WO2004041207A2 - Methodes de traitement de troubles lies au ghb - Google Patents

Methodes de traitement de troubles lies au ghb Download PDF

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WO2004041207A2
WO2004041207A2 PCT/US2003/035156 US0335156W WO2004041207A2 WO 2004041207 A2 WO2004041207 A2 WO 2004041207A2 US 0335156 W US0335156 W US 0335156W WO 2004041207 A2 WO2004041207 A2 WO 2004041207A2
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ghb
inhibitor
dopamine
agonist
toxicity
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WO2004041207A3 (fr
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Teodoro G. Bottiglieri
Damon A. Anderson
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Baylor Research Institute
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Publication of WO2004041207A3 publication Critical patent/WO2004041207A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings

Definitions

  • GHB garnma-hydroxybutyric acid
  • GHB prodrugs include 1,4-butanediol (also referred to as BDO; 1,4- BD; 1,4-tetramethylene glycol) and gamma hydroxyvalerate (GHV). These prodrugs can be rapidly absorbed and metabolized to GHB in mammals, and their toxicological profiles reflect that of GHB. Relating to use of "GHB", the term as used herein refers to GHB, GHB prodrugs or any combination thereof.
  • Garnma-hydroxybutyric acid is an endogenous metabolite of the central nervous system (CNS) neurotransmitter 4-aminobutyric acid (GAB A).
  • GHB is reportedly present in the mammalian CNS at a level of less than 1% that of GAB A, and appears to act as an agonist of GABA receptors.
  • Fig. 1 illustrates the metabolism pathway of GHB and GABA.
  • GABA is reversibly converted to succinic semialdehyde in the presence of enzyme GABA transaminase. If succinic semialdehyde dehydrogenase (SSADH) is available, succinic semialdehyde is converted to succinic acid which enters the Kreb's cycle for energy production. In cases where SSADH is deficient or blocked, succinic semialdehyde is converted to GHB by GHB dehydrogenase resulting in elevation of GHB level.
  • SSADH succinic semialdehyde is converted
  • GHB is reported to display many properties of a neurotransmitter or a neuromodulator, and has numerous neuropharmacologic and neurophysiologic effects. Its neuropharmacologic effects include decreasing brain acetylcholine, depressing dopaminergic impulse flow, kinetic activation of tyrosine hydroxylase, increasing hydrocortisone and growth hormone, and depressing glucose utilization in the brain without depressing oxygen consumption. Its neurophysiologic effects include blocking monosynaptic and polysynaptic reflex arcs, depressing surface negative components in cortical primary evoked potentials, depressing dopaminergic neuron firing, depressing short-term memory, and electroencephalographic-behavioral dissociation.
  • Fig. 2 summarizes the various pathways of GHB activity, and it illustrates the complex roles of GHB in affecting dopamine synthesis and release in the brain, growth hormone release, and binding GAB As receptors, GHB receptors, thalamic NMDA receptors, and opiate receptors. A number of important mechanisms contributing to the complex effects of GHB are described here.
  • GHB can be metabolized to and from GABA in vivo, thus affecting the pools of GABA ⁇ the primary inhibitory neurotransmitter in brain.
  • the GABA A receptor is a ligand-gated chloride (Cl " ) channel consisting of five subunits embedded in the membrane, while the GABA B receptor is a G-protein coupled receptor with seven membrane spans.
  • the binding of GABA to the type A receptor (a fast response) and type B receptors (a slower response) triggers inhibitory effects.
  • GHB is a weak reversible agonist to the GABA ⁇ receptor. Meanwhile, GHB does not display a measurable level of affinity to the GABA A receptor (Snead 1996; Serra et al. 1991).
  • GABA acts to reduce the dopaminergic impulse via increasing feedback inhibition.
  • GHB G protein superfamily
  • GHB affects the dopaminergic system in brain. Initially, it was thought that treatment of GHB results in upregulation of dopamine levels, this later was proved to be a secondary effect in response to the inhibition of dopamine release (Wong et al. 2003). hi vivo microdialysis studies show that dopamine release was inhibited upon GHB treatment (Hechler er al. 1991; Feigenbaum and Howard 1996). In summary, a collective body of evidence strongly supports that the pharmacological action of GHB is through stimulation of the GABA B receptor, which in turn, results in the inhibition of dopamine release and leads to the loss of locomotor activity in human and tested animals (Wong et al., 2003). Medical use of GHB
  • GHB was developed in 1961 in France, and was initially employed as an agent for induction of anesthesia in children, but interest in its use waned due to a lack of analgesic effects and the presence of epileptogenic side effects.
  • GHB is used experimentally, such as in the production of absence seizures in rodents.
  • Therapeutically, GHB is used for the treatment of narcolepsy and alcohol/opiate- withdrawal syndromes (U.S. Patent Nos. 4,983,632; 5,590,162; 5,840,331; and 6,436,998).
  • the Food and Drug Administration has recently approved Xylem marketed by Orphan Medical Inc. (Minnetonka, Minnesota 55305), a brand name containing the active ingredient GHB, to treat cataplexy attacks characterized by weak or paralyzed muscles in patients with narcolepsy.
  • GHB has a similar effect to alcohol such as inducing relaxation, increased sociability, decreased motor skills, and mild dizziness.
  • a medium dose (1-2.5 grams)
  • the relaxation and physical disequilibrium deepens. Many people report positive mood changes, increased appreciation to music and dancing, and positive sexual effects. However, side effects such as nausea have also been reported.
  • a heavy dose (2-3.5 grams)
  • GHB increases disequilibrium in many people and causes them to feel quite ill. Consumption of 3-5 grams could induce heavy sleep. Consumption of more than 5 grams could cause unrousable sleep, coma, convulsions, and vomiting. The consumption of 2 grams per kg of body weight is reportedly lethal to humans.
  • GHB was readily available in the 1980s in health stores in the United States, and was used by body builders as an alternative to steroids based on its ability to stimulate growth hormone release which reportedly aids fat reduction and muscle building (Takahara 1977).
  • the abuse and addiction of GHB is still widespread in the athletic world, and athletes who often use GHB on a daily basis are the ones considered most likely to experience addiction and/or overdose from its use.
  • GHB has gained the status of recreational drug and club drug. In the 1990s, it also gained the notoriety of a "date rape” drug. Participants of "rave” dance parties and dance clubs use GHB as a mood enhancer. At heavy doses of GHB, people reportedly experience extremely positive feelings such as euphoria, deep appreciation of music, joyous dancing, and uninhibition. However, there is a narrow margin between the concentration of GHB needed to obtain euphoria and the concentration resulting in an accidental overdose. GHB has also been used in acquaintance sexual assault (“date rape") because of its sedative and anecdotal amnesia-inducing effects.
  • GHB is present in some weight loss regimens and nutritional supplements, and consumption by unsuspicious users has led to numerous cases of overdose.
  • Other uses include taking GHB as a safe sleep-aid, and as an anti-aging compound.
  • Physical dependence on GHB can develop after prolonged high-dose use (Miotto et al. 2001; Craig et al. 2000), and there have also been numerous reports of toxicity, addiction, withdrawal-syndrome, and death.
  • Miotto et al. 2001; Craig et al. 2000 There have also been numerous reports of toxicity, addiction, withdrawal-syndrome, and death.
  • By 2000 there were reported 13,000 cases of overdose and 71 deaths related to GHB (Marsa 2002). hi 1990, prompted by dozens of reports of GHB' s adverse effects, the U.S. Food and Drug Administration issued a ban on GHB.
  • GHB has been classified as a Schedule I (the most severe) controlled substance by the Drug Enforcement Agency. Consumption of GHB prodrugs such as GBL, GHN, and 1,4-BD, neither of which are Schedule I controlled substances, has also increased, despite government warnings concerning risks associated with these compounds. For instance, in 2000, although the total GHB exposure cases remained constant, there was a marked increase (71%) of GHB analogues (Doyon 2000). Today, GBL, GHN, and 1,4-BD are still widely available at gyms, chemical supply stores, the Internet, and through mail order.
  • GHB, GHB prodrugs, and GHB analogues are rapidly metabolized.
  • the effect of GHB can be detected in as short as 10-15 minutes.
  • the half life of elimination is approximately one hour.
  • Treatment for overdose or addiction due to GHB or its prodrugs is primarily supportive (MuUer 2003).
  • Gastric decontamination methods such as lavage and activated charcoal are often, not useful due to the fast absorption and onset action. Hydration of the patient and intubation associated with benzodiazepene intervention have been used, as well as the use of anticholinesterases. Since there is no known antagonist to GHB, the use of reversal agents is controversial. Anecdotally, the administering of naloxone and flumazenil is not effective in treating GHB overdose (MuUer 2003).
  • GHB has a very complex pharmacological effects and acting through multiple pathways including GABA B receptors, GHB receptors and possible other pathways, hi one report, Lamb et al. (2003) examined the interaction of GHB with ethanol and NCS382, an GHB receptor antagonist in rats by behavioral studies. The effect of GHB and ethanol was found at most additive, contrary to the common believe that co-administration of GHB and alcohol produces synergetic effect. NCS382, an agonist of GHB receptors, has been reported to antagonize some but not all of the GHB effects (Mehta et al., 2001; Godbout et al., 1995; Cook et al., 2002). The studies by Lamb et al.
  • SSADH Succinic semialdehyde dehydrogenase
  • GABA gamma- hydroxybutyric aciduria
  • Vigabatrin is an irreversible inhibitor of GABA transaminase, which reportedly decreases the levels of GHB and elevates GABA levels.
  • the effects have been mixed, resulting improvement in some cases but severe side effects in others such as induction of seizures.
  • a mutant AldhSa ⁇ 1' breed of mice has been developed by deletion of the active site of Aldh5al by gene targeting, and as expected, no detectable enzyme activity of SSADH was found in all tissues tested (Hogema et al. 2001). i these mice, the levels of GHB and GABA have been elevated 30- to 45-fold and 2.5- to 3-fold, respectively.
  • the mutant Aldh5al ⁇ ⁇ mice weigh less than the heterozygous mice, but are otherwise normal in early days of life. Upon weaning, the AldhSa ⁇ 1' mice display locomotor problems, spasms, tonic-clonic seizures, leading to epilepsy and death at day 16-22.
  • the anticonvulsants phenytoin and phenobarbital have been ineffective in rescuing SSADH-/- mice.
  • Administration of vigabatrin at 50-800 milligrams/kilogram body weight significantly increased survival rate; however, treated mice manifested significant neurophysiological defects and low body weight (Hogema et al. 2001).
  • the GHB receptor antagonist NCS-382 has shown promise in therapeutic interventions, extending survival (60%) in mutant mice (Carai et al. 2001). However, preclinical data regarding its pharmacokinetics and toxicity do not exist. Finally, a gene-therapy experiment targeting the liver SSADH activity has significantly improved the life span of mutant mice (40%). This is based on the hypothesis that high levels of GHB in the brain were supplied peripherally by the liver which expresses comparable or higher levels of SSADH activity than the brain (Chambliss et al., 1995).
  • these previously reported agents and procedures have possible therapeutic relevance for treatment of human SSADH deficiency disease associated with in vivo GHB overproduction, which include GABA B receptor antagonist CGP 35348; GHB receptor antagonist NCS-382; a nonspecific protection agent taurine; and vigabatrin, an agent which inhibits the conversion of GABA to GHB.
  • GABA B receptor antagonist CGP 35348 GABA B receptor antagonist CGP 35348
  • GHB receptor antagonist NCS-382 GHB receptor antagonist NCS-382
  • taurine a nonspecific protection agent taurine
  • vigabatrin an agent which inhibits the conversion of GABA to GHB.
  • GHB inhibits dopamine release into the synaptic cleft
  • novel treatment methods for GHB toxicity and overdose have been found which block the deleterious effects of GHB by either postponing the removal of dopamine from the synaptic cleft or increasing the dopaminergic function therein.
  • the methods disclosed herein are effective for treating GHB toxicity due to SSADH deficiency disease, accidental GHB toxicity and overdose in therapeutic administration for treatment of narcolepsy and alcohol/opiate-withdrawal syndromes, and GHB toxicity or overdose due to inappropriate recreational use.
  • the invention is a method of treating or preventing GHB toxicity or overdose in a mammal comprising administering an effective amount of a therapeutic agent capable of postponing the removal of dopamine from the synaptic cleft.
  • a therapeutic agent capable of postponing the removal of dopamine from the synaptic cleft.
  • One such preferred therapeutic agent is an inhibitor to monoamine oxidase in the DA degradation pathway.
  • a preferred monoamine oxidase inhibitor is capable of inhibiting at least one of type A or type B of monoamine oxidase.
  • Preferred monoamine oxidase inhibitors are selected from the group consisting of benmoxin, echinopsidine iodide, etryptamine, furazolidone, furazolidone, iproclozide, iproniazid, isocarboxazid, mebanazine, metfendrazine, moclobamide, nialamide, pargyline, phenelzine, pheniprazine, phenoxypropazine, safrazine, selegiline, toloxatone, and tranylcypromine. More preferred monoamine oxidase inhibitors include pargyline and deprenyl.
  • Another preferred therapeutic agent is an inhibitor to catechol-o-methyl transferase in the DA degradation pathway.
  • Preferred inhibitors are entacapone and tolcapone.
  • Another preferred therapeutic agent is an inhibitor to the dopamine transporter.
  • Preferred dopamine transporter inhibitors are selected from the group consisting of nomifensine; cocaine analogs; 3 -bis-(4-fluorophenyl)methoxytropane hydrochloride; BTCP maleate; 3 -[(4-chlorophenyl)phenylmethoxy]-tro ⁇ ane hydrochloride; ⁇ -CIT; GBR 12783; GBR12909; GBR 12935; GBR 13069; Win35,065-2; and analogs thereof-
  • a more preferred dopamine transporter inhibitor is nomifensine.
  • the invention is a method of treating or preventing GHB toxicity or overdose by administering an effective amount of a therapeutic agent that is capable of acting as an agonist to the dopamine receptor to increase dopaminergic function in the synaptic cleft.
  • a therapeutic agent that is capable of acting as an agonist to the dopamine receptor to increase dopaminergic function in the synaptic cleft.
  • Preferred dopamine agonists are is selected from the group consisting of bromocriptine, dihydroergotamine, dopexamine, epinine, ibopamine, pergolide, propylbutyl dopamine, apomorphine, carmoxirole, lisuride, SKF 38393, pimozide, quinpirole, 7-OH-DPAT, pramipexole, and ropinirole.
  • a preferred therapeutic agent is an agonist to the D2 dopamine receptor.
  • a preferred agonist to the D2 dopamine receptor is selected from the group consisting of bromocriptine, quinpirol, 7-OH DP AT, pergolide, pramipexole, and ropinirole.
  • a more preferred D2 agonist is bromocriptine.
  • the invention is a method of reducing GHB toxicity in a mammalian tissue comprising contacting dopamine degradation enzymes with an effective amount of at least one inhibitor capable of blocking or reducing the degradative properties of dopamine degradation enzymes.
  • a preferred monoamine oxidase inhibitor is capable of inhibiting at least one of type A or type B of monoamine oxidase.
  • Preferred monoamine oxidase inhibitors are selected from the group consisting of benmoxin, echinopsidine iodide, etryptamine, furazolidone, furazolidone, iproclozide, iproniazid, isocarboxazid, mebanazine, metfendrazine, moclobamide, nialamide, pargyline, phenelzine, pheniprazine, phenoxypropazine, safrazine, selegiline, toloxatone, and tranylcypromine.
  • Preferred monoamine oxidase inhibitors include pargyline and deprenyl.
  • Another preferred therapeutic agent is an inhibitor to catechol-o-methyl transferase in the DA degradation pathway.
  • Preferred inhibitors are entacapone and tolcapone.
  • the invention is a method of reducing GHB toxicity in a mammalian tissue comprising contacting dopamine transporters with an effective amount of at least one inhibitor capable of blocking or reducing the uptake of dopamine from the synaptic cleft.
  • Preferred dopamine transporter inhibitors are selected from the group consisting of nomifensine; cocaine analogs; 3 ⁇ -bis-(4-fluorophenyl)methoxytropane hydrochloride; BTCP maleate; 3 ⁇ -[(4-chlorophenyl)-phenylmethoxy]-tropane hydrochloride; ⁇ -CIT; GBR 12783; GBR 12909; GBR 12935; GBR 13069; Win35,065- 2; and analogs thereof.
  • a more preferred dopamine transporter inhibitor is nomifensine.
  • the invention is a method of reducing GHB toxicity in a mammalian tissue comprising contacting tissue with a dopamine agonist.
  • a dopamine agonist are is selected from the group consisting of bromocriptine, dihydroergotamine, dopexamine, epinine, ibopamine, pergolide, propylbutyl dopamine, apomorphine, carmoxirole, lisuride, SKF 38393, pimozide, quinpirole, 7-OH-DPAT, pramipexole, and ropinirole.
  • a preferred therapeutic agent is an agonist to the D2 dopamine receptor.
  • a preferred agonist to the D2 dopamine receptor is selected from the group consisting of bromocriptine, quinpirol, 7-OH DP AT, pergolide, pramipexole, and ropinirole.
  • a more preferred D2 agonist is bromocriptine.
  • Fig. 1 depicts the metabolism of GHB and GABA.
  • Fig. 2 depicts various pathways of GHB activity.
  • Fig. 3 depicts the neurochemistry and pharmacology of dopaminergic neurons.
  • Fig. 4A depicts a continuous two-dimensional movement map as an example of the animal behavioral activity as measured by the Tru-Scan Activity Monitor used in the studies presented herein.
  • Fig. 4B depicts a graph showing the amount of time spent in each cell, as an example of behavioral activity measured by the Tru-Scan Activity Monitor.
  • a cell is an area that is created by the photobeams when the intersect is in the X-Y plane.
  • Fig. 5 A depicts a correlation between the activity levels in GHB treated rats with the level of 3-methoxytyramine (3-MT).
  • Fig. 5B depicts that the activity levels in GHB treated rats are not correlated with the level of total brain dopamine.
  • Fig. 6 depicts pargyline antagonizing the effect of GHB on locomotor function in the rat in terms of total movement episodes.
  • Fig. 7 depicts pargyline antagonizing the effect of GHB on locomotor function in the rat in terms of total movement time.
  • Fig. 8 depicts pargyline antagonizing the effect of GHB on locomotor function in the rat in terms of total movement distance.
  • Fig. 9 depicts pargyline antagonizing the effect of GHB on locomotor function in the rat in terms of vertical plane entries.
  • Fig. 10 depicts deprenyl antagonizing the effect of GHB on locomotor function in the rat in terms of total movement episodes.
  • Fig. 11 depicts deprenyl antagonizing the effect of GHB on locomotor function in the rat in terms of total movement time.
  • Fig. 12 depicts deprenyl antagonizing the effect of GHB on locomotor function in the rat in terms of total movement distance.
  • Fig. 13 depicts deprenyl antagonizing the effect of GHB on locomotor function in the rat in terms of vertical plane entries.
  • Fig. 14 depicts effect of GHB on locomotor activity in rat in terms of total movement episodes.
  • Fig. 15 depicts the effect of different dosages of GHB on locomotor activity in the rat in terms of total movement episodes.
  • Fig. 16 depicts the effect of different dosages of GHB on locomotor activity in the mouse in terms of total movement episodes.
  • Fig. 17 depicts the comparison of dose response to GHB in mouse and rat on locomotor activity in terms of total movement episodes.
  • GHB GHB prodrug
  • GHB prodrug including but not limited to gammabutyrolactone, 1,4-butandiol, or gammavalerolactone; or any mixture thereof.
  • GHB exerts complex pharmacological effects through several pathways; importantly, GHB stimulates the GABA B receptor which in turn results in the inhibition of dopamine release into the synaptic cleft (Wong et al. 2003).
  • the current invention relates to methods for elevating the dopamine level in the synaptic cleft as well as to methods for increasing the dopaminergic function in the synaptic cleft as means for treating GHB toxicity and overdose. These methods include administration of therapeutic agents that either postpone the removal of dopamine from the synaptic cleft or increase the dopaminergic function therein.
  • Dopamine is present in most parts of the central nervous system (CNS) but particularly in the nigrostriatal pathway. DA is thought to be involved in the initiation of vomiting, the secretion of prolactin, and control of motor and behavioral activity. The depletion of DA caused by the degeneration of the nigrostriatal pathway leads to Parkinson's disease, which can be treated by DA replacement therapies. On the other hand, dopamine level is elevated in schizophrenia which can be treated with antipsychotic drags such as DA receptor antagonists (Webster 2001).
  • DA is stored in vesicles in neurons, and a neuron impulse stimulates DA release into the synaptic cleft. A portion of the released DA can bind briefly to DA receptors on the adjacent post-synaptic neuron before it is re-released into the synaptic cleft.
  • DA receptors are G-protein coupled receptors with seven membrane spanning regions. The binding of DA to its receptor triggers a conformational change in the DA receptor, and causes it to couple to G-proteins which in turn interact with downstream effectors. This chain of action results in the activation or inhibition of adenylate cyclase, and thus changes in the level of secondary messenger cAMP. So far, five different types of DA receptors in two major classes have been identified, the Dl-like receptors including Dl and D5 receptors, and the D2-like receptors including the D2, D3 and D4 receptors.
  • the DA receptors differ in their binding affinity to DA and different DA agonists and antagonists, in their interaction with downstream G-proteins and effectors, and in their patterns of tissue distribution.
  • the D2 receptor is the most important one in terms of overall pharmocological effect and increasing locomotor activity, despite some synergistic effects observed with other types of DA receptors.
  • D2 antagonists are effective in treating schizophrenia patients, and D2 agonists are successfully used in alleviating symptoms in Parkinson's disease (Webster 2001).
  • DA synthesis initiates from the conversion of tyrosine to 3-hydroxytyrosine (DOPA) by tyrosine hydroxylase, which is then followed by decarboxylation by the 1-amino acid decarboxylase to form DA.
  • DOPA 3-hydroxytyrosine
  • the first step is the rate- limiting step, and inhibition of tyrosine dehydroxylase is effective in controlling the DA level in the brain (Webster 2001).
  • DA is released from the presynaptic neuron into the synaptic cleft to interact with DA receptors on the post-synaptic membrane to exert its action.
  • the level of DA release can also in part be attenuated by autoreceptors on the presynaptic DA neuron. It is important to maintain a low level of DA in the synaptic cleft by removing DA quickly in order to prevent over stimulation of DA receptors as to avoid desensitization. DA is removed from the synaptic cleft by one of two pathways as shown in Fig.
  • the present invention it is important to distinguish the amount of DA present in the synaptic cleft from the total amount of DA in the brain.
  • concentration of DA in striatum is high, in the range of 10 micrograms/gram (Webster 2001); on the contrary, the amount of DA in the synaptic cleft represents only a small fraction of the total DA amount (at nanomolar levels).
  • the present invention is concerned with increasing the amount of DA in the synaptic cleft and not in the total amount of DA in the brain.
  • the amount of DA in the synaptic cleft can be measured directly by microdialysis (Hechler et al., 1991; Feigenbaum and Howard, 1996), however such measurement method involves specialized analytical equipment and highly specialized expertise in that field. Investigators have shown that brain 3-MT levels are indicative of the amount of dopamine released into the synpatic cleft (Brown 1991). DA is inactivated in the synaptic cleft by the action of the COMT enzyme resulting in 3-MT formation; thus, the level of 3-MT can be used as a marker for DA release into the synaptic cleft. It has now been found that GHB-induced loss of locomoter activity correlates with a marked decrease in the 3-MT level in the synaptic cleft.
  • the presence of GHB is directly related to a decrease in DA levels in the synaptic cleft, as illustrated in Fig. 5.
  • the amount of isolated 3-MT decreased in relation to decreased locomotor activity levels in terms of total movement episodes.
  • the graph showed an increase in dopamine level upon GHB treatment.
  • the therapeutic agents useful in the treatment methods of the present invention for GHB overdose and toxicity are characterized by their ability to increase the concentration of DA in the synaptic cleft by postponing removal of DA from the synaptic cleft or by increasing dopaminergic function therm.
  • Increasing the concentration of DA in the synaptic cleft by postponing its removal can be accomplished by reducing or blocking either the enzymatic degradation of DA released into the synaptic cleft or by blocking the re-uptake of DA back into the presynaptic neuron.
  • Exemplary therapeutic agents include but are not limited to inhibitors of DA degradation enzymes such as COMT or MAO, and inhibitors of DA transporters which facilitate the return of DA back into the presynaptic neuron.
  • DA agonists capable of residing in the synaptic cleft are also contemplated as therapeutics for GHB overdose and toxicity. Effective amounts of the therapeutic compositions useful in the present invention to treat GHB toxicity or overdose will vary depending on each category of agent used.
  • the present invention is a method to prevent DA removal from the synaptic cleft by inhibiting the DA degradating enzymes. This can be accomplished by inhibiting at least one of the two degradative enzymes in the pathway, i.e., MAO and COMT.
  • MAO inhibitors There are two different types of MAO enzymes, MAO-A and MAO-B, and the protein tertiary structure of MAO-B has been solved (Binda et al. 2002).
  • the MAO-B is specific for DA metabolism.
  • nonspecific MAO inhibitors act on serotonergic, noradrenergic and dopaminergic pathways, indicating a broad role of MAO- A.
  • 1-Deprenyl, also known as selegiline is an irreversible and relatively selective MAO- B inhibitor, hi comparison, pargyline inhibits both MAO-B and MAO-A.
  • the crystal structure of MAO-B with pargyline shows that pargyline binds covalently to the flavin N5 atom of MAO-B (Binda 2002).
  • MAO inhibitors have been shown to be clinically effective in treating depression.
  • MAO inhibitor agents available in the United States which are irreversible blockers of MAO-A and MAO-B (Cole and Bodkin 2002). These agents are tranylcypromine, phenelzine, isocarboxazid, and selegiline. Selegiline at low dosages is used to treat Parkinsonism by prolonging the action of endogenous DA as well as that formed from DA-replacement therapies (Webster 2001). At a higher dosage (more than 20 milligrams/day), selegiline is a good antidepressant; however, it loses its selectivity on MAO-B (Cole and Bodkin 2002). There is a general concern associated with using MAO inhibitors medically due to its ineffectiveness when used at less than optimum dosage and the potential danger when combined with certain foods and supplements.
  • the MAO-inhibitors include but are not limited to the following list of agents (the drug names are in parenthesis): benmoxin (Nerusil, Neuralex), echinopsidine iodide (Adepren), etryptamine (Monase), furazolidone (Furoxone®), iproclozide (Sinderesin, Sursum®), iproniazid (Iprozid, Ipronid, Marsilid, Rivivol, Propilniazida), isocarboxazid (Enerzer, Marplan®, Marplon), mebanazine (Actamol), metfendrazine (H.M.-ll) moclobamide (Aurorix®, Manerix®), nialamide (Espril, Isalazina, Mygal, Niamid®, Niaquitil, Nuredal, Psicomidina, Surgex), pargyline (Eudatine, Eutony
  • pargyline and deprenyl inhibit MAO, and thus can block DA degradation in the synaptic cleft, it is contemplated that they could both restore the decreased level of synaptic DA and the loss of locomotor activity caused by GHB.
  • these two compounds differ in their ability to restore the DA level in the synaptic cleft and locomotor activity as described in detail in Examples 1 and 2.
  • an exemplary effective concentration of the MAO inhibitor is up to 100 milligrams per day for an average adult. It is understood that the effective concentrations of different inhibitors will vary, and Example 4 provides a method by which the effectiveness of a GHB inhibitor can be measured.
  • COMT is an extracellular enzyme in the CNS that catalyzes o-methylation to catecholamines including neurotransmitter such as DA (Webster 2001). Genetic polymorphism results in a 3- to 4-fold difference in COMT levels in human.
  • two COMT inhibitors including tolcapone (Tasmar® made by Hoffrnan-LaRoche) and entacapone (Comtan® marketed by Novartis Pharma AG) have been approved by FDA in adjunct to the treatment of Parkinson's disease. Tolcapone requires liver monitoring while entacapone is less likely to cause liver complications.
  • COMT inhibitors such as tolcapone and entacapone can be used to block the degradation of DA in the synaptic cleft.
  • COMT inhibitors can be employed to elevate DA levels to offset the GHB-induced decrease of DA in the synaptic cleft as means to treat GHB toxicity and overdose.
  • an exemplary effective concentration of the COMT inhibitor is up to 200 milligrams to 2 grams per day for an average adult.
  • Example 4 provides a method by which the effectiveness of a COMT inhibitor can be measured.
  • DA concentration in the synaptic cleft is to inhibit re-uptake of DA by DA transporters.
  • the DA transporter has 12 membrane spanning regions, and it is similar to the GABA and noradrenaline transporter at the amino acid sequence level (Webster 2001).
  • the DA transporter can be blocked by a specific inhibitor of a DA transporter such as nomifensine which has less effect on noradrenaline uptake, while some compounds such as amphetamine and 6-OHDA can be taken up by both types of transporters.
  • DA and blocking agents such as cocaine bind to the binding domains on the DA transporter formed by multiple amino acids in the tertiary structure, and binding of cocaine has been shown to cause a conformational change in the DA transporter (Chen and Reith 2000).
  • Several cocaine analogs and other dopamine transporter inhibitors including analogs of GBR12909 and Win35,065-2 have been shown to reduce cocaine self-administration in nonhuman primates (Ho well and Wilcox 2001).
  • inhibitors to the DA transporter can be used to elevate the synaptic DA level as a means in treating GHB toxicity and overdose.
  • a specific hihibitor to the DA transporter such as nomifensine is preferred over nonspecific inhibitors which can also bind to other types of neurontransmitter transporters. Such specific inhibitors are expected to generate less side effects.
  • Preferred DA transporter inhibitors useful in the present invention also include nomifensine, cocaine analogs and other dopamine transporter inhibitors such as 3 ⁇ -bis-(4-fluorophenyl)methoxytropane hydrochloride; BTCP maleate; 3 ⁇ -[(4-chlorophenyl)phenyhnethoxy]-tropane hydrochloride; ⁇ -CIT; GBR 12783; GBR12909; GBR 12935; GBR 13069; Win35,065-2; and their analogs. These inhibitors exhibit strong affinities to the DA transporter, with Ki values ranging from 0.2 to 30 nanomolar.
  • GBR 12909 exhibited potent and selective inhibition to striatal dopamine uptake ( 1 nanomolar), and its affinity to noradrenaline and 5-HT transporters are 100-fold less (Andersen 1989). Since DA transporter inhibitors are effective in reducing cocaine usage in nonhuman primates, it is contemplated such inhibitors could also be used to treat GHB addiction caused by prolonged use.
  • an exemplary effective concentration of a DA transporter inhibitor is about 200 milligrams per day.
  • Example 4 provides a method by which the effectiveness of a specific DA transporter inhibitor can be measured
  • a DA agonist binds to the DA receptor and mimicks the molecular action of dopamine.
  • exemplary DA agonists useful in the present invention include but are not limited to bromocriptine, dihydroergotamine, dopexamine, epinine, ibopamine, pergolide, propylbutyl dopamine, apomo hine, carmoxirole, lisuride, SKF 38393, pimozide, quinpirole, 7-OH-DPAT, pramipexole, and ropinirole. These compounds generally exhibit very different affinities to the two different classes of DA receptors, Dl-like receptors and the D2-like receptors.
  • SKF 38393 is an example of an agonist to the Dl- like receptors.
  • the agonists to the D2-like receptors include but are not limited to bromocriptine, quinpirol, 7-OH DP AT, pergolide, pramipexole, and ropinirole.
  • bromocriptine, quinpirol and 7-OH DP AT have 50-, 400-, and 5000-fold higher affinity to D2-like receptors than the Dl class, respectively (Webster 2001).
  • D2 receptor agonists are a preferred class of DA agonists for increasing the dopaminergic impulse in the synaptic cleft as a means in treating GHB toxicity and overdose.
  • D2 agonists approved by FDA and are available in the
  • DA agonists can be used to elevate and restore dopaminergic function levels caused by GHB uptake, and, thus as a means in treating GHB toxicity and overdose.
  • Preferred DA agonists for the present invention are D2 receptor agonists such as bromocriptine, quinpirol, 7-OH DP AT, pergolide, pramipexole, and ropinirole.
  • an exemplary effective concentration of the DA agonist ranges from 1.5-16 milligrams per day for an average adult.
  • the effectiveness of specific DA agonists can be measured according to Example 4.
  • compositions useful in the treatment methods of the present invention may be employed in any conventional manner for the treatment of GHB overdose or toxicity. Such methods of treatment, their dosage levels and requirements would be understood by one of ordinary skill in the art from available methods and techniques.
  • a composition useful in this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from GHB overdose or toxicity in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the GHB overdose or toxicity.
  • the therapeutic compositions useful in the present invention can include one or more of the therapeutic agents described herein.
  • the therapeutic agents useful in the present invention can also be co- administered either concommitantly or sequentially with other therapeutic drugs to increase the effect of therapy.
  • the compositions useful in the present invention can be administered concomitantly with other known GHB antagonists such as GABA B receptor antagonists, taurine, or vigabatrin.
  • the therapeutic compositions can also be administered prophylactically.
  • the therapeutic compositions comprising the therapeutic agents useful for treatment of GHB overdose or toxicity as disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the therapeutic compositions can also be administered by intravenous infusion in water, sodium chloride or any other suitable intravenous infusion solution.
  • compositions useful in the present invention for the treatment of GHB overdose or toxicity can be administered with any suitable pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and are disclosed, for instance, in Sprowl's American Pharmacy (Dittert 1974), and Remington 's Pharmaceutical Sciences (Gennaro 1985).
  • compositions useful in the present invention for the treatment of GHB overdose or toxicity may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution, but a lipopbilic carrier, such as propylene glycol optionally with an alcohol, can be used.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water of buffered sodium or ammonium acetate solution.
  • Such a formulation is especially suitable for parenteral administration, but can also be used for oral administration or contained in a metered dose inhaler of nebulizer for insufflation or spray or drops to the nasal mucosa. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the therapeutic compositions useful in the present invention for the treatment of GHB overdose or toxicity may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the preparations, or to facilitate preparation.
  • Liquid carriers include syrup, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water.
  • Solubilizing agents such as dimethylsulfoxide, ethanol or formamide, may also be added.
  • Carriers, such as oils, optionally with solubilizing excipients, are especially suitable. Oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid capable of dissolving lipophilic compounds.
  • Natural oils such as triglycerides are representative.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the therapeutic compositions can be made in solid form following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • a liquid formulation can be administered directly p.o. or filled into a soft gelatin capsule.
  • a pulverized powder of the therapeutic agents useful in the present invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • compositions useful in the present invention may be more effective in the treatment of GHB overdose or toxicity than others, hi order to determine the effectiveness of a therapeutic composition, prospective compositions can be screened by any means known in the art, for example, according to an animal model monitoring system such as the one described in Example 1 and 3 below.
  • Example 1 Efficacy of Pargyline as GHB antagonist in rats
  • Pargyline a nospecific MAO inhibitor, was shown to effectively block the deleterious affects of GHB on locomotor function in rats, demonstrating effectiveness of pargyline in treating and preventing GHB toxicity and overdose when administered before or after GHB intake.
  • mice Male Sprague Dawley rats weighing 200-250 grams from Harlan Laboratories (Houston, Texas) were used in the study.
  • Gamma-hydroxybutyrate (GHB) and pargyline,. were obtained from Sigma Chemical Company (St. Louis, MO). Saline solution was used to prepare all drugs for adminstration.
  • GHB 500 mg/kg
  • pargyline 100 mg/kg
  • saline control phosphate buffered saline (herein referred as saline) and saline (control); saline and GHB; pargyline and GHB; GHB and pargyline; pargyline and saline.
  • Activity monitoring began immediately following second injection.
  • the control group received a saline+saline combination with the same time interval.
  • the locomotor function of the treated rats was measured for 30 minutes post- treatment by monitoring "open-field behavior" using a Tru-Scan Activity Monitor (Coulbourn Instruments, Allentown, PA).
  • the monitor consists of a square floor plane surrounded by four walls and a Z ring set at about 3 inches above the floor plane. Sensors in the monitor are capable of recording timed movements as vectored X-Y coordinates and episodes in which a part of the animal was raised to enter the vertical plane denoted by the Z ring.
  • Figure 4A shows an example of a movement map depicting the locations of a test animal on the floor plane, which is divided into cells.
  • Such data is analyzed by a PC software, and an example is given in Figure 4B depicting the amount of time a test animal spent in each cell.
  • the monitoring system was used to measure various activities of the rodents: (1) total movement episodes, defined as a series of successive coordinate changes with no rest (same coordinates) for at least 1 sample interval; (2) total movement time, defined in the sum total of seconds engaged in movements; (3) total movement distance, defined as the sum total of all vectored X-Y coordinate changes in the floor plane; and (4) vertical plane entries, defined as the total number of times any part of the animal entered the vertical plane (Z ring).
  • administration of pargyline alone did not affect locomotor activity.
  • the administration of GHB was associated with impaired locomotor activity after 10 minutes post-injection.
  • Administration of pargyline either before or after GHB resulted in increased locomotor activity in pargyline/GHB and GHB/pargyline treated rats over that observed with saline/GHB treated rats for all measured parameters and at all time points.
  • pargyline was administered 5 minutes before or after GHB, it blocked largely the inhibitory effect of GHB on the motor activity in terms of total movement episodes (Fig. 6), total movement time (Fig.
  • DA Dopamine
  • DOPAC dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • 3-MT 3-methoxy- tyramine
  • a marked decrease in striatum 3-MT levels was observed in rats treated with GHB.
  • Significant increases in the amount of 3-MT were observed in striatum for rats treated with pargyline before or after GHB treatment, and in rats treated with pargyline/saline.
  • DA diopamine
  • DOPAC 3,4-dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • 3-MT 3-methoxytyramine.
  • b Values indicate mean+standard deviation ( ⁇ moJVg tissue).
  • c * p ⁇ 0.05.
  • Deprenyl was shown to effectively block the deleterious affects of GHB on locomotor function in rats, demonstrating the effectiveness of the use of deprenyl in preventing GHB toxicity and overdose.
  • Deprenyl was obtained from Sigma Chemical Company (St. Louis, MO). Deprenyl in the concentration of 10 milligrams/kilogram body weight was injected intraperitoneally into rat before or after the injection of 500 milligrams/kilograms body weight of GHB, with an interval of 5 minutes.
  • the sample combinations were as follows: saline and saline (control); saline and GHB; deprenyl and GHB; GHB and deprenyl, deprenyl and saline.
  • Activity monitoring with the TRU-SCA ⁇ monitoring system began immediately following second injection, and several parameters regarding the locomotor activity were measured including total movement episodes, total movement time, total movement distance, and vertical plane entries. The comparison of these parameters among each group showed the extent of the effect of deprenyl to restore the GHB-induced loss of locomotor activity.
  • Figs. 10-13 The antagonizing effects of deprenyl on the effect of GHB on locomotor function in the treated rats are illustrated in Figs. 10-13.
  • Administration of deprenyl saline did not affect locomotor activity.
  • the administration of GHB was associated with impaired locomotor activity after 10 minutes post-injection.
  • Administration of deprenyl before GHB resulted in increased locomotor activity in deprenyl/GHB treated rats over that observed with saline/GHB treated rats at all time points in terms of total movements episodes (Fig. 10), total movement time (Fig. 11), total movement distance (Fig. 12), and vertical plane entries (Fig. 13).
  • Fig. 10 total movement episodes
  • Fig. 11 total movement time
  • Fig. 12 total movement distance
  • Fig. 13 vertical plane entries
  • Table II shows the effects of deprenyl and GHB on dopamine metabolism in the rat striatum for each treatment group.
  • a marked decrease in striatum 3-MT levels an indicator of the amount of dopamine released into the synaptic terminal, was observed in rats treated with GHB.
  • Increases in the amount of 3-MT were observed in striatum for rats treated with deprenyl/GHB.
  • Example 3 The dose response curve of GHB in rats and mice The effect of GHB on the loss of locomotor activity in rats and mice was examined. Rats injected with 300 milligrams/kilogram body weight of GHB were shown to rapidly lose locomotor activity in the initial 30 minutes after injection in comparison to control rats injected with only saline. The loss of locomotor function in GHB treated rats was gradually restored over time (Fig. 14). Table II: Effect of Deprenyl and GHB on Dopamine Metabolism in the Rat Striatum
  • DA dopamine
  • DOPAC 3,4-dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • 3-MT 3-methoxytyramine.
  • b Values indicate mean+standard deviation ( ⁇ mol/g tissue).
  • c * p ⁇ 0.05.
  • the dose response to GHB given at 50, 100, 200, 300, and 500 mg/kg GHB was also examined in rats, and measured as the total movement episodes in 10-minute intervals.
  • dosages larger than 300 milligrams/kilogram body weight caused a significant reduction of locomotor activity (Fig. 15).
  • a similar type of experiment was performed in mice, and results showed that loss of locomotor activity occurred in mice in a shorter time and at a lower dosage (Fig. 16).
  • reduced locomotor activity was observed in less than 10 minutes after the injection of 300 milligrams/kilogram body weight of GHB, and after the injection of as low as 100 milligrams/kilogram body weight, loss of locomotor activity was triggered by 20 minutes post-injection.
  • Fig. 17 illustrates that mice are far more sensitive than rats in terms of GHB-triggered loss of locomotor activity.
  • Example 4 Method for measuring the effectiveness of a GHB inhibitor to increase DA in the synaptic cleft
  • GHB inhibitors to antagonize the effect of GHB in a test mammal are determined according to the method described in Example 1, wherein the GHB inhibitor is tested at various concentrations within its toxicity tolerance as previously determined for the specific mammal tested.
  • GHB 500 mg/kg
  • the GHB inhibitor, or saline control are administered by two separate intraperitoneal injections with a 5 minute period between the first and second injections as follows: saline and saline (control); saline and GHB; GHB inhibitor and GHB; GHB and inhibitor, or GHB inhibitor and saline.
  • Activity monitoring with TRU- SCAN begins immediately following second injection, and several parameters regarding the locomotor activity are measured including total movement episodes, total movement time , total movement distance, and vertical plane entries. The comparison of these parameters among each group shows the extent of the effect of the GHB inhibitor to restore the GHB-induced loss of locomotor activity.
  • test animals are sacrificed, and the level of several DA metabolites including dopamine, DOPAC, HVA and 3-MT in the striatum are examined using methods described in Example 1.
  • the comparison between the 3-MT level among the different test groups indicates the effect on dopamine release in the synaptic cleft.
  • An increase of 3-MT level in the GHB/GHB inhibitor treated test animal and the GHB inhibitor/GHB treated test animals in comparison to the GHB/saline or saline/GHB treated test animals, respectively indicates that GHB inhibitor is an effective agent for treating GHB toxicity or overdose.
  • An increase of 3-MT level in the GHB inhibitor/GHB treated test animals in comparison to the saline/GHB treated test animals indicates that GHB inhibitor is an effective prophylactic agent.

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Abstract

L'invention concerne des méthodes de traitement d'une intoxication au GHB ou d'une overdose de GHB, consistant à bloquer les effets néfastes du GHB par retardement de l'élimination de la dopamine de la fente synaptique ou par amélioration de la fonction dopaminergique à cet endroit. Ces méthodes permettent de traiter ou de prévenir de façon efficace une intoxication au GHB due à une carence en SSADH, une intoxication au GHB ou une overdose de GHB accidentelles dans le cadre d'une administration thérapeutique pour traiter la narcolepsie ou des syndromes de sevrage de l'alcool/des opiacés, ou une intoxication au GHB ou une overdose de GHB dues à un usage récréatif inapproprié.
PCT/US2003/035156 2002-11-01 2003-11-03 Methodes de traitement de troubles lies au ghb WO2004041207A2 (fr)

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Publication number Priority date Publication date Assignee Title
DE102006016990A1 (de) * 2006-04-11 2007-10-18 Hermann, Holger Lars, Dr. Verwendung von Baclofen und Baclofen-Derivaten zur Entzugs- und/oder Substitutionsbehandlung bei Abhängigkeit von GHB und/oder GHB-Analogen

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EP0635265A1 (fr) * 1993-07-22 1995-01-25 LABORATORIO FARMACEUTICO C.T. S.r.l. Composition pharmaceutique à libération contrôlée à base d'un ou plusieurs sels de l'acide gamma hydroxybutyrique pharmaceutiquement acceptables
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GB2023421A (en) * 1978-06-22 1980-01-03 Grissmann Chem Ltd gamma -Butyrolactone for therapy of insomnia and anxiety
EP0635265A1 (fr) * 1993-07-22 1995-01-25 LABORATORIO FARMACEUTICO C.T. S.r.l. Composition pharmaceutique à libération contrôlée à base d'un ou plusieurs sels de l'acide gamma hydroxybutyrique pharmaceutiquement acceptables
WO1998006690A1 (fr) * 1996-08-09 1998-02-19 Laboratorio Farmaceutico C.T. S.R.L. UTILISATION D'AMIDES DE L'ACIDE η-HYDROXYBUTYRIQUE DANS LE TRAITEMENT DES TOXICOMANIES ET NOTAMMENT DE L'ALCOOLISME

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MEHTA A.K. ET AL: 'Binding Characteristics of the gamma-hydroxybutyric acid receptor antagonist [3HÜ(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-b enzoÄaÜ[7Üannulen-6-ylidene ethanoic acid in the rat brain' THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS vol. 299, no. 3, 2001, pages 1148 - 1153, XP002981877 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006016990A1 (de) * 2006-04-11 2007-10-18 Hermann, Holger Lars, Dr. Verwendung von Baclofen und Baclofen-Derivaten zur Entzugs- und/oder Substitutionsbehandlung bei Abhängigkeit von GHB und/oder GHB-Analogen

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