Prescription & OTC Drugs – Charles France, Gregory Collins, University of Texas System
Abstract for “Methods and composition related to combination treatment for addiction”
“Certain embodiments address methods for treating or preventing addictive behavior in a subject. This is done by administering an effective amount to the subject of a 5-HT2C receptor agonist and a DA D3/D4 antagonist.
Background for “Methods and composition related to combination treatment for addiction”
“A. “A.
“B. “B.
“Recreational use and/or abuse drugs remain a serious public health problem. Worldwide estimates suggest that one in 20 adults (or a quarter of billion) used at least one drug of abuse (e.g. cocaine) in 2014. Although cocaine use by Americans reached its peak in 1980s, it has remained stable over the last 30 years. Recent estimates suggest that approximately 1.9 million Americans use cocaine regularly. There are also 19 million cocaine users worldwide. Despite decades of efforts to develop pharmacotherapies for cocaine abuse, the U.S. Food and Drug Administration has yet to approve any medication.
“Cocaine inhibits monoamine transport at DA (DAT), SERT (SERT), and NET (NET) transporters. However, abuse-related effects of cocaine are mediated primarily by its ability to increase DA neurotransmission. It is well-established that increases in synaptic levels DA, especially within the nucleus accumbens, play a crucial role in abuse-related effects not only of cocaine but also of a variety of drugs that interact with DAT indirectly, including opioids, ethanol and barbiturates. Drugs that target DA systems have been given a lot of attention because of their central role in cocaine abuse. Three main strategies have been used to develop pharmacotherapies against cocaine abuse. These include (1) direct or indirect DA receptor agonists that aim to replace cocaine use; (2) cocaine antagonists that block cocaine at the site(s) of its action; and (3) modulators, which alter the effects of cocaine by acting at other sites than DAT/DA receptors. These rational approaches to drug development are potentially transformative but come at a significant and growing cost. According to the Tufts Centre for the Study Drug Development, FDA approval of a new drug will take approximately 10 years and require $2.8 billion in R&D investment.
“There is a need for more therapies and regimens to treat different forms of addiction.”
“Antagonist” is the term used herein. A compound capable of: (i) altering the conformational status of a receptor, (or maintaining it in its inactive state to prevent it from binding its natural substance ligand), and/or (ii). binding to the receptor and preventing or decreasing activation. Partial agonists can be used as antagonists to activate the receptor at a low, but sufficient level. This effectively antagonizes the receptor’s down steam signaling pathways and inhibits its upstream activity.
“Anonym” is the term used herein to refer to a compound that can alter the conformational state of a receptor by stabilizing its active conformation and/or maintaining it in its active conformation. A compound capable of: (i) altering a receptor’s conformational state by stabilizing it and/or maintaining it in its active conformation, and/or (ii), binding to that receptor activating/increasing its activity.
“A ?combination therapy? A therapy in which both a DA D3/D4 antagonist and a (5?HT)2C receptor agonist are given to a subject. You can co-administer or have the (5-HT2C receptor agonist and the DA D3/D4 antagonist administered together. You can administer them separately or at separate times. Buspirone is a preferred antagonist of the DA D3/D4 receptor. Lorcaserin is a preferred (5-HTT)2C receptor antagonist. Combination therapy can be used to treat an addiction.
“Antagonists of DA D3/D4 can include buspirone, PG 01037 and SB 277011A, trifluoperazine (A-381393), L-745.870, L-741.667, L-741.742, L-741.742, L-741.742, L-741.742, L-741.742, L-741.742A, S18126, fananserin. Clozapine, FAUC 213, sonepihydrochloride, PD 168568, PNU 96415E, or their salts.
“Agonist of (5-HT)2C receptor can include, but is not limited to lorcaserin, CP 809101, Ro-60-0175, WAY 161503, WAY 163909, MK 212, meta-chlorophenylpiperazine (mCPP), 1-methylpsilocin, Org 12962 hydrochloride, or salts thereof.”
“?Treating?” refers to any action, e.g. lessening or reducing, modulating or eliminating that results in an improvement of the condition, disorder, etc.
“Preferably the term ‘Subject? The term subject refers to a mammal. The term subject is more preferred to refer to a primate. The term subject is more preferred to be a human.
“Pharmaceutically and Pharmacologically Acceptable?” Include molecular entities or compositions that don’t cause an untoward reaction when given to animals or humans.
“Pharmaceutically Acceptable Carriers? This includes all solvents, dispersion medium, coatings and antibacterial and/or fungal agents. It also includes isotonic or absorption delay agents. This is a well-known practice in the art. It is possible to use any of these media and agents in therapeutic compositions, except in cases where they are incompatible with the active ingredients. You can also include additional active ingredients into the compositions.
“The expression “therapeutically effective amount” is used herein. “The term “therapeutically effective amount” is used herein to refer to the amount of an agent or compound, drug, composition or drug combination that is effective in producing a desired therapeutic effect upon administration of the invention to a subject (e.g. a patient or human subject).
“Administering to a subject” or “administrating to a patient” refers to the act of injecting an agent, compound or drug, composition, or combination thereof into a subject’s or patient’s body using an art-recognized method of introduction (e.g. orally, transdermally or via injection
This application discusses other embodiments of the invention. Any embodiment that is discussed in relation to one aspect or part of the invention can also be applied to other aspects. All embodiments described herein are considered to be embodiments that can be applied to all aspects. Any embodiment described herein may be used with any method or composition according to the invention. You can also use compositions or kits of the invention to realize methods of the invention.
“The use of?a? “The use of the word?a?? oder?an? When used with the term “comprising” In the specification and claims, it may be referred to as?one? It is however consistent with the meanings of?one? and?more? It is also consistent with the meaning of?one or more,? “At least one”?
“The term ‘about? is used throughout this application. “About” is used in this application to indicate that a value includes any standard deviation of error due to the device or method being used to determine it.
“The term ‘or? is used in the claims. “The term?or” is used in the claims to refer to?and/or?” Except where it is explicitly stated that the alternative(s) are exclusive or mutually exclusive, the claims use?and/or?
“Comprising” is used in the claim(s) and specification. (and any other form of including, such as ‘comprise? ?comprises? ), ?having? (and any other form of having, like?have? (and any form of having, such as?have? ), ?including? (and any other form of including, such?includes? (and any form of including, such as?includes? or?containing? (And any other form of containing, like?contains? (and any form of containing, such as?contains? These terms are inclusive or open-ended, and they do not exclude any additional elements or steps.
The following description will reveal other objects, features, and advantages of this invention. However, it should be noted that while the examples and detailed description are intended to illustrate specific embodiments of this invention, they are only illustrations. Those skilled in the art will see many modifications and changes within the spirit and scope.
“DESCRIPTION DU DRAWINGS”
The following drawings are part of the present specification. They serve to demonstrate certain aspects of this invention. You may find the invention easier to understand if you refer to these drawings along with the detailed description of each embodiment of the specification presented herein.
“FIG. 1. Effects of a 1:1 mixture of lorcaserin and buspirone on self-administration of cocaine in rhesus monkeys
“FIG. 2. The effects of buspirone in responding are maintained at 0.032 mg/kg/inf cocaine (PR) or restored to 0.32 m/kg cocaine by 4 rhesus monkeys (2 females and 2 males).
“FIG. 3. Response to lorcaserin maintained at 0.032 mg/kg/inf cocain (PR), or restored by 0.32 m/kg cocaine (4 rhesus monkeys; 2 males and 2 women).
“FIG. 4. A simplified schematic of the mesolimbic DA systems showing the potential sites for interaction between buspirone and lorcaserin. GABAergic inhibition would be enhanced by activation of 5-HT2C-receptors located on GABAergic neuron within the VTA (labeled A in the Figure). Antagonism of the post-synaptic DA D3 (labeled C in the figure), within the NAcc would also enhance GABAergic inhibition mesolimbic DAergic nervetransmission.
“FIG. 5. Mixtures of lorcaserin/buspirone are effective. They can be administered at fixed doses of lorcaserin/buspirone of 3:1, 1:1, or 1:3. This is relative to the ED50 for each drug. It reduces PR response for cocaine (0.32 mg/kg/inf). To determine the expected additive effect level for each combination of doses, dose addition analyses were performed (total dose expressed in lorcaserin equivalents). Experimentally determined effects can be expressed as the group average for 4 rhesus monkeys, as well as 2 males and 2 women.
“FIG. 6. Hypothetical data showing rightward shifts of the cocaine dose-response curve, and estimation of ED2-fold values for a fixed-ratio combination of lorcaserin & buspirone.”
“DESCRIPTION”
“The following discussion will focus on various embodiments and uses of the invention. “Invention” is not intended to refer to any particular embodiment. The term “invention” does not refer to any specific embodiment. It is not meant to limit the scope of disclosure. While one or more embodiments may be preferred over another, the disclosed embodiments should not be taken to limit the disclosure’s scope, including the claims. One skilled in the art will also understand that the description of each embodiment has broad applicability. The discussion of any embodiment is intended only to illustrate that embodiment and is not meant to limit the disclosure, including the claims.
Buspar? is an anxiolytic medication that is used primarily to treat generalized anxiety disorder (GAD). Buspirone is often used to supplement antidepressants for the treatment of depression. Buspirone’s pharmacology is different from other anxiolytics. It is not similar to the benzodiazepines or barbiturates. Also, it is not a GABA agonist. Therefore, buspirone doesn’t carry the risks of dependence and withdrawal symptoms that are associated with these drug classes. Buspirone is not a drug-of abuse, it is less dangerous than traditional anxiolytics in overdose, and it is significantly less harmful at therapeutic doses.
“I. Dosages, Administration and Pharmaceutical Products
The skilled artisan can determine the appropriate dosages of drugs in combination therapy according the invention. This is done by observing the patient, including their overall health and response to the treatment. If a patient does not exhibit the desired therapeutic effect, or conversely, if they are experiencing unwanted or adverse side effects or severe symptoms, optimization may be required.
“Preferably, one of the components of the combination treatment of the invention is/are given at or below a routinely used dosage by the skilled physician (e.g. physician) to promote desired therapeutic effects of the drug when it is used as monotherapy.
“In one embodiment, the components of the combination (e.g. DA D3/D4 antagonist and/or a (5?HT)2C receptor agonist) are/are prescribed at a dose lower than the usual dose for each component as a monotherapy. You can either prescribe the components separately or in combination.
“In one embodiment, each of the components (e.g., DA D3/D4 antagonist and a 5-HT)2C receptor agonist) are prescribed at a dose higher than the usual monotherapy dose. You can either prescribe the components separately or in combination.
“In another embodiment, a prescribed dose of the DA D3/D4 antagonist is higher than the usual monotherapy dose. The (5-HT)2C agonist is prescribed at a dose that is equal or lower to the monotherapy dose. Another embodiment prescribes the DA D3/D4 antagonist at or below the monotherapy dose, while the (5-HT/2C receptor agonist at a dose that is higher than the monotherapy dose.
For ease of administration and uniform dosage, it is particularly advantageous to prepare compositions of the invention using a unit dosage form. What is the term “unit dosage forms?”? As used herein, the term “unit dosage forms” refers to physically distinct units that are suitable as unitary doses for individuals being treated. The compositions are divided into discrete dosage units that each contain a predetermined unit dosage. The active compound is calculated to have the desired therapeutic effect when combined with the appropriate pharmaceutical carrier. Specifications for the new dosage units of the invention depend on the specific characteristics of the composition containing DA D3/D4 receptor antagonist or (5-HT)2C receptor agonist, and the therapeutic effect that is to be achieved. The usual dosage and method of administration can also be used to determine the dose. The present invention also allows for the creation of a single, physically distinct dosage form containing each active ingredient of the combination treatment. For example, a single dosage formulation containing a DA D3/D4 antagonist and a (5?HT)2C receptor agonist.
The method of administering compositions or combinations will depend on which DA D3/D4 receptor antagonist is used and the (5-HT)2C receiver agonist. The DA D3/D4 antagonist and (5-HT]2C receptor agonist can be administered in one composition, or in combination in two different compositions. One or more DA D3/D4 antagonists and (5-HT]2C receptor agonists may be administered to a patient or subject in a therapeutic composition, or in combination with one or more other compositions, e.g. one or more compositions administered simultaneously, or sequentially. The type of DA D3/D4 receptor antagonist or (5-HT]2C receptor agonist will determine the schedule of administration.
A pharmaceutically acceptable carrier can be used to administer the “DA D3/D4 receptor antagonist or (5-HT)2C receptor agonist.” “Pharmaceutically acceptable carrier” is defined herein. Any solvents, dispersion medium, coatings, or antibacterial and/or fungal agents, as well as isotonic/absorption delay agents and the like. This is a well-known artifact. It is possible to use any of these media and agents in compositions according to the invention, except in the event that they are incompatible with the active substance.
Orally administered DA D3/D4 antagonists or (5-HT]2C receptor agonists are preferred. An inert diluent, or assimilable edible carriers may be used when the composition is administered orally. You can also include the composition with other ingredients in a capsule or tablet made of hard shell gelatin. The composition can be combined with excipients for oral therapeutic administration. It may be used as ingestible tablets or buccal tablets, troches and capsules. You can vary the percentages of compositions and preparations. It is possible to obtain a proper dosage by adjusting the amount of active compound contained in therapeutically useful compositions. The present invention provides a pharmaceutical composition that contains a therapeutically-effective amount of a DA D3/D4 antagonist and a (5?HT)2C receptor agonist. In one embodiment, the present invention includes a therapeutically-effective amount of a DA D3/D4 receptor antagonist and a (5-HT)2C receptor agonist packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). This packaging encourages patients to use the drug regimens and promotes products. These packaging can reduce confusion among patients. These kits are further described in the present invention.
Tablets, tablets, pills, capsules, and the like can also contain a binder or excipient. As coatings, or to modify the physical form the dosage unit in any other way, a variety of materials can be used. Shellac, sugar, or both can be used to coat tablets, capsules, and pills. Any material used to prepare any dosage unit form must be pharmaceutically pure, and in substantially low amounts.
A DA D3/D4 antagonist or a (5?HT)2C agonist can be administered alone or in combination DA D3/D4 antagonist or a (5?HT)2C agonist. It can also be administered subcutaneously, intravenously, or by injecting. Inhalation, transdermal or rectal administration. Depending on the route of administration the composition containing the DA/D3/D4 antagonist and/or (5/HT)2C receptor agonist can be coated with a material that protects the compound from the effects of acids or other natural conditions which could inactivate the compounds.
“To administer the compositions transdermally or via injection, it might be necessary to co-administer or coat the composition with a material to prevent inactivation. The composition can be administered in a suitable diluent, or in a carrier like liposomes to the individual. Saline and aqueous buffer solutions are both pharmaceutically acceptable diluents. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. (1984) J. Neuroimmunol. 7:27). Dispersions that contain a DA D3/D4 receptor antagonist or a (5-HT]2C receptor agonist can be administered intraperitoneally or parenterally in glycerol, liquid PEG, oils, or mixtures thereof. These preparations can contain a preservative to inhibit the growth of microorganisms under normal storage conditions.
“Compositions that are suitable for injection include sterile aqueous solutions where water is soluble, dispersions, and sterile powders to extemporaneously prepare sterile injectable solutions. The composition must be fluid and sterile in all cases. The compositions must be stable in storage and manufacture, and protected against microorganisms like bacteria and fungi. A solvent or dispersion media can be used as the carrier. It could contain water, ethanol, polyol (for instance, glycerol and propylene glycol), and suitable mixtures thereof. For example, a coating like lecithin can be used to maintain fluidity. Surfactants can also be used to maintain the required particle size for dispersion. Many antibacterial and antifungal substances can be used to prevent the microorganisms from acting. It is preferable to include in the composition isotonic ingredients, such as sugars, polyalcohols like mannitol or sorbitol, and sodium chloride. You can prevent prolonged absorption of injectable compositions by adding an agent that delays absorption to the composition, such as aluminum monostearate or gelatin.
One aspect of the invention is that it prescribes a DA-D3/D4 receptor antagonist as well as a (5HT)2C receptor agonist in order to treat addiction. The average daily dose of each component is between 2 and 600 mg, which includes doses of 2, 5, 10, 20, 30, 50, 70, 80 or 90. It also includes doses of 150, 200, 300 to 400 mg, 500 to 600 mg daily.
“Another embodiment of the invention includes pharmaceutical compositions, e.g. for oral administration, comprising DA 3D4 receptor antagonists and a (5-HT2C receptor agonist in a single pharmaceutical formula. These compositions can be used to increase patient compliance, for example by reducing the number required to achieve desired pharmacologic effects.
“A. Additivity/Synergy”
Combinations of one or more DA D3/D4 antagonists in combination with one (5-HT)2C agonist are synergistically efficient. Synergy refers to the interaction of multiple agents that has a greater effect than their individual effects. If drug A has a 25% effect on a disease, while drug B’s effect is 25% on the same disease, then synergy is when two or more agents work together to create a greater effect.
“Additivity” is the interaction between two or more agents such that their combined effect exceeds each individual and is as great as their sum.
An improvement in drug therapy can be defined as the combination of two or more agents that reduce the risk of adverse events (AEs) in either one or both of the agents. The administration of lower doses of one or both agents in co-therapy can result in a reduction in the incidences of AE. If Drug A alone has a 25% effect and there is a 45% AE incidence at the labeled dosage, and Drug B alone has a 25% effect and an AE incidence at the labeled dosage, then combining the two drugs at lower doses will result in enhancing the drug therapeutic regimen. The adverse incidence rate is 20% and the overall effect is 35%.
“B. “B.
Combination therapies allow DA D3/D4 receptor antagonists and (5-HT]2C receptor agonists to be administered at lower doses to minimize side effects. This allows for a reduction in the dosage of each compound required for monotherapy and an extension of the therapeutic range.
“C. Equivalents”
“Those who are skilled in the art will be able to recognize or determine using routine experimentation many alternatives to the procedures described herein. These equivalents are included in the scope of the invention. They are covered by the claims and current specification. You can make many substitutions, modifications, or alterations to the invention, without changing the spirit or scope of the invention, as described in the claims.
“II. Addiction”
Addiction refers to a psychological or physical dependence on a substance, or activity, that can be harmful or interfere with the addict?s daily life. A physical or psychological dependence can be caused by illegal and legal drugs. Prescription drugs may also be included. Illicit drug addiction can have a devastating effect on society as addicts often resort to criminal activity to fund their addiction. Illicit addictive substances include marijuana, cocaine, opiates and sedatives, as well as opiates and sedatives. Some prescription medications, caffeine, nicotine, and alcohol can all be addictive. Gambling, shopping, exercising, working, computer usage, internet use, sex and cleaning are all examples of addictive activities that can interfere with a person’s daily life.
Cocaine is an addictive and commonly used illicit drug that can be used to get high from the coca leaves. The signs of cocaine addiction include compulsive and obsessive drug use that is hard to stop. Statistics show that cocaine addicts who manage to quit using cocaine have a high chance of relapse. This is because their cravings for cocaine remain after they stop using. An abrupt stoppage of cocaine use can lead to withdrawal symptoms such as anxiety, depression, and sleep disturbances in addicted users. Although psychotherapy is a common treatment for cocaine addiction in rehab centers, dropout rates are high. It is difficult to provide a long-term treatment for cocaine addiction due to withdrawal symptoms and vulnerability to relapse.
Cue reactivity is an affliction that many addicts exhibit. Cue reactivity refers to the way an addict reacts physiologically or psychologically to a stimulus that is related to his addiction. Exposure to a cue that is associated with an addict’s previous use of cocaine can trigger or increase cravings in many cases. A person who is addicted to smoking cigarettes or someone trying to quit smoking may feel compelled to smoke a cigarette. An alcoholic, or an alcoholic in recovery, may feel a need to drink alcohol by hearing the wine glasses crackle. A cocaine addict may feel compelled to buy drug-related paraphernalia. Cue reactivity can continue long after an addict stops using, increasing the risk of relapse. Many rehab programs encourage addicts not to get addicted. They can also receive cues to help them in their recovery process.”
“In some embodiments, the addiction that is to be treated/prevented as disclosed herein may be a physical dependence on an agent (an addictive drug) or a specific behavioral pattern. An agent that causes a physical dependence can be any of the following: prescription drugs (and OTC drugs), illicit drugs, alcohol, or any combination thereof. This agent is called the “addictive agent”. The agent is generally a persistent compulsion to use or abuse the agent. This can be despite the potential for serious consequences to one’s mental and physical health. Addictive behavior is also known as “addictive behavior”. Similar to gambling and compulsive eating, the term “addictive behavior” refers to a behavioral compulsion.
“In some embodiments, addiction is caused and controlled by an addictive agent. This can be selected from addictive recreational drugs or addictive medications.
“In some embodiments the addictive agent may be selected from alcohol, nicotine, cannabis and Cannabis derivatives as well as opiates, morphine-like and phencyclidine compounds, phencyclidine or phencyclidine-like compound, sedatives hypnotics and psycho-stimulants and amphetamines-related drugs.”
“In additional embodiments, the addictive agent is selected from alcohol, caffeine, nicotine, Cannabis, morphine, heroin, codeine, cocaine, hydrocodone, hydromorphone, levorphanol, metapon, nalorphine, naloxone, naltrexone, oxycodone, oxymorphone, tramadol, ethoheptazine, fentanyl, levorphanol, meperidine, methadone, phenazocine, propoxyphene, sufentanil, phencyclidine, benzodiazepines, methaqualone, mecloqualone, etaqualone, pemoline, amphetamine, methamphetamine, methylenedioxymethamphetamine, dextroamphetamine, methylamphetamine, and synthetic derivatives of cathinone.”
“In other embodiments, the addictive agent is selected amongst pain-killer such as alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene sufentanil, tramadol, tilidine and any combination of any of the aforementioned agents.”
“In additional embodiments, an addictive agent can be selected from apomorphine (beta-hydroxy 3-methylfentanyl), carfentanil and dihydroetorphine as well as methadyl acetate. Papaverine, remifentanil. thebaine, or tramadol.
“In some instances, the addiction to cocaine is present.”
“Some embodiments of addiction are in the form of compulsive behaviors (addictive behaviour). These may include obsessive eating disorder, compulsive spending or gambling, pathological overeating and pathological electronic device and communication devices like cellular phones and cell phones, pathological electronic gaming, addiction to pornography, sex, eating disorders like anorexia, bulimia, and kleptomania as well as compulsive exercise and overwork.
“In some embodiments the addiction can be to one or more addictive drugs and/or addictive behaviors.” One or both addictions can be to an addictive agent in some embodiments.
“If treatment as described herein fails, it is possible to repeat the treatment, such as by following the treatment protocol.”
“III. Examples”
“The following examples and figures demonstrate preferred embodiments. Those skilled in the art should recognize that the techniques shown in the figures or examples are techniques that were discovered to work well in the practice and application of the invention. They can therefore be considered preferred methods for its use. However, those skilled in the art will appreciate that there are many modifications that can be made to the disclosed embodiments and still achieve a similar or comparable result. This is in keeping with the spirit and scope the invention.
“Therapeutic Potential for Drug Addiction Receptor Antagonists DA D3”
“DA receptor antagonists have been given a lot of attention due to their potential use as drugs for cocaine abuse, because of the important role of DA in mediating abuse-related effects of cocaine. D1-like (D1, D5, and D2) receptor antagonists decrease cocaine self-administration in laboratory animals. This suggests that all five subtypes of DA receptors may contribute to the abuse-related consequences of cocaine. Preclinical research has shown that the DA D1 antagonist ecopipam, SCH 39166, was effective at reducing cocaine self-administration in laboratory animals. However it failed to alter the subjective and reinforcing effects of cocaine in humans when administered in doses that didn’t produce sedation. Similar results have been observed for DA D2 antagonist-preferring antagonists such as haloperidol. However, it is not clear how these negative effects are affected by extrapyramidal side effect, which is typical of DA D2 antagonists.
“Although AEs prevent further development of DA D2 antagonists, the DA D3 agonist has been given considerable attention. This is based on three key characteristics of the receptor. (1) DA D3 receptive receptors are mainly expressed in limbic areas of the brain including the NAcc. (2) DA D3 receptive receptors are upregulated in rats that have had repeated cocaine administration. (3) An antagonists and partial agonists selective to the DA D3 receptor inhibit cocaine self-administration. These findings suggest that the DA D3 agonist should be a viable target for drugs aimed at treating cocaine addiction. However, FDA approval is not currently available to test this hypothesis in humans.
Buspirone has been a surprising candidate to test the DA D3 hypothesis of cocaine abuse in recent years. Buspirone, originally designed to block DA D2-like receptor antagonists, was later found to be more effective in treating anxiety than psychoses. This effect is believed to be due to buspirone’s partial agonist effects on 5-HT1A receptors, rather than its antagonist actions on DA D2 receptors. Buspirone was approved for the treatment of generalized anxiety disorder in 1986 at doses up to 60mg. Despite the apparent selectivity of 5-HT1A receptors (relatively to DA D2 receivers), recent research suggests that buspirone may be roughly equal at DA D3 and DA D4 receptors. Buspirone was approved by the FDA to be a valid, FDA-approved medication for testing the DA D3 hypothesis of cocaine abuse due to its highly selective binding profile (?5-70fold). Buspirone decreased self-administration of cocaine in rhesus monkeys and cynomolgus monkeys. However, it did not alter the reinforcing effect of cocaine in human laboratory studies (30 mg) or prolong abstinence in a pilot study (60 mg), which was randomized, double-blind and placebo-controlled. It is important to remember that Volkow and his colleagues have shown that buspirone needs to be administered at a threefold higher dose to treat addiction.
“Preliminary data from Bergman’s laboratory confirm and expand reports by Bergman, colleagues, and show that buspirone dose-dependently reduces the reinforcing efficacy of cocaine when responding to a progressive ratio schedule of reinforcement (FIG. 2; top panel), and the effectiveness of cocaine in restoring extinguished cocaine responding (FIG. 2; bottom panel). Preliminary data from four monkeys (male and female) suggest that buspirone is about?10-fold stronger in males than it is in females when it comes to decreasing cocaine self-administration according to the PR schedule (FIG. 2). This is supported by clinical data. The 60 mg buspirone dose was more effective in promoting abstinence for males than it was for females.
Preclinical evidence strongly suggests that buspirone may be an effective treatment for cocaine addiction. However, it failed to alter the clinical endpoints associated with cocaine abuse when given in doses greater than 60 mg. This suggests that higher doses or different formulations (e.g. buspirone:locaserin combinations) are required. In order to achieve clinically relevant outcomes, drug combinations containing a lower dose of buspirone than the FDA-approved maximum of 60 mg were considered by the inventors.
“Therapeutic Potential for 5-HT2C Receptor Aggonists for Drug Addiction.”
Serotonin (5HT) systems play a significant and well-documented part in modulating goal-directed behavior, such as feeding. Evidence that 5-HT2C receptors mediate hypophagic effects of indirect and direct-acting 5-HT receptor agonists has led to significant research into the development of selective 5-HT2C receptor agonists. These agonists are designed to decrease appetite and produce hallucinations (5-HT2A receptor mediated), which are common with less selective and/or indirect 5-HT drugs. This is a direct application of the fact that 5-HT2C receptor antagonists not only reduce food intake but also decrease self-administration. This is consistent with a larger role for 5-HT2C in regulating drug- and food-motivated behavior.
“In the years since the initial discovery, significant progress has been made in understanding the neuro-, behavioral, and molecular pharmacology (5HT2C receptors.” There is mounting evidence that 5-HT2C receptors in pro-opiomelanocortin neuronal regions are responsible for anti-obesity. However, the anti-addiction effects from 5-HT2C receptor agonists may be due to their ability to modulate mesolimbic DA neuraltransmission. In fact, 5-HT2C receptors can be found on the ventral tegmental areas (VTA), as well as the DA nerve terminals in the NAcc. This distribution pattern allows 5-HT2C to play an important role controlling the activity and DA systems in activated and basal conditions.
A variety of agonists that have preferential activity at 5-HT2C receptors (e.g. Ro 60-0175 and MK 212) have been shown in studies to reduce cocaine self-administration and/or to inhibit the reinsertion of a previously strengthened response to cocaine. These findings support the hypothesis that activating 5-HT2C receptors reduces drug abuse-related effects. However, it is not clear if 5-HT2C agonists can have similar effects on humans.
Based on functional assays using cells transfected by human 5-HT2C, 2B or 2C receptors, Lorcaserin has been shown to be?20-fold more selective for 5-HT2C than 5-HT2A receptors and ‘100-fold more selective for 5-HT2C than 5-HT2B receptors. A series of placebo-controlled, multicenter trials showed that lorcaserin was effective in reducing weight and improving health outcomes. The FDA approved lorcaserin in 2012 (maximum 10 mg twice daily) for obese adults with at-risk weight. Surpre-therapeutic doses (20-60 mg) of lorcaserin received subjective ratings of?high’,?good effects? from recreational drug users. lorcaserin was designated Schedule IV by the DEA due to its agonist effects at 5-HT2A receptors. These effects are consistent with agonist actions and cause?hallucination?. Recent reports have shown that lorcaserin causes 5-HT2A receptor-mediated headache-twitches in rodents, a model of hallucination. These effects are comparable to the doses required to lose body weight in rats.
According to the premise that 5-HT2C receptor agonists reduce the abuse-related side effects of drugs, inventors have recently reported that acute lorcaserin administration dose-dependently inhibits cocaineself-administration in rhesus monkeys under both fixed-ratio and PR reinforcement schedules. These studies also revealed that lorcaserin’s anti-cocaine effects were (1) evident at doses that also produced other 5-HT2C receptor mediated behavioral effects and (2) not due to a pharmacokinetic interactions between cocaine and lorcaserin. They also demonstrated that the effects lasted at least 14 days after repeated (daily), treatment with lorcaserin. Rats self-administering cocaine or nicotine have experienced similar acute effects to lorcaserin.
“Preliminary data were collected in the same four monkeys used to test buspirone (FIG. 2) confirm our initial findings and show that lorcaserin dose-dependently reduces the reinforcing efficacy of cocaine when it is administered under a PR reinforcement schedule (FIG. 3; top panel), and the effectiveness of cocaine in restoring an extinguished cocaine response (FIG. 3; bottom panel). Although the magnitude of these differences was smaller than that observed for buspirone in terms of potency, they were still significant in decreasing cocaine self-administration. However, females were slightly more sensitive to lorcaserin than males, and this was not unlike buspirone.
Clinical efforts have been made to quickly and rationally repurpose Lorcaserin for treatment of cocaine abuse disorder because of the consistent preclinical evidence. There are currently four safety and effectiveness trials that ClinicalTriails.gov has registered. Although no data is available on the effectiveness of Lorcaserin in reducing cocaine use in humans, they do have some published data. One Phase I trial was completed, but it has not been reported (NCT02393599), while two other Phase I trials (NCT02537873 & NCT02680288) are currently enrolling subjects. The registration of a Phase II multi-site trial of lorcaserin in the treatment of cocaine abuse disorder has been completed but it has not begun to recruit subjects. It is important to note that lorcaserin doses only slightly higher than the ones approved/required for its therapeutic effects can cause feelings of high? Feelings of?high? and?hallucinations have been reported. agonists at 5-HT2A receptors. Thus, there is a clear need to develop formulations/treatment strategies that minimize the total dose of lorcaserin required to effectively reduce cocaine use and/or prolonging abstinence from cocaine use. The hypothesis that drug combinations containing buspirone and lorcaserin are more potent or effective in decreasing cocaine self-administration, and/or inhibiting reinstatement of extinguished response for cocaine use, will be thoroughly tested.
“The inventors began to use non-human primates to test FDA-approved drugs for cocaine abuse. Although rational repurposing FDA-approved drugs can dramatically reduce the cost and time required to get effective treatment for cocaine abuse (and other drugs) into the clinic, it has been difficult to translate positive preclinical results to clinically relevant outcomes. Czoty, along with colleagues, used the case of lisdexamfetamine, a d-amphetamine drug prodrug, to illustrate some of the challenges in translating preclinical successes into effective treatments in the clinic. They describe that even though drugs like lisdexamfetamine reduce self-administration of cocaine in nonhuman primates they often fail to improve abstinence in clinical settings. Mooney and co-workers point out that although there were differences in the endpoints, i.e., the reduction in preclinical drug-taking and complete abstinence at the clinic, they did not evaluate lisdexamfetamine. They also noted that the clinical efficacy of the drug was only evaluated for the dosages approved for attention-deficit/hyperactivity disorder (ADHD). Larger doses would likely have had a positive clinical outcome. Similar conclusions were reached when buspirone was found to decrease cocaine intake in preclinical studies but not to maintain complete abstinence in clinical settings. Volkow and his colleagues found that buspirone must be administered at doses at minimum 3-fold higher than the 60 mg maximum dose for anxiety treatment in order to reach clinically relevant levels of DA D3 receptor occupancy. Therefore, it is imperative to not only develop new therapeutics but also to improve/augment drug potency/effectiveness so that users can abstain from using drugs that have been approved for other conditions.
“Studies that evaluate combinations of drugs that target pre- (e.g. 5-HT2C receptors), and post- (5HT2C receptors), synaptic regulators for DA neurotransmission have shown that they produce a therapeutic effect (e.g. decrease in drug intake, reinstatement, etc.). This is more than the effects of one drug alone (i.e. supra-additive interactions). Their ability to modulate activity of mesolimbic DA neuron (FIG. The FDA approved drug buspirone has antagonist DA D3 receptor properties. Lorcaserin is an FDA-approved drug that can agonist 5-HT2C receptors. It acts on 5-HT2C receptors in the NAcc and VTA that are responsible for GABAergic neurons (FIG. Lorcaserin inhibits mesolimbic DA neurons that project from the VTA into the NAcc (FIG. 4). This decreases the effectiveness of cocaine to increase synaptic DA levels. Similar effects can be seen by blocking the DA D3 receptors in the NAcc (FIG). Buspirone also inhibits cocaine-induced increases of DA signaling by antagonizing DA D3 receptors within the NAcc (FIG. The FDA approved both drugs used in this study to test the hypothesis. This will allow the FDA to translate the findings into clinical practice.
“The proposed studies will also combine state-of the-art self-administration (PR, food-cocaine choice), reinstatement protocols, radio-telemetric assessments and radio-telemetric evaluations of cardiovascular effects with sophisticated dose addition analyses (FIG. 5) to characterize and quantify the nature of interactions between lorcaserin (therapeutic) and buspirone (potentially AEs). The data from 4 rhesus monkeys shows that lorcaserin is more potent than buspirone and has a greater effect on cocaine self-administration when they are mixed at fixed dose ratios of their ED50. The dose-response curves of buspirone and lorcaserin in 1:1 and 1:3 combinations were, respectively, moved?3 to?5 times to the left than the additive dose-response, which indicates a supra-additive interaction. These results not only support the hypothesis, but also indicate that it is possible to lower the dosage of each drug while maintaining and possibly increasing the therapeutic efficacy of buspirone and lorcaserin.
“Interestingly, this is consistent with the large sex-related variations observed for buspirone (FIG. 2), sex-related variations were also observed for drug mixtures. Females were?10-fold more sensitive to 1:3 lorcaserin-buspirone mixture than their male counterparts (FIG. 5). This was surprising considering that females were more sensitive to buspirone (an effect consistent with clinical reports that buspirone has a lower effectiveness in promoting abstinence in males than in females). These findings suggest that combination of lorcaserin/buspirone may be especially effective in reducing cocaine use among females. It is not possible to say that the differences between male and female sexes are due to sex.
“Experimental Subjects. In confirmation studies, 20 adult rhesus monkeys (10 female and 10 male) will be used. The historical and preliminary data were used to perform power analyses for each assay (PR. choice. reinstatement. and cardiovascular). These results were used to calculate power (Student t test for independent samples; PASS 2011 Kaysville, Utah). A total of 10 (five males and five females) were found to be sufficient to detect with 80% power a shift of at most 2-fold in dose-response curves to self-administration or reinstatement (effects only of buspirone and lorcaserin), as well as a 20% difference between cardiovascular endpoints. These calculations assume that there are underlying sex-related differences for each endpoint and lead to studies that can detect significant effects using both within sex analysis and between.
“Inhibition Drug-Taking and Drug Seeking. The fact that pharmacotherapies to combat cocaine abuse must block the drug-seeking behavior and the reinforcing effects of cocaine is a problem. To demonstrate that buspirone and lorcaserin both decrease the reinforcing efficacy (PR) as well as the relapse-related effects of cocaine (reinstatement), studies used a simple (i.e. a single option; respond or not). FIG. 2 and FIG. 3. 3). Buspirone and lorcaserin both have the same effect (decreased responding), which means they can be used to perform dose-addition analyses to determine the nature of drug interactions. However, this method alone may not capture the complexity of human drug-taking behavior. In rhesus monkeys that respond to the food-cocaine choice process, combinations of lorcaserin or buspirone will be evaluated. This is in addition to PR and reinstatement procedures. Food-cocaine choice is advantageous because it allows for direct comparisons between assays (PR, choice, and laboratory).
“A. “A.
“Surgical preparation. “Surgical preparation. All monkeys will have an indwelling vein catheter connected to a subcutaneous access port in the mid-scapular area.
“Apparatus. “Apparatus. Monkeys will be seated in primate chairs and face an instrument panel that includes two response levers as well as a centrally placed food pellet receptacle. The stimulus lights above each lever can either be illuminated red or green to indicate cocaine availability or delivery. Infusions are delivered by a syringe driver that is connected to the vascular acces port via an IV extension set. It also includes a 20-g Huber point needle. A PC running Med-PC IV software is used to control and record experimental events (Med-Associates St. Albans Vt ).
Summary for “Methods and composition related to combination treatment for addiction”
“A. “A.
“B. “B.
“Recreational use and/or abuse drugs remain a serious public health problem. Worldwide estimates suggest that one in 20 adults (or a quarter of billion) used at least one drug of abuse (e.g. cocaine) in 2014. Although cocaine use by Americans reached its peak in 1980s, it has remained stable over the last 30 years. Recent estimates suggest that approximately 1.9 million Americans use cocaine regularly. There are also 19 million cocaine users worldwide. Despite decades of efforts to develop pharmacotherapies for cocaine abuse, the U.S. Food and Drug Administration has yet to approve any medication.
“Cocaine inhibits monoamine transport at DA (DAT), SERT (SERT), and NET (NET) transporters. However, abuse-related effects of cocaine are mediated primarily by its ability to increase DA neurotransmission. It is well-established that increases in synaptic levels DA, especially within the nucleus accumbens, play a crucial role in abuse-related effects not only of cocaine but also of a variety of drugs that interact with DAT indirectly, including opioids, ethanol and barbiturates. Drugs that target DA systems have been given a lot of attention because of their central role in cocaine abuse. Three main strategies have been used to develop pharmacotherapies against cocaine abuse. These include (1) direct or indirect DA receptor agonists that aim to replace cocaine use; (2) cocaine antagonists that block cocaine at the site(s) of its action; and (3) modulators, which alter the effects of cocaine by acting at other sites than DAT/DA receptors. These rational approaches to drug development are potentially transformative but come at a significant and growing cost. According to the Tufts Centre for the Study Drug Development, FDA approval of a new drug will take approximately 10 years and require $2.8 billion in R&D investment.
“There is a need for more therapies and regimens to treat different forms of addiction.”
“Antagonist” is the term used herein. A compound capable of: (i) altering the conformational status of a receptor, (or maintaining it in its inactive state to prevent it from binding its natural substance ligand), and/or (ii). binding to the receptor and preventing or decreasing activation. Partial agonists can be used as antagonists to activate the receptor at a low, but sufficient level. This effectively antagonizes the receptor’s down steam signaling pathways and inhibits its upstream activity.
“Anonym” is the term used herein to refer to a compound that can alter the conformational state of a receptor by stabilizing its active conformation and/or maintaining it in its active conformation. A compound capable of: (i) altering a receptor’s conformational state by stabilizing it and/or maintaining it in its active conformation, and/or (ii), binding to that receptor activating/increasing its activity.
“A ?combination therapy? A therapy in which both a DA D3/D4 antagonist and a (5?HT)2C receptor agonist are given to a subject. You can co-administer or have the (5-HT2C receptor agonist and the DA D3/D4 antagonist administered together. You can administer them separately or at separate times. Buspirone is a preferred antagonist of the DA D3/D4 receptor. Lorcaserin is a preferred (5-HTT)2C receptor antagonist. Combination therapy can be used to treat an addiction.
“Antagonists of DA D3/D4 can include buspirone, PG 01037 and SB 277011A, trifluoperazine (A-381393), L-745.870, L-741.667, L-741.742, L-741.742, L-741.742, L-741.742, L-741.742, L-741.742A, S18126, fananserin. Clozapine, FAUC 213, sonepihydrochloride, PD 168568, PNU 96415E, or their salts.
“Agonist of (5-HT)2C receptor can include, but is not limited to lorcaserin, CP 809101, Ro-60-0175, WAY 161503, WAY 163909, MK 212, meta-chlorophenylpiperazine (mCPP), 1-methylpsilocin, Org 12962 hydrochloride, or salts thereof.”
“?Treating?” refers to any action, e.g. lessening or reducing, modulating or eliminating that results in an improvement of the condition, disorder, etc.
“Preferably the term ‘Subject? The term subject refers to a mammal. The term subject is more preferred to refer to a primate. The term subject is more preferred to be a human.
“Pharmaceutically and Pharmacologically Acceptable?” Include molecular entities or compositions that don’t cause an untoward reaction when given to animals or humans.
“Pharmaceutically Acceptable Carriers? This includes all solvents, dispersion medium, coatings and antibacterial and/or fungal agents. It also includes isotonic or absorption delay agents. This is a well-known practice in the art. It is possible to use any of these media and agents in therapeutic compositions, except in cases where they are incompatible with the active ingredients. You can also include additional active ingredients into the compositions.
“The expression “therapeutically effective amount” is used herein. “The term “therapeutically effective amount” is used herein to refer to the amount of an agent or compound, drug, composition or drug combination that is effective in producing a desired therapeutic effect upon administration of the invention to a subject (e.g. a patient or human subject).
“Administering to a subject” or “administrating to a patient” refers to the act of injecting an agent, compound or drug, composition, or combination thereof into a subject’s or patient’s body using an art-recognized method of introduction (e.g. orally, transdermally or via injection
This application discusses other embodiments of the invention. Any embodiment that is discussed in relation to one aspect or part of the invention can also be applied to other aspects. All embodiments described herein are considered to be embodiments that can be applied to all aspects. Any embodiment described herein may be used with any method or composition according to the invention. You can also use compositions or kits of the invention to realize methods of the invention.
“The use of?a? “The use of the word?a?? oder?an? When used with the term “comprising” In the specification and claims, it may be referred to as?one? It is however consistent with the meanings of?one? and?more? It is also consistent with the meaning of?one or more,? “At least one”?
“The term ‘about? is used throughout this application. “About” is used in this application to indicate that a value includes any standard deviation of error due to the device or method being used to determine it.
“The term ‘or? is used in the claims. “The term?or” is used in the claims to refer to?and/or?” Except where it is explicitly stated that the alternative(s) are exclusive or mutually exclusive, the claims use?and/or?
“Comprising” is used in the claim(s) and specification. (and any other form of including, such as ‘comprise? ?comprises? ), ?having? (and any other form of having, like?have? (and any form of having, such as?have? ), ?including? (and any other form of including, such?includes? (and any form of including, such as?includes? or?containing? (And any other form of containing, like?contains? (and any form of containing, such as?contains? These terms are inclusive or open-ended, and they do not exclude any additional elements or steps.
The following description will reveal other objects, features, and advantages of this invention. However, it should be noted that while the examples and detailed description are intended to illustrate specific embodiments of this invention, they are only illustrations. Those skilled in the art will see many modifications and changes within the spirit and scope.
“DESCRIPTION DU DRAWINGS”
The following drawings are part of the present specification. They serve to demonstrate certain aspects of this invention. You may find the invention easier to understand if you refer to these drawings along with the detailed description of each embodiment of the specification presented herein.
“FIG. 1. Effects of a 1:1 mixture of lorcaserin and buspirone on self-administration of cocaine in rhesus monkeys
“FIG. 2. The effects of buspirone in responding are maintained at 0.032 mg/kg/inf cocaine (PR) or restored to 0.32 m/kg cocaine by 4 rhesus monkeys (2 females and 2 males).
“FIG. 3. Response to lorcaserin maintained at 0.032 mg/kg/inf cocain (PR), or restored by 0.32 m/kg cocaine (4 rhesus monkeys; 2 males and 2 women).
“FIG. 4. A simplified schematic of the mesolimbic DA systems showing the potential sites for interaction between buspirone and lorcaserin. GABAergic inhibition would be enhanced by activation of 5-HT2C-receptors located on GABAergic neuron within the VTA (labeled A in the Figure). Antagonism of the post-synaptic DA D3 (labeled C in the figure), within the NAcc would also enhance GABAergic inhibition mesolimbic DAergic nervetransmission.
“FIG. 5. Mixtures of lorcaserin/buspirone are effective. They can be administered at fixed doses of lorcaserin/buspirone of 3:1, 1:1, or 1:3. This is relative to the ED50 for each drug. It reduces PR response for cocaine (0.32 mg/kg/inf). To determine the expected additive effect level for each combination of doses, dose addition analyses were performed (total dose expressed in lorcaserin equivalents). Experimentally determined effects can be expressed as the group average for 4 rhesus monkeys, as well as 2 males and 2 women.
“FIG. 6. Hypothetical data showing rightward shifts of the cocaine dose-response curve, and estimation of ED2-fold values for a fixed-ratio combination of lorcaserin & buspirone.”
“DESCRIPTION”
“The following discussion will focus on various embodiments and uses of the invention. “Invention” is not intended to refer to any particular embodiment. The term “invention” does not refer to any specific embodiment. It is not meant to limit the scope of disclosure. While one or more embodiments may be preferred over another, the disclosed embodiments should not be taken to limit the disclosure’s scope, including the claims. One skilled in the art will also understand that the description of each embodiment has broad applicability. The discussion of any embodiment is intended only to illustrate that embodiment and is not meant to limit the disclosure, including the claims.
Buspar? is an anxiolytic medication that is used primarily to treat generalized anxiety disorder (GAD). Buspirone is often used to supplement antidepressants for the treatment of depression. Buspirone’s pharmacology is different from other anxiolytics. It is not similar to the benzodiazepines or barbiturates. Also, it is not a GABA agonist. Therefore, buspirone doesn’t carry the risks of dependence and withdrawal symptoms that are associated with these drug classes. Buspirone is not a drug-of abuse, it is less dangerous than traditional anxiolytics in overdose, and it is significantly less harmful at therapeutic doses.
“I. Dosages, Administration and Pharmaceutical Products
The skilled artisan can determine the appropriate dosages of drugs in combination therapy according the invention. This is done by observing the patient, including their overall health and response to the treatment. If a patient does not exhibit the desired therapeutic effect, or conversely, if they are experiencing unwanted or adverse side effects or severe symptoms, optimization may be required.
“Preferably, one of the components of the combination treatment of the invention is/are given at or below a routinely used dosage by the skilled physician (e.g. physician) to promote desired therapeutic effects of the drug when it is used as monotherapy.
“In one embodiment, the components of the combination (e.g. DA D3/D4 antagonist and/or a (5?HT)2C receptor agonist) are/are prescribed at a dose lower than the usual dose for each component as a monotherapy. You can either prescribe the components separately or in combination.
“In one embodiment, each of the components (e.g., DA D3/D4 antagonist and a 5-HT)2C receptor agonist) are prescribed at a dose higher than the usual monotherapy dose. You can either prescribe the components separately or in combination.
“In another embodiment, a prescribed dose of the DA D3/D4 antagonist is higher than the usual monotherapy dose. The (5-HT)2C agonist is prescribed at a dose that is equal or lower to the monotherapy dose. Another embodiment prescribes the DA D3/D4 antagonist at or below the monotherapy dose, while the (5-HT/2C receptor agonist at a dose that is higher than the monotherapy dose.
For ease of administration and uniform dosage, it is particularly advantageous to prepare compositions of the invention using a unit dosage form. What is the term “unit dosage forms?”? As used herein, the term “unit dosage forms” refers to physically distinct units that are suitable as unitary doses for individuals being treated. The compositions are divided into discrete dosage units that each contain a predetermined unit dosage. The active compound is calculated to have the desired therapeutic effect when combined with the appropriate pharmaceutical carrier. Specifications for the new dosage units of the invention depend on the specific characteristics of the composition containing DA D3/D4 receptor antagonist or (5-HT)2C receptor agonist, and the therapeutic effect that is to be achieved. The usual dosage and method of administration can also be used to determine the dose. The present invention also allows for the creation of a single, physically distinct dosage form containing each active ingredient of the combination treatment. For example, a single dosage formulation containing a DA D3/D4 antagonist and a (5?HT)2C receptor agonist.
The method of administering compositions or combinations will depend on which DA D3/D4 receptor antagonist is used and the (5-HT)2C receiver agonist. The DA D3/D4 antagonist and (5-HT]2C receptor agonist can be administered in one composition, or in combination in two different compositions. One or more DA D3/D4 antagonists and (5-HT]2C receptor agonists may be administered to a patient or subject in a therapeutic composition, or in combination with one or more other compositions, e.g. one or more compositions administered simultaneously, or sequentially. The type of DA D3/D4 receptor antagonist or (5-HT]2C receptor agonist will determine the schedule of administration.
A pharmaceutically acceptable carrier can be used to administer the “DA D3/D4 receptor antagonist or (5-HT)2C receptor agonist.” “Pharmaceutically acceptable carrier” is defined herein. Any solvents, dispersion medium, coatings, or antibacterial and/or fungal agents, as well as isotonic/absorption delay agents and the like. This is a well-known artifact. It is possible to use any of these media and agents in compositions according to the invention, except in the event that they are incompatible with the active substance.
Orally administered DA D3/D4 antagonists or (5-HT]2C receptor agonists are preferred. An inert diluent, or assimilable edible carriers may be used when the composition is administered orally. You can also include the composition with other ingredients in a capsule or tablet made of hard shell gelatin. The composition can be combined with excipients for oral therapeutic administration. It may be used as ingestible tablets or buccal tablets, troches and capsules. You can vary the percentages of compositions and preparations. It is possible to obtain a proper dosage by adjusting the amount of active compound contained in therapeutically useful compositions. The present invention provides a pharmaceutical composition that contains a therapeutically-effective amount of a DA D3/D4 antagonist and a (5?HT)2C receptor agonist. In one embodiment, the present invention includes a therapeutically-effective amount of a DA D3/D4 receptor antagonist and a (5-HT)2C receptor agonist packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). This packaging encourages patients to use the drug regimens and promotes products. These packaging can reduce confusion among patients. These kits are further described in the present invention.
Tablets, tablets, pills, capsules, and the like can also contain a binder or excipient. As coatings, or to modify the physical form the dosage unit in any other way, a variety of materials can be used. Shellac, sugar, or both can be used to coat tablets, capsules, and pills. Any material used to prepare any dosage unit form must be pharmaceutically pure, and in substantially low amounts.
A DA D3/D4 antagonist or a (5?HT)2C agonist can be administered alone or in combination DA D3/D4 antagonist or a (5?HT)2C agonist. It can also be administered subcutaneously, intravenously, or by injecting. Inhalation, transdermal or rectal administration. Depending on the route of administration the composition containing the DA/D3/D4 antagonist and/or (5/HT)2C receptor agonist can be coated with a material that protects the compound from the effects of acids or other natural conditions which could inactivate the compounds.
“To administer the compositions transdermally or via injection, it might be necessary to co-administer or coat the composition with a material to prevent inactivation. The composition can be administered in a suitable diluent, or in a carrier like liposomes to the individual. Saline and aqueous buffer solutions are both pharmaceutically acceptable diluents. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. (1984) J. Neuroimmunol. 7:27). Dispersions that contain a DA D3/D4 receptor antagonist or a (5-HT]2C receptor agonist can be administered intraperitoneally or parenterally in glycerol, liquid PEG, oils, or mixtures thereof. These preparations can contain a preservative to inhibit the growth of microorganisms under normal storage conditions.
“Compositions that are suitable for injection include sterile aqueous solutions where water is soluble, dispersions, and sterile powders to extemporaneously prepare sterile injectable solutions. The composition must be fluid and sterile in all cases. The compositions must be stable in storage and manufacture, and protected against microorganisms like bacteria and fungi. A solvent or dispersion media can be used as the carrier. It could contain water, ethanol, polyol (for instance, glycerol and propylene glycol), and suitable mixtures thereof. For example, a coating like lecithin can be used to maintain fluidity. Surfactants can also be used to maintain the required particle size for dispersion. Many antibacterial and antifungal substances can be used to prevent the microorganisms from acting. It is preferable to include in the composition isotonic ingredients, such as sugars, polyalcohols like mannitol or sorbitol, and sodium chloride. You can prevent prolonged absorption of injectable compositions by adding an agent that delays absorption to the composition, such as aluminum monostearate or gelatin.
One aspect of the invention is that it prescribes a DA-D3/D4 receptor antagonist as well as a (5HT)2C receptor agonist in order to treat addiction. The average daily dose of each component is between 2 and 600 mg, which includes doses of 2, 5, 10, 20, 30, 50, 70, 80 or 90. It also includes doses of 150, 200, 300 to 400 mg, 500 to 600 mg daily.
“Another embodiment of the invention includes pharmaceutical compositions, e.g. for oral administration, comprising DA 3D4 receptor antagonists and a (5-HT2C receptor agonist in a single pharmaceutical formula. These compositions can be used to increase patient compliance, for example by reducing the number required to achieve desired pharmacologic effects.
“A. Additivity/Synergy”
Combinations of one or more DA D3/D4 antagonists in combination with one (5-HT)2C agonist are synergistically efficient. Synergy refers to the interaction of multiple agents that has a greater effect than their individual effects. If drug A has a 25% effect on a disease, while drug B’s effect is 25% on the same disease, then synergy is when two or more agents work together to create a greater effect.
“Additivity” is the interaction between two or more agents such that their combined effect exceeds each individual and is as great as their sum.
An improvement in drug therapy can be defined as the combination of two or more agents that reduce the risk of adverse events (AEs) in either one or both of the agents. The administration of lower doses of one or both agents in co-therapy can result in a reduction in the incidences of AE. If Drug A alone has a 25% effect and there is a 45% AE incidence at the labeled dosage, and Drug B alone has a 25% effect and an AE incidence at the labeled dosage, then combining the two drugs at lower doses will result in enhancing the drug therapeutic regimen. The adverse incidence rate is 20% and the overall effect is 35%.
“B. “B.
Combination therapies allow DA D3/D4 receptor antagonists and (5-HT]2C receptor agonists to be administered at lower doses to minimize side effects. This allows for a reduction in the dosage of each compound required for monotherapy and an extension of the therapeutic range.
“C. Equivalents”
“Those who are skilled in the art will be able to recognize or determine using routine experimentation many alternatives to the procedures described herein. These equivalents are included in the scope of the invention. They are covered by the claims and current specification. You can make many substitutions, modifications, or alterations to the invention, without changing the spirit or scope of the invention, as described in the claims.
“II. Addiction”
Addiction refers to a psychological or physical dependence on a substance, or activity, that can be harmful or interfere with the addict?s daily life. A physical or psychological dependence can be caused by illegal and legal drugs. Prescription drugs may also be included. Illicit drug addiction can have a devastating effect on society as addicts often resort to criminal activity to fund their addiction. Illicit addictive substances include marijuana, cocaine, opiates and sedatives, as well as opiates and sedatives. Some prescription medications, caffeine, nicotine, and alcohol can all be addictive. Gambling, shopping, exercising, working, computer usage, internet use, sex and cleaning are all examples of addictive activities that can interfere with a person’s daily life.
Cocaine is an addictive and commonly used illicit drug that can be used to get high from the coca leaves. The signs of cocaine addiction include compulsive and obsessive drug use that is hard to stop. Statistics show that cocaine addicts who manage to quit using cocaine have a high chance of relapse. This is because their cravings for cocaine remain after they stop using. An abrupt stoppage of cocaine use can lead to withdrawal symptoms such as anxiety, depression, and sleep disturbances in addicted users. Although psychotherapy is a common treatment for cocaine addiction in rehab centers, dropout rates are high. It is difficult to provide a long-term treatment for cocaine addiction due to withdrawal symptoms and vulnerability to relapse.
Cue reactivity is an affliction that many addicts exhibit. Cue reactivity refers to the way an addict reacts physiologically or psychologically to a stimulus that is related to his addiction. Exposure to a cue that is associated with an addict’s previous use of cocaine can trigger or increase cravings in many cases. A person who is addicted to smoking cigarettes or someone trying to quit smoking may feel compelled to smoke a cigarette. An alcoholic, or an alcoholic in recovery, may feel a need to drink alcohol by hearing the wine glasses crackle. A cocaine addict may feel compelled to buy drug-related paraphernalia. Cue reactivity can continue long after an addict stops using, increasing the risk of relapse. Many rehab programs encourage addicts not to get addicted. They can also receive cues to help them in their recovery process.”
“In some embodiments, the addiction that is to be treated/prevented as disclosed herein may be a physical dependence on an agent (an addictive drug) or a specific behavioral pattern. An agent that causes a physical dependence can be any of the following: prescription drugs (and OTC drugs), illicit drugs, alcohol, or any combination thereof. This agent is called the “addictive agent”. The agent is generally a persistent compulsion to use or abuse the agent. This can be despite the potential for serious consequences to one’s mental and physical health. Addictive behavior is also known as “addictive behavior”. Similar to gambling and compulsive eating, the term “addictive behavior” refers to a behavioral compulsion.
“In some embodiments, addiction is caused and controlled by an addictive agent. This can be selected from addictive recreational drugs or addictive medications.
“In some embodiments the addictive agent may be selected from alcohol, nicotine, cannabis and Cannabis derivatives as well as opiates, morphine-like and phencyclidine compounds, phencyclidine or phencyclidine-like compound, sedatives hypnotics and psycho-stimulants and amphetamines-related drugs.”
“In additional embodiments, the addictive agent is selected from alcohol, caffeine, nicotine, Cannabis, morphine, heroin, codeine, cocaine, hydrocodone, hydromorphone, levorphanol, metapon, nalorphine, naloxone, naltrexone, oxycodone, oxymorphone, tramadol, ethoheptazine, fentanyl, levorphanol, meperidine, methadone, phenazocine, propoxyphene, sufentanil, phencyclidine, benzodiazepines, methaqualone, mecloqualone, etaqualone, pemoline, amphetamine, methamphetamine, methylenedioxymethamphetamine, dextroamphetamine, methylamphetamine, and synthetic derivatives of cathinone.”
“In other embodiments, the addictive agent is selected amongst pain-killer such as alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene sufentanil, tramadol, tilidine and any combination of any of the aforementioned agents.”
“In additional embodiments, an addictive agent can be selected from apomorphine (beta-hydroxy 3-methylfentanyl), carfentanil and dihydroetorphine as well as methadyl acetate. Papaverine, remifentanil. thebaine, or tramadol.
“In some instances, the addiction to cocaine is present.”
“Some embodiments of addiction are in the form of compulsive behaviors (addictive behaviour). These may include obsessive eating disorder, compulsive spending or gambling, pathological overeating and pathological electronic device and communication devices like cellular phones and cell phones, pathological electronic gaming, addiction to pornography, sex, eating disorders like anorexia, bulimia, and kleptomania as well as compulsive exercise and overwork.
“In some embodiments the addiction can be to one or more addictive drugs and/or addictive behaviors.” One or both addictions can be to an addictive agent in some embodiments.
“If treatment as described herein fails, it is possible to repeat the treatment, such as by following the treatment protocol.”
“III. Examples”
“The following examples and figures demonstrate preferred embodiments. Those skilled in the art should recognize that the techniques shown in the figures or examples are techniques that were discovered to work well in the practice and application of the invention. They can therefore be considered preferred methods for its use. However, those skilled in the art will appreciate that there are many modifications that can be made to the disclosed embodiments and still achieve a similar or comparable result. This is in keeping with the spirit and scope the invention.
“Therapeutic Potential for Drug Addiction Receptor Antagonists DA D3”
“DA receptor antagonists have been given a lot of attention due to their potential use as drugs for cocaine abuse, because of the important role of DA in mediating abuse-related effects of cocaine. D1-like (D1, D5, and D2) receptor antagonists decrease cocaine self-administration in laboratory animals. This suggests that all five subtypes of DA receptors may contribute to the abuse-related consequences of cocaine. Preclinical research has shown that the DA D1 antagonist ecopipam, SCH 39166, was effective at reducing cocaine self-administration in laboratory animals. However it failed to alter the subjective and reinforcing effects of cocaine in humans when administered in doses that didn’t produce sedation. Similar results have been observed for DA D2 antagonist-preferring antagonists such as haloperidol. However, it is not clear how these negative effects are affected by extrapyramidal side effect, which is typical of DA D2 antagonists.
“Although AEs prevent further development of DA D2 antagonists, the DA D3 agonist has been given considerable attention. This is based on three key characteristics of the receptor. (1) DA D3 receptive receptors are mainly expressed in limbic areas of the brain including the NAcc. (2) DA D3 receptive receptors are upregulated in rats that have had repeated cocaine administration. (3) An antagonists and partial agonists selective to the DA D3 receptor inhibit cocaine self-administration. These findings suggest that the DA D3 agonist should be a viable target for drugs aimed at treating cocaine addiction. However, FDA approval is not currently available to test this hypothesis in humans.
Buspirone has been a surprising candidate to test the DA D3 hypothesis of cocaine abuse in recent years. Buspirone, originally designed to block DA D2-like receptor antagonists, was later found to be more effective in treating anxiety than psychoses. This effect is believed to be due to buspirone’s partial agonist effects on 5-HT1A receptors, rather than its antagonist actions on DA D2 receptors. Buspirone was approved for the treatment of generalized anxiety disorder in 1986 at doses up to 60mg. Despite the apparent selectivity of 5-HT1A receptors (relatively to DA D2 receivers), recent research suggests that buspirone may be roughly equal at DA D3 and DA D4 receptors. Buspirone was approved by the FDA to be a valid, FDA-approved medication for testing the DA D3 hypothesis of cocaine abuse due to its highly selective binding profile (?5-70fold). Buspirone decreased self-administration of cocaine in rhesus monkeys and cynomolgus monkeys. However, it did not alter the reinforcing effect of cocaine in human laboratory studies (30 mg) or prolong abstinence in a pilot study (60 mg), which was randomized, double-blind and placebo-controlled. It is important to remember that Volkow and his colleagues have shown that buspirone needs to be administered at a threefold higher dose to treat addiction.
“Preliminary data from Bergman’s laboratory confirm and expand reports by Bergman, colleagues, and show that buspirone dose-dependently reduces the reinforcing efficacy of cocaine when responding to a progressive ratio schedule of reinforcement (FIG. 2; top panel), and the effectiveness of cocaine in restoring extinguished cocaine responding (FIG. 2; bottom panel). Preliminary data from four monkeys (male and female) suggest that buspirone is about?10-fold stronger in males than it is in females when it comes to decreasing cocaine self-administration according to the PR schedule (FIG. 2). This is supported by clinical data. The 60 mg buspirone dose was more effective in promoting abstinence for males than it was for females.
Preclinical evidence strongly suggests that buspirone may be an effective treatment for cocaine addiction. However, it failed to alter the clinical endpoints associated with cocaine abuse when given in doses greater than 60 mg. This suggests that higher doses or different formulations (e.g. buspirone:locaserin combinations) are required. In order to achieve clinically relevant outcomes, drug combinations containing a lower dose of buspirone than the FDA-approved maximum of 60 mg were considered by the inventors.
“Therapeutic Potential for 5-HT2C Receptor Aggonists for Drug Addiction.”
Serotonin (5HT) systems play a significant and well-documented part in modulating goal-directed behavior, such as feeding. Evidence that 5-HT2C receptors mediate hypophagic effects of indirect and direct-acting 5-HT receptor agonists has led to significant research into the development of selective 5-HT2C receptor agonists. These agonists are designed to decrease appetite and produce hallucinations (5-HT2A receptor mediated), which are common with less selective and/or indirect 5-HT drugs. This is a direct application of the fact that 5-HT2C receptor antagonists not only reduce food intake but also decrease self-administration. This is consistent with a larger role for 5-HT2C in regulating drug- and food-motivated behavior.
“In the years since the initial discovery, significant progress has been made in understanding the neuro-, behavioral, and molecular pharmacology (5HT2C receptors.” There is mounting evidence that 5-HT2C receptors in pro-opiomelanocortin neuronal regions are responsible for anti-obesity. However, the anti-addiction effects from 5-HT2C receptor agonists may be due to their ability to modulate mesolimbic DA neuraltransmission. In fact, 5-HT2C receptors can be found on the ventral tegmental areas (VTA), as well as the DA nerve terminals in the NAcc. This distribution pattern allows 5-HT2C to play an important role controlling the activity and DA systems in activated and basal conditions.
A variety of agonists that have preferential activity at 5-HT2C receptors (e.g. Ro 60-0175 and MK 212) have been shown in studies to reduce cocaine self-administration and/or to inhibit the reinsertion of a previously strengthened response to cocaine. These findings support the hypothesis that activating 5-HT2C receptors reduces drug abuse-related effects. However, it is not clear if 5-HT2C agonists can have similar effects on humans.
Based on functional assays using cells transfected by human 5-HT2C, 2B or 2C receptors, Lorcaserin has been shown to be?20-fold more selective for 5-HT2C than 5-HT2A receptors and ‘100-fold more selective for 5-HT2C than 5-HT2B receptors. A series of placebo-controlled, multicenter trials showed that lorcaserin was effective in reducing weight and improving health outcomes. The FDA approved lorcaserin in 2012 (maximum 10 mg twice daily) for obese adults with at-risk weight. Surpre-therapeutic doses (20-60 mg) of lorcaserin received subjective ratings of?high’,?good effects? from recreational drug users. lorcaserin was designated Schedule IV by the DEA due to its agonist effects at 5-HT2A receptors. These effects are consistent with agonist actions and cause?hallucination?. Recent reports have shown that lorcaserin causes 5-HT2A receptor-mediated headache-twitches in rodents, a model of hallucination. These effects are comparable to the doses required to lose body weight in rats.
According to the premise that 5-HT2C receptor agonists reduce the abuse-related side effects of drugs, inventors have recently reported that acute lorcaserin administration dose-dependently inhibits cocaineself-administration in rhesus monkeys under both fixed-ratio and PR reinforcement schedules. These studies also revealed that lorcaserin’s anti-cocaine effects were (1) evident at doses that also produced other 5-HT2C receptor mediated behavioral effects and (2) not due to a pharmacokinetic interactions between cocaine and lorcaserin. They also demonstrated that the effects lasted at least 14 days after repeated (daily), treatment with lorcaserin. Rats self-administering cocaine or nicotine have experienced similar acute effects to lorcaserin.
“Preliminary data were collected in the same four monkeys used to test buspirone (FIG. 2) confirm our initial findings and show that lorcaserin dose-dependently reduces the reinforcing efficacy of cocaine when it is administered under a PR reinforcement schedule (FIG. 3; top panel), and the effectiveness of cocaine in restoring an extinguished cocaine response (FIG. 3; bottom panel). Although the magnitude of these differences was smaller than that observed for buspirone in terms of potency, they were still significant in decreasing cocaine self-administration. However, females were slightly more sensitive to lorcaserin than males, and this was not unlike buspirone.
Clinical efforts have been made to quickly and rationally repurpose Lorcaserin for treatment of cocaine abuse disorder because of the consistent preclinical evidence. There are currently four safety and effectiveness trials that ClinicalTriails.gov has registered. Although no data is available on the effectiveness of Lorcaserin in reducing cocaine use in humans, they do have some published data. One Phase I trial was completed, but it has not been reported (NCT02393599), while two other Phase I trials (NCT02537873 & NCT02680288) are currently enrolling subjects. The registration of a Phase II multi-site trial of lorcaserin in the treatment of cocaine abuse disorder has been completed but it has not begun to recruit subjects. It is important to note that lorcaserin doses only slightly higher than the ones approved/required for its therapeutic effects can cause feelings of high? Feelings of?high? and?hallucinations have been reported. agonists at 5-HT2A receptors. Thus, there is a clear need to develop formulations/treatment strategies that minimize the total dose of lorcaserin required to effectively reduce cocaine use and/or prolonging abstinence from cocaine use. The hypothesis that drug combinations containing buspirone and lorcaserin are more potent or effective in decreasing cocaine self-administration, and/or inhibiting reinstatement of extinguished response for cocaine use, will be thoroughly tested.
“The inventors began to use non-human primates to test FDA-approved drugs for cocaine abuse. Although rational repurposing FDA-approved drugs can dramatically reduce the cost and time required to get effective treatment for cocaine abuse (and other drugs) into the clinic, it has been difficult to translate positive preclinical results to clinically relevant outcomes. Czoty, along with colleagues, used the case of lisdexamfetamine, a d-amphetamine drug prodrug, to illustrate some of the challenges in translating preclinical successes into effective treatments in the clinic. They describe that even though drugs like lisdexamfetamine reduce self-administration of cocaine in nonhuman primates they often fail to improve abstinence in clinical settings. Mooney and co-workers point out that although there were differences in the endpoints, i.e., the reduction in preclinical drug-taking and complete abstinence at the clinic, they did not evaluate lisdexamfetamine. They also noted that the clinical efficacy of the drug was only evaluated for the dosages approved for attention-deficit/hyperactivity disorder (ADHD). Larger doses would likely have had a positive clinical outcome. Similar conclusions were reached when buspirone was found to decrease cocaine intake in preclinical studies but not to maintain complete abstinence in clinical settings. Volkow and his colleagues found that buspirone must be administered at doses at minimum 3-fold higher than the 60 mg maximum dose for anxiety treatment in order to reach clinically relevant levels of DA D3 receptor occupancy. Therefore, it is imperative to not only develop new therapeutics but also to improve/augment drug potency/effectiveness so that users can abstain from using drugs that have been approved for other conditions.
“Studies that evaluate combinations of drugs that target pre- (e.g. 5-HT2C receptors), and post- (5HT2C receptors), synaptic regulators for DA neurotransmission have shown that they produce a therapeutic effect (e.g. decrease in drug intake, reinstatement, etc.). This is more than the effects of one drug alone (i.e. supra-additive interactions). Their ability to modulate activity of mesolimbic DA neuron (FIG. The FDA approved drug buspirone has antagonist DA D3 receptor properties. Lorcaserin is an FDA-approved drug that can agonist 5-HT2C receptors. It acts on 5-HT2C receptors in the NAcc and VTA that are responsible for GABAergic neurons (FIG. Lorcaserin inhibits mesolimbic DA neurons that project from the VTA into the NAcc (FIG. 4). This decreases the effectiveness of cocaine to increase synaptic DA levels. Similar effects can be seen by blocking the DA D3 receptors in the NAcc (FIG). Buspirone also inhibits cocaine-induced increases of DA signaling by antagonizing DA D3 receptors within the NAcc (FIG. The FDA approved both drugs used in this study to test the hypothesis. This will allow the FDA to translate the findings into clinical practice.
“The proposed studies will also combine state-of the-art self-administration (PR, food-cocaine choice), reinstatement protocols, radio-telemetric assessments and radio-telemetric evaluations of cardiovascular effects with sophisticated dose addition analyses (FIG. 5) to characterize and quantify the nature of interactions between lorcaserin (therapeutic) and buspirone (potentially AEs). The data from 4 rhesus monkeys shows that lorcaserin is more potent than buspirone and has a greater effect on cocaine self-administration when they are mixed at fixed dose ratios of their ED50. The dose-response curves of buspirone and lorcaserin in 1:1 and 1:3 combinations were, respectively, moved?3 to?5 times to the left than the additive dose-response, which indicates a supra-additive interaction. These results not only support the hypothesis, but also indicate that it is possible to lower the dosage of each drug while maintaining and possibly increasing the therapeutic efficacy of buspirone and lorcaserin.
“Interestingly, this is consistent with the large sex-related variations observed for buspirone (FIG. 2), sex-related variations were also observed for drug mixtures. Females were?10-fold more sensitive to 1:3 lorcaserin-buspirone mixture than their male counterparts (FIG. 5). This was surprising considering that females were more sensitive to buspirone (an effect consistent with clinical reports that buspirone has a lower effectiveness in promoting abstinence in males than in females). These findings suggest that combination of lorcaserin/buspirone may be especially effective in reducing cocaine use among females. It is not possible to say that the differences between male and female sexes are due to sex.
“Experimental Subjects. In confirmation studies, 20 adult rhesus monkeys (10 female and 10 male) will be used. The historical and preliminary data were used to perform power analyses for each assay (PR. choice. reinstatement. and cardiovascular). These results were used to calculate power (Student t test for independent samples; PASS 2011 Kaysville, Utah). A total of 10 (five males and five females) were found to be sufficient to detect with 80% power a shift of at most 2-fold in dose-response curves to self-administration or reinstatement (effects only of buspirone and lorcaserin), as well as a 20% difference between cardiovascular endpoints. These calculations assume that there are underlying sex-related differences for each endpoint and lead to studies that can detect significant effects using both within sex analysis and between.
“Inhibition Drug-Taking and Drug Seeking. The fact that pharmacotherapies to combat cocaine abuse must block the drug-seeking behavior and the reinforcing effects of cocaine is a problem. To demonstrate that buspirone and lorcaserin both decrease the reinforcing efficacy (PR) as well as the relapse-related effects of cocaine (reinstatement), studies used a simple (i.e. a single option; respond or not). FIG. 2 and FIG. 3. 3). Buspirone and lorcaserin both have the same effect (decreased responding), which means they can be used to perform dose-addition analyses to determine the nature of drug interactions. However, this method alone may not capture the complexity of human drug-taking behavior. In rhesus monkeys that respond to the food-cocaine choice process, combinations of lorcaserin or buspirone will be evaluated. This is in addition to PR and reinstatement procedures. Food-cocaine choice is advantageous because it allows for direct comparisons between assays (PR, choice, and laboratory).
“A. “A.
“Surgical preparation. “Surgical preparation. All monkeys will have an indwelling vein catheter connected to a subcutaneous access port in the mid-scapular area.
“Apparatus. “Apparatus. Monkeys will be seated in primate chairs and face an instrument panel that includes two response levers as well as a centrally placed food pellet receptacle. The stimulus lights above each lever can either be illuminated red or green to indicate cocaine availability or delivery. Infusions are delivered by a syringe driver that is connected to the vascular acces port via an IV extension set. It also includes a 20-g Huber point needle. A PC running Med-PC IV software is used to control and record experimental events (Med-Associates St. Albans Vt ).
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