CA2414500A1 - Agonist-aversive combination medicines - Google Patents
Agonist-aversive combination medicines Download PDFInfo
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- CA2414500A1 CA2414500A1 CA002414500A CA2414500A CA2414500A1 CA 2414500 A1 CA2414500 A1 CA 2414500A1 CA 002414500 A CA002414500 A CA 002414500A CA 2414500 A CA2414500 A CA 2414500A CA 2414500 A1 CA2414500 A1 CA 2414500A1
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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
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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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
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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
- A61K31/55—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
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- 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
Abstract
ABSTRACT
Alcohol disorders have been treated with a variety of therapies, including pharmaceutical. Benzodiazepines, are one type of pharmaceutical that has aided in treating the anxiety associated with alcohol disorders, however there are serious risks of abuse and dependence. Disulfiram is another pharmaceutical that provides a deterrent against consuming alcohol since it causes a person to become very ill when combined with alcohol. The deterrent effect of disulfiram is only effective when taken and non-compliance is a major limitation. This invention relates to a combination pharmaceutical medicine of disulfiram and a benzodiazepine that acts in an agonist-aversive manner for people with alcohol disorders. The combination of disultiram and a benzodiazepine acts to reduce anxiety and deter alcohol consumption at the same time. This invention also relates to other combinations of agonist and aversive medicines to reduce anxiety and 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 by the consumption of ethanol.
Alcohol disorders have been treated with a variety of therapies, including pharmaceutical. Benzodiazepines, are one type of pharmaceutical that has aided in treating the anxiety associated with alcohol disorders, however there are serious risks of abuse and dependence. Disulfiram is another pharmaceutical that provides a deterrent against consuming alcohol since it causes a person to become very ill when combined with alcohol. The deterrent effect of disulfiram is only effective when taken and non-compliance is a major limitation. This invention relates to a combination pharmaceutical medicine of disulfiram and a benzodiazepine that acts in an agonist-aversive manner for people with alcohol disorders. The combination of disultiram and a benzodiazepine acts to reduce anxiety and deter alcohol consumption at the same time. This invention also relates to other combinations of agonist and aversive medicines to reduce anxiety and 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 by the consumption of ethanol.
Description
AGONIST-AVERSIVE COMBINATION MEDICINES
Field of the Invention This invention relates to a combination pharmaceutical medicine that acts in an agonist-aversive manner for people with alcohol related disorders. The 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 by the consumption of ethanol.
Background of the Invention Alcohol dependent patients with complaints of anxiety commonly approach physicians for assistance. According to a 1990 study, those with an anxiety disorder had a 50% increase in the odds of being diagnosed with an alcohol disorder.
~ 5 A 1997 study also indicated a doubting to quadrupling of risk for alcohol and drug dependence given the presence of an anxiety disorder.-' Rates of anxiety disorders in the alcohol dependent population range from 20-50%. While rates of anxiety disorders in the general population are generally I 5-20°/~.
Anxiety is known to be the predominant complaint of alcohol dependent 2o 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. ~ Many argue that a sub-acute alcohol withdrawal syndrome exists even beyond the four week acute withdrawal period and this 2S withdrawal is responsible for many ongoing complaints of anxiety, insomnia and irritability and depression in abstinent alcohol dependent patients.' Alcohol seems to be anxiolytic while it is being consumed yet anxiogenic over the long terms Reducing anxiety symptom in-patients improves alcoholism treatment outcomes'', and ongoing problems with panic and anxiety predict relapse.' Even in prolonged periods of abstinence, alcohol dependent patients claim incapacitating anxiety as a common reason for return to drinking.
Benzodiazepines are the easiest way to relieve this anxiety. With their favourable side effect profile and wide therapeutic window, benzodiazepines are the treatment of choice for early withdrawal symptoms. Benzodiazepines also prevent and treat withdrawal seizures and withdrawal induced delirium tremens in patients.
There has been controversy over whether benzodiazepines should be used to treat anxiety symptoms and withdrawal symptoms in alcoholic outpatients.'' The dangers of dose escalation of the benzodiazepine and combination of the t o benzodiazepine with alcohol prevent most physicians from using benzodiazepines to treat early alcohol withdrawal symptoms in outpatients. When benzodiazepines are mixed with alcohol, a severe form of intoxication occurs and the mixture of these two substances can lead to blackouts, coma and possibly even death.'°
Because of the risk of dual intoxication most experts feel that ~ 5 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 2o 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." If 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 25 patient with the medicine.'' The hesitancy to use benzodiazepines in the substance using population is understandable yet unfortunate. Anxiety disorders in the substance using population are notoriously difficult to treat. Anxiety tends to be chronic, with high rates of morbidity and mortality and many agents such as antidepressants, buspirone, 30 neuroleptics or mood stabilizers otter only partial relief." 'there is strong evidence suggesting that anxiety is associated with craving and relapse. And those negative affective states serve as powerful internal cues that frequently precede relapse.
Benzodiazepines are highly effective anxiolytics and patients may benefit greatly from a short course of treatment with subgroups of chronically anxious patients needing long term treatment."
Unfortunately benzodiazepines can be used by patients to intoxicate themselves just as the patient used alcohol to intoxicate himself or herself.'S 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." When benzodiazepines are consumed with alcohol a more impaired state and possibly lethal state can arise. As most alcohol using patients are treated as outpatients, they are at risk to drink alcohol during treatment with all the subsequent potential dangers a possibility. As alcohol and benzodiazepines have equivalent intoxicating effects, the ~ 5 co-morbid overuse of the two substances is prevalent. "' Physicians are used to giving disultiram to aid patients in their quest to refrain from alcohol. Although 250-SOOmg of disulfiram is recommended in North America, it appears that some patients may need up to one gram of disulfiram to get a proper aversive reaction to alcohol.'' Although disultiram is a deterrent medicine that ?o was approved 50 years ago for the treatment of alcoholism, it has unfortunately not consistently been shown to be efficacious.~~ Disulliram inhibits aldehyde dehydrogenase, the enzyme that catalyzes the oxidation of acetylaldehyde, a metabolite formed when the body breaks down alcohol. If alcohol is ingested while this enzyme is inhibited by disulfiram, blood acetylaldehyde rises causing an aversive z5 reaction. This aversive reaction includes facial flush, hot flashes, conjunctiva injection, palpitations, headache, and hypotension. It is these negative reactions that are responsible fox a patient's aversion to drinking when he or she has ingested disulfiram. The most common side effects of the disulliram without any alcohol having been consumed are drowsiness, headaches and GI discomfort.
Abstinence occurs when using disulfiram only if there is medication compliance.''' 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.'"
One must weigh carefully the risks and benefits of initiating or not initiating a benzodiazepine treatment in the alcohol dependent population, particularly for outpatients. The effectiveness of disulfiram treatment depends on compliance.
Alcohol use and abuse complicates many disease states and interferes with treatment and rehabilitation.'' Men and women who fullfill the criteria for alcohol use disorders decrease their life span by approximately 15 years, with abuse and dependence responsible for almost 25% of premature deaths in men and 15% in women, figures that represent a three- to sixfold odds ratio of early death even among people with higher levels of education and socio-economic functioning.'-Alcohol use is a common co-morbid psychiatric disorder of depression.
~ 5 For example elderly depressed patients are three to four times more likely to have an alcohol use disorder compared with non-depressed elderly subjects, with a prevalence of 15 to 30% in patients with late life major depression. Successful treatment of depression with reducing alcohol use leads to the best possible outcomes."
Viewed from a different vantage point, depressive symptoms can be found in as many as 30%
of those who abuse alcohol so that abstinence is crucial to treatment.' Summary of the Invention 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 aldehydc 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 naltrexone;
anxiolytic and disulfiram or calcium carbimide; anxiolytic and acamprosate or ~ 5 naltrexone; anti-depressant and disulfiram or calcium carbimide; anti-depressant and acamprosate or naltrexone; sedative and disulfiram or calcium carbimide;
sedative and acamprosate or naltrexone; hypnotic and disulfiram or calcium carbimide;
hypnotic and acamprosate or naltrexone; opioid and disulfiram or calcium carbimide;
opioid and acamprosate or naltrexone; histamine H2 receptor antagonist and disulfiram or 2o calcium carbimide; histamine H2 receptor antagonist and acamprosate or naltrexone;
proton pump inhibitor and disulliram or calcium carbimide; and proton pump inhibitor and acamprosate or naltrexone.
This invention relates to a combination medicine comprising a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and disulfiram or calcium ?s carbimide; and a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and acamprosate or naltrexone.
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.
Detailed Description of the Invention The inventor determined that by combining disulfiram with a benzodiazepine one will improve compliance with the ingestion of disultiram.
The patient knows that disulfiram ingestion will result in an aversion reaction.
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-disultiram combination medicine in order to avoid this withdrawal anxiety. Increased compliance ensures that the patient has a sufficient concentration of disulliram 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 ~ 5 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 2o delirium tremens. As the combination medicine also contains disulfiram it would prevent the patient from drinking alcohol while taking the benzodiazepine.
Thus preventing the toxicity that occurs when benzodiazepines are mixed with alcohol, such as, severe intoxication, blackouts, coma, and possibly even death. A
combination of a benzodiazepine with disulfiram treats the underlying condition and 25 reduces the probability of relapse to drinking alcohol.
Prescriptions of small quantities of the combination medicine and frequent contact between the patient and the clinician are also essential to good therapeutic management. Judicious prescribing and careful monitoring can minimize the risk of abuse of the benzodiazepine and allow physicians to educate the patient about risks to their health if they attempt to drink while taking the disulfiram containing combination medicine.
One has to ensure an adequate dose of both medicines is achieved. Even though 250-SOOmg of disultiram is recommended in North America, it appears that some patients may need up to one gram of disulfiram to get a proper aversive reaction to alcohol. The proper dose of benzodiazepine is also a contentious subject.
Too much benzodiazepine causes over sedation, memory impairment and decreased ability to function cognitively. This includes impaired ability to operated mechanical and electronic equipment, such as motor vehicles etc. Combining disulfiram with various amounts of a benzodiazepine allows the physician to use a benzodiazepine to treat early withdrawal symptoms at the same time as the disulfiram prevents a return to drinking. Thus, there is no risk of the benzodiazepine being mixed with 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 ~ 5 which the benzodiazepine is being used as a treatment. See the table below for a list of benzodiazepines and the probable daily dose. 'Che 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 disultiram to as much as 4.5 milligram of a benzodiazepine to I
?o milligram of disultiram. 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.
Ratio of Benzodiazepine to Disulfiram Benzodiazepine A Probable Disulfiram Daily ~ Daily Dose Dose 10 mg 000 mg I
Alprazolam _ 0. ; 0.003 I 3 mg i Bromazepam 12 mg 1.2 0.012 Chlordiazepoxide30 mg 3 0.03 Clobazam 30 mg 3 0.03 Clonazepam 5 mg ~ 0.5 0.005 I
Clorazepate '- 3 -30 mg 0.03 i Diazepam 20 mg ? 0.02 Flurazepam 30 mg ~ 3 0.03 Halazepam 100 mg 10 0.1 Lorazepam 3 mg 0.3 0.003 Nitrazepam 10 mg 1 0.01 Oxazepam 45 mg ~ 4.5 0.045 Prazepam 30 mg 3 0.03 Temazepam ' 30 mg 3 0.03 Triazolam 0.25 0.025 0.00025 For example 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 disultiram (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 disulf ram stays the same (ratio 2/250 or 0.008 mg of clonazepam to 1 mg of disulliram). In the treatment of an elderly low body weight patient 0.5 mg of clonazepam and 62.5 mg of disultiram may be enough (ratio 0.5/62.5 or 0.004 mg oFclonazepam to 1 mg of disulliram). The absolute amounts of each drug differ under different clinical circumstances, as do the ratios of the two ingredients with respect to each other.
_g_ To avoid the risk of the patient over-using this combination medicine 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. For example, 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 disultiram 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 15 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 2o 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 disulliram in a form in which the patient is not able to take one without also ingesting or absorbing the other.
25 Preparation of a disultiram-benzodiazepine combination medicine Disulfiram Premix Each gram of the disulfiram premix contains Disulfiram 1 gram Fumed silica0.030 gram Clonazepam Premix The clonazepam premix of about 160 grams may be prepared as outlined in the table below:
Clonazepam ~ 2.0 Lactose Monohydrate USP 64.2 Microcrystalline Cellulose80.
Croscarmellose sodium 9.
NF
Magnesium Stearate NF 4.8 The two ingredients were mixed together in sufficient quantity to yield the required amount of disulllram and clonazepaan to yield capsules containing the inseparable combination of clonazepam 1 mg. and disulliram 250 mg or 2 mg and disulfiram 250.
I o An example of an alternative formula using the following ingredients is presented below:
Ingredient Amount in Mg Disulfiram 250 Clonazepam 2 Cornstarch 40 Magnesium stearate 2 Povidone 4 Veegum 2 Total weight 300 (tablet or capsule contents) Many other formulations for capsules, caplets, tablets, wafers, suspensions and oral liquids will be evident to those skilled in the art of product formulation.
Given that alochol use is a common co-morbid psychiatric disorder of depression, a combination of an antidepressant with disultiram would treat a patient's depressive state and ensure the abstinence from alcohol. Examples of antidepressants with which disulfiram can be combined are presented below:
Class Antidepressant 'Tricyclics Amitriptyline Clomipramine Doxepin Imipramine Secondary Amine Tricyclics Amoxapine ~
Desipramine Maprotiline Nortriptyline Serotonin-Reuptake Inhibitors Fluoxetine hluvoxamine Paroxetine Sertral ine Venlafaxine Atypical Antidepressants l3upropion Nefazodone Trazodone Monoamine Oxidase Inhibitors Phenelzine Tranylcypromine Selegiline i This list in not meant to be exhaustive but merely to show examples of antidepressants that could be combined with disulliram. Treatment with an antidepressant helps the patient overcome feelings of worthlessness and hopelessness.
To achieve this benefit from the antidepressant the patient is also required to take the disulfiram as part of the combination disulfiram-antideprssant medicine. The disulfiram in turn discourages the patient from consuming alcohol. Abstinence from alcohol is important in the overall management of depression.
While alcohol can help someone to fall asleep, it also "fragments" the sleep pattern. 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.2' 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. It is also very difficult for a patient to break a long established habit of consuming alcoholic beverages in the evening. Short term treatment with a combination of a suitable sedative or hypnotic with an appropriate amount of dislufiram will give the patient the. sleep they desire and help them break their ritualized automatic evening alcohol consumption behaviors. 'The sedative or t 5 hypnotic in this case may be but need not be a member of the benzodiazepine class.
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 2o 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.'-g. Heroin use may be associated with alcohol abuse and can complicate rehabilitation. A
25 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 disultiram would help the patient avoid alcohol consumption.
Chronic pain management with opioids may be associated with excessive a0 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.
Some examples of opioids to which disultiram 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~ receptor antagonist and proton pump inhibitors (or H+, K+ ATPase inhibitor) provide the patients with relief of symptoms such as pain.
l s Examples of histamine H, receptor antagonist are cimetidine, famotidine, ranitidine and nizatidine and 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 2o discouraged from consuming alcohol because of the disulfiram content of the medicine containing a histamine H, receptor antagonist or a proton pump inhibitor.
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.
25 the reduction of alcohol consumption in a clinical situation in which alcohol complicates the treatment of an undelying illness, are calcium carbimide, naltrexone, and acamprosate. Calcium carbimide, like disulfiram is an aldehyde dehydrogenase inhibitor. Naltrexone is an opioid antagonist and acamprosate interferes with central neurotransmitter effects of ale.ohol, both of which block the effects of alcohol 3o although the exact mechanism of action is not yet fully understood.
A benzodiazepine naltrexone combination medicine could contain 1 mg clonazepam and 50 mg of naltrexone. Other strengths of clonazepam may be used.
Naltrexone 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 I 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 disultiram, calcium carbimide, naltrexone ~ s 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, naltrexone or acamprosate with a pharmaceutical for the treatment of a disease or condition that is negatively affected by alcohol consumption such as anxiety, 2o depression, pain, insomnia, alcohol abuse, drug abuse, gastric or duodenal ulcer, epilepsy. The combination medicine can be comprised of disultiram, calcium carbimide, naltrexone or acamprosate with a pharmaceutical from the group of anxiolytics, anti-depressants, sedatives, hypnotics, opioids, histamine H2 receptor antagonists, proton pump inhibitors.
2s Example No. One A 43-year-old female suffers from chronic depression, panic disorder with agoraphobia and post-traumatic stress disorder. l:Ier 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. In order to control her drinking her clonazepam was replaced with the combination medicine consisting of clonazepam mg and disulfiram 250 mg . This combination prevented her from drinking. Her anxiety and insomnia improved and she was able to function much better.
Example No. Two This 42-year-old mother of two has a struggle 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 dysfhymia and generalized anxiety. Two week prior to treatment 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.
While in hospital the patient was started on a clonazepam I mg and disuli-iram 250 mg ~ 5 combination medicine. At discharge she was given a clonazepam 0.5 mg and disulfiram 125 mg combination medicine. On this medicine she has been able to control her urges to drink. As a result she has been able to improve her relationship with her husband and to re-enter the work force. After 2 months of use, her complete blood count was normal as were her liver and renal function tests. Her urine tested 2o negative for drugs of abuse. Five months after initiation of the combination clonazepam disulfiram combination medicine the patient remains on drug and is doing well.
Here we see this combination disulfiram-benzodiazepine medicine acts in an agonist-aversive manner that parallels but differs from the agonist-antagonist 25 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 -l._5-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 oi~this combined medicine but also long term effects of using a benzodiazepine to treat anxiety in an alcohol dependent patient.
Various embodiments of the present invention having been thus described in detail by way of example, it will be apparent to those skilled in the art that variations and modifications may be made without departing from the invention. The invention includes all such variations and modifications as fall within the scope of the appended claims.
References 1. Regier, D. A., M. E. Farmer, et al. ( 1990). "Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study." .lama 264( 19): 2511-8.
2. Kessler, R. C., R. M. Crum, et aI. (1997). "Lifetime co-occurrence of DSM-III-R
alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey." Arch Gen Psychiat~ 54(4): 313-21.
Field of the Invention This invention relates to a combination pharmaceutical medicine that acts in an agonist-aversive manner for people with alcohol related disorders. The 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 by the consumption of ethanol.
Background of the Invention Alcohol dependent patients with complaints of anxiety commonly approach physicians for assistance. According to a 1990 study, those with an anxiety disorder had a 50% increase in the odds of being diagnosed with an alcohol disorder.
~ 5 A 1997 study also indicated a doubting to quadrupling of risk for alcohol and drug dependence given the presence of an anxiety disorder.-' Rates of anxiety disorders in the alcohol dependent population range from 20-50%. While rates of anxiety disorders in the general population are generally I 5-20°/~.
Anxiety is known to be the predominant complaint of alcohol dependent 2o 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. ~ Many argue that a sub-acute alcohol withdrawal syndrome exists even beyond the four week acute withdrawal period and this 2S withdrawal is responsible for many ongoing complaints of anxiety, insomnia and irritability and depression in abstinent alcohol dependent patients.' Alcohol seems to be anxiolytic while it is being consumed yet anxiogenic over the long terms Reducing anxiety symptom in-patients improves alcoholism treatment outcomes'', and ongoing problems with panic and anxiety predict relapse.' Even in prolonged periods of abstinence, alcohol dependent patients claim incapacitating anxiety as a common reason for return to drinking.
Benzodiazepines are the easiest way to relieve this anxiety. With their favourable side effect profile and wide therapeutic window, benzodiazepines are the treatment of choice for early withdrawal symptoms. Benzodiazepines also prevent and treat withdrawal seizures and withdrawal induced delirium tremens in patients.
There has been controversy over whether benzodiazepines should be used to treat anxiety symptoms and withdrawal symptoms in alcoholic outpatients.'' The dangers of dose escalation of the benzodiazepine and combination of the t o benzodiazepine with alcohol prevent most physicians from using benzodiazepines to treat early alcohol withdrawal symptoms in outpatients. When benzodiazepines are mixed with alcohol, a severe form of intoxication occurs and the mixture of these two substances can lead to blackouts, coma and possibly even death.'°
Because of the risk of dual intoxication most experts feel that ~ 5 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 2o 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." If 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 25 patient with the medicine.'' The hesitancy to use benzodiazepines in the substance using population is understandable yet unfortunate. Anxiety disorders in the substance using population are notoriously difficult to treat. Anxiety tends to be chronic, with high rates of morbidity and mortality and many agents such as antidepressants, buspirone, 30 neuroleptics or mood stabilizers otter only partial relief." 'there is strong evidence suggesting that anxiety is associated with craving and relapse. And those negative affective states serve as powerful internal cues that frequently precede relapse.
Benzodiazepines are highly effective anxiolytics and patients may benefit greatly from a short course of treatment with subgroups of chronically anxious patients needing long term treatment."
Unfortunately benzodiazepines can be used by patients to intoxicate themselves just as the patient used alcohol to intoxicate himself or herself.'S 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." When benzodiazepines are consumed with alcohol a more impaired state and possibly lethal state can arise. As most alcohol using patients are treated as outpatients, they are at risk to drink alcohol during treatment with all the subsequent potential dangers a possibility. As alcohol and benzodiazepines have equivalent intoxicating effects, the ~ 5 co-morbid overuse of the two substances is prevalent. "' Physicians are used to giving disultiram to aid patients in their quest to refrain from alcohol. Although 250-SOOmg of disulfiram is recommended in North America, it appears that some patients may need up to one gram of disulfiram to get a proper aversive reaction to alcohol.'' Although disultiram is a deterrent medicine that ?o was approved 50 years ago for the treatment of alcoholism, it has unfortunately not consistently been shown to be efficacious.~~ Disulliram inhibits aldehyde dehydrogenase, the enzyme that catalyzes the oxidation of acetylaldehyde, a metabolite formed when the body breaks down alcohol. If alcohol is ingested while this enzyme is inhibited by disulfiram, blood acetylaldehyde rises causing an aversive z5 reaction. This aversive reaction includes facial flush, hot flashes, conjunctiva injection, palpitations, headache, and hypotension. It is these negative reactions that are responsible fox a patient's aversion to drinking when he or she has ingested disulfiram. The most common side effects of the disulliram without any alcohol having been consumed are drowsiness, headaches and GI discomfort.
Abstinence occurs when using disulfiram only if there is medication compliance.''' 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.'"
One must weigh carefully the risks and benefits of initiating or not initiating a benzodiazepine treatment in the alcohol dependent population, particularly for outpatients. The effectiveness of disulfiram treatment depends on compliance.
Alcohol use and abuse complicates many disease states and interferes with treatment and rehabilitation.'' Men and women who fullfill the criteria for alcohol use disorders decrease their life span by approximately 15 years, with abuse and dependence responsible for almost 25% of premature deaths in men and 15% in women, figures that represent a three- to sixfold odds ratio of early death even among people with higher levels of education and socio-economic functioning.'-Alcohol use is a common co-morbid psychiatric disorder of depression.
~ 5 For example elderly depressed patients are three to four times more likely to have an alcohol use disorder compared with non-depressed elderly subjects, with a prevalence of 15 to 30% in patients with late life major depression. Successful treatment of depression with reducing alcohol use leads to the best possible outcomes."
Viewed from a different vantage point, depressive symptoms can be found in as many as 30%
of those who abuse alcohol so that abstinence is crucial to treatment.' Summary of the Invention 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 aldehydc 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 naltrexone;
anxiolytic and disulfiram or calcium carbimide; anxiolytic and acamprosate or ~ 5 naltrexone; anti-depressant and disulfiram or calcium carbimide; anti-depressant and acamprosate or naltrexone; sedative and disulfiram or calcium carbimide;
sedative and acamprosate or naltrexone; hypnotic and disulfiram or calcium carbimide;
hypnotic and acamprosate or naltrexone; opioid and disulfiram or calcium carbimide;
opioid and acamprosate or naltrexone; histamine H2 receptor antagonist and disulfiram or 2o calcium carbimide; histamine H2 receptor antagonist and acamprosate or naltrexone;
proton pump inhibitor and disulliram or calcium carbimide; and proton pump inhibitor and acamprosate or naltrexone.
This invention relates to a combination medicine comprising a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and disulfiram or calcium ?s carbimide; and a pharmaceutical that has deleterious or reduced effects when alcohol is ingested and acamprosate or naltrexone.
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.
Detailed Description of the Invention The inventor determined that by combining disulfiram with a benzodiazepine one will improve compliance with the ingestion of disultiram.
The patient knows that disulfiram ingestion will result in an aversion reaction.
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-disultiram combination medicine in order to avoid this withdrawal anxiety. Increased compliance ensures that the patient has a sufficient concentration of disulliram 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 ~ 5 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 2o delirium tremens. As the combination medicine also contains disulfiram it would prevent the patient from drinking alcohol while taking the benzodiazepine.
Thus preventing the toxicity that occurs when benzodiazepines are mixed with alcohol, such as, severe intoxication, blackouts, coma, and possibly even death. A
combination of a benzodiazepine with disulfiram treats the underlying condition and 25 reduces the probability of relapse to drinking alcohol.
Prescriptions of small quantities of the combination medicine and frequent contact between the patient and the clinician are also essential to good therapeutic management. Judicious prescribing and careful monitoring can minimize the risk of abuse of the benzodiazepine and allow physicians to educate the patient about risks to their health if they attempt to drink while taking the disulfiram containing combination medicine.
One has to ensure an adequate dose of both medicines is achieved. Even though 250-SOOmg of disultiram is recommended in North America, it appears that some patients may need up to one gram of disulfiram to get a proper aversive reaction to alcohol. The proper dose of benzodiazepine is also a contentious subject.
Too much benzodiazepine causes over sedation, memory impairment and decreased ability to function cognitively. This includes impaired ability to operated mechanical and electronic equipment, such as motor vehicles etc. Combining disulfiram with various amounts of a benzodiazepine allows the physician to use a benzodiazepine to treat early withdrawal symptoms at the same time as the disulfiram prevents a return to drinking. Thus, there is no risk of the benzodiazepine being mixed with 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 ~ 5 which the benzodiazepine is being used as a treatment. See the table below for a list of benzodiazepines and the probable daily dose. 'Che 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 disultiram to as much as 4.5 milligram of a benzodiazepine to I
?o milligram of disultiram. 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.
Ratio of Benzodiazepine to Disulfiram Benzodiazepine A Probable Disulfiram Daily ~ Daily Dose Dose 10 mg 000 mg I
Alprazolam _ 0. ; 0.003 I 3 mg i Bromazepam 12 mg 1.2 0.012 Chlordiazepoxide30 mg 3 0.03 Clobazam 30 mg 3 0.03 Clonazepam 5 mg ~ 0.5 0.005 I
Clorazepate '- 3 -30 mg 0.03 i Diazepam 20 mg ? 0.02 Flurazepam 30 mg ~ 3 0.03 Halazepam 100 mg 10 0.1 Lorazepam 3 mg 0.3 0.003 Nitrazepam 10 mg 1 0.01 Oxazepam 45 mg ~ 4.5 0.045 Prazepam 30 mg 3 0.03 Temazepam ' 30 mg 3 0.03 Triazolam 0.25 0.025 0.00025 For example 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 disultiram (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 disulf ram stays the same (ratio 2/250 or 0.008 mg of clonazepam to 1 mg of disulliram). In the treatment of an elderly low body weight patient 0.5 mg of clonazepam and 62.5 mg of disultiram may be enough (ratio 0.5/62.5 or 0.004 mg oFclonazepam to 1 mg of disulliram). The absolute amounts of each drug differ under different clinical circumstances, as do the ratios of the two ingredients with respect to each other.
_g_ To avoid the risk of the patient over-using this combination medicine 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. For example, 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 disultiram 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 15 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 2o 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 disulliram in a form in which the patient is not able to take one without also ingesting or absorbing the other.
25 Preparation of a disultiram-benzodiazepine combination medicine Disulfiram Premix Each gram of the disulfiram premix contains Disulfiram 1 gram Fumed silica0.030 gram Clonazepam Premix The clonazepam premix of about 160 grams may be prepared as outlined in the table below:
Clonazepam ~ 2.0 Lactose Monohydrate USP 64.2 Microcrystalline Cellulose80.
Croscarmellose sodium 9.
NF
Magnesium Stearate NF 4.8 The two ingredients were mixed together in sufficient quantity to yield the required amount of disulllram and clonazepaan to yield capsules containing the inseparable combination of clonazepam 1 mg. and disulliram 250 mg or 2 mg and disulfiram 250.
I o An example of an alternative formula using the following ingredients is presented below:
Ingredient Amount in Mg Disulfiram 250 Clonazepam 2 Cornstarch 40 Magnesium stearate 2 Povidone 4 Veegum 2 Total weight 300 (tablet or capsule contents) Many other formulations for capsules, caplets, tablets, wafers, suspensions and oral liquids will be evident to those skilled in the art of product formulation.
Given that alochol use is a common co-morbid psychiatric disorder of depression, a combination of an antidepressant with disultiram would treat a patient's depressive state and ensure the abstinence from alcohol. Examples of antidepressants with which disulfiram can be combined are presented below:
Class Antidepressant 'Tricyclics Amitriptyline Clomipramine Doxepin Imipramine Secondary Amine Tricyclics Amoxapine ~
Desipramine Maprotiline Nortriptyline Serotonin-Reuptake Inhibitors Fluoxetine hluvoxamine Paroxetine Sertral ine Venlafaxine Atypical Antidepressants l3upropion Nefazodone Trazodone Monoamine Oxidase Inhibitors Phenelzine Tranylcypromine Selegiline i This list in not meant to be exhaustive but merely to show examples of antidepressants that could be combined with disulliram. Treatment with an antidepressant helps the patient overcome feelings of worthlessness and hopelessness.
To achieve this benefit from the antidepressant the patient is also required to take the disulfiram as part of the combination disulfiram-antideprssant medicine. The disulfiram in turn discourages the patient from consuming alcohol. Abstinence from alcohol is important in the overall management of depression.
While alcohol can help someone to fall asleep, it also "fragments" the sleep pattern. 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.2' 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. It is also very difficult for a patient to break a long established habit of consuming alcoholic beverages in the evening. Short term treatment with a combination of a suitable sedative or hypnotic with an appropriate amount of dislufiram will give the patient the. sleep they desire and help them break their ritualized automatic evening alcohol consumption behaviors. 'The sedative or t 5 hypnotic in this case may be but need not be a member of the benzodiazepine class.
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 2o 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.'-g. Heroin use may be associated with alcohol abuse and can complicate rehabilitation. A
25 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 disultiram would help the patient avoid alcohol consumption.
Chronic pain management with opioids may be associated with excessive a0 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.
Some examples of opioids to which disultiram 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~ receptor antagonist and proton pump inhibitors (or H+, K+ ATPase inhibitor) provide the patients with relief of symptoms such as pain.
l s Examples of histamine H, receptor antagonist are cimetidine, famotidine, ranitidine and nizatidine and 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 2o discouraged from consuming alcohol because of the disulfiram content of the medicine containing a histamine H, receptor antagonist or a proton pump inhibitor.
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.
25 the reduction of alcohol consumption in a clinical situation in which alcohol complicates the treatment of an undelying illness, are calcium carbimide, naltrexone, and acamprosate. Calcium carbimide, like disulfiram is an aldehyde dehydrogenase inhibitor. Naltrexone is an opioid antagonist and acamprosate interferes with central neurotransmitter effects of ale.ohol, both of which block the effects of alcohol 3o although the exact mechanism of action is not yet fully understood.
A benzodiazepine naltrexone combination medicine could contain 1 mg clonazepam and 50 mg of naltrexone. Other strengths of clonazepam may be used.
Naltrexone 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 I 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 disultiram, calcium carbimide, naltrexone ~ s 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, naltrexone or acamprosate with a pharmaceutical for the treatment of a disease or condition that is negatively affected by alcohol consumption such as anxiety, 2o depression, pain, insomnia, alcohol abuse, drug abuse, gastric or duodenal ulcer, epilepsy. The combination medicine can be comprised of disultiram, calcium carbimide, naltrexone or acamprosate with a pharmaceutical from the group of anxiolytics, anti-depressants, sedatives, hypnotics, opioids, histamine H2 receptor antagonists, proton pump inhibitors.
2s Example No. One A 43-year-old female suffers from chronic depression, panic disorder with agoraphobia and post-traumatic stress disorder. l:Ier 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. In order to control her drinking her clonazepam was replaced with the combination medicine consisting of clonazepam mg and disulfiram 250 mg . This combination prevented her from drinking. Her anxiety and insomnia improved and she was able to function much better.
Example No. Two This 42-year-old mother of two has a struggle 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 dysfhymia and generalized anxiety. Two week prior to treatment 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.
While in hospital the patient was started on a clonazepam I mg and disuli-iram 250 mg ~ 5 combination medicine. At discharge she was given a clonazepam 0.5 mg and disulfiram 125 mg combination medicine. On this medicine she has been able to control her urges to drink. As a result she has been able to improve her relationship with her husband and to re-enter the work force. After 2 months of use, her complete blood count was normal as were her liver and renal function tests. Her urine tested 2o negative for drugs of abuse. Five months after initiation of the combination clonazepam disulfiram combination medicine the patient remains on drug and is doing well.
Here we see this combination disulfiram-benzodiazepine medicine acts in an agonist-aversive manner that parallels but differs from the agonist-antagonist 25 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 -l._5-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 oi~this combined medicine but also long term effects of using a benzodiazepine to treat anxiety in an alcohol dependent patient.
Various embodiments of the present invention having been thus described in detail by way of example, it will be apparent to those skilled in the art that variations and modifications may be made without departing from the invention. The invention includes all such variations and modifications as fall within the scope of the appended claims.
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19. Kristenson, H. ( 1990. "How to get the best out of antabuse." Alcohol Alcohol 30(6): 775-83.
20. Fuller, R. K., L. Branchey, et al. (1986). "Disulfiram treatment of alcoholism. A
Veterans Administration cooperative study." Jama 256( 11 ): 1449-55.
21. Blow, F.C. (2000) ''Treatment of Older Women with Alcohol Problems:
Meeting the Challenge for a Special Population." Alcohol Clin Exp Res 24:1257-66.
22. Alcohol and Alcoholism. Page 2562 Harrison's Principles of Internal Medicine 15''' Edition 2001 McGraw-Hill 'Toronto.
23. Devanand, D.P. (2002) "(.'omorbid Psychiatric Disorders in Late Life Depression"
- 2~ -Biol Psychiatry 52:236-42.
24. Nierenberg, A.A. (2001) "Current Perspectives on the Diagnosis and Treatment of Major Depressive Disorder" Am J Manag Care 7(1 I Suppl):5353-66.
25. Benzodiazepine Monograph Page I 87 Compendium of Pharmaceuticals and Specialties 2001Thirty-sixth Edition Canadian Pharmacists Association Ottawa Ontario Canada.
26. Compounds Used For Anxiety Page 422. Goodman & Gilman's The Pharmacological Basis of Therapeutics 9"' Edition McGraw-Hill Toronto.
27. Medication-, Drug-, or Acohol-Dependant Insomnia. Page I 58 Harrison's Principles of Internal Medicine I S''' Edition 2001 McGraw-Hill Toronto.
28. Opioid Drug Abuse and Dependence. Page 2569 Harrison's Principles of Internal Medicine I5''' Edition 2001 McGraw-Hill Toronto.
review of the alcohol-disulliram reaction in practice." Br J Psychiatry 144: 200-2.
I 8. Kranzler, H. R. (2000). "Pharmacotherapy of alcoholism: gaps in knowledge and opportunities for research." Alcohol Alcohol 35(6): 537-47.
19. Kristenson, H. ( 1990. "How to get the best out of antabuse." Alcohol Alcohol 30(6): 775-83.
20. Fuller, R. K., L. Branchey, et al. (1986). "Disulfiram treatment of alcoholism. A
Veterans Administration cooperative study." Jama 256( 11 ): 1449-55.
21. Blow, F.C. (2000) ''Treatment of Older Women with Alcohol Problems:
Meeting the Challenge for a Special Population." Alcohol Clin Exp Res 24:1257-66.
22. Alcohol and Alcoholism. Page 2562 Harrison's Principles of Internal Medicine 15''' Edition 2001 McGraw-Hill 'Toronto.
23. Devanand, D.P. (2002) "(.'omorbid Psychiatric Disorders in Late Life Depression"
- 2~ -Biol Psychiatry 52:236-42.
24. Nierenberg, A.A. (2001) "Current Perspectives on the Diagnosis and Treatment of Major Depressive Disorder" Am J Manag Care 7(1 I Suppl):5353-66.
25. Benzodiazepine Monograph Page I 87 Compendium of Pharmaceuticals and Specialties 2001Thirty-sixth Edition Canadian Pharmacists Association Ottawa Ontario Canada.
26. Compounds Used For Anxiety Page 422. Goodman & Gilman's The Pharmacological Basis of Therapeutics 9"' Edition McGraw-Hill Toronto.
27. Medication-, Drug-, or Acohol-Dependant Insomnia. Page I 58 Harrison's Principles of Internal Medicine I S''' Edition 2001 McGraw-Hill Toronto.
28. Opioid Drug Abuse and Dependence. Page 2569 Harrison's Principles of Internal Medicine I5''' Edition 2001 McGraw-Hill Toronto.
Claims (45)
1. 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.
2. 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.
3. A combination medicine comprising pharmaceutically effective amounts of a first pharmaceutical and a second pharmaceutical, wherein the second pharmaceutical is an aldehyde dehydrogenase inhibitor.
4. The combination medicine of claims 1, 2 and 3, wherein said first pharmaceutical and second pharmaceutical are intimately co-mixed.
5. The combination medicine of claims 1, 2 and 3, wherein said combination medicine is in the form of one of the following: capsule, tablet, oral solution, suspension, water, suppository, transdermal patch, sublingual tablet, buccal tablet.
6. The combination medicine of claims l, 2 and 3, wherein the first pharmaceutical is chosen from the following group: anxiolytics, anti-depressants, sedatives, hypnotics, opioids, histamine H2 receptor antagonists, proton pump inhibitors.
7. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical treats one of the following: anxiety, depression, pain, insomnia, alcohol abuse, drug abuse, gastric or duodenal ulcer, epilepsy.
8. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is an anxiolytic.
9. The combination medicine of claim 8, wherein the first pharmaceutical is a benzodiazepine.
10. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is a benzodiazepine and the second pharmaceutical is disulfiram or calcium carbimide.
11. The combination medicine of claim 2, wherein the first pharmaceutical is a benzodiazepine and the second pharmaceutical is acamprosate or naltrexone.
12. The combination medicine of claim 10, wherein the benzodiazepine is chosen from the following: alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flurazepam, halazepam, lorazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam.
13. The combination medicine of claim 11, wherein the benzodiazepine is chosen from the following: alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flurazepam, halazepam, lorazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam.
14. The combination medicine of claims l, 2 and 3, wherein the first pharmaceutical is an anti-depressant.
15. The combination medicine of claim 14 wherein the said anti-depressant is chosen from the following group: tricyclics, secondary amine tricyclics, serotonin reuptake inhibitors, atypical antidepressants, monoamine oxidase inhibitors.
16. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: tricyclics, secondary amine tricyclics, serotonin reuptake inhibitors, atypical antidepressants, monoamine oxidase inhibitors; and the second pharmaceutical is disulfiram or calcium carbimide.
17. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: tricyclics, secondary amine tricyclics, serotonin reuptake inhibitors, atypical antidepressants, monoamine oxidase inhibitors; and the second pharmaceutical is acamprosate or naltrexone.
18. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: amitriptyline, clomipramine, doxepin, imipramine, amoxapine, desipramine, maprotiline, nortriptyline, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, bupropion, nefazodone, trazodone, phenelzine, tranylcypromine, selegiline; and the second pharmaceutical is disultiram or calcium carbimide.
19. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: amitriptyline, clomipramine, doxepin, imipramine, amoxapine, desipramine, maprotiline, nortriptyline, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, bupropion, nefazodone, trazodone, phenelzine, tranylcypromine, selegiline; and the second pharmaceutical is acamprosate or naltrexone.
20. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is a sedative.
21. The combination medicine of claim 20 wherein the said sedative is chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital.
22. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital; and the second pharmaceutical is disulfiram or calcium carbimide.
23. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital; and the second pharmaceutical is acamprosate or naltrexone.
24. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is a hypnotic.
25. The combination medicine of claim 24 wherein the said hypnotic is chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital.
26. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyrimidines, barbiturates, zopiclone, zaleplon, secobarbital; and the second pharmaceutical is disulfiram or calcium carbimide.
27. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: benzodiazepine, cyclopyrrolone derivatives, pyrazolopyritnidines, barbiturates, zopiclone, zaleplon, secobarbital; and the second pharmaceutical is acamprosate or naltrexone.
28. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is an opioid.
29. The combination medicine of claim 28 wherein the said opioid is chosen from the following group: methadone, codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, pentazocine, meperidine, propoxyphene.
30. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: methadone, codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, pentazocine, meperidine, propoxyphene; and the second pharmaceutical is disulfiram or calcium carbimide.
31. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: methadone, codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, pentazocine, meperidine, propoxyphene; and the second pharmaceutical is acamprosate or naltrexone.
32. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is a histamine H2 receptor antagonist.
33. The combination medicine of claim 32 wherein the said histamine H2 receptor antagonist is chosen from the following group: cimetidine, ranitidine or famotidine.
34. The combination medicine of claims l and 3, wherein the first pharmaceutical is chosen from the following group: cimetidine ranitidine or famotidine; and the second pharmaceutical is disulfiram or calcium carbimide.
35. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: cimetidine ranitidine or famotidine; and the second pharmaceutical is acamprosate or naltrexone.
36. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical is a proton pump inhibitor.
37. The combination medicine of claim 36 wherein the said proton pump inhibitor is chosen from the following group: omeprazole, lansoprazole, rabeprazole, pantoprazole or esomeprazole.
38. The combination medicine of claims 1 and 3, wherein the first pharmaceutical is chosen from the following group: omeprazole , lansoprazole, rabeprazole, pantoprazole or esomeprazole.; and the second pharmaceutical is disulliram or calcium carbimide.
39. The combination medicine of claim 2, wherein the first pharmaceutical is a chosen from the following group: omeprazole , lansoprazole, rabeprazole, pantoprazole or esomeprazole; and the second pharmaceutical is acamprosate or naltrexone.
40. The combination medicine of claims 1, 2 and 3, wherein the first pharmaceutical has deleterious or reduced effects when alcohol is ingested.
41. The combination medicine of claims 1 and 3, wherein the first pharmaceutical has deleterious or reduced effects when alcohol is ingested and the second pharmaceutical is disulliram or calcium carbimide.
42. The combination medicine of claim 2, wherein the first pharmaceutical has deleterious or reduced effects when alcohol is ingested and the second pharmaceutical is acamprosate or naltrexone.
43. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41, wherein the pharmaceutically effective amount of disulfiram is between 10 mg and 1000 mg daily.
44. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41, wherein the pharmaceutically effective amount of disulliram is between 250 mg and 500 mg daily.
45. The combination medicine of claims 10, 16, 18, 22, 26, 30, 34, 38 and 41, wherein the pharmaceutically effective amount of calcium carbimide is between 5 and 500 mg daily.
Priority Applications (3)
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CA002414500A CA2414500A1 (en) | 2002-12-17 | 2002-12-17 | Agonist-aversive combination medicines |
AU2003303015A AU2003303015A1 (en) | 2002-12-17 | 2003-06-25 | Combinations of medicaments comprising an alcohol deterrent for treating alcohol dependence or alcohol abuse |
PCT/CA2003/000990 WO2004054570A1 (en) | 2002-12-17 | 2003-06-25 | Combinations of medicaments comprising an alcohol deterrent for treating alcohol dependence or alcohol abuse |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002414500A CA2414500A1 (en) | 2002-12-17 | 2002-12-17 | Agonist-aversive combination medicines |
Publications (1)
Publication Number | Publication Date |
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CA2414500A1 true CA2414500A1 (en) | 2004-06-17 |
Family
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CA002414500A Abandoned CA2414500A1 (en) | 2002-12-17 | 2002-12-17 | Agonist-aversive combination medicines |
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AU (1) | AU2003303015A1 (en) |
CA (1) | CA2414500A1 (en) |
WO (1) | WO2004054570A1 (en) |
Cited By (1)
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WO2019147606A1 (en) * | 2018-01-26 | 2019-08-01 | Presti Michael | Combination treatments for opioid crisis |
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RU2350327C2 (en) | 2003-04-29 | 2009-03-27 | Ориксиджен Серапьютикс, Инкорпорэйтд | Compounds causing weight loss |
EP3132792B1 (en) | 2005-11-22 | 2019-09-11 | Nalpropion Pharmaceuticals, Inc. | Composition and methods for increasing insulin sensitivity |
US8916195B2 (en) | 2006-06-05 | 2014-12-23 | Orexigen Therapeutics, Inc. | Sustained release formulation of naltrexone |
WO2008045641A2 (en) * | 2006-10-10 | 2008-04-17 | The University Of Chicago | Composition s comprising a benzodiazepine, an alcohol aversive agent and an abuse aversive agent |
KR20140088619A (en) | 2006-11-09 | 2014-07-10 | 오렉시젠 세러퓨틱스 인크. | Unit dosage packages |
JP5651818B2 (en) | 2007-12-17 | 2015-01-14 | パラディン ラブス インコーポレーテッド | Controlled release formulation to prevent misuse |
MX2010012909A (en) | 2008-05-30 | 2011-02-25 | Orexigen Therapeutics Inc | Methods for treating visceral fat conditions. |
CA2746888C (en) | 2008-12-16 | 2015-05-12 | Labopharm (Barbados) Limited | Misuse preventative, controlled release formulation |
JP6196041B2 (en) | 2010-01-11 | 2017-09-13 | オレキシジェン・セラピューティクス・インコーポレーテッド | Methods for providing weight loss therapy in patients with major depression |
JP6355921B2 (en) * | 2010-09-01 | 2018-07-11 | 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TONIX Pharmaceuticals, Inc. | Treatment of addiction to cocaine |
MA37714A1 (en) | 2012-06-06 | 2017-12-29 | Orexigen Therapeutics Inc | Methods of treating overweight and obesity |
EP2705843A1 (en) * | 2012-09-05 | 2014-03-12 | Pharnext | Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis |
CN110420190B (en) * | 2019-08-29 | 2021-07-09 | 湖南洞庭药业股份有限公司 | Clonazepam tablets and preparation method thereof |
CN111420062A (en) * | 2020-04-29 | 2020-07-17 | 漳州卫生职业学院 | Synergistic agent for benzodiazepine drugs |
WO2022016097A1 (en) * | 2020-07-16 | 2022-01-20 | Musc Foundation For Research Development | G9a inhibition decreases stress-induced and dependence-induced escalation of alcohol drinking |
US20220117916A1 (en) * | 2020-10-19 | 2022-04-21 | SafeRx Pharmaceuticals, LLC | Combination Products to Mitigate the Risk of Non-Benzodiazepine Benzodiazepine Agonist Adverse Reaction and Overdose |
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US4873076A (en) * | 1988-04-29 | 1989-10-10 | Baker Cummins Pharmaceuticals, Inc. | Method of safely providing anesthesia or conscious sedation |
WO1992005787A1 (en) * | 1990-10-01 | 1992-04-16 | Radecki Thomas E | Drug therapy for alcohol abusers |
US5512593A (en) * | 1993-03-02 | 1996-04-30 | John S. Nagle | Composition and method of treating depression using natoxone or naltrexone in combination with a serotonin reuptake inhibitor |
-
2002
- 2002-12-17 CA CA002414500A patent/CA2414500A1/en not_active Abandoned
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2003
- 2003-06-25 AU AU2003303015A patent/AU2003303015A1/en not_active Abandoned
- 2003-06-25 WO PCT/CA2003/000990 patent/WO2004054570A1/en not_active Application Discontinuation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019147606A1 (en) * | 2018-01-26 | 2019-08-01 | Presti Michael | Combination treatments for opioid crisis |
US10478408B2 (en) | 2018-01-26 | 2019-11-19 | Michael Presti | Combination treatments for opioid crisis |
US10881625B2 (en) | 2018-01-26 | 2021-01-05 | Michael Presti | Combination treatments for opioid crisis |
US11786490B2 (en) | 2018-01-26 | 2023-10-17 | Michael Presti | Combination treatments for opioid crisis |
Also Published As
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AU2003303015A1 (en) | 2004-07-09 |
WO2004054570A1 (en) | 2004-07-01 |
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