WO2004054570A1 - Combinaisons de medicaments comprenant un agent de dissuasion contre l'alcool destinees a traiter la dependance a l'alcool ou l'abus d'alcool - Google Patents

Combinaisons de medicaments comprenant un agent de dissuasion contre l'alcool destinees a traiter la dependance a l'alcool ou l'abus d'alcool Download PDF

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Publication number
WO2004054570A1
WO2004054570A1 PCT/CA2003/000990 CA0300990W WO2004054570A1 WO 2004054570 A1 WO2004054570 A1 WO 2004054570A1 CA 0300990 W CA0300990 W CA 0300990W WO 2004054570 A1 WO2004054570 A1 WO 2004054570A1
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Prior art keywords
pharmaceutical
combination medicine
alcohol
disulfiram
chosen
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PCT/CA2003/000990
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English (en)
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Christopher S. DOYLE
Willem Wassenaar
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Purepharm Inc.
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Priority to AU2003303015A priority Critical patent/AU2003303015A1/en
Publication of WO2004054570A1 publication Critical patent/WO2004054570A1/fr

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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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse

Definitions

  • This invention relates to a combination pharmaceutical medicine that acts in an agonist-aversive manner for people with alcohol related disorders.
  • the 5 combination of an agonist such as a benzodiazepine combined with a medicine such as disulfiram or calcium carbimide or naltrexone or acamprosate is used to treat alcohol-associated anxiety and also acts to deter alcohol consumption.
  • This invention also relates to aversive medicines combined with other agents to treat medical conditions, which medical conditions or agents' effectiveness are negatively impacted 10 by the consumption of ethanol.
  • Anxiety is known to be the predominant complaint of alcohol dependent 20 patients in the first four weeks of early withdrawal from alcohol. Common complaints include tension, difficulty concentrating, fear, fatigue, restlessness and irritability. Other withdrawal symptoms include headaches, insomnia, sweating, tremor, anorexia and dizziness. 3 Many argue that a sub-acute alcohol withdrawal syndrome exists even beyond the four week acute withdrawal period and this 25 withdrawal is responsible for many ongoing complaints of anxiety, insomnia and irritability and depression in abstinent alcohol dependent patients. 4
  • benzodiazepines should not be used to treat anxiety or withdrawal complaints in alcohol abusing outpatients.
  • Alternative agents such as antidepressants and buspirone are recommended as the therapeutic agents of choice for the complaints of anxiety and insomnia that occur in early withdrawal. These alternative agents are thought to have less of a risk for abuse.
  • Current standards of care indicate that if a patient has been treatment resistant to these alternative agents and has ongoing complaints of anxiety a benzodiazepine can still be considered as long as the patient is abstinent from alcohol and stable in their recovery.
  • a benzodiazepine is used to treat the anxiety the physician should closely monitor the dose. It is often useful if a family member is included in the therapeutic alliance so that they can provide the alcohol dependent patient with the medicine. 12
  • benzodiazepines are often used by patients to intoxicate themselves just as the patient used alcohol to intoxicate himself or herself.
  • Short- term side effects include sedation, ataxia, psychomotor slowing, poor concentration and anterograde amnesia.
  • Other side effects include impaired driving, increased risk of falls by the elderly and paradoxical effects of increased anger and hostility. 13
  • benzodiazepines are consumed with alcohol a more impaired state and possibly lethal state can arise.
  • alcohol using patients are treated as outpatients, they are at risk to drink alcohol during treatment with all the subsequent potential dangers a possibility.
  • alcohol and benzodiazepines have equivalent intoxicating effects, the co-morbid overuse of the two substances is prevalent. 18
  • Disulfiram inhibits aldehyde dehydrogenase, the enzyme that catalyzes the oxidation of acetylaldehyde, a metabolite formed when the body breaks down alcohol.
  • aversive reaction includes facial flush, hot flashes, conjunctiva injection, palpitations, headache, and hypotension. It is these negative reactions that are responsible for a patient's aversion to drinking when he or she has ingested disulfiram.
  • the most common side effects of the disulfiram without any alcohol having been consumed are drowsiness, headaches and GI discomfort.
  • Abstinence occurs when using disulfiram only if there is medication compliance. 21 It is well known to practitioners that patients often do not take their disulfiram so that they can continue drinking alcohol. Compliance rates as low as 20% have been reported. 22 The effectiveness of disulfiram treatment depends on compliance. Methods developed to improve compliance and thus treatment outcomes include behavioral monitoring, group supports, contingency contracting and supervised administration. An advantage of the present invention is that the concurrent administration of the benzodiazepine should also increase compliance.
  • Drinking alcohol adversely interacts with many medication treatments, exacerbates many medical illnesses.
  • 23 Alcohol use is known to worsens psychiatric symptoms of depression and anxiety. ' Chronic high-dose alcohol use can affect several different organ systems, including the gastrointestinal tract, the cardiovascular system, and the central and peripheral nervous systems. Alcohol-dependent patients also experience higher then average rates of cancer, and lower there life expectancy by 15 years. Thus it is important to design a medication that will effectively treat this serious illness.
  • This invention relates to a combination medicine comprising pharmaceutically effective amounts of a first pharmaceutical and a second pharmaceutical, wherein the second pharmaceutical causes illness when alcohol is ingested.
  • This invention also relates to a combination medicine comprising pharmaceutically effective amounts of a first pharmaceutical and a second pharmaceutical, wherein the second pharmaceutical blocks the usual effects of alcohol ingestion.
  • This invention also relates to a combination medicine comprising pharmaceutically effective amounts of a first pharmaceutical and a second pharmaceutical, wherein the second pharmaceutical is an aldehyde dehydrogenase inhibitor.
  • the first and second pharmaceuticals of the combination medicine are intimately co- mixed and may be in any form, such as, capsule, tablet, oral solution, suppository, transdermal patch, sublingual tablet, buccal tablet.
  • the first pharmaceutical of the combination medicine is chosen from the following group: anxiolytics, anti-depressants, sedatives, hypnotics, opioids , histamine H2 receptor antagonists, proton pump inhibitors or is chosen to treat the following: anxiety, depression, pain, insomnia, alcohol abuse, drug abuse, epilepsy gastric or duodenal ulcer.
  • the invention relates to a combination medicine comprising: benzodiazepine and disulfiram or calcium carbimide; benzodiazepine and acamprosate or naltiexone; anxiolytic and disulfiram or calcium carbimide; anxiolytic and acamprosate or naltiexone; anti-depressant and disulfiram or calcium carbimide; anti-depressant and acamprosate or naltiexone; sedative and disulfiram or calcium carbimide; sedative and acamprosate or naltiexone; hypnotic and disulfiram or calcium carbimide; hypnotic and acamprosate or naltiexone; opioid and disulfiram or calcium carbimide; opioid and acamprosate or naltiexone; histamine H2 receptor antagonist and disulfiram or calcium carbimide; histamine H2 receptor antagonist and acamprosate or naltiexone; proton pump inhibitor and
  • This invention relates to a combination medicine comprising a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and disulfiram or calcium carbimide; and a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and acamprosate or naltiexone.
  • the combination medicine comprising disulfiram has a quantity of disulfiram of between 10 mg and 1000 mg daily.
  • the combination medicine comprising calcium carbimide has a quantity of calcium carbimide of between 5 mg and 500 mg daily.
  • the desire to avoid this aversion reaction will encourage the patients to refrain from drinking alcohol.
  • the benzodiazepine in turn will treat any underlying anxiety and thus be rewarding in and of itself and also serve to lessen the need for the anxiolytic activity of ethanol. If the combined preparation is taken regularly even missing a dose will create some benzodiazepine withdrawal anxiety that will result in more regular taking of the benzodiazepine-disulfiram combination medicine in order to avoid this withdrawal anxiety.
  • Increased compliance ensures that the patient has a sufficient concentration of disulfiram in the body so as to induce an aversion reaction should the patient ingest ethanol.
  • the desire to avoid the negative experience associated with the aversion reaction will discourage the patient from ingesting ethyl alcohol.
  • the combination medicine of disulfiram combined with a benzodiazepine would be the ideal compound to treat the alcohol dependent patients that complain of anxiety symptoms for which a benzodiazepine is a clinically appropriate treatment.
  • This combination medicine could be used to treat early alcohol withdrawal symptoms and chronic anxiety symptoms, provide prophylaxis against seizures and prevent delirium tremens.
  • As the combination medicine also contains disulfiram it would prevent the patient from drinking alcohol while taking the benzodiazepine.
  • disulfiram it would prevent the patient from drinking alcohol while taking the benzodiazepine.
  • a combination of a benzodiazepine with disulfiram treats the underlying condition and reduces the probability of relapse to drinking alcohol.
  • the actual ratio of the benzodiazepine to disulfiram will depend on the specific benzodiazepine chosen as well as the severity of the underlying condition for which the benzodiazepine is being used as a treatment. See the table below for a list of benzodiazepines and the probable daily dose.
  • the ratio of benzodiazepine to disulfiram is dependent on the benzodiazepine chosen and the daily dose of disulfiram. The ratio can range from as little a 0.00025 milligram of a benzodiazepine to 1 milligram of disulfiram to as much as 4.5 milligram of a benzodiazepine to 1 milligram of disulfiram. Ratios higher or lower than this may also be of therapeutic benefit since the list in the table is not exhaustive of all available benzodiazepines or the daily doses that might be used.
  • a young patient may be treated with a high dose of clonazepam during the initial withdrawal from alcohol in order to avoid delirium tremens.
  • This patient may be given a combination of 6 mg of clonazepam and 250 mg of disulfiram (ratio of 6/250 or 0.024 mg of clonazepam for every mg of disulfiram) As the patient gets better 2 mg of clonazepam is sufficient to control their anxiety but the amount of disulfiram stays the same (ratio 2/250 or 0.008 mg of clonazepam to 1 mg of disulfiram).
  • clonazepam and 62.5 mg of disulfiram may be enough (ratio 0.5/62.5 or 0.004 mg of clonazepam to 1 mg of disulfiram).
  • ratio 0.5/62.5 or 0.004 mg of clonazepam to 1 mg of disulfiram The absolute amounts of each drag differ under different clinical circumstances, as do the ratios of the two ingredients with respect to each other.
  • the prescription should be only given on a bi-weekly basis.
  • a limitation in the prescription availability lessens the chance of the patient consuming a dangerously high amount of disulfiram in order to consume a large amount of the benzodiazepine.
  • Dispensing the combination medicine in a weekly amount ameliorates the risk of benzodiazepine overuse.
  • the combination medicine must be given in a presentation such that the disulfiram should not be capable of being separated from the benzodiazepine, or at least not be visible to the patient as two separate substances, that is, intimately co- mixed.
  • a combination medicine could have both disulfiram and a benzodiazepine present as a finely ground powder of the same colour so that the patient is not capable of separating the disulfiram powder from the benzodiazepine powder. If the powders are of different colour, dyes can be used to mask this difference and make the powders indistinguishable. These powders can then be mixed with excipients so as to be formed into a tablet, caplet or filled into a capsule.
  • the combination medicine can also be formulated by dissolving both in a suitable solvent. This solution can then have added to it appropriate types and amounts of excipients to make a pleasant tasting and aesthetically pleasing oral solution.
  • a solution containing both ingredients can also be placed in soft gelatine capsules.
  • Other presentations could include suppositories, sublingual or buccal tablets, transdermal patches or any other presentation that is capable of delivery the appropriate amount of a benzodiazepine and disulfiram in a form in which the patient is not able to take one without also ingesting or absorbing the other.
  • Clonazepam Premix The clonazepam premix of about 160 grams may be prepared as outlined in the table below:
  • the two ingredients were mixed together in sufficient quantity to yield the required amount of disulfiram and clonazepam to yield capsules containing the inseparable combination of clonazepam 1 mg and disulfiram 250 mg or 2 mg and disulfiram 250.
  • Alcohol dependent insomnia is a state in which even the consumption of moderate amounts of alcohol increases awakenings in the second half of the night. 29 Patients will seek sedatives or hypnotics to treat this type of insomnia. It is often difficult for patients to break the habit of an evening alcoholic or drink or two. For the clinician, prescribing sedatives or hypnotics to such a patient is problematic because the patient may become dependent on the sedative or hypnotic. The real problem is evening time alcohol consumption. Once a pattern of alcohol and sedative hypnotic consumption is established it is very difficult to get a patient off the sedative or hypnotic.
  • Non-benzodiazepine examples include zopiclone a cyclopyrrolone derivative, zaleplon a member of the pyrazolopyrimidine class and secobarbital of the barbiturate class.
  • Substance abuse often involves multiple substances. For example some patients abuse opioids and alcohol or opioids, cocaine and alcohol. Rehabilitation of opioid dependent persons may involve a methadone maintenance program or maintenance with an anolgue of methadone. Methadone has almost all of the properties of heroin but to blocks the euphoria associated with heroin use. 30 Heroin use may be associated with alcohol abuse and can complicate rehabilitation. A combination of methadone and disulfiram would be usefull in the treatment of patients with both opioid and alcohol abuse. The patient is incented to consume methadone in order to manage their opioid addiction. The concommitant consumption of disulfiram would help the patient avoid alcohol consumption.
  • Chronic pain management with opioids may be associated with excessive alcohol consumption. Alcohol acts as a relaxant and also has some analgesic properties. Alcohol abuse can however be a block to rehabilitation.
  • a combination opioid analgesic with disulfiram would be helpful in managing the alcohol use and abuse component of the patients clinical situation. The patient would be incented to take the combination medicine inorder to get pain relief and would be discouraged from consuming alcohol because of the disulfiram content of the pain medicine.
  • opioids to which disulfiram could be added include methadone, codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, pentazocine, meperidine, and propoxyphene.. Many physical conditions are exacerbated if the the patient consumes alcohol.
  • Alcohol intake can result in inflammation of the stomach resulting from an increase in gastric acid production and damage to the gastric mucosal barrier. This may exacerbate pain associate with gastric and duodenal ulcers..
  • Treatment with agents such as histamine H 2 receptor antagonist and proton pump inhibitors (or H+, K+ ATPase inhibitor) provide the patients with relief of symptoms such as pain.
  • histamine H 2 receptor antagonist are cimetidine, famotidine, ranitidine and nizatidine
  • examples of a proton pump inhibitor are omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole.
  • Combining these agents with disulfiram can result in improved healing of the gasric or duodenal ulcer.
  • the patient would be incented to take the combination medicine inorder to get pain relief and would be discouraged from consuming alcohol because of the disulfiram content of the medicine containing a histamine H 2 receptor antagonist or a proton pump
  • Disulfiram is of course only one of many aversive medicines available on the market.
  • Other medicines that could be substituted for disulfiram in the combination medicines outlined above, to achieve the same fundamental purpose i.e. the reduction of alcohol consumption in a clinical situation in which alcohol complicates the treatment of an undelying illness are calcium carbimide, naltiexone, and acamprosate.
  • Calcium carbimide, like disulfiram is an aldehyde dehydrogenase inhibitor.
  • Naltiexone is an opioid antagonist and acamprosate interferes with central neurotransmitter effects of alcohol, both of which block the effects of alcohol although the exact mechanism of action is not yet fully understood.
  • a benzodiazepine naltiexone combination medicine could contain 1 mg clonazepam and 50 mg of naltiexone. Other strengths of clonazepam may be used. Naltiexone is usually administered at a dose of 50 mg per day.
  • Acamprosate clonazepam combination medicine could contain 0.5 mg clonaepam and 666 mg of acamprosate. Such a combination given three time per day would give an effective amount of clonazepam and acamprosate. In other circumstances 1 mg clonazepam and 666 mg of acamprosate given twice daily would also provide an effective amount of both medicines.
  • Calcium carbimide clonazepam combination medicine could contain 0.5 mg clonaepam and 100 mg of calcium carbimide. Such a combination given twice a day would give an effective amount of clonazepam and calcium carbimide.
  • the above examples relate to treatment of a variety of disease states, addictions and ailments for which alcohol consumption has deleterous effects.
  • the invention also relates to the combination of disulfiram, calcium carbimide, naltiexone or acamprosate with another pharmaceutical when that pharmaceutical has deleterious effects or reduced benefits when alcohol is consumed.
  • the combination medicine can be comprised of disulfiram, calcium carbimide, naltiexone or acamprosate with a pharmaceutical for the treatment of a disease or condition that is negatively affected by alcohol consumption such as anxiety, depression, pain, insomnia, alcohol abuse, drug abuse, gastric or duodenal ulcer, epilepsy.
  • the combination medicine can be comprised of disulfiram, calcium carbimide, naltiexone or acamprosate with a pharmaceutical from the group of anxiolytics, anti-depressants, sedatives, hypnotics, opioids, histamine H2 receptor antagonists, proton pump inhibitors.
  • a 43-year-old female suffers from chronic depression, panic disorder with agoraphobia and post-traumatic stress disorder.
  • Her alcohol abuse resulted in ineffective psychiatric rehabilitation because it led to drinking and isolation.
  • the patient is taking fluoxetine 40 mg, olanzapine 10 mg, clonazepam 0.5 mg during the day and clonazepam 1.5 mg at bed time.
  • clonazepam was replaced with the combination medicine consisting of clonazepam 2 mg and disulfiram 250 mg . This combination prevented her from drinking.
  • Her anxiety and insomnia improved and she was able to function much better.
  • This 42-year-old mother of two has a straggle controlling her drinking and marijuana use. She numbs herself with alcohol and this has resulted in poor self-care. Two months prior to treatment she was admitted to hospital with pneumonia. She is taking citalopram 40 mg and lorazepam 1 mg to manage her chronic dysthymia and generalized anxiety. Two week prior to tieatment she entered a pharmacy in an intoxicated state for a renewal of her benzodiazepine prescription. She was hospitalized for two weeks to detoxify from her bout of alcohol abuse.
  • disulfiram-benzodiazepine medicine acts in an agonist-aversive manner that parallels but differs from the agonist-antagonist properties of methadone. If the alcohol itself is the cause of the patient's anxiety symptoms an alcohol induced anxiety disorder is diagnosed. This diagnosis is given whether the anxiety comes on during the intoxication or withdrawal phase of the alcohol. Removal of the alcohol is always the initial intervention. Even if the patient's anxiety were directly caused by alcohol a disulfiram-benzodiazepine pill would be useful for treatment. The disulfiram-benzodiazepine medicine would treat this anxiety at the same time as it prevented the patient from being able to drink comfortably. There are not only short term benefits of this combined medicine but also long term effects of using a benzodiazepine to treat anxiety in an alcohol dependent patient.

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Abstract

Selon l'invention, les troubles liés à l'alcool sont traités par diverses thérapies, y compris avec des produits pharmaceutiques. Les benzodiazépines constituent un type de produit pharmaceutique qui a contribué à traiter l'anxiété associée aux troubles liés à l'alcool, sans toutefois neutraliser les graves risques d'abus et de dépendance. Le disulfirame est un autre produit pharmaceutique qui agit de manière dissuasive contre la consommation d'alcool, puisqu'il rend une personne très malade lorsqu'il est associé à l'alcool. L'action dissuasive du disulfirame n'est efficace que lorsque le médicament est pris, et l'inobservation de cette prise est un obstacle majeur. Cette invention concerne une combinaison de produits pharmaceutiques à base de disulfirame et de benzodiazépines, qui agit comme un agoniste-aversif sur des personnes souffrant de troubles liés à l'alcool. L'action du disulfirame et des benzodiazépines combinés réduit l'anxiété en même temps qu'elle dissuade de la consommation d'alcool. L'invention concerne également des médicaments aversifs combinés à d'autres agents pour traiter des troubles médicaux, dont l'efficacité est amoindie par la consommation d'éthanol.
PCT/CA2003/000990 2002-12-17 2003-06-25 Combinaisons de medicaments comprenant un agent de dissuasion contre l'alcool destinees a traiter la dependance a l'alcool ou l'abus d'alcool WO2004054570A1 (fr)

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AU2003303015A AU2003303015A1 (en) 2002-12-17 2003-06-25 Combinations of medicaments comprising an alcohol deterrent for treating alcohol dependence or alcohol abuse

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CA2,414,500 2002-12-17
CA002414500A CA2414500A1 (fr) 2002-12-17 2002-12-17 Association de medicaments agoniste et aversif

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WO2008045641A2 (fr) * 2006-10-10 2008-04-17 The University Of Chicago Composition et procédé permettant de traiter l'alcoolisme et les addictions à d'autres substances
US8486449B2 (en) 2008-12-16 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
JP2013536837A (ja) * 2010-09-01 2013-09-26 トニックス ファーマスーティカルズ，インコーポレイテッド コカイン嗜癖の治療
EP2705843A1 (fr) * 2012-09-05 2014-03-12 Pharnext Approches thérapeutiques pour le traitement de l'épilepsie et de troubles associés par réduction de l'épileptogenèse
US8916195B2 (en) 2006-06-05 2014-12-23 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
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US9457005B2 (en) 2005-11-22 2016-10-04 Orexigen Therapeutics, Inc. Compositions and methods for increasing insulin sensitivity
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US10238647B2 (en) 2003-04-29 2019-03-26 Nalpropion Pharmaceuticals, Inc. Compositions for affecting weight loss
CN110420190A (zh) * 2019-08-29 2019-11-08 湖南洞庭药业股份有限公司 氯硝西泮片及其制备方法
CN111420062A (zh) * 2020-04-29 2020-07-17 漳州卫生职业学院 一种用于苯二氮卓类药物的协同增效剂
WO2022016097A1 (fr) * 2020-07-16 2022-01-20 Musc Foundation For Research Development Inhibition de g9a pour diminuer l'escalade, induite par le stress et induite par la dépendance, de la consommation d'alcool
WO2022086835A1 (fr) * 2020-10-19 2022-04-28 Presti Michael Produits de combinaison pour atténuer le risque de réaction indésirable d'agoniste de benzodiazépine non-benzodiazépine et de surdose
US11324741B2 (en) 2008-05-30 2022-05-10 Nalpropion Pharmaceuticals Llc Methods for treating visceral fat conditions

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US10478408B2 (en) 2018-01-26 2019-11-19 Michael Presti Combination treatments for opioid crisis

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