US20080207601A1 - Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence - Google Patents

Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence Download PDF

Info

Publication number
US20080207601A1
US20080207601A1 US11/910,988 US91098806A US2008207601A1 US 20080207601 A1 US20080207601 A1 US 20080207601A1 US 91098806 A US91098806 A US 91098806A US 2008207601 A1 US2008207601 A1 US 2008207601A1
Authority
US
United States
Prior art keywords
gaba
dose
day
receptor
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/910,988
Other languages
English (en)
Inventor
Sanjay Sabnani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Catasys Inc
Original Assignee
Catasys Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Catasys Inc filed Critical Catasys Inc
Priority to US11/910,988 priority Critical patent/US20080207601A1/en
Assigned to HYTHIAM, INC. reassignment HYTHIAM, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SABNANI, SANJAY
Publication of US20080207601A1 publication Critical patent/US20080207601A1/en
Assigned to GOLDMAN SACHS SPECIALTY LENDING GROUP, L.P. reassignment GOLDMAN SACHS SPECIALTY LENDING GROUP, L.P. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HYTHIAM, INC (N/K/A CATASYS, INC.)
Assigned to ONTRAK, INC. (FORMERLY KNOWN AS CATASYS, INC.) reassignment ONTRAK, INC. (FORMERLY KNOWN AS CATASYS, INC.) RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: GOLDMAN SACHS SPECIALTY LENDING GROUP, L.P., AS COLLATERAL AGENT
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relies on, for priority, U.S. Provisional Patent Application No. 60/669,033, entitled “Improved Method for the Treatment of Substance Abuse”, filed on Apr. 7, 2005, U.S. Provisional Patent Application No. 60/728,979 entitled “Methods for the Treatment of Substance Abuse and Dependence”, filed on Oct. 21, 2005, and U.S. Provisional Patent Application No. 60/729,013 entitled “Methods for Treating Anxiety-Related Diseases”, filed on Oct. 21, 2005.
  • the present invention relates to improved methods of, and compositions for, preventing psychological addiction to and physiological dependence upon exogenous and endogenous substances. More specifically, the present invention relates to methods of, and compositions for, administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to prevent endogenous neurosteroid production. The present invention also relates to administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to avoid cross-tolerance effects of both the endogenous and exogenous substance.
  • the present invention also relates to methods of, and compositions for, directly or indirectly, preventing the modulation of GABA A by the progesterone metabolite allopregnanolone. More specifically, the present invention relates to combining the therapeutic activity of conventional pharmaceutical compounds with the therapeutic activity of inhibitors of neurosteroid production that inhibit the production of allopregnanolone.
  • the present invention also relates to methods for using pharmaceutical compositions from a class of compounds that directly or indirectly modulates GABA A by modulating the expression of the GABA A receptor ⁇ 4 subunit.
  • Substance addiction and abuse is a multi-factorial neurological disease. Over time, repeated exposure to various substances, both endogenous and exogenous, causes modification of the neurotransmission circuits and adaptations in post-receptor signaling cascades. There are several effects of this neuronal modification. Among them, there is a reduction in the ability of natural rewards to activate the reward pathways leading to depressed motivation and mood and an increased compulsion to compensate for the physiological change.
  • addiction While the common perception underlying addiction is that of a “reward circuit”, pleasure may not necessarily be a strong enough impetus to drive people towards their addictions. Rather, addictive behavior arises from an intense desire to manage and/or avoid the anxiety that arises when someone is experiencing withdrawal. Similarly, anxiety-related diseases are caused by behavior that arises from an intense desire to manage and/or avoid the anxiety experienced during endogenous neurosteroid withdrawal.
  • the present invention is directed towards improved methods of, and compositions for, preventing psychological addiction to and physiological dependence upon exogenous and endogenous substances. More specifically, the present invention relates to methods of, and compositions for, administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to prevent endogenous neurosteroid production. The present invention also relates to administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to avoid cross-tolerance and compounded withdrawal effects of both the endogenous and exogenous substance.
  • the present invention is also directed towards methods of, and compositions for, directly or indirectly preventing the modulation of GABA A by progesterone.
  • the present invention is also directed towards methods of, and compositions for, directly or indirectly preventing the modulation of GABA A by progesterone metabolite allopregnanolone. More specifically, the present invention is directed towards combining the therapeutic activity of conventional pharmaceutical compounds with the therapeutic activity of inhibitors of neurosteroid production that inhibit the production of allopregnanolone.
  • compositions are also provided that include a substance with addictive properties in combination with an inhibitor of neurosteroid production. Methods of administration of these compounds are also provided herein. Such substances with addictive properties may include stimulants, contraceptives, tranquilizers, sedatives, hypnotics, benzodiazepines, analgesics and barbiturates. These compositions may optionally include a modulator of receptor subunit expression.
  • the present invention is directed towards compositions of a therapeutically effective dose of a pharmaceutical compound in combination with a therapeutically effective dose of an inhibitor of endogenous neurosteroid production to prevent addiction to, or dependence on, a substance of abuse.
  • the present invention is directed towards methods of administering a pharmaceutical compound, without habit-forming or addictive side effects to prevent addiction or reduce dependence, comprising administering a therapeutically effective dose of a pharmaceutical compound in combination with a therapeutically effective dose of an inhibitor of endogenous neurosteroid production to prevent addiction or reduce dependence on the pharmaceutical compound.
  • Another object of the invention is to provide for the use of a neurosteroid production inhibitor in the preparation of a medicament to prevent addition or dependence on a substance of abuse.
  • Another object of the invention is to provide for the use of a neurosteroid production inhibitor and a pharmaceutical compound in the preparation of a medicament to prevent addition or dependence on a substance of abuse.
  • FIG. 1 illustrates the spectrum between inhibition and substantially or completely reduced inhibition via the direct and/or indirect allosteric modulation of GABA A .
  • FIG. 2 illustrates the internal thought filtering mechanism in a person's brain.
  • FIG. 3 a is a first schematic presentation of a plurality of GABA A receptor subunits.
  • FIG. 3 b is a second schematic presentation of a plurality of GABA A receptor subunits.
  • FIG. 3 c is an illustration of the insensitivity of the modulated GABA A receptor to benzodiazepines. Note the ⁇ 1 subunit: ⁇ 1 ⁇ 2 ⁇ 2-containing GABA A receptors are the most common GABA receptors in the brain.
  • FIG. 4 is a chemical diagram of the blockade of the conversion of progesterone to allopregnanolone via inhibitors of neurosteroid production.
  • the present invention is directed towards improved methods of, and compositions for, preventing psychological addiction to and physiological dependence upon exogenous and endogenous substances.
  • the term “substance of abuse” refers to addiction forming substances such as but not limited to opioids, benzodiazepines, cannabis, caffeine, nicotine, and other drugs that stimulate neural reward pathways and promote addiction. More specifically, the present invention relates to methods of, and compositions for, administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to prevent endogenous neurosteroid production. The present invention also relates to administering a pharmaceutical compound in combination with an inhibitor of neurosteroid production to avoid cross-tolerance and compounded withdrawal effects of both the endogenous and exogenous substance.
  • the present invention is also directed towards methods of, and compositions for, directly or indirectly preventing the modulation of GABA A by progesterone.
  • the present invention is also directed towards methods of, and compositions for, directly or indirectly preventing the modulation of GABA A by progesterone metabolite allopregnanolone. More specifically, the present invention is directed towards combining the therapeutic activity of conventional pharmaceutical compounds with the therapeutic activity of inhibitors of neurosteroid production that inhibit the production of allopregnanolone.
  • effective prevention of endogenous neurosteroid production and cross-tolerance between endogenous and exogenous substances requires addressing the underlying pathophysiology that occurs prior to addiction resulting from various substances, namely the conversion of progesterone and deoxycorticosterone (DOC) and their metabolites allopregnanolone and tetrahydrodeoxycorticosterone, which, upon chronic exposure to and withdrawal, result in the increased expression of the GABA A receptor ⁇ 4 subunit relative to the ⁇ 1 subunit.
  • DOC deoxycorticosterone
  • an effective composition is one which combines the therapeutic activity of a conventional pharmaceutical compound with the therapeutic activity of an inhibitor of neurosteroid production.
  • an effective composition is one which prevents psychological addiction to, and physiological dependence upon, prescription or over the counter medicines.
  • the pharmaceutical compound is selected from the class of compounds that comprise opioids and their derivatives.
  • the pharmaceutical compound is selected from the class of compounds that comprise tetrahydrocannibol and its derivatives.
  • the pharmaceutical compound is selected from the class of compounds that comprise benzodiazepines.
  • the pharmaceutical compound is selected from the class of compounds that comprise tranquilizers, sedatives, hypnotics, and barbiturates.
  • the pharmaceutical compound is selected from the class of compounds that comprise contraceptives.
  • the pharmaceutical compound is selected from the class of compounds that comprise stimulants and their derivatives.
  • the inhibitor of neurosteroid production is a 5-alpha-reductase inhibitor.
  • the 5-alpha-reductase inhibitor is finasteride.
  • the 5-alpha-reductase inhibitor is dutasteride.
  • the 5-alpha-reductase inhibitor is an organic medicinal, such as, but not limited to saw palmetto and spironolactone.
  • the inhibitor of neurosteroid production is a 3-alpha-hydroxysteroid oxidoreductase inhibitor.
  • the 3-alpha-hydroxysteroid oxidoreductase inhibitor is indomethacin.
  • dependence upon, tolerance to, and cross-tolerance between endogenous and exogenous substances can further be prevented by optionally administering a pharmaceutical composition from a class of compounds that directly or indirectly modulates GABA A by modulating the expression of the GABA A receptor ⁇ 4 subunit.
  • the compound is one that serves as an agonist at the GABA A receptor, and more specifically, at either the ⁇ 4 subunit or ⁇ 6 subunit, and is capable of positively potentiating GABA current.
  • the compound from the class of compounds that directly or indirectly modulates GABA A by modulating the expression of the GABA A receptor ⁇ 4 subunit is flumazenil.
  • flumazenil is administered in a controlled-release formulation.
  • flumazenil is administered via a subcutaneous implant.
  • flumazenil is administered via a transdermal patch.
  • the term “substance abuse” is used to refer to the various physical and psychological states that manifest an individual's impaired control over substance use, continued substance use despite adverse consequences, compulsive substance use, and/or drug cravings.
  • the term is intended to include psychological dependence, physical dependence, tolerance, a maladaptive pattern of substance use, preoccupation with substance use, and/or the presence of withdrawal symptoms upon cessation of use.
  • the terms “addiction” and “dependency” are used interchangeably throughout this text.
  • GABA Gamma-Aminobutyric Acid
  • GABA is a neurotransmitter that acts at inhibitory synapses in the brain and spinal cord.
  • the GABA system is found, among other places, in the hippocampus, an area of the brain associated with memory formation.
  • Glutamic acid, or glutamate is important in brain function, as an excitatory neurotransmitter and as a precursor for the synthesis of GABA in GABAergic neurons.
  • Glutamate activates both ionotropic and metabotropic glutamate receptors, described in further detail below. GABA signals interfere with registration and consolidation stages of memory formation.
  • the GABA receptors are a group of receptors with GABA as their endogenous ligand.
  • GABA receptors include ionotropic receptors, which are ion channels themselves, and metabotropic receptors, which are G-protein coupled receptors that open ion channels via intermediaries. Glutamate and GABA mediate their actions by the activation of their receptors.
  • GABA A receptors The ionotropic GABA receptors (GABA A receptors) are based on the presence of eight subunit families consisting of 21 subunits ( ⁇ 1-6 , ⁇ 1-4 , ⁇ 1-4 , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ 1-3 ) and display an extraordinarily structural heterogeneity. GABA A receptors are composed of five circularly arranged, homologous subunits and are important sites of drug action. Most often, the GABA A receptor isomers comprise two ⁇ subunits, two ⁇ subunits and one ⁇ subunit.
  • the metabotropic GABA receptors (GABA B receptors) consist of two subunits: GABA B1 and GABA B2 . Physiological responses following activation of GABA B receptors require the co-assembly of GABA B1 and GABA B2 . GABA C receptors also exist natively.
  • GABA A receptor system is implicated in a number of central nervous system disorders, making GABA A receptor ligands potential therapeutic agents.
  • GABA A receptors are ligand-gated ion channels that belong to the same super family of receptors as glycine, nicotinic cholinergic, and serotonin 5HT 3 receptors. Enhanced function of several GABA A receptors accounts for the major actions of benzodiazepines, described in greater detail below. In addition, a number of compounds have exhibited functional selectivity for GABA A receptors.
  • the GABA A receptor complex is a pentameric receptor protein structure formed by co-assembly of subunits from seven different classes. Five subunits are situated in a circular array surrounding a central chloride-permeable pore. It has been suggested that the mechanism for ligand-induced channel opening in nicotinic acetylcholine receptors involves rotations of the subunits in the ligand binding domain. Assuming that GABA A receptors utilize a similar mechanism for channel opening, since GABA A receptors belong to the same super family as the nicotinic acetylcholine receptors, large substituents may interfere with the channel opening (steric hindrance) resulting in antagonistic effects of certain compounds. In addition, the activation of GABA receptors will influence several other systems, ultimately resulting in a general acute modification of the overall function of the central nervous system.
  • the particular combination of subunits yields receptors with different pharmacological and physiological properties, however, the GABA A receptor composition is not immutable.
  • the ⁇ subunit is often associated with GABA A receptor subtypes containing the ⁇ 4 subunit.
  • GABA and GABA A receptors are involved in disease states such as seizures, depression, anxiety and sleep disorders.
  • GABA and some of the other indirectly or directly acting GABA A receptor agonists (GABA-mimetics), including allopregnanolone and tetrahydrodeoxycorticosterone respectively, bind specifically to a recognition site located at the interface between an ⁇ and a ⁇ subunit.
  • GABA-mimetics indirectly or directly acting GABA A receptor agonists
  • the classical benzodiazepines however, such as diazepam and flunitrazepam, bind to an allosteric site located at the interface between an ⁇ and a ⁇ subunit.
  • GABA binds to the cleft between ⁇ and ⁇ subunits, an action which gates open the chloride channel to allow for the influx of chloride ions into the cell. This typically hyperpolarizes the cell, having an inhibitory action on neuronal activity, by making the membrane potential of the cell more negative, and consequentially, increases the depolarization threshold to generate an action potential.
  • depressant and sedative drugs such as the benzodiazepine tranquilizers, barbiturates, anesthetics and alcohol are believed to have a modulatory effect on the GABA A receptor at unique sites where they can enhance the actions of GABA in accumulating negatively charged chloride ions into the cell, inducing sedative or anesthetic effects.
  • GABA A receptor determines their affinity for benzodiazepine receptor ligands as well as the efficacy of these ligands.
  • classical benzodiazepine agonists e.g. diazepam
  • imidazopyridines imidazoquinolones
  • pyrazolopyrimidines show no affinity for or efficacy at GABA A receptors that contain ⁇ 4 or ⁇ 6 subunits.
  • the subunit composition of native GABA A receptors plays an important role in defining their physiological and pharmacological function. It is possible to characterize the physiological, pharmacological, and pathological roles of GABA A receptors by understanding the mechanisms by which the subunit composition of GABA A receptors is regulated. Thus, the expression of specific GABA A receptor subunit genes may be affected by various physiological and pharmacological modulators, including but not limited to, pharmacological agents, endogenous neurosteroids, and food.
  • benzodiazepines For example, long-term exposure to and subsequent withdrawal of benzodiazepines, zaleplon, zolpidem, or neurosteroids result in selective changes in the expression of specific GABA A receptor mRNA, including an increase of the ⁇ 4 subunit mRNA, and polypeptide subunits and in GABA A receptor function in cultured cells. Withdrawal from diazepam or imidazenil was associated with both a reduced ability of diazepam to potentiate GABA action and the ability of flumazenil to potentiate GABA action. Chronic benzodiazepine treatment and subsequent withdrawal lead to a change in the receptor subunit composition, and these new synthesized receptors are less responsive to benzodiazepines.
  • the up-regulation of the ⁇ 4 subunit may be necessarily coupled with the down-regulation of other subunits for the development of benzodiazepine dependence.
  • Ethanol withdrawal-induced increases in the amounts of ⁇ 4 subunit mRNA and protein are associated with reduced sensitivity of GABA A receptors to GABA and benzodiazepines.
  • the effects of alcohol are similar to those of drugs that enhance the function of GABA A receptors, which gate the Cl-currents that mediate most inhibitory neurotransmission in the brain, as described above.
  • Acutely high doses of alcohol potentiate GABA-gated currents at both native and recombinant GABA A receptors, and chronically alter GABA A receptor expression.
  • Ethanol elicits its central effects through modulation of neurotransmission mediated by various receptors, especially that mediated by GABA A receptors.
  • ⁇ 4 subunit in recombinant GABA A receptors is associated with a reduced sensitivity to classical benzodiazepine agonists and to zolpidem as well as with a distinct pattern of regulation (positive rather than no allosteric modulation) by flumazenil.
  • chronic treatment with agonists that act at different sites of the GABA A receptor results in changes in the biochemical and functional properties of the receptor that are accompanied by changes in the abundance of specific receptor subunit mRNAs.
  • chronic treatment with substances that modulate GABA A function via a neurosteroid pathway results in changes in the biochemical and functional properties of the receptor that are accompanied by changes in the abundance of specific receptor subunit mRNAs.
  • GABA A receptor subunit genes Characterizations of the role of GABA A receptors require an understanding of the mechanisms by which subunit composition is regulated.
  • the neuroactive steroids 3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one (allopregnanolone) and 3 ⁇ ,21-dihydroxy-5 ⁇ -pregnan-20-one induce anxiolytic, sedative, hypnotic, and anticonvulsant effects similar to benzodiazepines and other anxiolytic drugs.
  • concentrations of these neurosteroids are increased in the brain of humans both in response to treatment with anxiogenic, antidepressant or antipsychotic drugs as well as physiological or pathological conditions (such as depression, stress, the luteal phase of the menstrual cycle, and pregnancy) that affect mood and emotional state. Additional studies implicate endogenous allopregnanolone as a physiological regulator of both basal and stress-induced dopamine release in the rat brain.
  • Steroid metabolites react with the GABA receptor complex to alter brain excitability.
  • Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids.
  • Neurosteroids are synthesized in the peripheral and central nervous system, from cholesterol or steroidal precursors imported from peripheral sources. Both progesterone and estrogen alter excitability of neurons of the central nervous system. For example, estrogen reduces inhibition at the GABA A receptor, enhances excitation at the glutamate receptor, and increases the number of excitatory neuronal synapses.
  • progesterone enhances GABA-mediated inhibition, increases GABA synthesis, and increases the number of GABA A receptors.
  • progesterone and its metabolites have been demonstrated to have profound effects on brain excitability.
  • progesterone and its metabolites vary with the phases of the menstrual cycle, decreasing prior to the onset of menses.
  • Progesterone is readily converted to allopregnanolone (3 ⁇ -OH-5 ⁇ -pregnan-20-one or 3 ⁇ ,5 ⁇ -THP) in human brains.
  • Allopregnanolone is a positive potent modulator of the GABA A receptor and enhances the action which gates open the chloride channel to allow influx of chloride ions into the cell. This typically hyperpolarizes the cell, having an inhibitory action on neuronal activity, and thus allopregnanolone acts as a sedative or anxiolytic agent and decreases anxiety.
  • GABA A -modulatory allopregnanolone is also responsible for producing anxiogenic withdrawal symptoms.
  • the withdrawal profile shown therein is similar to that reported for other GABA A -modulatory drugs such as the benzodiazepines, barbiturates, and ethanol.
  • GABA A -modulatory drugs such as the benzodiazepines, barbiturates, and ethanol.
  • the actions of neuroactive steroids on traditional transmitter receptor in the brain lead to alterations in the GABA A receptor subunit composition that result in changes in the intrinsic channel properties of the receptor and behavioral excitability. Changes are also associated with significant increases in both the mRNA and protein for the ⁇ 4 subunit of the GABA A receptor in the hippocampus.
  • the endogenous neurosteroid allopregnanolone exhibits withdrawal properties, similar to GABA-modulators, as described above, increasing anxiety susceptibility following abrupt discontinuation after chronic administration.
  • the increase in neuronal excitability has been attributed to upregulation of the GABA A ⁇ 4 subunit.
  • the ⁇ 4 ⁇ 2 ⁇ is preferentially expressed following hormone withdrawal. Blockade of the ⁇ 4 gene transcript prevents withdrawal properties.
  • the increase in expression of the GABA A receptor ⁇ 4 subunit relative to the GABA A receptor ⁇ 1 subunit can be attributed to many factors. These include, but are not limited to 1) compositions, both endogenous and exogenous, which, upon withdrawal, increase the GABA A receptor ⁇ 4 subunit relative to the GABA A receptor ⁇ 1 subunit; and 2) compositions, both exogenous or endogenous that result in the increase of expression of the GABA A receptor ⁇ 4 subunit or the decrease of expression of the GABA A receptor ⁇ 1 subunit.
  • Most substances that cross the blood-brain barrier in sufficient quantity can stimulate a neuroprotective, neurosteroid response.
  • the more neuroexcitatory the substance the more neurosteroid response is achieved.
  • GABA A receptor activity is enhanced, causing a constant state of activation which, over time, may cause neurosteroid tolerance. Therefore, once the neuroexcitatory substance is no longer present, the brain's neurosteroid levels will decrease to natural levels, causing the individual to go through a state of “withdrawal” from the neurosteroid.
  • GABA A receptor subunits may be expressed, or suppressed, in a manner that causes the person's brain to be susceptible to greater feelings of anxiety.
  • his brain's GABA A receptor ⁇ 1 subunits decrease in relative amounts to GABA A receptor ⁇ 4 subunits.
  • the GABA receptor is no longer effectively modulated by GABA, and, therefore, results in the person experiencing a greater sense of anxiety.
  • an individual's lowered degree of inhibitory control over his thoughts is caused by the modification of the receptivity of the synaptic GABA A receptors to the neurotransmitter GABA in the individual's brain.
  • substance abuse diminishes GABA receptivity; thus, the exogenous substance or “drug” modulates the GABA A receptor.
  • the receptor is not effectively modulated by GABA, thus causing anxiety.
  • FIG. 1 illustrates the spectrum between inhibition and disinhibition via the direct and/or indirect allosteric modulation of GABA A .
  • Spectrum 100 further depicts the range between inhibition 105 and disinhibition 110 .
  • An increase in an exogenous or endogenous substance that directly or indirectly enhances the function of GABA or the GABA A receptor 115 can result in an increase in GABA agonism and thus an increase in inhibition, anxiolysis, amnesia, and sedation, and even a comatose state.
  • Anxiety may be defined in a plurality of ways, including a vague unpleasant emotion that is experienced in anticipation of some, often ill-defined misfortune, a complex combination of the feeling of fear, apprehension and worry often accompanied by physical sensations such as palpitations, chest pain and/or shortness of breath, a feeling of apprehension, fear, nervousness, or dread accompanied by restlessness or tension, and/or a debilitating condition of fear, which interferes with normal life functions.
  • anxiety comprises a physiological state in which an individual has a lowered degree of inhibitory control over his thoughts, as described above with respect to FIG. 1 .
  • Such lowered degree of inhibitory control may be caused by the turning off, inhibition, or otherwise down-modulation of an internal thought filtering mechanism in the person's brain.
  • the internal thought filtering mechanism 200 comprises certain centers within a person's prefrontal cortex 205 , including the orbitofrontal cortex 210 , which is considered responsible for exerting control, and the anterior cingulate 215 , which is considered responsible for motivation and drive impulses.
  • These brain centers are substantially affected by certain physiological inputs, such as a reward circuit that comprises the nucleus accumbens 220 and ventral tegmental 225 areas of the brain.
  • the orbitofrontal cortex 210 When normally regulated, the orbitofrontal cortex 210 can exert control over a person's thoughts and avoid having an individual feel “overwhelmed” by vague, unpleasant emotions and feelings of fear, apprehension and worry. If GABA A receptor functionality is somehow impaired, however, GABA dysregulation occurs and can result in an impaired ability of the orbitofrontal cortex 210 to exert control over a person's thoughts and, therefore, a lowered degree of inhibitory control.
  • the individual becomes compulsively driven to “address” this anxiety by making sure he obtains whatever substance, or engage in whatever activity, his brain believes it needs in order to eliminate the feelings of anxiety, e.g. regain inhibitory control over his thoughts. Therefore, it is the physiological drive to address feelings of anxiety that causes an individual to consciously engage in behavior which could be classified as self-destructive, such as substance abuse.
  • Exogenous substances such as opioids, benzodiazepines, cannabis, caffeine, nicotine, and other drugs, directly or indirectly affect GABA A receptor functionality and, when those exogenous substances are withheld from an individual, cause the expression of the GABA A receptor ⁇ 4 subunit (hereinafter generally referred to as the ⁇ 4 subunit) to increase relative to the expression of the ⁇ 1 subunit.
  • GABA-modulatory steroids such as progesterone and deoxycorticosterone (DOC) and their metabolites allopregnanolone and tetrahydrodeoxycorticosterone respectively, affect GABA A receptor functionality and thus, when progesterone or DOC is decreased or “withdrawn” in an individual, cause the expression of the GABA A receptor ⁇ 4 subunit to increase relative to the expression of the ⁇ 1 subunit.
  • DOC deoxycorticosterone
  • such substances may directly or indirectly stimulate GABA A via a neurosteroid mediated pathway.
  • GABA A may directly or indirectly stimulate GABA A via a neurosteroid mediated pathway.
  • the amount of ⁇ 4 subunits relative to ⁇ 1 subunits increases. This ratio change is often temporary and is subject to reversal.
  • a distinct pathophysiology emerges when it becomes non-reversing, namely when ⁇ 4 subunits no longer down-regulate relative to ⁇ 1 subunits.
  • the GABA A receptor therefore becomes less sensitive to benzodiazepines and effectively, modulation by the neurotransmitter GABA, and is less capable of exerting inhibitory control over an individual's thoughts and behavior.
  • GS Score GABA-active steroid score
  • the GS Score correlates direct agonism of GABA A and the indirect modulation of GABA A via a neurosteroid mediated pathway, such as, but not limited to allopregnanolone.
  • a neurosteroid mediated pathway such as, but not limited to allopregnanolone.
  • cocaine has a lower GS Score than aspartame, since cocaine is more potent and it takes a lower threshold dose of cocaine to raise levels of GABA-active steroids.
  • the GS Score is a methodology for measuring and assigning a numeric value to the relative addictive properties of substances.
  • a benzodiazepine sensitive GABA A receptor 300 a is shown.
  • the GABA A receptor comprises a plurality of subunits, including two ⁇ 2 subunits 305 a , a ⁇ 2 subunit 310 a , and two ⁇ 1 subunits 315 a .
  • certain endogenous and exogenous substances cause the expression of the GABA A receptor ⁇ 4 subunit to increase relative to the expression of the ⁇ 1 subunit.
  • the modified GABA A receptor 300 b comprises a plurality of subunits, including two ⁇ 2 subunits 305 b , a ⁇ 2 subunit 310 b , and two ⁇ 4 subunits 315 b .
  • the GABA A receptor therefore becomes less sensitive to benzodiazepines and effectively, modulation by the neurotransmitter GABA, and is less capable of exerting inhibitory control over an individual's thoughts and behavior.
  • Compositions for use in the present invention include alcohol, nicotine, caffeine, tea, coffee, tobacco, 1-(1-Phenylcyclohexyl)pyrrolidine, 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine, 1-[1-(2-Thienyl)cyclohexyl]piperidine, 1-[1-(2-Thienyl)cyclohexyl]pyrrolidine, 13 Beta-ethyl-17beta-hydroxygon-4-en-3-one, 17Alpha-methyl-3alpha,17beta-dihydroxy-5alpha-androstane, 17Alpha-methyl-3beta, 17beta-dihydroxy-5alpha-androstane, 17Alpha-methyl-3beta,17beta-dihydroxyandrost-4-ene, 17Alpha-methyl-4-hydroxynandrolone (17alpha-methyl-4-hydroxy-17beta-hydroxyestr-4-en-3-one),17Alpha-methyl-delt
  • compositions that fall within the classes of compositions listed below are provided in Table 1. It should be noted that the list contains exemplary compounds for use with the present invention and is not exhaustive.
  • a woman's progesterone is actively modulated by the administration of prescription hormones, such as, but not limited to, contraception with progesterone, that keeps the woman on a constant progesterone cycle.
  • prescription hormones such as, but not limited to, contraception with progesterone
  • Contraceptive medications contain hormones (estrogen and progesterone, or progesterone alone).
  • the medications are available in various forms, such as pills, injection (into a muscle), topical (skin) patches, and slow-release systems (vaginal rings, skin implants, and contraceptive infused intrauterine devices.
  • the rate of absorption of progesterone is highly dependent upon the administration route.
  • the altered tolerance liability of a person to exogenous sources of progesterone and other hormones may be due to the cross-tolerance effects between administered and endogenous progesterone.
  • endogenous levels of progesterone and its metabolites such as allopregnanolone, fluctuate, thus resulting in the altered tolerance liability of a patient to administered progesterone.
  • Stimulants can be used as recreational drugs or therapeutic drugs to increase alertness. They are also used to boost endurance and productivity as well as to suppress appetite.
  • the class of compounds that comprises stimulants includes, but is not limited to caffeine, amphetamines, ecstasy, and cocaine.
  • Stimulants increase the amount of norepinephrine and dopamine in the brain, which increases blood pressure and heart rate, constricts blood vessels, increases blood glucose, and increases breathing. Effects can feel like an increase alertness, attention, and energy along with a sense of euphoria.
  • Stimulants can be addictive in that individuals begin to use them compulsively. Taking high doses of some stimulants repeatedly over a short time can lead to feelings of hostility or paranoia. Additionally, high doses of a stimulant may result in dangerously high body temperatures and an irregular heartbeat.
  • Caffeine also known as trimethylxanthine, is a naturally occurring cardiac stimulant and mild diuretic. Caffeine induces nervousness and insomnia in normal individuals, and it increases the level of anxiety in patients prone to anxiety and panic attacks. As an anxiogenic, caffeine changes brain and body functions and results in a rapid release of adrenaline, thereby causing a rapid heartbeat, increased blood pressure, and rapid, shallow breathing.
  • Caffeine may directly or indirectly act on the GABA receptor GABA A , the activation of which dampens higher neuronal activity.
  • neuroactive steroids modulate the stimulant and anxiogenic effects of caffeine. More specifically, Concas et al. demonstrated that IP administration of caffeine resulted in dose-dependent increases in the plasma and brain concentrations of allopregnanolone as well as in those of its precursors pregnenolone and progesterone. Thus, the effects of caffeine on the plasma and brain concentrations of neuroactive steroids was shown to be similar to those of anxiogenic drugs, including those of direct and indirect inhibitors of the GABA A receptor complex that induce experimental anxiety in humans. It was also demonstrated that these effects are antagonized by systemic administration of anxiolytic drugs, further demonstrating that both pharmacologic treatments and experimental conditions that induce anxiety-like or conflict behavior also induces increases in the plasma and brain concentrations of neuroactive steroids.
  • caffeine induces both neurotransmitter release and anxiety-like behavior associated with increases in the plasma and brain concentrations of neuroactive steroids that the HPA axis might mediate such actions of caffeine.
  • the transient increase in the brain concentration of allopregnanolone triggered by caffeine may reflect a physiological mechanism for reducing the activation of the neuroendocrine and neurochemical pathways associated with the state of arousal and for limiting the extent of neuronal excitability; consistent with the fact that neuroactive steroids function to counteract overexcitation of the CNS.
  • Caffeine can induce physical dependence and is addictive, thus long-term use can be problematic due to the development of tolerance and dependency. An abrupt discontinuation of substance use may result in anxiety and confusion.
  • Attention Deficit Disorder is often treated using stimulant medications, the most popular of which includes methylphenidate, which is more commonly known by its trade name, Ritalin; amphetamine, which may be sold as a mixture with dextroamphetamine and commonly known by its trade name Adderall; and dextroamphetamine, which is more commonly known by its trade name Dexedrine.
  • stimulant medications include methylphenidate, which is more commonly known by its trade name, Ritalin; amphetamine, which may be sold as a mixture with dextroamphetamine and commonly known by its trade name Adderall; and dextroamphetamine, which is more commonly known by its trade name Dexedrine.
  • An analgesic more commonly referred to as painkillers is any member of the group of drugs used to relieve pain and to achieve analgesia. They include paracetemol, the non-steroidal anti-inflammatory drugs such as aspirin, and the opioids, such as morphine.
  • Opioid is a term used for the class of drugs with opium-like and/or morphine-like pharmacological action.
  • An opioid is any agent that binds to opioid receptors, which are mainly found in the central nervous system and gastrointestinal tract.
  • opioids There are many types of opioids, including endogenous opioids produced in the body (endorphins, dynorphins, enkephalins); opium alkaloids found in the opium plant (morphine, codeine, thebaine); semi-synthetic opioid derivatives (heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphine, oxymorphone, nicomorphine); and wholly synthetic opioid derivatives (phenylheptylamines, phenylpiperidines, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives, loperimide, diphenoxylate).
  • endorphins endorphins, dynorphins, enkephalins
  • opium alkaloids found in the opium plant
  • semi-synthetic opioid derivatives herein, oxycodone, hydrocodone, dihydrocodeine, hydromorphine,
  • opiates shall refer to any compound that binds to opioid receptors, including natural opium alkaloids, semi-synthetic opioids derived therefrom, and synthetic opioids that have a similar physiochemistry to natural opiates and generally metabolize to morphine.
  • opioids are used as analgesics and for relieving chronic and/or severe pain and other disease symptoms. Some opioids, however, are abused or used illegally for their euphoria-inducing properties when administered intravenously or when smoked.
  • Cannabis, or marijuana is a plant containing THC (delta-9-tetrahydrocannabinol), a psychoactive chemical. When smoked, THC readily diffuses into an individual's lungs and, consequently, into his bloodstream. THC changes brain and body functions and initially results in a feeling of haziness and light-headedness and deleterious effect on short-term memory, coordination, learning, and problem-solving.
  • THC delta-9-tetrahydrocannabinol
  • THC may directly or indirectly act on the GABA receptor GABA A , the activation of which dampens higher neuronal activity.
  • THC use can result in a variety of side effects, including, but not limited to learning and memory problems, distorted perception, anxiety, paranoia, and panic attacks.
  • THC induces physical dependence and is addictive.
  • Typical treatments for THC abuse have been based on cognitive-behavioral therapy and weaning a patient off of the drug. These methods, however, fail in that they do not address the physiochemical changes that occur with addiction.
  • cannabis Although considered illegal in the United States, in some areas, cannabis is prescribed under strict supervision for medicinal purposes. Medically, cannabis is most often used as an appetite stimulant and pain reliever for certain terminal illnesses. It is also used to relieve glaucoma and certain neurological illnesses, such as epilepsy, migraine and bipolar disorder.
  • Barbiturates are drugs that act as central nervous system (CNS) depressant, producing a wide range of effects—from mild sedation to anesthesia.
  • CNS central nervous system
  • barbiturates are infrequently used as anticonvulsants and for the induction of anesthesia.
  • two or more barbiturates are combined in a single tablet or capsule.
  • Barbiturates enhance the functioning of GABA and are general depressants to nerve and muscle tissue. Mild to moderate barbiturate toxicity mimics alcohol intoxication. Severe acute barbiturate toxicity results in CNS problems, including lethargy and coma.
  • benzodiazepine refers to a class of drugs with hypnotic, anxiolytic, anticonvulsant, amnestic and muscle relaxant properties. Benzodiazepines are divided into three groups—short-acting (less than six hours); intermediate-acting (six to ten hours); and long-acting (strong sedative effects that persist).
  • Benzodiazepines are often used for short-term relief of severe, disabling anxiety or insomnia. Long-term use can be problematic due to the development of tolerance and dependency. As described in detail above, they act on the GABA receptor GABA A , the activation of which dampens higher neuronal activity. Benzodiazepine use can result in a variety of side effects, including, but not limited to drowsiness, ataxia, confusion, vertigo, and impaired judgment. In addition, benzodiazepines induce physical dependence and are potentially addictive. An abrupt discontinuation of substance use may result in convulsions, confusion, psychosis, or effects similar to delirium tremens.
  • Onset of withdrawal syndrome may be delayed and is characterized by insomnia, anxiety, tremor, perspiration, loss of appetite, and delusions.
  • Typical treatments for benzodiazepine abuse have been based on cognitive-behavioral therapy, weaning a patient off of the drug, and, in some cases, administering a benzodiazepine antagonist to counteract the drug's effects. These methods, however, fail in that they do not address the physiochemical changes that occur with addiction.
  • Non-benzodiazepine hypnotics are used for the short term treatment of insomnia (or difficulty in getting to sleep or staying asleep). Some, like chlormethiazole, can be used to help with agitation and restlessness, and to help with alcohol withdrawal symptoms.
  • Clinical depression is a health condition with both mental and physical components. Physiological symptoms of depression may be due to changes or imbalances of chemicals which transmit information in the brain, called neurotransmitters. Many modern anti-depressant drugs attempt to increase levels of certain neurotransmitters, like serotonin. Further, it has been shown that progesterone and its effects on GABA have been implicated in depression and anti-depressant dependence.
  • Cessation of a CNS drug may cause withdrawal, an increased total GABA A receptor ⁇ 4 subunits relative to GABA A receptor ⁇ 1 subunits, which in turn, causes anxiety.
  • SSRIs Selective Serotonin Reuptake Inhibitors
  • Selective serotonin reuptake inhibitors relieve depression by increasing the availability of one of the body's natural mood-enhancing chemicals, the neurotransmitter serotonin.
  • SSRIs trigger chemical activity along more than one track at a time.
  • Fluoxetine (Prozac®), paroextine (Paxil®), and sertraline (Zoloft®) all show a dramatic, positive effect (10 to 30-fold) on the levels of allopregnanolone, a steroid made in the brain, which modulates mood and plays a role in heightened anxiety and depression found in severe premenstrual disorders and other conditions.
  • allopregnanolone boosts mood-enhancing neurotransmitter receptors by increasing how many and how long certain openings in the ion channels remain open.
  • fluoxetine and fluvoxamine increase the brain and cerebrospinal fluid content of allopregnanolone.
  • the present invention is directed towards a method of using a compound from a class of compounds that competitively bind to the GABA A receptor neurosteroid binding site.
  • the compound is one that inhibits allopregnanolone from binding to the GABA A receptor.
  • the compound is one that, upon withdrawal, does not result in the increase of the ⁇ 4 subunit relative to the ⁇ 1 subunit.
  • Maitra et al. demonstrated that the 3beta-pregnane isomers epipregnanolone and isopregnanolone both inhibited the ability of allopregnanolone and alphaxalone to potentiate GABA A receptor function.
  • the present invention is directed towards a method of using a compound from a class of compounds that inhibit neurosteroid production (“Inhibitors of Neurosteroid Production”).
  • the compound is one that inhibits the conversion of progesterone to its metabolite allopregnanolone.
  • the compound is one that inhibits the conversion of progesterone metabolite 5 ⁇ -dihydroprogesterone into allopregnanolone.
  • progesterone is first converted to 5 ⁇ -dihydroprogesterone via an enzyme called 5 ⁇ -reductase.
  • 5 ⁇ -dihydroprogesterone is then converted to 5 ⁇ ,3 ⁇ -pregnenolone (allopregnanolone) via the 3 ⁇ -hydroxysteroid oxidoreductase enzyme.
  • an individual is administered a therapeutically effective amount of a 5-alpha-reductase inhibitor which blocks the conversion of progesterone into allopregnanolone.
  • a 5-alpha-reductase inhibitor is finasteride or analogs or derivatives thereof.
  • the 5 ⁇ -reductase inhibitor is capable of acting as a Type I inhibitor, a Type II inhibitor, or a combination thereof, and inhibits the 5 ⁇ -reductase enzyme from converting progesterone to 5 ⁇ -dihydroprogesterone and thus from creating progesterone metabolite allopregnanolone.
  • an individual is administered a therapeutically effective amount of a 3-alpha-hyrodxysteroid oxidoreductase inhibitor which blocks the conversion of progesterone metabolite 5 ⁇ -dihydroprogesterone into allopregnanolone.
  • a 3-alpha-hyrodxysteroid oxidoreductase is indomethacin or analogs or derivatives thereof.
  • dosing regimens for 3-alpha-hyrodxysteroid oxidoreductase inhibitors contemplates operating in a dosing range of established safety and efficacy in order to maximally decrease the production of progesterone and make the individual most receptive to treatment.
  • the 5 ⁇ -reductase inhibitors are a group of drugs with anti-androgenic activity that effectively decrease the amount of the 5 ⁇ -reductase enzyme and thus inhibit neurosteroid production.
  • Finasteride is a synthetic 4-azasteroid compound, and is a 5alpha-reductase inhibitor. Finasteride is 4-azaandrost-1-ene-17-carboxamide,N-(1,1-dimethylethyl)-3-oxo-,(5 ⁇ , 17 ⁇ )-.
  • the empirical formula of finasteride is C 23 H 36 N 2 O 2 and its molecular weight is 372.55.
  • Finasteride is a competitive and specific 5 ⁇ -reductase inhibitor. Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects.
  • Progesterone is metabolically converted to the GABA A receptor-potentiating neuroactive steroid allopregnanolone by 5 ⁇ -reductase isoenzymes followed by 3 ⁇ -hydroxysteroid oxidoreduction. Finasteride acts as a competitive 5 ⁇ -reductase inhibitor and thus blocks the production of allopregnanolone from progesterone.
  • finasteride is delivered using at least one oral tablet with a total daily dose of less than 10 mg, preferably less than 5 mg. It should be appreciated that, to the extent approved by regulatory authorities, finasteride can also be delivered in gel capsules or via injection or infusion. Finasteride should not be used by women of childbearing age. Finasteride's side effects include breast enlargement and tenderness, skin rash, swelling of lips, abdominal pain, back pain, decreased libido, decreased volume of ejaculate, diarrhea, dizziness, headache, impotence, and testicular pain.
  • Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the Type I and Type II isoforms of the steroid 5 ⁇ -reductase, an intracellular enzyme.
  • Dutasteride is chemically designated as (5 ⁇ ,17 ⁇ )-N- ⁇ 2,5 bis(trifluoromethyl)phenyl ⁇ -3-oxo-4-azaandrost-1-ene-17-carboxamide.
  • the empirical formula of dutasteride is C 27 H 30 F 6 N 2 O 2 , representing a molecular weight of 528.5.
  • dutasteride As a competitive Type I and Type II 5 ⁇ -reductase inhibitor, dutasteride inhibits the conversion of progesterone to allopregnanolone. Dutasteride does not bind to the human androgen receptor.
  • dutasteride is delivered using at least one capsule with a total daily dose of less than 10 mg, preferably less than 0.5 mg. It should be appreciated that, to the extent approved by regulatory authorities, dutasteride can also be delivered in tablets or via injection or infusion. Dutasteride should not be used by women of childbearing age.
  • Dutasteride's side effects include cough, difficulty swallowing, dizziness, fast heartbeat, hives or welts, itching skin, puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue, redness of skin, shortness of breath, skin rash, swelling of face, fingers, feet, and/or lower legs, tightness in chest, unusual tiredness or weakness, wheezing, abnormal ejaculation, decreased interest in sexual intercourse, decreased sexual performance or desire, impotence, inability to have or keep an erection, loss in sexual ability, desire, drive, or performance, or swelling of the breasts or breast soreness.
  • the present invention also encompasses the use of other 5-alpha reductase inhibitors, including a) 4-aza-4-methyl-5 alpha-pregnane-3,20-dione (AMPD), which inhibits pituitary progesterone 5-alpha reduction, b) cyproterone acetate, and c) spironolactone, which is a diuretic that blocks two pathways to the production of androgens, or male hormones, one of which is the inhibition of 5 ⁇ -reductase.
  • AMPD 4-aza-4-methyl-5 alpha-pregnane-3,20-dione
  • spironolactone which is a diuretic that blocks two pathways to the production of androgens, or male hormones, one of which is the inhibition of 5 ⁇ -reductase.
  • the present invention also encompasses the use of organic sources of 5-alpha reductase inhibition, including organic sources such as saw palmetto.
  • Saw palmetto (Serenoa repens) is a natural source of a 5 ⁇ -reductase inhibitor. Some studies suggest that it may be comparable to finasteride if taken for six months. Saw Palmetto is advantageous because it is 1) substantially free of side effects and 2) cost effective.
  • the present invention further includes the use of 3 ⁇ -hydroxysteroid oxidoreductase blockers.
  • Gallo and Smith (1993) suggest that the anxiogenic withdrawal property of progesterone could be prevented by previous administration of a 3 ⁇ -hydroxysteroid oxidoreductase blocker.
  • indomethacin is used.
  • Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that reduces fever, pain and inflammation. It is similar to ibuprofen and naproxen. Indomethacin is effective in reducing the production of prostaglandins.
  • NSAID non-steroidal anti-inflammatory drug
  • compositions that can be used to inhibit neurosteroid production can be used in the present invention.
  • compounds are preferably screened to determine whether they can be used in the treatment methodologies of the present invention.
  • an appropriate cellular model is used to model the inhibition of neurosteroid production.
  • the efficacy of the composition is measured by measuring the relative levels of progesterone and allopregnanolone in a model prior to the administration of the composition and after the administration of the composition.
  • the composition may be suitable as an inhibitor to neurosteroid production.
  • the level of efficacy of a partial agonist/antagonist depends upon the disease or dependence in question.
  • the level of efficacy or activity of a partial agonist/antagonist at a receptor site it is possible to determine what the disease state is and determine what conformational changes have occurred in the GABA A receptor subunits. Based upon this information, certain compositions can be classified according to the changes they cause in GABA A subunits.
  • the GABA binding site in the GABA A receptor is located at the interface between ⁇ and ⁇ subunits, the GABA A antagonists can bind to and stabilize a distinct inactive receptor conformation.
  • the present invention is directed towards using a compound from a class of compounds that modulates the expression of certain GABA A receptor subunits. More specifically, the compound is one that serves as an agonist at the GABA A receptor, and more specifically, at either the ⁇ 4 subunit or ⁇ 6 subunit, and is capable of positively potentiating GABA current.
  • the compound of choice is one that effectuates an increase in the expression of the GABA A receptor ⁇ 1 subunit relative to the expression of the ⁇ 4 subunit.
  • This increase in expression of the ⁇ 1 subunit may be effectuated by one or more of the following: a) upregulating the expression of ⁇ 1 subunits; b) downregulating the expression of ⁇ 4 subunits; c) masking ⁇ 4 subunits; or d) preventing the upregulation of the ⁇ 4 subunit.
  • the focus is thus on using a compound from the class of compounds that modulates the expression of certain GABA A receptor subunits, and more specifically, moves the relative balance of the ⁇ 4 subunit to the ⁇ 1 subunit closer to a normal state from an abnormal, allostatic state.
  • the present invention relates to the use of a therapeutically effective quantity of a drug, and more specifically, one that modulates the expression of GABA A subunits, such as, but not limited to, flumazenil, in a methodology for treatment of substance abuse.
  • the compound may comprise certain imidazobenzodiazepines and derivatives of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate, including various substitutions of the carboxylate functional group, such as carboxylic acids, esters, acyl chlorides, acid anhydrides, amides, nitriles, alkyls, alkanes, cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salts thereof.
  • carboxylate functional group such as carboxylic acids, esters, acyl chlorides, acid anhydrides, amides, nitriles, alkyls, alkanes, cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salt
  • the compound comprises flumazenil or carboxylic acids, esters, acyl chlorides, acid anhydrides, amides, nitriles, alkyls, alkanes, cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salts thereof.
  • Flumazenil acts a partial agonist of GABA A , inhibits the upregulation of the ⁇ 4 subunit and/or increases the amount of the ⁇ 1 subunit relative to the amount of the ⁇ 4 subunit, and does not cause the upregulation of the ⁇ 4 subunit and/or does not cause the amount of the ⁇ 4 subunit to increase relative to the amount of the ⁇ 1 subunit once the compound is no longer present in the patient's system.
  • a method for the treatment of substance abuse that includes the administration to a patient in need of said treatment of a therapeutically effective quantity of flumazenil, usually between 0.5 mg/day and 20 mg/day, between 0.5 mg/day and 15 mg/day, specifically between 1.0 and 3.0 mg/day, and more specifically between 1.5 and 2.5 mg/day, of flumazenil, broken down into multiple doses of flumazenil between 0.1 and 0.3 mg and intended for administration during predetermined time periods or intervals, until said therapeutically effective quantity of flumazenil has been reached.
  • the predetermined time period is in the range of 1 and 15 minutes and the “per dose” quantity of flumazenil is between 0.1 and 0.3 mg.
  • the individual doses can range in amount, and the time interval between the individual doses can range in amount, provided that the total dose delivered is in the range of 0.5 mg/day and 20 mg/day, between 0.5 mg/day and 15 mg/day, between 1.0 and 3.0 mg/day, and or between 1.5 and 2.5 mg/day. In one embodiment, the dose is in the range of 1.0 mg/day and 3.0 mg/day.
  • the individual doses are delivered at relatively consistent time intervals. Therefore, the time period intervals can range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or minutes or fractions thereof.
  • Doses delivered at each time period, separated by the time intervals can be between 0.1 and 0.3 mg, or fractions thereof, keeping in mind the total drug delivered is preferably less than 3.0 mg/day.
  • the present invention therefore provides for the delivery of multiple, sequential doses, delivered at substantially consistent time intervals.
  • flumazenil Conventional uses of flumazenil comprise either singular doses or much larger doses over shorter periods of time and are directed toward reversing sedative effects of anesthesia, conscious sedation, or benzodiazepine overdose.
  • ROMAZICON® a brand name for flumazenil marketed by Roche, is expressly indicated to complicate the management of withdrawal syndromes for alcohol, barbiturates and cross-tolerant sedatives and was shown to have an adverse effect on the nervous system, causing increased agitation and anxiety.
  • a single dose to address anesthesia and conscious sedation it is conventionally recommended to use a dose of 0.2 mg to 1 mg of ROMAZICON® with a subsequent dose in no less than 20 minutes.
  • 1 mg doses may be delivered over five minutes up to 3 mg doses over 15 minutes.
  • a larger dose may be administered over short periods of time, such as 3 mg doses administered within 6 minutes.
  • the physician in charge should make a determination, prior to treatment, if a patient diagnosed with any symptom or disorder, other than substance dependence, should receive medication for this disorder. For example, a patient diagnosed with arterial hypertension should be prescribed with the appropriate medication or continue with any existing medication if they are not contraindicated for use with the compositions used in the treatment methodology of the present invention.
  • the present invention is broadly directed toward the combination of any Conventional Composition, in any dosage form or amount, with any Inhibitor of Neurosteroid Production, in the same dosage form and in any amount.
  • any Conventional Composition in any dosage form or amount
  • any Inhibitor of Neurosteroid Production in the same dosage form and in any amount.
  • specific novel compositions will be described below. It should be appreciated that the actual dosage and administration route of the Conventional Compositions vary greatly and depend upon the status of an individual patient. It should also be appreciated that, accordingly, the actual dosage and administration route of the Inhibitor of Neurosteroid Production will vary as well. However, a person of ordinary skill in the medical art would be able to appropriately select a dosage amount for the Conventional Composition and the Inhibitor of Neurosteroid Production should be provided in the same dosage form and in a sufficient amount to be therapeutically effective at blocking neurosteroid production.
  • a “therapeutically effective amount” of a composition of the present invention refers to a sufficient amount to reduce or prevent neurosteroid production.
  • the therapeutically effective amount is also an amount effective to reduce, alleviate or ameliorate symptoms of dependency such as for example, anxiety.
  • a reduction or amelioration of the symptoms may be determined using standard clinical tests where a reduction or amelioration of the symptoms indicates a therapeutically effective amount has been administered. Examples of such clinical tests are the Hamilton Anxiety Rating Scale and the Beck Anxiety Inventory for anxiety where an improvement in an individual's test score indicates a therapeutically effective amount has been administered.
  • Therapeutically effective amounts for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve circulating concentration that has been found to be effective in animals. Useful animal models of anxiety are well known in the art.
  • the compounds useful in the present invention, or pharmaceutically acceptable salts thereof, can be delivered to a patient using a wide variety of routes or modes of administration.
  • routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
  • These methods also include the use of the aforementioned compounds in the manufacture of compositions, drugs or medicaments useful for reducing the production of neurosteroids.
  • the claimed methods also include the use of the aforementioned compounds in the manufacture of compositions, drugs or medicaments useful for treating, reducing or ameliorating addictive properties of certain substances.
  • salts means those salts which retain the biological effectiveness and properties of the compounds used in the present invention, and which are not biologically or otherwise undesirable. Such salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethanine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example carboxylic acid amides, including carboxamides, lower alkyl carboxamides, di(lower alkyl) carboxamides, and the like.
  • the compounds, or pharmaceutically acceptable salts thereof may be administered singly, in combination with other compounds, and/or in cocktails combined with other therapeutic agents.
  • therapeutic agents that can be co-administered with the compounds of the invention will depend, in part, on the condition being treated.
  • the active compounds may be administered per se or in the form of a pharmaceutical composition wherein the active compound(s) is in admixture or mixture with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores can be provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may be formulated as a sustained release preparation.
  • sustained release preparations Numerous techniques for formulating sustained release preparations are described in the following references—U.S. Pat. Nos. 4,891,223; 6,004,582; 5,397,574; 5,419,917; 5,458,005; 5,458,887; 5,458,888; 5,472,708; 6,106,862; 6,103,263; 6,099,862; 6,099,859; 6,096,340; 6,077,541; 5,916,595; 5,837,379; 5,834,023; 5,885,616; 5,456,921; 5,603,956; 5,512,297; 5,399,362; 5,399,359; 5,399,358; 5,725,883; 5,773,025; 6,110,498; 5,952,004; 5,912,013; 5,897,876; 5,824,638; 5,464,633; 5,422,123; and 4,839,
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in a conventional manner.
  • the active compound(s) may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compound(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a further embodiment of the present invention is related to a nanoparticle.
  • the compounds of the present invention may be incorporated into the nanoparticle.
  • the nanoparticle within the scope of the invention is meant to include particles at the single molecule level as well as those aggregates of particles that exhibit microscopic properties. Methods of using and making the above-mentioned nanoparticle can be found in the art (U.S. Pat. Nos.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions suitable for use in the present invention include compositions wherein the active ingredient is contained in a therapeutically or prophylactically effective amount, i.e., in an amount effective to achieve therapeutic or prophylactic benefit, as previously discussed.
  • a therapeutically or prophylactically effective amount i.e., in an amount effective to achieve therapeutic or prophylactic benefit, as previously discussed.
  • the actual amount effective for a particular application will depend on the condition being treated and the route of administration. Determination of an effective amount is well within the purview of those skilled in the art, especially in light of the disclosure herein.
  • the methods of the present invention include the use of the aforementioned compounds in the manufacture of compositions, drugs or medicaments useful for reducing the addictive and habit-forming properties of certain compounds in the classes described above. These methods also include the use of the aforementioned compounds in the manufacture of compositions, drugs or medicaments useful for reducing the production of neurosteroids. The claimed methods also include the use of the aforementioned compounds in the manufacture of compositions, drugs or medicaments useful for reducing the tolerance of certain compounds in the classes described above.
  • An orally administered tablet comprises between 100 mg and 1000 mg, preferably 300, 325, 400, 500, 650, or 750 mg, of VICODIN® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 100 mg and 1000 mg, preferably 325, 500, or 650 mg, of PERCOCET® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.1 and 5 mg, preferably 0.25, 0.5, 1, 2, or 3 mg, of XANAX® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg and 200 mg, preferably 10, 20, 40, or 90 mg, of PROXAC® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg and 50 mg, preferably 2, 5, or mg, of VALIUM® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg and 200 mg, preferably 5, 10, 20, 30, 40, 80, 100, or 160 mg, of OXYCONTIN® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 10 mg and 1000 mg, preferably 100, 325, 500, and 650 mg, of DARVOCET® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg and 50 mg, preferably 5, 6.25, or 10 mg, of zolpidem and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg and 200 mg, preferably 10, 12.5, 20, 30, or 40 mg, of PAXIL® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.5 mg and 100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of diazepam and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.5 mg and 100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of methadone and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.01 mg and 1000 mg of any of the aforementioned conventional compositions and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.01 mg and 1000 mg of any of the aforementioned conventional compositions and 0.1 to 1000 mg of any of the inhibitors of neurosteroid production.
  • An orally administered capsule comprises between 150 mg and 750 mg, preferably 500 mg, of VICODIN® and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 100 mg and 1000 mg, preferably 500 mg, of PERCOCET® and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 1 mg and 250 mg, preferably 10, 20, or 40 mg, of PROZAC® and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 1 mg and 50 mg, preferably 10, 15, 2.5, 20, or 5 mg, of VALIUM® and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 1 mg and 200 mg, preferably 5 mg, of OXYCONTIN® and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 0.5 mg and 100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of diazepam and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 1 mg and 500 mg, preferably 10, 15, 30, 20, 100, 120 mg, of morphine and 0.1 to 100 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered capsule comprises between 10 mg to 1000 mg, preferably 100, 200 or 400 mg, of CELEBREX® and 0.1 to 5 mg, preferably 0.5 mg, of dutasteride.
  • An orally administered tablet comprises between 1 mg and 100 mg, preferably 15, 30, or 60 mg, of codeine and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 1 mg to 500 mg, preferably 25, 50, or 100 mg, of ZOLOFT® and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • a nicotine patch having between 0.1 to 150 mg, preferably 5 mg, of finasteride therein.
  • a solution comprising any amount of wine, beer, or other alcoholic beverage, such as 6 ounces, 12 ounces, 1 pint, or 1 quart, and 0.1 to 150 mg, preferably 5 mg, of finasteride dissolved therein.
  • An orally administered tablet comprises 0.25 mg norgestimate, 0.035 mg ethinyl estradiol, and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • An orally administered tablet comprises between 0.5 mg and 1 mg of norethindrone, 0.035 mg ethinyl estradiol, and 0.1 to 150 mg, preferably 5 mg, of finasteride.
  • Continuous Infusion (To provide attenuation of response to intubation and incision): Infusion rates are variable and should be treated to the desired clinical effect.
  • Induction of Analgesia 50-75 mcg/kg; Maintenance of Analgesia: 0.5 to 3 mcg/kg/min (Average rate 1 to 1.5 mg/kg/min); Total dose: Dependent on duration of procedure.
  • Anesthetic Induction Induction of Analgesia: 130-245 mcg/kg; Maintenance of Analgesia: 0.5 to 1.5 mcg/kg/min or general anesthetic; Total dose: Dependent on duration of procedure.
  • truncal rigidity should be expected and a muscle relaxant should be utilized; Administer slowly (over 3 minutes); Concentration of inhalation agents reduced by 30-50% for initial hour.
  • MONITORED ANESTHESIA CARE (MAC) (For sedated and responsive, spontaneously breathing patients): Induction of M.C. 3-8 mcg/kg; Maintenance of M.C. 3-5 mcg/kg q 5-20 min or 0.25 to 1 mcg/kg/min; Total dose: 3-40 mcg/kg
  • BUPRENORPHINE Administered sublingually as a single daily dose in the range of 12 to 16 mg/day. Buprenorphine is also delivered transdermally in 25, 50, and 75 mcg/hour.
  • BUTORPHANOL This formulation of butorphanol is administered every 3-4 hours either as a nasal spray or injected into the buttock or hip muscle or into a vein.
  • the FDA does not regulate Stadol ® in most states.
  • CODEINE also METHYL MORPHINE
  • Codeine and codeine-combo preparations are usually taken every 4-6 hours.
  • Adults 15 to 60 mg every 4 to 6 hours (usual adult dose, 30 mg).
  • Children 1 Year of Age and Older - 0.5 mg/kg of b.d. weight or 15 mg/m2 of b.d. surface every 4 to 6 hours.
  • 200 mg (oral) of codeine is about equal to 30 mg (oral) of morphine.
  • CODEINON See Hydrocodone for details.
  • PROPOXYPHENE Acetaminophen (Tylenol) and propoxyphene. (DARVOCET) It is formulated as a tablet taken every 4 hours by mouth.
  • DEXTROPROPOXYPHENE Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin.
  • Dextropropoxyphene is prescribed for relief of mild to moderate pain.
  • HEROIN ILLICIT SUBSTANCE/NO APPROVED DOSING DIHYDROCODEINE Dihydrocodeine is approximately twice as potent as codeine; this is taken into consideration while dosing dihydrocodeine.
  • Patients who are considered opioid- tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic dose of another opioid.
  • HYDROCODONE DIHYDROCODEINONE Five mg of hydrocodone is equivalent to 30 mg of codeine when administered orally. Also, a dose of 15 mg (1 ⁇ 4 gr) of hydrocodone is equivalent to 10 mg (1 ⁇ 6 gr) of morphine. The typical therapeutic dose of 5 to 10 mg is pharmacologically equivalent to 30 to 60 mg of oral codeine.
  • HYDROMORPHONE Dilaudid ® is formulated as oral tablets and liquid, rectal suppository, intra-muscular (buttock or hip muscle) injection, and intravenous (I.V.) solution. Dosing is every 4-6 hours for the oral forms and every 6-8 hours for the suppository. An I.V. drip allows for continuous administration and around-the-clock pain relief. It can be given intravenously, intramuscularly, rectally, or orally. LAAM The initial dose street addicts should be 20 to 40 mg.
  • Each Levomethadyl Acetate subsequent dose, administered at 48- or 72-hour intervals, may be Hydrochloride, also known as adjusted in increments of 5 to 10 mg until a pharmacokinetic and Levo-alpha-acetylmethadol or pharmacodynamic steady-state is reached. Patients dependent on Levacetylmethadol (LAM) methadone may require higher initial doses.
  • LAM Levacetylmethadol
  • METHADONE It comes as tablets, dispersible tablets, liquid, and liquid concentrate. Patients take it every 3-4 hours for severe pain and every 6-8 hours for chronic pain.
  • MORPHINE SULFATE MS Contin ® comes in the form of tablets, capsules, liquid, and rectal suppository, which are taken every 4 hours. Long-acting tablets and capsules can be taken every 8-12 hours or 1-2 per day, respectively.
  • OPIUM (NATURAL) ILLEGAL - NO FDA RECOMMENDED USAGE OXYCODONE OxyContin ® comes in liquid and tablet forms taken every 6 hours. Long-acting tablets are available to take every 12 hours.
  • OXYMORPHONE Injection Subcutaneous or intramuscular administration: initially 1 mg to 1.5 mg, repeated every 4 to 6 hours as needed. Intravenous: 0.5 mg initially. For analgesia during labor 0.5 mg to 1 mg intramuscularly is recommended.
  • Rectal Suppositories One suppository, 5 mg, every 4 to 6 hours.
  • PETHIDINE (MEPERIDINE) Adults: The usual dosage is 50 mg to 150 mg intramuscularly, subcutaneously, or orally, every 3 or 4 hours as necessary. Children: The usual dosage is 0.5 mg/lb to 0.8 mg/lb intramuscularly, subcutaneously, or orally up to the adult dose, every 3 or 4 hours as necessary.
  • REMIFENTANIL During Induction of Anesthesia ULTIVA should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia.
  • an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.
  • SUFENTANIL Not more than 3 total doses. Each dose must be at least one hour apart.
  • THEBAINE Thebaine is not used therapeutically, but is converted into a variety of compounds including codeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.
  • TRAMADOL Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50-400 mg daily, with up to 600 mg daily when given IV/IM.
  • TETRAHYRDOCANNIBINOL/THC MARINOL Marinol widely available through prescription. It comes in the THC form of a pill and is also being studied by researchers for suitability and some via other delivery methods, such as an inhaler or patch.
  • the active other ingredient of Marinol is synthetic THC, which has been found to cannibinoids, have relieve the nausea and vomiting associated with chemotherapy and analgesic the loss of appetite associated with various other disease states. properties.
  • Intravenous Route The initial dose of ketamine administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to produce five to ten minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb).
  • Intramuscular Route The initial dose of ketamine administered intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgical anesthesia.
  • BARBITURATES ALLOBARBITAL MRTD (Maximum Recommended Therapeutic Dose) - 3.33000 mg/kg- body weight (bw)/day based upon an average adult weighing 60 kg.
  • APROBARBITAL MRTD (Maximum Recommended Therapeutic Dose) - 2.67000 mg/kg- body weight (bw)/day based upon an average adult weighing 60 kg.
  • BARBEXACLONE 100 mg of barbexaclone is equivalent to 60 mg of phenobarbital.
  • BARBITAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- (VERONAL) body weight (bw)/day based upon an average adult weighing 60 kg - 10.00000
  • BUTABARBITAL Butabarbital Oral is used to treat the following: Severe Anxiety, Additional Agent to Induce General Anesthesia, Abnormal Trouble Sleeping MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- body weight (bw)/day based upon an average adult weighing 60 kg - 2.000
  • BUTALBITAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- Butalbital, 5-allyl-5- body weight (bw)/day based upon an average adult weighing isobutylbarbituric acid.
  • Butobarbital and acetaminophen butalbital, acetaminophen, and caffeine butalbital and aspirin butalbital, aspirin, and caffeine BUTOBARBITAL 50 mg of Butobarbital is equivalent to 10 mg of Diazepam; Acc. to (SONERYL) Nordic Statistics on Medicines, the Defined Daily Dose of Butobarbital is 150 mg. No data available from FDA. CYCLOBARBITAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- body weight (bw)/day based upon an average adult weighing 60 kg - 6.67000 ETHALLOBARBITAL N.A.
  • HEPTABARBITAL Defined Daily Dose - 0.2 g, No data available from FDA.
  • HEXOBARBITAL MRTD Maximum Recommended Therapeutic Dose in mg/kg- body weight (bw)/day based upon an average adult weighing 60 kg - 8.33000
  • MEPHOBARBITAL Epilepsy Average dose for adults: 400 mg to 600 mg daily; children (METHYLPHENOBARBITAL) under 5 years: 16 mg to 32 mg three or four times daily; children over 5 years: 32 mg to 64 mg three or four times daily. Sedation: Adults: 32 mg to 100 mg optimum dose, 50 mg three to four times daily. Children: 16 mg to 32 mg three to four times daily.
  • METHARBITAL METHOHEXITAL For induction of anesthesia, a 1% solution is administered at a rate of about 1 mL/5 seconds.
  • the dose required for induction may range from 50 to 120 mg or more but averages about 70 mg.
  • the usual dosage in adults ranges from 1 to 1.5 mg/kg.
  • Maintenance of anesthesia may be accomplished by intermittent injections of the 1% solution or, more easily, by continuous intravenous drip of a 0.2% solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a 1% solution) may be given as required, usually every 4 to 7 minutes.
  • the average rate of administration is about 3 mL of a 0.2% solution/minute (1 drop/second).
  • PENTOBARBITAL The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg as a single IM injection; the recommended pediatric dosage ranges from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg. The rate of IV injection should not exceed 50 mg/min for pentobarbital sodium.
  • PHENOBARBITAL Pediatric Oral Dosage (as recommended by the American Academy of Pediatrics): Preoperative: 1 to 3 mg/kg.
  • Anticonvulsant 50 to 100 mg 2 to 3 times daily.
  • PRIMIDONE Adult Dosage Patients 8 years of age and older who have received no previous treatment may be started on primidone according to the following regimen using Primidone 250 mg tablets. Days 1-3: 100 to 125 mg at bedtime; Days 4-6: 100 to 125 mg b.i.d.; Days 7-9: 100 to 125 mg t.i.d.; Day 10-maintenance; 250 mg t.i.d. For most adults and children 8 years of age and over, the usual maintenance dosage is three to four 250 mg primidone tablets daily in divided doses (250 mg t.i.d. or q.i.d.). If required, an increase to five or six 250 mg tablets daily may be made but daily doses should not exceed 500 mg q.i.d.
  • Pediatric Dosage For children under 8 years of age, the following regimen may be used: Days 1-3: 50 mg at bedtime; Days 4-6: 50 mg b.i.d.; Days 7-9: 100 mg b.i.d.; Day 10-maintenance: 125. mg t.i.d. to 250 mg t.i.d. For children under 8 years of age, the usual maintenance dosage is 125 to 250 mg three times daily, or 10-25 mg/kg/day in divided doses.
  • SECOBARBITAL For oral dosage form (capsules): For trouble in sleeping: Adults-100 milligrams (mg) at bedtime. Children-Dose must be determined by your doctor. For daytime sedation: Adults-30 to 50 mg three or four times a day.
  • Children-Dose is based on body weight or size and must be determined by your doctor.
  • the usual dose is 2 mg per kilogram (kg) (0.9 mg per pound) of body weight three times a day.
  • For sedation before surgery Adults-200 to 300 mg one or two hours before surgery.
  • Children-Dose is based on body weight and must be determined by your doctor.
  • the usual dose is 2 to 6 mg per kg (0.9 to 2.7 mg per pound) of body weight one or two hours before surgery. However, the dose is usually not more than 100 mg.
  • the usual dose is 3 to 5 mg per kg (1.4 to 2.3 mg per pound) of body weight, injected into a muscle. However, the dose is usually not more than 100 mg.
  • Adults-Dose is based on body weight and must be determined by your doctor.
  • the usual dose is 1.1 to 2.2 mg per kg (0.5 to 1 mg per pound) of body weight, injected into a muscle ten to fifteen minutes before the procedure. Children-Dose must be determined by your dentist.
  • For sedation before a nerve block Adults-100 to 150 mg, injected into a vein.
  • Children-Dose is based on body weight and must be determined by your doctor.
  • TALBUTAL MRTD Maximum Recommended Therapeutic Dose
  • mg/kg- (Lotusate ®) also called 5-allyl- body weight (bw)/day based upon an average adult weighing 5-sec-butylbarbituric acid.
  • Pentothal Thiopental Sodium for Injection, USP
  • Pentothal is injected at a slow rate of 100 mg/mm (4 mL/min of a 2.5% solution) with the patient counting backwards from 100. Shortly after counting becomes confused but before actual sleep is produced, the injection is discontinued. Allow the patient to return to a semidrowsy state where conversation is coherent.
  • Pentothal may be administered by rapid I.V. drip using a 0.2% concentration in 5% dextrose and water.
  • VINBARBITAL MRTD Maximum Recommended Therapeutic Dose in mg/kg- Vinbarbital (5-Ethyl-5-(1- body weight (bw)/day based upon an average adult weighing methyl-1-butenyl)barbituric 60 kg - 3.33000 acid).
  • VINYLBITAL Defined Daily Dose - 0.15 g, No data available from FDA.
  • Oral (For panic disorder): Start: 0.5 mg 3 times daily. Increases: 1 mg daily in 3 to 4 day intervals. Maximum: 10 mg in 24 hours.
  • BROMAZEPAM Not commercially available in the U.S. BROTIZOLAM Brotizolam is not approved for sale in the United States or Canada.
  • CAMAZEPAM Defined Daily Dose - 30 mg, No data available from FDA.
  • CHLORDIAZEPOXIDE For relief of mild and moderate anxiety disorders and symptoms of anxiety: 5 mg or 10 mg, 3 or 4 times daily. For relief of server anxiety disorders and symptoms of anxiety: 20 mg or 25 mg, 3 or 4 times daily.
  • Geriatric patients or in the presence of debilitating disease 5 mg, 2 to 4 times daily.
  • CLONAZEPAM Seizure Disorders Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg. Pediatric Patients: Klonopin is administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.
  • Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.
  • Panic Disorder Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day.
  • CLOTIAZEPAM Clotiazepam is not approved for sale in the United States or Canada
  • CLORAZEPATE ORAL START: 15 mg/daily INCREASES: As needed.
  • MAXIMUM 60 mg in 24 hours
  • CLOXAZOLAM Cloxazolam is not approved for sale in the United States or Canada.
  • DELORAZEPAM Defined Daily Dose - 3 mg, No data available from FDA. DIAZEPAM Management of Anxiety Disorders and Relief of Symptoms of Anxiety: Depending upon severity of symptoms - 2 mg to 10 mg, 2 to 4 times daily. Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed.
  • Adjunctively for Relief of Skeletal Muscle Spasm 2 mg to 10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily. Geriatric Patients, or in the presence of debilitating disease: 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated. Pediatric patients: Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated. ESTAZOLAM The recommended initial dose for adults is 1 mg at bedtime; however, some patients may need a 2 mg dose.
  • HALAZEPAM For oral dosage form (tablets): For anxiety: Adults-20 to 40 milligrams (mg) three or four times a day. Children younger than 18 years of age-Use and dose must be determined by your doctor. Older adults-20 mg one or two times a day.
  • HALOXAZOLAM Defined Daily Dose - 7.50 mg, No data available from FDA.
  • LOPRAZOLAM It is available in 1 mg tablets. The usual adult dose is 1-2 mg at bedtime, the higher dose being recommended for patients who have previously been treated with benzodiazepines for severe persistent insomnia. An initial dose of 0.5 mg-1.0 mg is recommended in elderly and debilitated patients.
  • LOREZEPAM The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.
  • the daily dosage may vary from 1 to 10 mg/day.
  • a single daily dose of 2 to 4 mg may be given, usually at bedtime.
  • an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated.
  • MEDAZEPAM Defined daily dose as used in the Nordic Statistics on Medicines - 20 mg; No data available from FDA.
  • MIDAZOLAM For preoperative sedation/anxiolysis/amnesia. Intramuscular - The recommended premedication dose of VERSED for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery. The dose must be individualized and reduced when IM VERSED is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants.
  • VERSED In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of VERSED produced adequate sedation during the preoperative period. The dose of 1 mg IM VERSED may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. Intravenous - VERSED 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water. 1.
  • Healthy Adults Below the Age of 60 Titrate slowly to the desired effect (eg, the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 2.5 mg should be given over a period of at least 2 minutes. A total dose greater than 5 mg is not usually necessary to reach the desired endpoint. If narcotic premedication or other CNS depressants are used, patients will require approximately 30% less VERSED than unpremedicated patients. 2. Patients Age 60 or Older, and Debilitated or Chronically Ill Patients: Titrate slowly to the desired effect (eg, the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes.
  • NIMETAZEPAN MRTD Maximum Recommended Therapeutic Dose
  • bw body weight
  • NITRAZEPAM Nitrazepam shortens the time required to fall asleep and lengthens the duration of this sleep. Typically, it may work within an hour and allow the individual to maintain sleep for 4 to 6 hours. It is no longer available in the United States.
  • Older patients with anxiety, tension, irritability, and agitation Initial dosage - 10 mg, 3 times daily. if necessary, increase cautiously to 15 mg, 3 or 4 times daily.
  • Alcoholics with acute inebriation, tremulousness, or anxiety on withdrawal 15 to 30 mg, 3 or 4 times daily.
  • OXAZOLAM 20 mg is equivalent to 10 mg of Diazepam.
  • MRTD Maximum Recommended Therapeutic Dose
  • PINAZEPAM MRTD Maximum Recommended Therapeutic Dose
  • PRAZEPAM MRTD Maximum Recommended Therapeutic Dose
  • the recommended initial dose is 15 milligrams daily. Your doctor may later reduce this dosage to 7.5 milligrams.
  • TEMAZEPAM While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly and/or debilitated patients it is recommended that therapy be initiated with 7.5 mg until individual responses are determined.
  • a dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight).
  • a dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered.
  • a dose of 0.5 mg should not be exceeded.
  • the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in this group and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients.
  • HORMONES/CONTRACEPTIVES ESTROGENS See other columns.
  • Hormone-Containing Contraceptives include: ethinyl Combination contraceptives are those containing both estrogen and estradiol and progesterone. mestranol.
  • combination birth control pills including PROGESTERONES monophasic pills, biphasic pills, triphasic pils, and 91-day cycle include: pills.
  • Norethynodrel, USE Starting at the beginning of the pill pack, take one each day at norethindrone, approximately the same time every day to increase efficacy.
  • norethindrone WHEN TO BEGIN The following regimens may be used when acetate, first starting on birth control pills: norgestimate, Taking one pill each day, starting on the fifth day after the desogestrel, onset of menses and continuing for 21 or 28 days. ethyndiol Beginning pills on the first day of the menstrual period. diacetate, Beginning on the first Sunday after the menstrual period norgestrel, starts. levonorgestrel, 21-DAY PILL CONTAINER: Take one pill daily for 21 days, stop drospirenone. for 7 days, then resume taking the pills with a new container of pills. 28-DAY PILL CONTAINER: Start with the first pill in the container and swallow one daily for 28 days.
  • 91-DAY PILL CONTAINER One pill is taken daily for 12 weeks, followed by one week of inactive pills. A menstrual period occurs during the week of inactive pills, so women on this regimen have a period only once every three months.
  • Monophasic Pills Alesse, Brevicon, Demulen, Desogen, Levlen, Levlite, Loestrin, Microgestin, Modicon, Necon, Nelova, Nordette, Norinyl, Ortho-Cept, Ortho-Cyclen, Ortho-Novum, Ovcon, Ovral, Yasmin, Zovia.
  • Monophasic pills have a constant dose of estrogen and progestin in each of the hormonally active pills through the entire cycle (21 days of ingesting active pills).
  • Several of the brands listed above may be available in several strengths of estrogen or progesterone, from which doctors choose according to a woman's individual needs.
  • Biphasic Pills Jenest, Mircette, Necon 10/11, Nelova 10/11, and Ortho-Novum 10/11 Biphasic Pills typically contain two different progesterone doses. The progesterone dose is increased about halfway through the cycle.
  • Triphasic Pills Cyclessa, Estrostep, Ortho-Novum 7/7/7, Ortho Tri- Cyclen, Ortho Tri-Cyclen LO, Tri-Levlen, Tri-Norinyl, Triphasil, Trivora Triphasic pills gradually increase the dose of estrogen during the cycle (some pills also increase the progesterone dose). Three different increasing pill doses are contained in each cycle.
  • Ninety-One Day BCP Levonorgestrel/ethynl estradiol (Seasonale) These pills are monophasic birth control pills that have been approved for use on a daily basis for 84 days without interruption. Users have fewer schedules menstrual cycles (only 1 period every 3 months).
  • Topical Contraceptive Patch Norelgestromin/ethinyl estradiol (Ortho Evra) A new patch is applied on the same day of the week, each week for three weeks in a row. The first patch is applied on either the first day of the menstrual period or on the Sunday following menses. On the fourth week, no patch is applied. Another 4-week cycle is started by applying a new patch following the 7-day patch free period.
  • Long-Acting, Injectable, Progesterone-Only Contraceptives Medroxyprogesterone acetate (Depo-Provera) The first injection is given within five days following the onset of menstruation. After that, an injection is needed every 11-13 weeks. Unlike pills, the injection works right away.
  • Progesterone-Only Pills Norethindrone (Nor-QD) Progesterone-only pills, also known as mini-pills, are not used widely in the US. POPs are ingested once daily, every day. They may be started on any day, and there are no pill-free days or different colored pills to track. Since progesterone is the only hormonal ingredient, estrogen-related side effects are avoided.
  • Vaginal Ring Etonogestrel/ethinyl estradiol (NuvaRing) The ring is self-inserted into the vagina. Exact positioning is not required for it to be effective. The vaginal ring must be inserted within 5 days of the onset of the menstrual period, even if bleeding is still occurring.
  • NON-BENZODIAZEPINE CHLORAL HYDRATE The usual hypnotic dose is 500 mg to 1 g, taken 15 to 30 minutes ANXIOLYTICS SEDATIVES before bedtime or 1 ⁇ 2 hour before surgery.
  • the usual sedative dose is HYPNOTICS TRANQUILIZERS 250 mg three times daily after meals. Generally, single doses or daily dosage should not exceed 2 g.
  • ETHCHLORVYNOL Due to the problems it can cause, it is unusual for ethchlorvynol to be prescribed for periods exceeding seven days.
  • PROMETHIAZINE Administration of 12.5 to 25 mg Phenergan by the oral route or by rectal suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.
  • ZALPELON The recommended dose of Sonata for most nonelderly adults is 10 mg. (imidazopyridine) For certain low weight individuals, 5 mg may be a sufficient dose.
  • STIMULANTS CAFFEINE Caffeine Oral is used to treat the following: Absence of Breathing in the Newborn Caffeine Oral may also be used to treat: Drowsiness, Low Energy Caffeine citrate is indicated for the short term treatment of apnea of prematurity in infants between 28 and ⁇ 33 weeks gestational age.
  • Caffeine Citrate Loading Dose - 20 mg/kg Maintenance Dose - 5 mg/kg NICOTINE
  • NICOTROL Inhaler is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms.
  • NICOTROL Inhaler therapy is recommended for use as proof of a comprehensive behavioral smoking cessation program. It it supplied as 42 cartridges each containing 10 mg (4 mg is delivered) nicotine.
  • GHB is used for the treatment of alcoholism (50 to 100 mg per kg per day, in 3 or more divided doses), both for acute alcohol withdrawal and medium to long term detoxification.
  • LD50 of GHB is estimated to be between 1100 mg/kg and 2000 mg/kg in rodents and is almost certainly lower in humans.
  • MEPROBROMATE Meprobromate is available in 200 mg and 400 mg tablets for oral administration. Symptoms of meprobromate overdose include coma, drowsiness, loss of muscle control, severly impaired breathing, shock, sluggishness, and unresponsiveness.
  • NITROUS OXIDE Nitrous Oxide is a weak general anesthetic, and is generally not used alone. It has a very low short-term toxicity and is an excellent analgesic. In general anesthesia it is often used in a 2:1 ratio with oxygen in addition to more powerful general anesthetic agents. Possession of nitrous oxide is illegal in most localities in the United States for the purposes of inhaling or ingesting if not under the care of a physician or dentist.
  • Salvinorin A is the main active Salvinorin A is a dissociative hallucinogenic compound that is psychotropic constituent of the active at the extremely low doses of 0.2-0.5 mg, second only to plant Salvia divinorum LSD in quantitative potency, making it the most potent naturally (diviner's sage, Mexican mint).
  • St John's wort preparations vary greatly between Refers to the species Hypericum formulations, due to variability in the plant source and preparation perforatum . processes.
  • the doses of St. John's wort extract used in clinical trials generally range from 350 to 1800 mg daily (equivalent to 0.4 to 2.7 mg hypericin depending on the preparation).
  • ESCITALOPRAM OXALATE LEXAPRO (escitalopram) is indicated for the treatment of major LEXAPRO TM depressive disorder and Generalized Anxiety Disorder (GAD).
  • the recommended dose of LEXAPRO is 10 mg once daily.
  • FLUOXETINE Prozac is indicated for the treatment of: Major Depressive Disorder: HYDROCHLORIDE a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.
  • the maximum fluoxetine dose should not exceed 80 mg/day.
  • Obsessive Compulsive Disorder a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.
  • the maximum fluoxetine dose should not exceed 80 mg/day.
  • Bulimia Nervosa the recommended dose is 60 mg/day, administered in the morning.
  • Panic Disorder Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day.
  • PAROXETINE Major Depressive Disorder The recommended initial dose is HYDROCHLORIDE 20 mg/day. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day.
  • Obsessive Compulsive Disorder The recommended dose of PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. The maximum dosage should not exceed 60 mg/day.
  • Panic Disorder The target dose of PAXIL in the treatment of panic disorder is 40 mg/day. The maximum dosage should not exceed 60 mg/day.
  • Social Anxiety Disorder The recommended and initial dosage is 20 mg/day.
  • Generalized Anxiety Disorder The recommended starting dosage and the established effective dosage is 20 mg/day.
  • Posttraumatic Stress Disorder The recommended starting dosage and the established effective dosage is 20 mg/day.
  • FLUVOXAMINE MALEATE Fluvoxamine is indicated in the treatment of depression and for (LUVOX).
  • Obsessive Compulsive Disorder (OCD) The recommended starting dose for LUVOX Tablets in adult patients is 50 mg, administered as a single daily dose at bed time. The maximum therapeutic dose should not to exceed 300 mg per day.
  • SERTRALINE Major Depressive Disorder and Obsessive-Compulsive Disorder HYDROCHLORIDE ZOLOFT treatment should be administered at a dose of 50 mg once daily.
  • Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder ZOLOFT treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
  • Premenstrual Dysphoric Disorder ZOLOFT treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.
  • AMITRIPTYLINE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states.
  • Oral Dosage 75 mg of amitriptyline HCl a day in divided doses. If necessary, this may be increased to a total of 150 mg per day.
  • Desipramine hydrochloride is indicated for relief of symptoms in HYDROCHLORIDE various depressive syndromes, especially endogenous depression. The usual adult dose is 100 to 200 mg per day. Dosages above 300 mg/day are not recommended. Not recommended for use in children.
  • NORTRIPTYLINE Nortriptyline HCl is indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. It is not recommended for children.
  • DULOXETINE Cymbalta is indicated for the treatment of major depressive disorder HYDROCHLORIDE (MDD) and pain associated with diabetic peripheral neuropathy.
  • MDD major depressive disorder
  • Cymbalta should be administered at a total dose of 40 mg/day
  • Diabetic Peripheral Neuropathic Pain Cymbalta should be administered at a total dose of 60 mg/day given once a day
  • VENLAFAXINE Effexor venlafaxine hydrochloride
  • the recommended starting dose for Effexor is 75 mg/day, up to a maximum of 375 mg/day, generally in three divided doses PHENELZINE SULFATE
  • the usual starting dose of Nardil is one tablet (15 mg) three times a day. Maintenance dose may be as low as one tablet, 15 mg, a day or every other day, and should be continued for as long as is required.
  • TRANYLCYPROMINE For the treatment of Major Depressive Episode Without (Parnate) Melancholia.
  • the usual effective dosage is 30 mg per day, usually given in divided doses; may be extended to a maximum of 60 mg per day.
  • monoamine oxidase activity is recovered in 3 to 5 days, although the drug is excreted in 24 hours.
  • MIRTAZEPINE Indicated for the treatment of major depressive disorder.
  • the recommended starting dose for REMERON ® (mirtazapine) Tablets is 15 mg/day, up to a maximum of 45 mg/day.
  • NEFAZODONE SERZONE nefazodone hydrochloride
  • SERZONE nefazodone hydrochloride
  • TRAZODONE DESYREL is indicated for the treatment of depression.
  • HYDROCHLORIDE An initial dose of 150 mg/day in divided doses is suggested, up to DESYREL but not in excess of 600 mg/day in divided doses.
  • BUPROPION WELLBUTRIN is indicated for the treatment of depression.
  • HYDROCHLORIDE The usual adult dose is 300 mg/day, given 3 times daily.
  • WELLBUTRIN bupropion WELLBUTRIN should be discontinued in patients who do not hydrochloride
  • the usual dose is 75 mg per day.
  • Isocarboxazid The maximum daily dose of isocarboxazid is 60 mg.
  • Moclobemide Depression The initial dose is 300 mg daily in 2 or 3 divided doses.
  • Social Phobia The recommended dose is 600 mg daily in 2 or 3 divided doses.
  • a single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition on any of the neurotransmitters occurs.
  • NEUROSTEROID 5-ALPHA- INHIBITORS REDUCTASE INHIBITORS FINASTERIDE The recommended dosage is 1 mg orally once per day. It may be administered with or without meals. An alternate dosage of 5 mg orally once per day is also included. It may be administered with or without meals.
  • dutasteride In general, daily use for three months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit, which should be re-evaluated periodically. Withdrawal of treatment leads to reversal of effect within 12 months.
  • DUTASTERIDE The recommended therapeutic dose of dutasteride is 0.5 mg taken orally once per day. Dutasteride pharmacokinetics has not been investigated in subjects less than 18 years of age. No dose adjustment is necessary in the elderly. In volunteer studies, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns.
  • Rectal Suppositories A dose of 640 milligrams once daily has been used. Rectal use of saw palmetto is no better than taking saw palmetto by mouth. Tea. Tea made from berries may not be effective because the proposed active ingredient does not dissolve in water.
  • SPIRONOLACTONE Treatment protocols may involve continuous spironolactone use at 50 mg to 200 mg per day or cyclic use; for example, 50 mg or 100 mg twice daily from the 4 th to the 22 nd day of the menstrual cycle. Numerous treatment protocols involving spironolactone have been used in different studies, but no particular treatment approach has been shown to be significantly superior.
  • 3-ALPHA REDUCTASE INHIBITORS INDOMETHACIN Indomethacin can be administered in the form of capsules (25 mg and 50 mg); sustained-release capsules (75 mg); a suspension (25 mg/ml); or a suppository (50 mg).
  • the recommended dose for adults is 50-200 mg per day split into 2-3 doses.
  • CLASS OF COMPOUNDS THAT FLUMAZENIL ROMAZICON is indicated for the complete or partial reversal of SELECTIVELY MODULATES (Romazicon) the sedative effects of benzodiazepines in cases where general GABA A RECEPTORS anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose.
  • Reversal of Conscious Sedation The recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 15 seconds.
  • a second dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).
  • the recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).
  • the recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 30 seconds. if the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL) can be administered over another 30 seconds. Further doses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.
  • MILTIRONE The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.
  • Flavonols including Quercetin, Kaempferol, Myricetin, Isorhamnetin Flavones, including Luteolin, Apigenin Flavanones, including Hesperetin, Naringenin, Eriodictyol Flavan-3-ols, including (+)- Catechin, (+)-Gallocatechin, ( ⁇ )- Epicatechin, ( ⁇ )- *Epigallocatechin, ( ⁇ )- Epicatechin 3-gallate, ( ⁇ )- Epigallocatechin 3-gallate, Theaflavin, Theaflavin 3- gallate, Theaflavin 3′-gallate, Theaflavin 3,3′ digallate, Thearubigins Isoflavones, including Genistein, Daidzein, Glycitein Anthocyanidins, including Cyanidin, Delphinidin, Malvidin, Pel
  • For oral dosage forms capsules and tablets: For infertility, male hormone problem (male hypogonadism), starting the menstrual cycle (amenorrhea), or stopping abnormal milk secretion from nipples (galactorrhea): Adults and teenagers 15 years of age or older-At first, 1.25 to 2.5 milligrams (mg) once a day taken at bedtime with a snack. Then your doctor may change your dose by 2.5 mg every three to seven days as needed. Doses greater than 5 mg a day are taken in divided doses with meals or at bedtime with a snack. Teenagers less than 15 years of age and children-Use and dose must be determined by your doctor.
  • For lowering growth hormone (acromegaly): Adults and teenagers 15 years of age or older-At first, 1.25 to 2.5 milligrams (mg) once a day taken at bedtime with a snack for three days. Then your doctor may change your dose by 1.25 or 2.5 mg every three to seven days as needed. Doses greater than 5 mg are divided into smaller doses and taken with meals or at bedtime with a snack. Teenagers less than 15 years of age and children-Use and dose must be determined by your doctor.
  • For Parkinson's disease Adults and teenagers 15 years of age or older-At first, 1.25 milligrams (mg) one or two times a day taken with meals or at bedtime with a snack.
  • Average dosage is 20 to 30 mg daily. Some patient may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate.
  • Narcolepsy Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used.
  • the suggested initial dose for patients aged 6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
  • DEXEDRINE Narcolepsy Usual dose 5 to 60 mg per day in divided doses, depending on the individual patient response. Narcolepsy seldom occurs in children under 12 years of age; however, when it does Dexedrine (dextroamphetamine sulfate) may be used.
  • the suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained.
  • daily dose may be raised in increments of 10 mg at weekly intervals until optimal response is obtained.
  • bothersome adverse reactions appear e.g. insomnia or anorexia
  • dosage should be reduced.
  • Spansule capsules may be used for once-a-day dosage wherever appropriate. With tablets give first dose on awakening, additional doses (1 or 2) at intervals of 4 to 6 hours. Attention Deficit Disorder with Hyperactivity. Not recommended for pediatric patients under 3 years of age.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Steroid Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US11/910,988 2005-04-07 2006-04-06 Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence Abandoned US20080207601A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/910,988 US20080207601A1 (en) 2005-04-07 2006-04-06 Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US66903305P 2005-04-07 2005-04-07
US72901305P 2005-10-21 2005-10-21
US72897905P 2005-10-21 2005-10-21
PCT/US2006/013296 WO2006110642A2 (en) 2005-04-07 2006-04-06 Improved methods of and compositions for the prevention of anxiety, substance abuse, and dependence
US11/910,988 US20080207601A1 (en) 2005-04-07 2006-04-06 Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence

Publications (1)

Publication Number Publication Date
US20080207601A1 true US20080207601A1 (en) 2008-08-28

Family

ID=37087555

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/910,988 Abandoned US20080207601A1 (en) 2005-04-07 2006-04-06 Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence
US11/910,967 Expired - Fee Related US8012958B2 (en) 2005-04-07 2006-04-07 Methods for treating anxiety related disorders
US11/910,966 Abandoned US20080255097A1 (en) 2005-04-07 2006-04-07 Methods for the Treatment of Substance Abuse and Dependence

Family Applications After (2)

Application Number Title Priority Date Filing Date
US11/910,967 Expired - Fee Related US8012958B2 (en) 2005-04-07 2006-04-07 Methods for treating anxiety related disorders
US11/910,966 Abandoned US20080255097A1 (en) 2005-04-07 2006-04-07 Methods for the Treatment of Substance Abuse and Dependence

Country Status (12)

Country Link
US (3) US20080207601A1 (es)
EP (3) EP1868593A2 (es)
JP (3) JP2008538748A (es)
KR (2) KR20080004580A (es)
AU (3) AU2006235318A1 (es)
BR (2) BRPI0609744A2 (es)
CA (3) CA2604887A1 (es)
CR (2) CR9410A (es)
IL (2) IL186450A0 (es)
MX (2) MX2007012353A (es)
NO (2) NO20075161L (es)
WO (3) WO2006110642A2 (es)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080280885A1 (en) * 2005-04-07 2008-11-13 Hythiam, Inc. Methods for Treating Anxiety Related Disorders
US20110159048A1 (en) * 2009-12-22 2011-06-30 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US20120122851A1 (en) * 2009-02-20 2012-05-17 Palmaya Pty Ltd Pharmaceutical preparation and delivery system
US20150125570A1 (en) * 2010-12-29 2015-05-07 Mead Johnson Nutrition Company Milk-based nutritional compositions containing lactoferrin and uses thereof
US20160120877A1 (en) * 2010-07-16 2016-05-05 James S Rowe Pharmaceutical compositions for sustained delivery of benzodiazepine antagonists
WO2019055942A1 (en) * 2017-09-18 2019-03-21 SEN-JAM Pharmaceutical LLC METHODS AND COMPOSITIONS FOR INHIBITING OPIOID TOLERANCE
WO2019055939A1 (en) * 2017-09-18 2019-03-21 SEN-JAM Pharmaceutical LLC METHODS AND COMPOSITIONS FOR INHIBITING SYMPTOMS ASSOCIATED WITH OPIOID WEANING
WO2019060171A1 (en) * 2017-09-20 2019-03-28 Calista Capital, Llc METHOD FOR STOPPING TOBACCO
WO2019195813A1 (en) * 2018-04-06 2019-10-10 Ovid Therapeutics Inc. Use of gaboxadol in the treatment of substance use disorders
US10765666B2 (en) 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
CN114555070A (zh) * 2019-08-26 2022-05-27 经期药丸私人有限责任公司 月经周期诱发的症状治疗

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050192271A1 (en) 2003-07-15 2005-09-01 Hythiam, Inc. Use of selective chloride channel modulators to treat alcohol and/or stimulant substance abuse
US20090269795A1 (en) * 2007-03-09 2009-10-29 The Research Foundation Of State University Of New York Mutant alpha4betadelta GABAA receptor and methods of treating anxiety or irritability
US8586634B2 (en) 2007-06-15 2013-11-19 University Of Florida Research Foundation, Inc. Therapeutic compounds
CA2707980C (en) 2007-12-17 2015-05-12 Labopharm Inc. Misuse preventative, controlled release formulation
ITRM20080436A1 (it) * 2008-08-06 2010-02-07 Francesco Marrosu Uso della finasteride e di altre sostanze inibenti l'enzima 5-a-reduttasi per la prevenzione e la cura dei disturbi dell'impulso e dell'aggressivita'
TWI541246B (zh) 2008-12-08 2016-07-11 歐陸斯迪公司 二氫羥戊甲嗎啡
JP5667575B2 (ja) 2008-12-16 2015-02-12 パラディン ラブス インコーポレーテッド 誤用を防止する放出制御製剤
US20120295893A1 (en) * 2009-12-14 2012-11-22 Coeruleus Ltd. Compositions and methods of counteracting residual sedative effects of sleep/ hypnotic drugs
WO2013043985A1 (en) 2011-09-23 2013-03-28 The Regents Of The University Of California Edible oils to enhance delivery of orally administered steroids
US20150018327A1 (en) 2012-01-23 2015-01-15 Sage Therapeutics, Inc. Neuroactive steroid formulations and methods of treating cns disorders
KR102305359B1 (ko) * 2012-08-21 2021-09-24 세이지 테라퓨틱스, 인크. 간질 또는 간질지속 상태를 치료하는 방법
EP2925327B1 (en) 2012-11-30 2024-01-10 The Regents of The University of California Allopregnanolone for treating, reducing or mitigating symptoms of post-partum depression
GB201309654D0 (en) 2013-05-30 2013-07-17 Euro Celtique Sa Method
EP3160969B1 (en) * 2014-06-26 2023-09-13 The Johns Hopkins University Peripherally restricted gaba positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system
IL300422A (en) 2016-03-08 2023-04-01 Sage Therapeutics Inc Neuroactive steroids, preparations and their uses
US20180050005A1 (en) * 2016-08-16 2018-02-22 Janssen Pharmaceutica Nv Concentrated Solution of 17-Hydroxydocosahexaenoic Acid
CA3046128A1 (en) * 2017-01-09 2018-07-12 Asarina Pharma Ab Injectable suspensions
KR20200072445A (ko) * 2017-03-28 2020-06-22 엘디엔 파마 리미티드 암의 치료를 위한 세포 사멸의 bcl2-관련 효능제의 발현을 증가시키는 제제
GB201704909D0 (en) * 2017-03-28 2017-05-10 Ldn Pharma Ltd Cancer therapy
KR101898814B1 (ko) 2017-09-07 2018-09-13 백창목 도어 개폐용 도어록
EP3482751A1 (en) * 2017-11-14 2019-05-15 LDN Pharma Limited Cancer treatment
JP2021519799A (ja) * 2018-04-05 2021-08-12 アサリナ ファーマ エーピーエス 物質離脱障害を治療するためのｇａｂａ−ａアンタゴニスト
WO2020181340A1 (en) * 2019-03-14 2020-09-17 Palmaya Pty Ltd Treatment of inflammatory diseases of the central nervous system

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034087A (en) * 1973-12-17 1977-07-05 The Regents Of The University Of Michigan Pharmaceutical composition and process of treatment
US4595684A (en) * 1985-08-16 1986-06-17 Ciba-Geigy Corporation Method of suppressing benzodiazepine induced sedation with 2-(p-methoxypenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one or a salt thereof
US5175155A (en) * 1991-10-07 1992-12-29 Sterling Winthrop Inc. Win 49596-finasteride method of use and compositions
US5512590A (en) * 1994-05-10 1996-04-30 Synthelabo 5,6-dihydro-4h-imidazo 2',1':2,3!imidazo- 4,5,1-ij!quinoline and 4,5-dihydroimidazo- 1,2-a!pyrolo 1,2,3-cd!benzimidazole derivatives, their preparation and application in therapeutics
US5521181A (en) * 1995-01-27 1996-05-28 Abbott Laboratories Bicyclic substituted hexahydrobenz[e]isoindole α-1 adrenergic antagonists
US5824667A (en) * 1993-12-22 1998-10-20 Schering Aktiengesellschaft Composition for contraception
US20010020002A1 (en) * 1997-08-28 2001-09-06 Vela Pharmaceuticals Inc. Androgen activity antagonists as therapies for anorexia, anorexia nervosa and disorders characterized by a pathologically underweight condition
US6403640B1 (en) * 1999-08-27 2002-06-11 Merck & Co., Inc. Method for treating chronic prostatitis or chronic pelvic pain syndrome
US20020173495A1 (en) * 2000-08-24 2002-11-21 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US6632447B1 (en) * 1998-05-07 2003-10-14 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1274481B (it) * 1995-05-12 1997-07-17 Indena Spa Composizioni farmaceutiche per il trattamento della alcol-dipendenza
AU4100699A (en) 1998-05-28 1999-12-13 Sepracor, Inc. Compositions and methods employing r(-) fluoxetine and other active ingredients
AU2002226427B2 (en) 2001-01-17 2006-11-16 Hythiam, Inc. Use of flumazenil in developing a drug for the treatment of alcohol dependence
IL157144A0 (en) 2001-02-15 2004-02-08 Hythiam Inc Use of flumazenil to produce a medicament for the treatment of cocaine dependency
GB0311859D0 (en) * 2003-05-22 2003-06-25 Merck Sharp & Dohme Therapeutic agents
ES2515092T3 (es) * 2003-12-11 2014-10-29 Sunovion Pharmaceuticals Inc. Combinación de un sedante y un modulador neurotransmisor y métodos de mejorar la calidad del sueño y de tratar la depresión
WO2006110642A2 (en) * 2005-04-07 2006-10-19 Hythiam, Inc. Improved methods of and compositions for the prevention of anxiety, substance abuse, and dependence

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034087A (en) * 1973-12-17 1977-07-05 The Regents Of The University Of Michigan Pharmaceutical composition and process of treatment
US4595684A (en) * 1985-08-16 1986-06-17 Ciba-Geigy Corporation Method of suppressing benzodiazepine induced sedation with 2-(p-methoxypenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one or a salt thereof
US5175155A (en) * 1991-10-07 1992-12-29 Sterling Winthrop Inc. Win 49596-finasteride method of use and compositions
US5824667A (en) * 1993-12-22 1998-10-20 Schering Aktiengesellschaft Composition for contraception
US5512590A (en) * 1994-05-10 1996-04-30 Synthelabo 5,6-dihydro-4h-imidazo 2',1':2,3!imidazo- 4,5,1-ij!quinoline and 4,5-dihydroimidazo- 1,2-a!pyrolo 1,2,3-cd!benzimidazole derivatives, their preparation and application in therapeutics
US5521181A (en) * 1995-01-27 1996-05-28 Abbott Laboratories Bicyclic substituted hexahydrobenz[e]isoindole α-1 adrenergic antagonists
US20010020002A1 (en) * 1997-08-28 2001-09-06 Vela Pharmaceuticals Inc. Androgen activity antagonists as therapies for anorexia, anorexia nervosa and disorders characterized by a pathologically underweight condition
US6632447B1 (en) * 1998-05-07 2003-10-14 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer
US6403640B1 (en) * 1999-08-27 2002-06-11 Merck & Co., Inc. Method for treating chronic prostatitis or chronic pelvic pain syndrome
US20020173495A1 (en) * 2000-08-24 2002-11-21 Dalton James T. Selective androgen receptor modulators and methods of use thereof

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080280885A1 (en) * 2005-04-07 2008-11-13 Hythiam, Inc. Methods for Treating Anxiety Related Disorders
US8012958B2 (en) 2005-04-07 2011-09-06 Hythlam, Inc. Methods for treating anxiety related disorders
US9283212B2 (en) * 2009-02-20 2016-03-15 Palmaya Pty Ltd Pharmaceutical preparation and delivery system
US20120122851A1 (en) * 2009-02-20 2012-05-17 Palmaya Pty Ltd Pharmaceutical preparation and delivery system
AU2010215075B2 (en) * 2009-02-20 2015-08-20 Palmaya Pty Ltd Pharmaceutical preparation and delivery system
US8372414B2 (en) 2009-12-22 2013-02-12 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US8617577B2 (en) 2009-12-22 2013-12-31 Pondera Biotechnologies Inc. Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US8741319B2 (en) 2009-12-22 2014-06-03 Pondera Biotechnologies, Inc. Methods and compositions for treating anxiety disorders or symptoms thereof
US8202525B2 (en) 2009-12-22 2012-06-19 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US20110159048A1 (en) * 2009-12-22 2011-06-30 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US20160120877A1 (en) * 2010-07-16 2016-05-05 James S Rowe Pharmaceutical compositions for sustained delivery of benzodiazepine antagonists
US20150125570A1 (en) * 2010-12-29 2015-05-07 Mead Johnson Nutrition Company Milk-based nutritional compositions containing lactoferrin and uses thereof
US9737089B2 (en) * 2010-12-29 2017-08-22 Mead Johnson Nutrition Company Milk-based nutritional compositions containing lactoferrin and uses thereof
WO2019055939A1 (en) * 2017-09-18 2019-03-21 SEN-JAM Pharmaceutical LLC METHODS AND COMPOSITIONS FOR INHIBITING SYMPTOMS ASSOCIATED WITH OPIOID WEANING
WO2019055942A1 (en) * 2017-09-18 2019-03-21 SEN-JAM Pharmaceutical LLC METHODS AND COMPOSITIONS FOR INHIBITING OPIOID TOLERANCE
US11129803B2 (en) 2017-09-18 2021-09-28 SEN-JAM Pharmaceutical LLC Methods and compositions to inhibit tolerance to opioids
US11911355B2 (en) 2017-09-18 2024-02-27 Sen-Jam Pharmaceutical Inc. Methods and compositions to inhibit tolerance to opioids
WO2019060171A1 (en) * 2017-09-20 2019-03-28 Calista Capital, Llc METHOD FOR STOPPING TOBACCO
US10966988B2 (en) * 2017-09-20 2021-04-06 Calista Capital, Llc Method for smoking cessation
WO2019195813A1 (en) * 2018-04-06 2019-10-10 Ovid Therapeutics Inc. Use of gaboxadol in the treatment of substance use disorders
CN112601524A (zh) * 2018-04-06 2021-04-02 奥维德医疗公司 加波沙朵在治疗物质使用障碍中的用途
US10765666B2 (en) 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
CN114555070A (zh) * 2019-08-26 2022-05-27 经期药丸私人有限责任公司 月经周期诱发的症状治疗

Also Published As

Publication number Publication date
BRPI0609744A2 (pt) 2010-04-27
WO2006110557A2 (en) 2006-10-19
BRPI0610693A2 (pt) 2016-11-22
KR20080004580A (ko) 2008-01-09
MX2007012353A (es) 2008-01-16
JP2008535852A (ja) 2008-09-04
EP1901727A4 (en) 2009-11-11
US8012958B2 (en) 2011-09-06
CR9410A (es) 2008-02-21
AU2006235257A1 (en) 2006-10-19
US20080280885A1 (en) 2008-11-13
CA2604887A1 (en) 2006-10-19
KR20080004581A (ko) 2008-01-09
US20080255097A1 (en) 2008-10-16
AU2006235318A1 (en) 2006-10-19
WO2006110557A3 (en) 2009-04-16
NO20075155L (no) 2008-01-07
WO2006110580A3 (en) 2007-08-16
MX2007012355A (es) 2008-01-16
JP2008538748A (ja) 2008-11-06
EP1868593A2 (en) 2007-12-26
JP2008535850A (ja) 2008-09-04
CA2603519A1 (en) 2006-10-19
WO2006110642A2 (en) 2006-10-19
EP1901727A2 (en) 2008-03-26
IL186447A0 (en) 2008-08-07
WO2006110642A3 (en) 2009-04-23
EP1868432A2 (en) 2007-12-26
NO20075161L (no) 2008-01-07
CA2603533A1 (en) 2006-10-19
CR9413A (es) 2008-01-21
WO2006110580A2 (en) 2006-10-19
EP1868432A4 (en) 2009-11-04
AU2006235234A1 (en) 2006-10-19
IL186450A0 (en) 2008-01-20
AU2006235257B2 (en) 2010-11-04

Similar Documents

Publication Publication Date Title
US20080207601A1 (en) Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence
US8309535B2 (en) Compositions and methods to treat recurrent medical conditions
US20080274061A1 (en) Method for Treating a Restless Limb Disorder
KR20030025902A (ko) 덱스트로메토르판 및 옥시다제 억제제의 환자의 마약 및항진정제의 중단을 위한 용도
MX2012013380A (es) Atomizador nasal liquido que contiene naltresona de dosis baja.
US20210060009A1 (en) Novel methods
AU2003227304B2 (en) Pharmaceutical formulation comprising melatonin
JP2003500446A (ja) メラトニンの治療的使用法
US10300068B2 (en) Method of treating insomnia
US20160213680A1 (en) Compositions and methods using flumazenil with opioid analgesics for treating pain and/or addiction, and with diversion and/or overdose mitigation
US20200345655A1 (en) Treatment of opioid use disorder, opioid withdrawal symptoms, and chronic pain
US8791093B2 (en) Pharmaceutical delivery systems for treatment of substance abuse and other addictions
US6194400B1 (en) Use of amino acid precursors for the treatment of addictions
KR20200022026A (ko) 치료 방법 및 이의 약형
US20140148465A1 (en) Compositions and Methods to Improve Treatment of Medical Conditions Using D-Cycloserine
Fitzpatrick Melatonin in health and disease
WO2023028519A2 (en) Methods of treating substance use disorder
Catalano et al. Drug Therapy for Depression and Anxiety
WO2023114529A2 (en) Pharmacoactive formulations for delivery of psychedelic compounds
JP2003523933A (ja) 組成物および処方剤、およびその痛覚剤、抗不安剤およびタンパク同化剤としての使用
van den Brink Evidence-based pharmacotherapy of dependence nicotine and alcohol
Hollister Marijuana (Cannabis) As Medicine
JP2002529416A (ja) 嗜癖の治療のためのグルココルチコステロイド・レセプターおよび／またはミネラルコルチコステロイド・レセプターのアゴニスト、特にコルチコステロイドの使用

Legal Events

Date Code Title Description
AS Assignment

Owner name: HYTHIAM, INC.,CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SABNANI, SANJAY;REEL/FRAME:020090/0994

Effective date: 20071025

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: GOLDMAN SACHS SPECIALTY LENDING GROUP, L.P., TEXAS

Free format text: SECURITY INTEREST;ASSIGNOR:HYTHIAM, INC (N/K/A CATASYS, INC.);REEL/FRAME:051767/0204

Effective date: 20190924

AS Assignment

Owner name: ONTRAK, INC. (FORMERLY KNOWN AS CATASYS, INC.), NEVADA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:GOLDMAN SACHS SPECIALTY LENDING GROUP, L.P., AS COLLATERAL AGENT;REEL/FRAME:060672/0554

Effective date: 20220715