocking dopamine transporters (classified as a dopamine transporter (DAT) inhibitor or dopamine reuptake (DAR) inhibitor) and thereby enhances the activity of dopamine receptors (Volkow, Journal of Neuroscience 2001, 21: RC121:1-5).
  • DAT dopamine transporter
  • DAR dopamine reuptake
  • Methylphenidate is most commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD). It is also effective as an anti-fatigue drug and as a stimulant in circumstances requiring extraordinary alertness such as those endured by military pilots flying combat missions. Further, it is used to treat narcolepsy (a sleep disorder that causes excessive daytime sleepiness and sudden attacks of sleep) (Fry et al., Neurology 50 (2 Suppl 1): S43-8). Recent reports have shown that methylphenidate can be used to treat children with autism spectrum disorders to improve their social behaviors (Parkomi et al., J Autism Dev Disord 39 (3): 395-404).
  • ADHD attention-deficit hyperactivity disorder
  • methylphenidate has been investigated as a chemical replacement for the treatment of cocaine dependence (Grabowski et al., J Clin Psychopharmacol 17 (6): 485-8 1997; Karila et al., Int. J. Neuropsychopharmacol. 11 (3): 425-38).
  • methylphenidate can be used for adjunctive therapy.
  • methylphenidate can be administered to individuals with cancer in order to ameliorate opioid-induced somnolence, to augment the analgesic effects of opioids, to treat depression, and to improve cognitive function (Rozans et al., J. Clin. Oncol. 20 (1): 335-9).
  • methylphenidate can be used to improve depression in several groups including stroke, cancer, and HIV-positive patients (Leonard et al., Hum Psychopharmacol 19 (3): 151-80).
  • the drug for which the methods and compositions described herein is appropriate activates one or more dopamine receptors.
  • Dopamine receptors are members of the G protein-linked receptor family with seven hydrophobic domains, an extracellular N terminus and an intracellular C terminus. They are prominent in the central nervous system (CNS), and the primary endogenous ligand for dopamine receptors is the neurotransmitter dopamine.
  • D 1 , D 2 , D 3 , D 4 , and D 5 There are at least five subtypes of dopamine receptors, D 1 , D 2 , D 3 , D 4 , and D 5 .
  • the D 1 and D 5 receptors are members of the D 1 -like family of dopamine receptors, whereas the D 2 , D 3 and D 4 receptors are members of the D 2 -like family.
  • D 1 receptors At a global level, D 1 receptors have widespread expression throughout the brain.
  • D 1-2 receptor subtypes are found at 10-100 times the levels of the D 3-5 subtypes (Hurley M J et al., Pharmacol Ther 2006. 111 (3): 715).
  • the D 1 receptor of the central nervous system is defined as an adenylate cyclase stimulatory receptor.
  • the location of the prototypic D 1 receptor is the bovine parathyroid gland, where dopamine agonists stimulate cAMP synthesis via adenylate cyclase, accompanied by parathyroid hormone release.
  • Dopamine-stimulated adenylate cyclase activity and parathyroid hormone release are sensitive to both GTP and cholera toxin. This suggests that the D 1 receptor is associated with a G s guanine nucleotide binding protein.
  • the D 2 receptor inhibits adenylate cyclase activity, and appears to be the primary target of most neuroleptic drugs (Niznik, H. B.
  • Drugs that activate, directly or indirectly, one or more dopamine receptors are appropriate for the methods and compositions described herein. These include drugs that active the dopamine receptor directly (e.g., agonists) or indirectly.
  • Indirect activation of the dopamine receptor can be accomplished, for example, by agents that augment dopamine synthesis, by blocking reuptake of extracellular dopamine into dopamine neurone, or by releasing of dopamine from dopamine neurons.
  • agents include, L-DOPA; amphetamine formulations, including formulations of specific stereoisomers such as d-amphetamine; methylphenidate formulations, including formulations of specific stereoisomers; buproprion; serotonin dopamine reuptake inhibitors including but not limited to sertraline; serotonin norepinephrine reuptake inhibitors including but not limited to duloxetine, venlaxafin or desvenlafaxin, triple reuptake inhibitors such as JNJ 7925476, tesofensine, and DOV216303; selective norepinephrine reuptake inhibitors such as but not limited to atomoxetine formulations; as well as atypical antipsychotic drugs such as clo
  • Non-limiting examples of drugs that increase the extracellular concentration of dopamine by decreasing metabolic degradation of dopamine include inhibitors of monoamine oxidase and catechol- ⁇ -methyl transferase.
  • inhibitors of monoamine oxidase and catechol- ⁇ -methyl transferase include, but are not limited to, phenelzine, tranylcypromine, selegiline, rasagiline, and tolcapone.
  • DAT or DAR inhibitors such as Amineptine (Survector, Maneon, Directim); Benzatropine/Benztropine (Cogentin); Bupropion (Wellbutrin, Zyban); Dexmethylphenidate (Focalin); Esketamine (Ketanest S); Etybenzatropine/Ethybenztropine (Panolid, Ponalid, Ponalide); Fencamfamine (Glucoenergan, Reactivan); Fencamine (Altimina, Sicoclor); Ketamine (Ketalar, Ketaset, Ketanest, Ketaject); Lefetamine (Santenol); Medifoxamine (Cledial); Mesocarb (Sidnocarb, Sydnocarb); Methylphenidate (Ritalin, Concerta); Nefopam (Acupan); Nomifensine (Merital); Pipradrol (Mere
  • Amineptine Sudvector, Maneon, Direct
  • methylphenidate is an indirect dopamine agonist.
  • dopamine agonists that activate dopamine receptor can thus be useful for the purposes of this invention.
  • Dopamine agonists include, but not limited to: amphetamines; methylphenidate; ephedrine; parlodel (bromocriptine); Dostinex (cabergoline); Permax (pergolide); Mirapex and Sifrol (pramipexole); Requip (ropinirole); Apokyn (apomorphine); Neupro (rotigotine).
  • dopamine agonists that can be used for the present invention include, but not limited to, the compounds disclosed in U.S. Pat. No. 5,212,178; U.S. Pat. No. 5,547,958; U.S. Pat. No. 4,528,290; U.S. Pat. No. 4,552,956; U.S. Pat. No. 4,963,569; U.S. Pat. No. 5,670,511; EP0,172,697, U.S. Pat. No. 4,698,347, the contents of which are included herein by reference.
  • Activation of the ⁇ opioid receptor (MOPR) and the ⁇ opioid receptor (DOPR) is associated with euphoria leading to addiction whereas activation of the ⁇ opioid receptor (KOPR) is associated with dysphoria leading to aversion (Trigo et al., Drug Alcohol Depend. 2010 May 1; 108(3):183-94).
  • a number of agents that inhibit opioid receptor are known in the art, and can be used in the compositions and methods described herein.
  • a given agent may inhibit more than one type of opioid receptor.
  • Some inhibitors act on the different opioid receptor types to varying degrees.
  • a dose of such an inhibitor can be determined by the skilled artisan, that results in increased inhibition of one receptor (e.g., MOPR) over one or more other opioid receptor types (e.g, KOPR and/or DOPR).
  • MOPR one receptor
  • KOPR KOPR
  • DOPR opioid receptor inhibitors
  • the use of a combination of one or more opioid receptor inhibitors is also envisioned.
  • the opioid receptor antagonist may be an opioid analogue, e.g., (CAS number given in parenthesis where appropriate) Naloxone (465-65-6); Naloxonazine (82824-01-9); Cyprodime (118111-54-9); ⁇ -Funaltrexamine (72782-05-9); Nalbuphine (20594-83-6); RX 8008M (40994-80-7); SDZ 210-096 (109026-86-0); Clocinnamox (117332-69-1); NIH 10236 (88167-37-7); BU 165 (173321-27-2); BU 164 (173429-52-2); BU 158 (173429-53-3); BU 160 (173429-56-6); BU 161 (173429-57-7); BU 162 (173429-58-8); Buprenorphine (52485-79-7); IOXY (141392-28-1); NPC 168 (115160-07-1); Naloxazone (73674-85-8); N-Methylna
  • opioid receptor antagonists particularly the ⁇ -receptor, and assays for determining their efficacy in binding to the receptors have been disclosed in e.g., WO 02/098422, U.S. Pat. No. 5,270,328, US 2001/0036951 A, WO 01/42207, WO 01/37785, WO 01/41705, WO 03/101963, WO 2004/005294, WO 2004/014310, WO 2004/038005, and WO 2004/051264, the contents of which are included herein by reference.
  • opioid receptor antagonists which have been disclosed in US 20090325857 comprise Epigallocatechin 3,5-Digallate (37484-73-4), Irigenol Hexaacetate (103652-04-6), Irigenol ex Iris spp (4935-93-7), Berbamine Hydrochloride (5956-76-3), Quercetagetin (90-18-6), Acetylshikonin (24502-78-1), 2′,3′,4′,3,4-Pentahydroxychalcone (484-76-4), beta,beta-Dimethylacryl shikonin (24502-79-2), 2,3-Dimethoxy-5-methyl-1,4-benzoquinone (605-94-7), 2,3-Dimethoxy-5-methylhydroquinone (3066-90-8), 2,3-Dimethoxy-1,4-benzoquinone (3117-02-0), 2,3-Dimethoxyhydroquinone (52643-52-4), Delphinidin chloride (528-53-0), Aureusidin (38216-54-5
  • opioid receptor antagonists which can be used for the purposes of the present invention are disclosed in JP 63290897, U.S. Pat. No. 4,906,655, WO 9302707, CA 2064373, U.S. Pat. No. 5,270,220, U.S. Pat. No. 5,352,680, WO 9504734, WO 9513071, EP 657428, WO 9606855, WO 9640208, U.S. Pat. No. 5,641,861, WO 9733174, DE 19622866, U.S. Pat. No. 5,919,897, U.S. Pat. No. 5,948,807, U.S. Pat. No.
  • Typical ⁇ -opioid receptor antagonists for use herein include, but are not limited to, Naloxone; Levallorphan; Nalorphine; Naloxonazine; piperidine derivatives; Cyprodime; ⁇ -Funaltrexamine, Nalbuphine, CTAP, TCTOP, TCTAP, CTOP, Quadazocine, Flumazenil, RX 8008M, SDZ 210-096, Tyr MIF-1, CCK-8, CG 3703, Clocinnamox, peptides such as disclosed in Peptide Research 1995, 8(3), 124-37, Proceedings of the National Academy of Sciences of the United States of America (1993), 90(22), 10811-15, Regulatory Peptides (1994), (Suppl.
  • Useful kappa receptor antagonists include, for example, nor-binaltorphimine (norBNI), GNTI (5′-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5 ⁇ -epoxy-3,14-dihydroxy-6,7-2′,3′-indolomorphinan), and DIPPA (2-(3,4-dichorophenyl)-N-methyl-N-[(IS)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide).
  • norBNI nor-binaltorphimine
  • GNTI 5′-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5 ⁇ -epoxy-3,14-dihydroxy-6,7-2′,3′-indolomorphinan
  • DIPPA 2,3-dichorophenyl
  • kappa receptor antagonists for use herein also include, but not limited to, the ones disclosed in U.S. Pat. No. 6,559,159, U.S. Pat. No. 7,709,522, EP 1,363,629, U.S. 20020143145, US 20090181999, US20090186873, US 20100035873.
  • inhibitors for use herein include, but are not limited to: N-Methylnaloxonium Iodide, 3-Methoxynaltrexone Hydrochloride; 7-Benzylidenenaltrexone, Ginseng root extract as disclosed in Journal of Ethnopharmacology (1994), 42(1), 45-51; Rimcazole, Naltrindole Isothiocyanate, BNTX, TIPP, Naltriben, Naltrexone, ICI 154129, MR 2266, WIN 44441-3, Nalmefene,13-Chlornaltrexamine, ICI 174864, Diprenorphine, nor-Binaltorphimine and Naltrindole.
  • the drugs and other compounds described herein may also be used in the form of physiologically acceptable salts, with inorganic acids, e.g. hydrochlorides, hydrobromides, sulfates, phosphates, or organic acids, e.g. methanesulfonates, p-toluenesulfonates, carbonates, formats, acetates, oxalates, lactates; or as hydrates as appropriate.
  • the drugs or their salts may be used as racemates or as pure enantiomers, or diastereomers or mixtures thereof.
  • derivatives of these compounds as appropriate such as esters, amides, nitriles, oximes, imines, hydrazones, ethers, acetals, semiacetals may also find use.
  • the present invention relates to the herein described compositions, methods, and respective component(s) thereof, as essential to the invention, yet open to the inclusion of unspecified elements, essential or not (“comprising).
  • other elements to be included in the description of the composition, method or respective component thereof are limited to those that do not materially affect the basic and novel characteristic(s) of the invention (“consisting essentially of”). This applies equally to steps within a described method as well as compositions and components therein.
  • the inventions, compositions, methods, and respective components thereof, described herein are intended to be exclusive of any element not deemed an essential element to the component, composition or method (“consisting of”).
  • the present invention may be as defined in any one of the following numbered paragraphs.
  • a pharmaceutical composition comprising a central nervous system stimulant and an opioid receptor antagonist.
  • the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof.
  • the CNS stimulant is selected from the group consisting of methylphenidate, amphetamine, modafinil, and combinations thereof.
  • the pharmaceutical composition of paragraphs 1-4 that is formulated for enteral administration. 6.
  • the opioid receptor antagonist is formulated such that when ingested, the opioid receptor antagonist remains intact.
  • a method of reducing or preventing the development of aversion to a CNS stimulant in a subject comprising, administering a therapeutic amount of the neurological stimulant and administering an antagonist of the kappa opioid receptor, to thereby reduce or prevent the development of aversion to the CNS stimulant in the subject. 10.
  • the method of paragraph 9, further comprising selecting a subject at risk for the development of aversion to the CNS stimulant, prior to the administering.
  • the method of paragraphs 9-10 wherein the subject is diagnosed with attention deficit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue syndrome, or depression.
  • ADHD attention deficit hyperactivity disorder
  • narcolepsy narcolepsy
  • chronic fatigue syndrome or depression.
  • a method to decrease the dysphoria associated with the use of therapeutic doses of a CNS nervous system stimulant comprising administering a therapeutic amount of the CNS stimulant and administering a kappa opioid receptor antagonist, to thereby decrease the dysphoria.
  • a method to decrease the euphoria associated with the use of therapeutic doses of a CNS nervous system stimulant comprising administering a therapeutic amount of the CNS stimulant and administering a mu opioid receptor antagonist, to thereby decrease the euphoria.
  • a method of reducing or preventing the development of addiction to a CNS stimulant in a subject comprising, administering the CNS stimulant and administering a mu opioid receptor antagonist to thereby reduce or prevent the development of addiction to the CNS stimulant in the subject. 17.
  • the method of paragraph 16 further comprising selecting a subject at risk for the development of addiction to the CNS stimulant, prior to the administering.
  • a method of treating a subject for ADHD comprising administering a therapeutically effective amount of methylphenidate and administering an opioid receptor antagonist to thereby treat the subject for ADHD.
  • 20. The method of paragraphs 9-19 wherein the CNS stimulant is selected from the group consisting of methylphenidate, amphetamine, modafinil, and combinations thereof. 21.
  • the dopamine receptor is selected from the group consisting of D1, D2, D3, D4, D5, and combinations thereof.
  • the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof.
  • the administering is oral.
  • the CNS stimulant and the opioid receptor antagonist are administered in the same pharmaceutical composition.
  • the CNS stimulant and the opioid receptor antagonist are administered sequentially.
  • the opioid receptor antagonist is administered in the dosage of from about 50 to about 100 mg.
  • Opioid receptors in the brain fall into 3 subtypes: Mu ( ⁇ ), delta ( ⁇ ) and kappa ( ⁇ ).
  • Mu ( ⁇ ), delta ( ⁇ ) and kappa ( ⁇ ) The caudate-putamen, nucleus accumbens, frontal cortex and ventral midbrain, all of which are intricately involved in the reward and addiction circuitry, are enriched in these receptors 18 .
  • Each receptor is believed to facilitate different aspects of reward circuits via interactions with opioids and neurotransmitters including dopamine 18 .
  • Activation of the ⁇ opioid receptor (MOPR) and the ⁇ opioid receptor (DOPR) is associated with euphoria leading to addiction whereas activation of the ⁇ opioid receptor (KOPR) is associated with dysphoria leading to aversion 18 .
  • MPH administered at high, supra-therapeutic doses activates MOPR.
  • a key requirement for testing this hypothesis in a mouse model was identifying therapeutic dose of MPH in a mouse. It was established that 0.75 mg/kg MPH administered to adult mice produced serum and brain concentrations of d-methylphenidate (the pharmacologically active isomer) that were equivalent to its serum and brain (estimated) concentrations in ADHD patients taking therapeutic doses of MPH 19 . Therefore, 0.75 mg/kg MPH was considered as therapeutic equivalent dose in mice and 7.5 mg/kg (10 times the therapeutic equivalent dose) as supra-therapeutic or high dose, similar to that used by MPH abusers.
  • a conditioned place preference (CPP) paradigm was used to establish whether supra-therapeutic doses of MPH (7.5 mg/kg) produced reinforcement in a mouse model.
  • the CPP paradigm consists of training mice to develop an association between drug state and environmental cues. 3 drug stimuli were used: cocaine (10 mg/kg) as a positive control drug because it reliably produces reinforcement, supra-therapeutic MPH (7.5 mg/kg), and therapeutic MPH (0.75 mg/kg). Saline was used as a negative control. The mice exposed to supra-therapeutic dose of MPH or cocaine showed significant place preference, while the mice exposed to low dose MPH or saline did not ( FIG. 1A ).
  • the basal [ 35 S]GTP ⁇ S binding (i.e. unstimulated binding) was not significantly different among the different groups.
  • Low dose (0.75 mg/kg) MPH did not produce significant enhancements in DAMGO-stimulated [ 35 S]GTP ⁇ S binding.
  • MPH-induced CPP Since the high dose MPH-induced CPP is associated with MOPR activation, it was examined whether an opioid antagonist could attenuate MPH-induced CPP.
  • CPP assays were performed, in which naltrexone, a mixed opioid antagonist, was administered 30 min prior to MPH (7.5 mg/kg). 3 doses of naltrexone (1, 5 or 10 mg/kg) and high dose of MPH (7.5 mg/kg) were used, which reliably induces CPP as well as MOPR activation ( FIG. 1 ). As controls, saline, MPH (7.5 mg/kg) alone or 1 and 10 mg/kg naltrexone alone were used. MPH (7.5 mg/kg) on its own induced CPP ( FIG. 3A ).
  • the D1-receptor antagonist Schering 23390 (0.2 mg/kg) and the D2-receptor antagonist raclopride (0.5 mg/kg) were used. These dosages of the receptor antagonists had been used previously in a rat model of MPH-induced CPP 22 . It was discovered that administration of Schering 23390 but not raclopride 10 min prior to the administration of supra-therapeutic doses of MPH prevented development of CPP ( FIG. 4 ). Since MOPR activation was required for MPH-induced CPP, supra-therapeutic MPH-induced activation of the D1-receptor can lead to activation of MOPR and development of the CPP.
  • a three-chamber place preference apparatus (Med Associates Inc., St. Albans Vt., USA) was used.
  • the apparatus has two equally sized (16.8 ⁇ 12 cm) preference chambers connected by a central chamber (7.2 ⁇ 12 cm), and is outfitted with sliding guillotine-style doors between each chamber.
  • Photobeams wired to a computer can record animal location (time spent in the chamber).
  • the central chamber has a smooth floor with gray color.
  • Each preference chamber is either white with a mesh floor or black with a bar floor.
  • the CPP procedure included three phases. (1) The pre-conditioning phase was performed on day 1 (two sessions daily, AM and PM). In each preconditioning session, mice were initially placed in the central gray chamber for 2 min and then allowed free access to the white and black chambers for 20 min.
  • the conditoning phase the non-preferred chamber (i.e. the chamber in which less time was spent) was designated as the drug-paired chamber and the preferred chamber (i.e. the chamber in which more time was spent) was designated as the vehicle-paired chamber.
  • the conditioning phase was carried out on each of days 2 to 6 [two sessions daily, AM and PM one each for vehicle-paired (saline as vehicle) and drug-paired (cocaine or MPH as drugs) sessions]. In the vehicle-paired session mice were injected with saline (i.p.) and placed in the central gray chamber for 2 min (to isolate injection effect to the central chamber) and then confined to the vehicle-paired chamber for 30 min.
  • the membranes (10 ⁇ g protein) were incubated in buffer (50 mM HEPES/pH 7.4, 100 mM NaCl, 5 mM MgCl 2 and 1 mM EDTA/pH8.0) containing [ 35 S]GTP ⁇ S (100,000 dpm, 80 ⁇ M) and 100 ⁇ M GDP with or without DAMGO in a total volume of 0.5 ml for 60 min at 30° C.
  • Nonspecific binding was defined by incubation in the presence of 10 ⁇ M GTP ⁇ S, Nonspecific binding was found to be similar in the presence or absence of agonist and was subtracted from total stimulated and total basal binding.
  • Bound and free [ 35 S] GTP ⁇ S were separated by filtration with GF/B filters under reduced pressure.
  • MPH and amphetamines remain mainstays of treatment in pediatric and adult ADHD (Brown et al., 2005).
  • treatment with stimulants is compounded by the dual concerns about their euphoric and dysphoric effects. While the euphoric effects raise concerns about addiction, the dysphoria, irritability and anxiety associated with stimulant treatment are equally taxing to patients and families. Unfortunately, the dysphoric effects do not catch the public's eye as much as the addiction potential. Yet, dysphoric effects are key causes of the serious problem of non-adherence to stimulant treatment regimens. Since the animal model experiment results show that these adverse effects of stimulants can be ascribed to their actions on brain opioid receptors, pharmacological approaches of blocking the opioid receptors can help mitigate these adverse effects. To this end our main goal is to verify the efficacy of the mixed opioid receptor antagonist naltrexone in mitigating MPH-induced euphoria and dysphoria in human volunteers.
  • locomotor activity which is a frequently used as a measure of drug sensitization, was also measured. 7.5 mg/kg MPH significantly increased locomotor activity compared to saline ( FIG. 5 ) but 0.75 mg/kg MPH had no significant effect, once again illustrating dose-dependent nature of MPH action.
  • Naltrexone did not block the MPH-induced increases in locomotor activity ( FIG. 5 ). This illustrates dissociation between naltrexone's ability to block MPH-induced place preference versus locomotion. This indicates that euphoric or dysphoric effects of MPH may be antagonized by naltrexone but therapeutic effects can be spared.
  • DQRS has been used in over 27 published studies assessing the abuse liability of stimulants (Jasinski and Henningfield, 1989; Jasinski, 2000; Kollins et al., 2001). Constituent elements of the DQRS scale have been standardized by comparison to responses to known drugs of abuse and validated against observer ratings and physiologic changes (Jasinski and Henningfield, 1989).
  • IR immediate release
  • OROS osmotic controlled-release
  • MPH-induced conditioned place preference correlates with upregulation of mu or delta opioid receptor activity whereas MPH-induced conditioned place aversion correlates with upregulation of kappa opioid receptor activity in the striatum.
  • Naltrexone-MPH co-administration attenuates both types of changes in opioid receptor activity observed when MPH is administered alone. In each set of studies, activity of all three opioid receptors—mu, delta and kappa—will be analyzed and the receptor activity to behavioral outcome will be compared.
  • KOPR and delta opioid receptor (DOPR) activities are affected by therapeutic doses.
  • Preliminary data examined MOPR activity only in the striatum and in one case also the nucleus accumbens ( FIG. 6 ).
  • KOPR and delta opioid receptor (DOPR) activities are affected by therapeutic doses.
  • therapeutic doses of MPH (0.75 mg/kg) produce place aversion and naltrexone can block aversive effects of MPH.
  • repeated daily exposure to therapeutic doses of MPH beginning in the adolescent period (postnatal day 25) and lasting for 35 days, until young adulthood (postnatal day 60) will be shown to produce changes in MPH-induced conditioned place preference or aversion and in the activity of the 3 types of opioid receptors.
  • naltrexone co-aversion of opioid receptor activity.
  • the effects of short-term (5 days) MPH administration in these young mice on place preference/aversion and opioid receptor activity will be shown. This is especially relevant to ADHD because MPH treatment for ADHD frequently begins at school age and can last until young adulthood (Safer et al., 1996; Zito et al., 2000). Therefore, the mouse model will establish that MPH administration can lead to euphoric or dysphoric effects in young individuals following short- or long-term MPH administration. Repeated administration of naltrexone+MPH will be shown to prevent MPH-induced addiction or aversion in these developing mice.
  • Postnatal days 25 and 60 in mice represents adolescence and young-adulthood, respectively in humans (Spear, 2000; Andersen et al., 2002b; Andersen et al., 2002a). Mice will not be treated with MPH or naltrexone treatment prior to postnatal day 25 because the stress of weaning (weaning occurs on day 21) could confound the data if drug treatment began before postnatal day 25.
  • mice C57/B16 male mice (Charles River Laboratories, Wilmington, Mass.) in the experiments of Experiments 1, 2 and 3 will be used. The mice will be maintained in the institutional animal facility. The methods of conditioned place preference and opioid receptor activity assays were described in the previous example.
  • the selective MOPR agonist DAMGO, selective KOPR agonist U50,488 and selective DOPR agonist DPDPE ([D-Pen 2,5 ]-Enkephalin hydrate) for G-protein coupling assays (all chemicals purchased from Sigma) will be used. MPH and other drugs will be administered twice daily intraperitoneally.
  • Conditioned place aversion employs additional steps compared to conditioned place preference assay.
  • an unbiased place conditioning procedure will be used (Tzschentke, 1998). Briefly, to control for apparatus bias, a set of criteria are applied to the preconditioning data. Mice that do not fit the criteria will be excluded from the study. First, any mouse that spends more than 500 seconds of the 1200-second test period in the central chamber will be excluded. Of the mice that qualify, the time spent in the central chamber will be subtracted from 1200 (the total test time), and divided by two to give a “half-time” (equal to the amount of time the mouse would spend in each chamber, saline-paired and drug-paired, if it had absolutely no preference).
  • the half-time will be multiplied by 0.2 and this value will be added or subtracted to the half time to give a range of allowable time a mouse can spend in either chamber. If the time spent in one chamber exceeds the upper or lower limits of the range then the mouse is assumed to have an apparatus bias and will be removed from the study. Mice will be then randomly assigned to a given treatment group. The remainder of the procedure will be the same as that described for conditioned place preference. The data will be analyzed by ANOVA. Differences between two given experimental groups will be tested for significance by using t-test.
  • mice administered 0.75 mg/kg MPH for 5 days will show place aversion as opposed to the place preference produced by 7.5 mg/kg dose. It is expected that 0.75 mg/kg MPH will upregulate KOPR activity in the caudate-putamen, nucleus accumbens and frontal cortex.
  • MPH (0.75 mg/kg) administration for 5 or 35 days beginning at postnatal day 25 is also expected to produce place aversion and upregulate KOPR activity, based on reports cited above. DOPR activity will be expected to parallel MOPR activity and KOPR activity will be the opposite. 7.5 mg/kg MPH administered to 25-day old mice for 5 days will be expected to produce similar effects as those in 90-day old mice, i.e. place preference and MOPR upregulation. Co-administration of naltrexone and MPH is expected to block MPH-induced aversion. Since MOPR, KOPR and DOPR activity will be measured in each experiment, the ratio between activities of euphoria- and dysphoria-associated receptors, i.e.
  • Amphetamine (2.5 mg/kg; s.c.) modulates KOPR signaling in the nucleus accumbens in a region-specific manner (Xia et al., 2007).
  • therapeutic effects of MPH likely require region-specific changes in neurotransmitters. Therefore, 0.75 mg/kg MPH may affect opioid receptor activity selectively in the frontal cortex. If therapeutic doses of MPH+naltrexone altered opioid receptor activities in regions other than frontal cortex, it may be reflected in changes in attention in Experiment 2.
  • MPH for use will be a) 1.5 mg/kg of MPH, or b) 0.75 or 1.5 mg/kg MPH administered for a longer period, 15 days.
  • naltrexone may not block MPH-induced place aversion even at 10 mg/kg (the dose that blocks MPH place preference).
  • Alternative doses of naltrexone for use will be 15 or 20 mg/kg naltrexone.
  • a selective KOPR antagonist bupronorphine will be used in place of naltrexone. Since place aversion is mediated via KOPR, and since naltrexone blocks all 3 opioid receptors, using a selective KOPR antagonist may be more effective in blocking the aversion. It is important to note that MPH intolerance is typically observed in human subjects (Spencer et al., 2006a; Spencer et al., 2006b).
  • the principal assay will be the 2-CSRT assay recently developed in Dr. Dodart's lab (Dillon et al., 2009). This is a novel attention task that overcomes some of the limitations of the other attentional task used in rodents, the 5-CSRT task.
  • the 5-CSRT requires an average training period of 3-4 months for normal rodents (i.e. rats or mice) to reach a 70-80% criterion level of performance.
  • the 2-CSRT can be performed in 8-10 days.
  • the 2-CSRT does not involve extensive training period, multiple attentional tests, nor potential confounds across different behavioral endpoints.
  • visual discrimination learning will be first compared under different operant training conditions. Then the mice will be tested in a novel mixed-trial attention paradigm combining four different stimulus durations within a single session (0.5, 1, 2, or 10 s).
  • the stimulus durations used during attention testing will provide within session controls, such that chance level performance will occur at the shortest stimulus duration (0.5 s) and optimal attention-independent performance at the longest stimulus duration (10 s).
  • the attentional demand at the longest stimulus duration should be minimal; therefore performance deficits during these trials might indicate either motivational and/or motor alterations.
  • the 2-CSRT testing apparatus is a standard rat operant chamber (Med Associates, St Albans, Vt.).
  • a pellet receptacle will be placed in the center of one end-wall with a small yellow stimulus light located directly overhead.
  • Two retractable lever-press devices will be located on each side of the end-wall opposite to the pellet receptacle.
  • a large stimulus light is located directly above each lever to operate as a direct cue during the discrimination and attention tasks.
  • the visual discrimination learning and attention procedures are described in detail in a recent publication from Dr. Dodart's lab (Dillon et al., 2009).
  • the test includes 4 phases: (1) A single habituation session: The food-restricted mice are exposed to the operant chamber for 45 min without access to the operant levers but receive 24 exposures to a 1-s receptacle-light stimulus with an inter-trial interval (ITI) of 120 s. The presentation of the receptacle-light stimulus coincides with the delivery of a 20-mg food pellet; (2) 2-daily shaping sessions: Only one lever (left or right) is available indefinitely concurrently with random light presentation until the subject makes a response. Following each response the lever is retracted, food receptacle light turned on, and a single 20-mg food pellet is delivered. Each additional trial begins 10 s following the retrieval of the food reward.
  • ITI inter-trial interval
  • Shaping sessions last for a maximum of 30 min or 60 trials; (3) 8-daily discrimination training sessions: Each daily session includes 80 trials beginning with the presentation of both levers accompanied by a cued stimulus light directly above one of the levers. Light-lever is randomly paired and counterbalanced across trials. Animals have to press the lever signaled by the light stimulus to obtain food reward. The stimulus light remains illuminated until a lever-press is made or for a maximum duration of 30 s. Following a correct response levers are retracted, a reward is delivered into the receptacle and the receptacle light remains turned on until the pellet is retrieved. The animal visits the receptacle in a 10-s ITI during which the house light remains turned on.
  • Attention sessions last for ⁇ 35 min in run time.
  • significant increases in errors in the 0.5, 1, and/or 2 s stimulus durations represents attention deficit whereas increased errors in the 10 s duration likely represents changes in motivation and/or motor activity (Dillon et al., 2009).
  • mice In separate cohorts of mice from each experimental group (and controls) mentioned above, operant extinction learning performance will be assessed. The mice will be trained in a lever-press task under continuous reinforcement and extinction learning performance will be assessed. This paradigm provides behavioral measures of response inhibition and frustration (Dillon et al., 2008), which is associated with attention deficits caused, for example by prenatal nicotine exposure in children (Huijbregts et al., 2008). This test is considered to be a good indicator of the “therapeutic” benefits of MPH and whether naltrexone produces adverse effects on the potency of MPH in this test. Prior to training, food-restricted mice will be exposed to the operant chambers (Med Associates, St.
  • operant chambers are configured with one pellet receptacle placed in the center of one end-wall (with a small yellow stimulus light located directly above the receptacle) and one lever placed adjacent to the receptacle (this lever is available to the animal at all time during acquisition and extinction sessions.
  • the mice receive 20 exposures to a 1-s light stimulus with an inter-trial interval of 120 s.
  • Each stimulus light display is paired with the delivery of a food pellet.
  • Training begins 24 h following habituation and consists of daily 30-min sessions under continuous reinforcement (FR1 schedule). Extinction training begins 24 h after the final training session.
  • mice prior to and following naltrexone (5 or 10 mg/kg) plus MPH (0.75/mg/kg) administration.
  • naltrexone 5 or 10 mg/kg plus MPH (0.75/mg/kg) administration.
  • Separate set of studies will be performed to determine if developmental MPH or naltrexone+MPH administration produces different effects on attention by administering MPH (0.75 mg/kg) or naltrexone (5 or 10 mg/kg)+MPH (0.75 mg/kg) daily for 35 days beginning at postnatal day 25.
  • the 2-CSRT testing for this group of mice will begin at postnatal day 60.
  • naltrexone is needed to block reinforcing properties of 7.5 mg/kg MPH.
  • Higher doses of naltrexone will also be used to block MPH-induced aversion.
  • Suitable doses are expected to be between 10 and 15 mg/kg.
  • the dose of MPH will be 60 mg (Spencer et al., 2006b; Spencer et al., 2006c), the dose of naltrexone will be 50 mg (Jayaram-Lindstrom et al., 2004). These doses are consistent with current FDA-approved guidelines. Venous blood will be drawn for quantification of peak plasma concentration of d-MPH and naltrexone. Each study day subjects will receive both doses of medication [MPH plus naltrexone, MPH without naltrexone (placebo)] in the morning and then complete hourly DQRS.
  • the DQRS is a subjective drug effects scale that has been used to measure a factor in abuse liability.
  • the liking question assesses potential for euphoria, disliking measures dysphoria.
  • Constituent elements of the scale have been standardized by comparison to responses to known drugs of abuse and validated against observer ratings and physiologic changes (Jasinski and Henningfield, 1989). This measure and related scales have been used in over 27 published studies assessing the abuse liability of methylphenidate (Jasinski and Henningfield, 1989; Jasinski, 2000; Kollins et al., 2001). Subjects will complete the DQRS hourly for 10 hours on each of the study days (Spencer et al., 2006c).
  • Categorical data will be analyzed with chi-square tests, continuous parametric data with unpaired t or F tests, and nonparametric data with the rank sum test. Associations between continuous variables will be evaluated by Pearson's product-moment correlation. Multiple comparisons will be controlled by using Holm's sequential Bonferroni method. In computing Holm's test, Nyholt's method (Nyholt, 2004) will be used to adjust the total number of tests that were assumed.
  • naltrexone for all the studies is expected to be 5 to 15 mg/kg. However, higher and lower doses are also envisioned.

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