WO2016027259A1 - Cns pharmaceutical compositions and methods of use - Google Patents
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- WO2016027259A1 WO2016027259A1 PCT/IB2015/056356 IB2015056356W WO2016027259A1 WO 2016027259 A1 WO2016027259 A1 WO 2016027259A1 IB 2015056356 W IB2015056356 W IB 2015056356W WO 2016027259 A1 WO2016027259 A1 WO 2016027259A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the field of the invention relates to pharmaceutical compositions and methods of use in general, more particularly, neuromodulator stimulators used in combination with a central nervous system (CNS) active agent to reduce side-effects associated with different use of certain CNS active agents.
- CNS central nervous system
- CNS active agents undergo tachyphylaxis and cause severe side-effects that generally worsen with increasing doses.
- CNS active agents When administered alone, CNS active agents usually require large and increasing doses.
- Some classes of CNS active agents that require increasing doses include pain reducing drugs, selective serotonin reuptake inhibitors, antidepressants, anti-convulsants, hypnotics, anesthetics, sedative agents, angiolytics, NSAIDs, xanthines, antipsychotics, appetite suppressants, sleep agents, antibiotics, antivirals, insulin resistance drugs, antihypertensives, and anti-asthma drugs.
- a wide range of current neuropsychiatric drugs have undesirable side effects, such as dose-dependent neurotoxicity, metabolic side effects, locomotor side effects, sedation (includes concentration difficulties, low alertness, and fatigue) and others.
- Various studies in the literature would suggest the current standard of care for treatment success with treatment- resistant patients is in some cases as low as 10-15%.
- Other published estimates of the incidence of treatment resistance in mental disorders are generally between 20%, 30%, and 40%.
- a portion of these treatment-resistant/failure patients is from treatment discontinuation due to side effects.
- There is a need for an adjunctive to current medications that allows for the benefits of the medications while decreasing the undesirable side effects.
- the present invention is directed to pharmaceutical compositions comprising a central nervous system (CNS) active agent selected from the group consisting of: an anxiolytic, an anti-psychotic, an anticonvulsant, an antidepressant, and a neurotransmitter precursor; pseudoephedrine (PSE), phenylephrine (PHE), or both.
- the compositions typically further comprise a pharmaceutically acceptable vehicle, carrier or diluent.
- the CNS active agent is selected from the group consisting of: amitriptyline, a benzodiazepine, cannabidiol, clozapine, haloperidol, levodopa, medical cannabis, and sodium valproate.
- the pharmaceutical compositions may advantageously further comprise a mechanoreceptor stimulator.
- the mechanoreceptor stimulator is preferable in a delayed form for synchronization with the CNS active agent. There is a chronological overlap in physiological activity of the CNS active agent and of the mechanoreceptor stimulator in certain preferred embodiments.
- the mechanoreceptor stimulator may be selected from the group consisting of: a mucomodulator and a surfactant, for example, guaifenesin (GUA).
- GUI guaifenesin
- the CNS active agent is preferably selected from the group consisting of: a benzodiazepine, cannabidiol, clozapine, and medical cannabis.
- the pharmaceutical composition of the invention consists of: an anti-psychotic, an anticonvulsant, an antidepressant, or a neurotransmitter Attorney Docket No. 26737.013 precursor; PHE; and a pharmaceutically acceptable vehicle, carrier or diluent.
- the CNS active agent is amitriptyline, haloperidol, levodopa, or sodium valproate.
- the present invention is also directed to pharmaceutical compositions comprising a CNS active agent selected from the group consisting of: an anxiolytic, an anti-psychotic, an anticonvulsant, an antidepressant, and a neurotransmitter precursor; pseudoephedrine (PSE), phenylephrine (PHE), or both, in an amount sufficient to reduce a side-effect associated with the CNS active agent selected from the group consisting of: sedation, somnolence, sleepiness, memory impairment, amnesia, impairment of cognitive and learning function, ataxia, impaired night sleep/day alertness, impaired memory, impaired concentration, impaired appetite, drowsiness, hypotension, fatigue, kinetic disorders, catalepsy, movement disorders, bowel irritation, and impaired reaction time; and a pharmaceutically acceptable vehicle, carrier or diluent.
- a CNS active agent selected from the group consisting of: an anxiolytic, an anti-psychotic, an anticonvulsant, an antidepressant, and a neurotransmit
- the pharmaceutical composition comprises at least 10 mg of PSE or about 60 mg of PSE.
- the mechanoreceptor stimulator may be selected from the group consisting of: a mucomodulator and a surfactant, for example guaifenesin (GUA).
- a mucomodulator for example a surfactant, for example guaifenesin (GUA).
- GUA guaifenesin
- the amount of GUA is at least 100 mg, about 400 mg, or about 600 mg.
- the pharmaceutical composition consists of an antipsychotic, an anticonvulsant, an antidepressant, or a neurotransmitter precursor; PHE; and a pharmaceutically acceptable vehicle, carrier or diluent.
- the anti-psychotic, the anticonvulsant, the antidepressant, or the neurotransmitter precursor in this particular embodiment is preferably selected from the group consisting of: amitriptyline, haloperidol, levodopa, and sodium valproate.
- the side-effect associated with the CNS active agent selected from the group consisting of: sedation, somnolence, sleepiness, ataxia, impaired night sleep/day alertness, drowsiness, fatigue, kinetic disorders, catalepsy, and movement disorders.
- the amount of PHE is 0.02 mg/kg, 0.2 mg/kg, 0.3 mg/kg, or 0.5 kg/mg.
- the present invention is also directed to a method of reducing at least one side- effect of a central nervous system (CNS) active agent in a subject.
- the method in a particular embodiment comprises administering to a subject the CNS active agent, selected from the group consisting of: an anxiolytic, an anti-psychotic, an anticonvulsant, an antidepressant; and a neurotransmitter precursor; and administering to the subject pseudoephedrine (PSE), phenylephrine (PHE), or both, in an amount sufficient to reduce the side-effect associated with the CNS active agent without reducing the therapeutic efficacy of the CNS active agent.
- PSE pseudoephedrine
- PHE phenylephrine
- the PSE and/or PHE administration is advantageously synchronized with the administering of the CNS active agent so that there is a chronological overlap in physiological activity of the CNS active agent and PSE, PHE, or both.
- the at least one side-effect that is reduced by the method is preferably selected from the group consisting of: sedation, somnolence, sleepiness, memory impairment, amnesia, impairment of cognitive and learning function, ataxia, impaired night sleep/day alertness, impaired memory, impaired concentration, impaired appetite, drowsiness, hypotension, fatigue, kinetic disorders, catalepsy, movement disorders, bowel irritation, and impaired reaction time.
- the PSE, PHE, or both may be administered with the CNS active agent or administered before or after the CNS active agent.
- the method consists of: administering to the subject the CNS active agent selected from the group consisting of: an anti-psychotic, an anticonvulsant, an antidepressant, and a neurotransmitter precursor; and administering to the subject PHE, wherein the side- effect reduced is selected from the group consisting of: sedation, somnolence, sleepiness, ataxia, impaired night sleep/day alertness, drowsiness, fatigue, kinetic disorders, catalepsy, and movement disorders.
- the method further comprises administering to the subject a mechanoreceptor stimulator in an amount sufficient to reduce the side-effect associated with the CNS active agent without reducing the therapeutic efficacy of the CNS active agent.
- administering the mechanoreceptor is synchronized with the administering of the CNS active agent so that there is chronological overlap in physiological activity of the CNS active agent and of the mechanoreceptor stimulator.
- the mechanoreceptor stimulator may be selected from the group consisting of: a mucomodulator Attorney Docket No. 26737.013 and a surfactant, for example guaifenesin (GUA).
- the mechanoreceptor stimulator may be administered with the CNS active agent or before or after the CNS active agent. In some embodiments, the mechanoreceptor stimulator may be administered at least 15 minutes, about 15 to about 30 minutes, or about 15 minutes after the administration of the CNS active agent.
- FIG. 1 illustrates a dosage form presented as a fixed kit, wherein the kit allows for the simple administration of day time and night time dosage forms.
- FIG. 2 illustrates another dosage form presented as a fixed kit, wherein the kit allows for the simple administration of day time and night time dosage forms.
- FIG. 3 illustrates yet another dosage form presented as a fixed kit, wherein the kit allows for the simple administration of day time and night time dosage forms.
- FIG. 4 illustrates a dosage form presented as a fixed kit, comprising a single package with a double dual reservoir that does not require the dosage forms to be in contact with each other before opening by the patient or caregiver.
- FIG. 5 illustrates the study scheme used in Examples 7 and 9; medications consisted of 1 mg alprazolam “ALP” (Xanax), 1 mg LRZ lorazepam “LRZ” (Activan), neuromodulors "NM”, and a placebo “PLZ”; subjects were monitored over the course of six hours.
- ALP alprazolam
- LRZ lorazepam
- NM neuromodulors
- PTZ placebo
- FIG. 6 shows a bar graph and corresponding table indicating the time spent sleeping by subjects in Examples 7 (subjects 101-104; alprazolam “ALP”) and 9 (subjects 105-108; lorazepam “LRZ”).
- FIG. 7 illustrates the study scheme used in Example 10; medications consisted of active pharmaceutical ingredients "API” (alprazolam [Xanax] or lorazepam [Activan]), pseudoephedrine "NM1", guaifenesin “NM2”, or a placebo "PLAC”.
- API active pharmaceutical ingredients
- NM1 guaifenesin
- NM2 guaifenesin
- PLAC placebo
- FIG. 8 shows the effect of lorazepam with the placebo treatment and with the combination of NM (specifically pseudoephedrine, PSE, and guaifenesin, GUA) on a subject's complex attention. Results depicted are the mean number of errors ⁇ SEM.
- FIG. 9 shows the effect of administration of placebo or clozapine ("CLZ") on a schizophrenia animal model (i.e., the MK-801 -induced schizophrenia model) in rats and the resulting side effects observed when CLZ was administered alone; with PSE and GUA; or Attorney Docket No. 26737.013 with PSE, GUA, and lidocaine.
- FIG. 9A depicts ataxia levels
- FIGs. 9B and 9C show horizontal and vertical activity levels, respectively, of the rats in the different treatment groups.
- FIG. 10 shows the effect of administration of placebo or diazepam on korazol (corazolum) seizure severity in rats and the resulting side effects observed when diazepam was administered alone; with PSE and GUA; with PSE, GUA, and lidocaine; with PSE; or with GUA.
- FIG. 10A depicts seizure severity
- FIGs. 10B and IOC show horizontal and vertical activity levels, respectively, of the rats in the different treatment groups.
- FIG. 11 shows the effect of administration of double-distilled water (“DDW”) or amitriptyline on a depression animal model (i.e., the Porsolt test model) in rats and the resulting side effects observed when amitriptyline was administered alone; PVN was administered alone; or amitriptyline and PVN were administered together.
- FIG. 11A depicts the total immobilization time (seconds) in the Porsolt test
- FIGs. 11B and 11C show horizontal and vertical activity levels, respectively, of the rats in the different treatment groups.
- FIG. 12 shows the effect of administration of double-distilled water (“DDW”) or haloperidol on a schizophrenia animal model (i.e., the MK-801 -induced schizophrenia model) in rats and the resulting side effects observed when haloperidol was administered alone; PVN was administered alone; or haloperidol and PVN were administered together.
- FIG. 12A depicts the MK-801 -induced ataxia scores
- FIGs. 12B and 12C show horizontal and vertical activity levels, respectively, of the rats in the different treatment groups.
- FIG. 13 shows the effect of administration of double-distilled water (“DDW”) or sodium valproate on an epilepsy animal model (i.e., the pentylenetetrazol (“PTZ”) kindling model) in rats and the resulting side effects observed when sodium valproate was administered alone; phenylephrine and guaifenesin (“PVN”) were administered alone; or sodium valproate and PVN were administered together.
- FIG. 13A depicts the average severity of the kindling seizures
- FIGs. 13B and 13C show horizontal and vertical activity levels, respectively, of the rats in the different treatment groups.
- the present invention is directed to pharmaceutical compositions and methods for administering the pharmaceutical compositions.
- the pharmaceutical compositions combining at least two therapeutic agents, at least one of which is the CNS active agent.
- the other therapeutic agent comprises at least one vagal neuromodulator, which is a neuromodulator of the efferent or afferent vagal nerve.
- the advantage of the pharmaceutical composition of the present invention is that the disclosed combination reduce a side-effect associated with the CNS active agent and/or that the therapeutically effective amount of CNS active agent used in conjunction with the combination of neuromodulators of present invention is 1.2-100 folds lower than the conventionally accepted effective dosage of same CNS active agent when used alone.
- the present invention involves the selection of neuromodulators that are active at the target-site, such as stimulators of mechanoreceptors of vagal nerve afferents of upper GI (stomach duodenum).
- the disclosed drug compositions may therefore combine at least two, and, preferably three, therapeutic agents. One of these would be a CNS active agent, while the others would be neuromodulators modulating the activity of the afferent vagal nerve.
- vagal nerve activity modulation is postulated to be a novel pharmacological target in the treatment of stress-resistant neuropsychological, cardiovascular and metabolic disorders (Zagon A. Trends in Neuroscience. 24: 11 (2011)).
- vagal neuromodulators for the disclosed compositions proven specific mechanoreceptor stimulators may be selected, for example, mucomodulators and vasoconstrictors.
- multiparticulate systems may be used to achieve flexible and accurate pulsatile drug delivery without enteric coating.
- specific multiparticulate dosage forms are composed of small beads, with each bead composed of many layers (Troy Harmon (September 2006) Tablets & Capsules- Emerging Technology.)
- an expectorant such as guaifenesin may be used.
- Mucomodulators act as irritants to gastric vagal receptors and recruit efferent parasympathetic reflexes that cause the glandular exocytosis of a less viscous mucus mixture (Yuta & Baraniuk, 2005) Attorney Docket No. 26737.013
- vasoactive agents local mucosal vasoconstrictors, such as Phenylephrine (PHE), epinephrine, or pseudoephedrine can be used as vagal afferent modulators.
- Epinephrine adrenalin
- the epinephrine-mediated memory-enhancing effect is dependent upon gastric vagal afferent activity (Krahl et al. Epilepsy Res. 38(2-3): 171-175 (2000)).
- the pharmaceutical composition of the present invention will now be described in more detail.
- the CNS active agent of the present invention may be described according to various classifications and categories, including antidepressants, such as norepinephrine- reuptake inhibitors, serotonin-reuptake inhibitors, monoamine-oxidase inhibitors, serotonin- and noradrenalin-reuptake inhibitors, corticotrophin-releasing-factor antagonists, a- adrenoreceptor antagonists, 5-HT1A receptor antagonists and partial agonists, N-methyl-D- aspartate receptor antagonists, and GABA analogues, intermediates and modulators, and NK- 1-receptor antagonists.
- antidepressants such as norepinephrine- reuptake inhibitors, serotonin-reuptake inhibitors, monoamine-oxidase inhibitors, serotonin- and noradrenalin-reuptake inhibitors, corticotrophin-releasing-factor antagonists, a-
- CNS agents include benzodiazepines, barbiturates, opioids and other addictive drugs, analgesics, antipsychotics (e.g., clozapine and haloperidol), antidepressants, muscle relaxants and nonbenzodiazepines, antihistamines and drugs for treatment of neurodegenerative diseases. It should be recognized that some CNS active agents fall into more than one category.
- the CNS active agent of the present invention may contain one or more chiral centers and/or double bonds and, therefore, includes all stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, and diastereomers.
- CNS active agents discussed herein also include all pharmaceutically acceptable salts, complexes (e.g., hydrates, solvates, and clathrates) and prodrugs thereof.
- pharmaceutically acceptable salts, complexes e.g., hydrates, solvates, and clathrates
- prodrugs e.g., prodrugs thereof.
- Antidepressant means any compound or composition that, when tested according to standard in vivo or in vitro assays, displays receptor-binding properties or other mechanistic properties associated with the clinically approved antidepressants or any compound or composition known or to be discovered that has demonstrated clinical efficacy in treating depression in mammals including those compounds and compositions that have been approved for treating depression in humans.
- Classes of antidepressants include norepinephrine -reuptake inhibitors (NRIs), selective-serotonin-reuptake inhibitors (SSRIs), monoamine-oxidase inhibitors (MAOIs), serotonin-and-noradrenaline-reuptake inhibitors Attorney Docket No. 26737.013
- SNRIs corticotrophin-releasing factor
- CRF corticotrophin-releasing factor
- a-adrenoreceptor antagonists a-adrenoreceptor antagonists
- NK1 -receptor antagonists 5-HTlA-receptor agonist, antagonists, and partial agonists, atypical antidepressants, and other antidepressants.
- Norepinephrine-reuptake inhibitors are compounds that when administered systemically in a mammal, inhibit norepinephrine- reuptake or that display receptor-binding properties or other mechanistic properties associated with norepinephrine -reuptake inhibitors when tested according to standard in vivo or in vitro assays, such as are described in Wong et al, 61 J. Pharm. Exp. Therap. 222 (1982); P. Skolnick et al., 86 BR. J.
- Norepinephrine -reuptake inhibitors comprise amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine-oxide, trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, and tianeptine.
- Other norepinephrine -reuptake inhibitors include
- Serotonin-reuptake inhibitors are compounds that inhibit reuptake of serotonin when systemically administered in mammals or that display receptor-binding properties or other mechanistic properties associated with serotonin-reuptake inhibitors when tested according to standard in vivo or in vitro assays such as are described in Wong, et al, 8 Neuropsychopharmacology 337 (1993); U.S. Pat. No. 6,225,324; and U.S. Pat. No. 5,648,396, which are incorporated herein by reference.
- serotonin-reuptake inhibitors comprise binedaline, m-chloropiperzine, citalopram, duloxetine, etoperidone, escitalopram, femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, nefazodone, oxaflazone, paroxetine, prolintane, ritanserin, sertraline, tandospirone, venlafaxine and zimeldine.
- MAOIs monoamine -oxidase inhibitors
- MAOIs are compounds that, when administered systemically in a mammal, inhibit monoamine oxidase when tested according to standard in vivo or in vitro assays, such as assays adapted from the monoamine- oxidase inhibitory assay described in 12 Biochem. Pharmacol. 1439 (1963) and Kinemuchi et Attorney Docket No. 26737.013 al, 35 J. Neurochem. 109 (1980); U.S. Pat. No. 6,096,771, which are incorporated by reference.
- non-selective MAOIs comprise amiflamine, vanoxerine boxeprazine, AGN 2253 (Nicholas Kiwi), iproniazid, isocarboxazid, M-3-PPC (Draxis), nialamid, phenelzine, pargyline, and tranylcypromine and pharmaceutically acceptable salts thereof.
- Examples of selective MAOIs comprise clorgyline, cimoxatone, befloxatone, brofaromine, apelinaprine, BW-616U (Burroughs Wellcome), BW-1370U87 (Burroughs Wellcome), CS- 722 (PvS-722) (Sankyo), E-2011 (Eisai), harmine, harmaline, moclobemide, PharmaProjects 3975 (Hoechst), RO 41-1049 (Roche), RS-8359 (Sankyo), T-794 (Tanabe Seiyaku), toloxatone, K-Y 1349 (Kalir and Youdim), LY-51641 (Lilly), LY-121768 (Lilly), M&B 9303 (May & Baker), MDL 72394 (Marion Merrell), MDL 72392 (Marion Merrell), sercloremine, and MO 1671.
- MAOIs comprise budipine, caroxazone, D-1711 (Biocodex), fezolamine, FLA-334 (RAN-1 13) (Astra), FLA-289 (FLA-299, FLA-365, FLA-384, FLA- 463, FLA-727) (Astra), K-1 1566 (Pharmacia Upjohn, Farmitalia), K-1 1829 (Pharmacia Upjohn, Farmitalia), metralindole, MPCPAM (Yissum), PharmaProjects 227 (Syntex/Roche), PharmaProjects 2806 (Fournier), PharmaProjects 1122, PharmaProjects 3311 (Roche), PharmaProjects 4433 (Roche), RS-2232 (Sankyo), and UP-614-04 (Bristol-Myers).
- MAOIs comprise bifemelane, brofaromide, hypericin, iproclozide, medifoxamine, nialamide, octamoxin, phenoxypropaazine, pivalyl benzhydrazine, prodipine, selegiline, and benmoxine.
- CNS active agents of the present invention also include "serotonin- and noradrenalin-reuptake inhibitors" (SNRIs).
- SNRIs are compounds that, when administered systemically in a mammal, act as serotonin- and noradrenaline -reuptake inhibitors or that display receptor-binding properties or other mechanistic properties associated with serotonin- and noradrenalin-reuptake inhibitors when tested according to standard in vivo or in vitro assays, such as are described in U.S. Pat. No. 6, 172,097, which is incorporated by reference.
- Examples of SNRIs comprise mirtazapine, and venlafaxine.
- Corticotropin-releasing-factor antagonists are also CNS active agents.
- CRF antagonists are compounds that, when administered systemically in a mammal, act as corticotropin-releasing factor antagonists or that display receptor-binding properties or other mechanistic properties associated with CRF antagonists, when tested according to standard in vivo or in vitro assays, such as are described in U.S. Pat. No. 6,218,391, which is incorporated by reference.
- Examples of CRF antagonists comprise those described in U.S. Pat. Nos. 6, 191, 131; 6, 174, 192; 6, 133,282; PCT Patent Application Publication Nos. WO Attorney Docket No. 26737.013
- a-Adrenoreceptor antagonists are compounds that, when administered systemically in a mammal, act as a-adrenoreceptor antagonists or that act as a-adrenoreceptor antagonists when tested according to standard in vivo or in vitro assays, such as are described in U.S. Pat. No. 6,150,389, which is incorporated by reference.
- Examples of ⁇ -adrenoreceptor antagonists comprise phentolamine and those described in U.S. Pat. No. 6,150,389, which is incorporated by reference.
- 5-HTlA-receptor agonist, antagonists, and partial agonists will now be described.
- 5-HT1A agents are compounds that when administered systemically in a mammal, act as 5-HTlA-receptor agonist, antagonists, and partial agonists or that act as 5- HTlA-receptor agonist, antagonists, and partial agonists, when tested according to standard in vivo or in vitro assays, such as might be adapted from the 5-HT1A receptor binding assays described in U.S. Pat. Nos. 6,255,302 and 6,239, 194, are expressly incorporated by reference.
- 5-HT1A agents comprise buspirone, flesinoxan, gepirone, and ipsapirone, and those disclosed in U.S. Pat. Nos. 6,255,302; 6,245,781 and 6,242,448.
- An example of a compound with 5-HT1A receptor antagonist/partial agonist activity is pindolol.
- N-methyl-D-aspartate receptor antagonists represent another CNS active agent.
- the NMDA receptor is a cell-surface protein complex in the class of ionotropic- glutamate receptors, with a structure comprising a ligand-gated/voltage-sensitive ion channel.
- the NMDA receptor is believed to contain at least five distinct binding (activation) sites: a glycine -binding site, a glutamate-binding site (NMDA-binding site); a phencyclidine (PCP)- binding site, a polyamine -binding site, and a zinc-binding site.
- a receptor antagonist is a molecule that blocks or reduces the ability of an agonist to activate the receptor.
- NMDA-receptor antagonist is any compound or composition that, when contacted with the NMDA receptor in vivo or in vitro, inhibits the flow of ions through the NMDA- receptor ion channel.
- NMDA-receptor antagonist suitable for use in the invention can be identified by testing NMDA-receptor antagonist for local anesthetic and peripheral antinociceptive properties according to standard pain models. See e.g., J. Sawynok et al, 82 Pain 149 (1999); J. Sawynok et al, 80 Pain 45 (1999).
- the NMDA-receptor antagonist is a non-competitive NMDA- receptor antagonist, preferably, ketamine and/or ketamine hydrochloride.
- NMDA-receptor antagonist is a non-competitive NMDA- receptor antagonist, preferably, ketamine and/or ketamine hydrochloride.
- NMDA-receptor antagonist further comprises any compound or composition that antagonizes the NMDA receptor by binding at the glycine site.
- NMDA-receptor antagonists can be identified by standard in vitro and in vivo assays, such as are described in U.S. Pat. No. 6,251,903; U.S. Pat. No. 6, 191, 165; Grimwood et al. 4 Molecular Pharmacology 923 (1992); Yoneda et al 62 J. Neurochem. 102 (1994); and Mayer et al. J. Neurophysiol. 645 (1988), which are incorporated by reference.
- Glycine-site NMDA-receptor antagonists comprise glycinamide, threonine, D-serine, felbamate, 5,7-dichlorokynurenic acid, and 3-amino-l- hydroxy-2-pyrrolidone (HA-966), diethylenetriamine, 1, 10-diaminodecane, 1,12- diaminododecane, and ifenprodil and those described in U.S. Pat. Nos. 6,251,903; 5,914,403; 5,863,916; 5,783,700; and U.S. Pat. No. 5,708, 168, which are incorporated by reference.
- the NMDA-receptor antagonist comprises any compound or composition that antagonizes the NMDA receptor by binding at the glutamate site, also known as “competitive NMDA-receptor antagonists.
- “Competitive NMDA receptor antagonists comprise 3-(2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP); 3-[(R)-2- carboxypiperzin-4-yl)-prop-2-enyl-l-phosphonic acid (CPP-ene); l-(cis-2-carboxypiperidine- 4-yl)methyl-l-phosphonic acid (CGS 19755), D-2-Amino-5-phosphonopentanoic acid (AP5); 2-amino-phosphonoheptanoate (AP7); D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethyl ester (CGP39551); 2-amino-4-methyl-5-
- NMDA-receptor antagonists include Jia-He Li, et al., 38 J. Med. Chem. 1955 (1995); Steinberg et al, 133 Neurosci. Lett. 225 (1991); Meldrum et al, 11 Trends Pharmacol. Sci., 379 (1990); Willetts et al, 11 Trends Pharmacol. Sci. 423 (1990); Faden et al., 13 Trends Pharmacol. Sci. 29 (1992); Rogawski 14 Trends Pharmacol. Sci. 325 (1993); Albers et al, 15 Clinical Neuropharm. 509 (1992); Wolfe et al, 13 Am. J Emerg. Med., 174 (1995); and Bigge, 45 Biochem. Pharmacol. 1547 (1993), which are incorporated by reference.
- Still another NMDA receptor antagonist comprises any compound or composition that antagonizes the NMDA receptor by binding at the PCP binding site, also known as “noncompetitive NMDA-receptor antagonists.”
- Non-competitive NMDA-receptor antagonists can be identified using routine assays, such as those described in U.S. Pat. Nos. 6,251,948; No. 5,985,586; and 6,025,369; Jacobson et al., 110 J. Pharmacol. Exp. Ther. 243 (1987); and Thurêtet al, 31 J. Med. Chem. 2257 (1988), which are incorporated by reference.
- the NMDA-receptor antagonist comprises compounds that block the NMDA receptor at the polyamine binding site, the zinc -binding site, and other NMDA-receptor antagonists that are either not classified according to a particular binding site or that block the NMDA receptor by another mechanism.
- NMDA-receptor antagonists that bind at the polyamine site comprise spermine, spermidine, putrescine, and arcaine.
- Assays useful to identify NMDA-receptor antagonists that act at the zinc or polyamine binding site are disclosed in U.S. Pat. No. 5,834,465, which is incorporated by reference.
- Other NMDA-receptor antagonists comprise amantadine, eliprodil, iamotrigine, riluzole, aptiganel, flupirtine, celfotel, and levemopamil.
- the NMDA receptor also comprises pyroloquinolin quinone, cis-4- (phosphonomethyl)-2-piperidine carboxylic acid, MK801, memantine, and D-methadone.
- NMDA-receptor antagonist in compositions of the invention will vary according to the type and identity of the NMDA-receptor antagonist, the concentration Attorney Docket No. 26737.013 and identity of the antidepressant, and the painful indication treated. Dosages and concentrations for a particular NMDA-receptor antagonist can be optimized according to routine experiments using well-known pain models, for example, those described in J. Sawynok et al, 82 Pain 149 (1999) and J. Sawynok et al., 80 Pain 45 (1999).
- the amount of NMDA-receptor antagonist in the pharmaceutical composition of the present invention ranges from about 0.1 percent to about 5 percent of the total weight of the composition, preferably, from about 0.3 percent to about 0.5 percent of the total weight of the composition.
- the therapeutically effective amounts of NMD A receptor antagonist are approximately 1.2-100 folds lower than conventionally accepted effective dosage when the NMDA-receptor antagonist is used alone.
- GVG GABA-transaminase
- GABA-T GABA-transaminase
- GABA-T GABA-transaminase
- GHB g-Hydroxybutyric acid
- GHB is another CNS active agent.
- GHB is also known as sodium oxybate, sodium oxybutyrate, and others.
- GHB has been used for intravenous induction of anesthesia, treatment of alcohol dependence and opiate withdrawal.
- GHB is a schedule I controlled substance in the U.S. The drug is rapidly absorbed orally with an onset of action within 15 minutes.
- the Tmax of GHB is approximately 30 minutes.
- the Tmax occurs around 45 minutes.
- Oral ingestion of GHB 75-100 mg/kg in humans results in peak blood levels of approximately 90- 100 ⁇ g/ml at 1-2 hours after ingestion.
- GHB at 50 mg/kg/day has been given orally to treat the symptoms of acute alcohol withdrawal and to facilitate both short- and long-term abstinence from alcohol. It also was given to treat opiate withdrawal, often in higher dosages of 50-300 mg/kg/day.
- CNS active agents also include NKl-receptor antagonists, which are compounds that when administered systemically in a mammal, act as NKl-receptor antagonists (Neurokinn 1 substance P receptor antagonists) or that acts as NKl-receptor antagonists, when tested according to standard in vivo or in vitro assays, such as may be adapted from the NKl -receptor-binding assay described in U.S. Pat. No. 6, 117,855, which is incorporated by Attorney Docket No. 26737.013 reference.
- Examples of NKl -receptor antagonists comprise those described in PCT Patent Application Publication Nos. WO 95/16679, WO 95/18124, WO 95/23798, and European Patent Specification No. 0 577 394.
- Antidepressants comprise tricyclic antidepressants, such as amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine; tetracyclic antidepressants, such as mianserin; MOAIs such as isocarboxazid, phenelizine, tranylcypromine and moclobemide; and selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline.
- tricyclic antidepressants such as amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine
- tetracyclic antidepressants such as mianserin
- MOAIs such as isocarboxa
- the antidepressant is a norepinephrine- reuptake inhibitor, a tricyclic antidepressant, amitriptyline, or, more preferably, amitriptyline hydrochloride.
- CNS active agents also include atypical antidepressants, such as bupropion, dimethazan, fencamine, fenpentadiol, levophacetoperance, metralindone, mianserin, cotinine, rolicyprine, rolipram, nefopam, lithium, trazodone, viloxazine, and sibutramine and pharmaceutically acceptable salts thereof.
- atypical antidepressants such as bupropion, dimethazan, fencamine, fenpentadiol, levophacetoperance, metralindone, mianserin, cotinine, rolicyprine, rolipram, nefopam, lithium, trazodone, viloxazine, and sibutramine and pharmaceutically acceptable salts thereof.
- Antidepressants also include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (tricyclics). Tricyclics include amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil) and nortriptyline (Aventyl, Pamelor). Other antidepressants have mechanisms than are markedly different from SSRIs and tricylics. Common antidepressants are venlafaxine (Effexor), nefazadone (Serzone), bupropion (Wellbutrin), mirtazapine (Remeron) and trazodone (Desyrel).
- MEOIs monomine oxidase inhibitors
- phenelzine Nardil
- tranylcypromine Parnate
- Mirtazapine may be used in combination with SSRIs to boost antidepressive effect, improve sleep and avoid sexual side-effects.
- the conventionally accepted effective dose is 15- 45 mg/day.
- CNS active agents comprise a wide variety of other drugs that are thought to have antidepressant activity including, nomifensine, oxitriptan, oxypertine, thiazesim, adrafinil, benactyzine, butacetin, dioxadrol, febarbamate, hematoporphyrin, minaprine, piberaline, pyrisuccideanol, roxindole, rubidium chloride, sulpride, thozalinone, tofenacin, 1- tryptophan, alaproclate, amitriptyline-chlordiazepoxide combination, atipamezole, azamianserin, chiliinaprine, befuraline, binodaline, bipenamol, cericlamine, cianopramine, cimoxatone, clemeprol, clovoxamine, dazepinil, deanol, en
- the amount of antidepressant in compositions of the invention will vary according to the type and identity of the antidepressant, the concentration and identity of the NMDA- receptor antagonist, and the painful indiction treated. Dosages and concentrations for a particular antidepressants can be optimized according to routine experiments using well- known pain models, for example, those described in J. Sawynok et al., 82 Pain 149 (1999) and J. Sawynok et al, 80 Pain 45 (1999). In general, the amount of antidepressant in the pharmaceutical composition of the present invention ranges from about 0.1 percent to about 10 percent of the total weight of the pharmaceutical, preferably from about 1 percent to about 5 percent of the total weight of the composition. In another embodiment, the amount of antidepressant ranges from about 0.5 percent to about 8 percent.
- Barbituate is known CNS active agent.
- Barbituric acid and its derivatives are known to act mainly as sedatives, hypnotics and anesthetics.
- Certain derivatives, such as 5- ethyl-5-phenyl barbituric acid (Phenobarbital) have an anticonvulsive effect and are therefore employed in the treatment of epilepsy.
- Phobarbital has also sedative and hypnotic effects that are disadvantageous in the treatment of epilepsy.
- Phenobarbital Depression sedation, sleep disturbances, psychosis, cognitive
- Benzodiazepines Agitation, sedation, hallucinations, psychosis, cognitive impairment, delirium, withdrawal syndrome
- Barbiturates in high concentrations may also prove neuroprotective; however, the dosages necessary to confer neuroprotection are toxic and cause lethargy, stupor, coma, or are lethal, making accepted dosages of barbiturates unsuitable for treatment of ischemia and other neurodegenerative diseases.
- lower therapeutically effective dosages may be achieved.
- opioid means all agonists and antagonists of opioid receptors, such as mu (which can be denoted by mu or ⁇ ), kappa (which can be denoted by kappa or K), and delta (which can be denoted by delta or ⁇ ) opioid receptors and subtypes thereof.
- opioid means all agonists and antagonists of opioid receptors, such as mu (which can be denoted by mu or ⁇ ), kappa (which can be denoted by kappa or K), and delta (which can be denoted by delta or ⁇ ) opioid receptors and subtypes thereof.
- opioid drugs are any substance that is consumed by a mammal and causes addiction related behavior, cravings for the substance, rewarding/incentive effects, dependency characteristics, or any combination thereof. Addictive drugs comprise psychostimulants, narcotic analgesics, alcohols and addictive alkaloids, such as nicotine, or combinations thereof.
- Examples of psychostimulants include amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, diethylpropion, methylphenidate, cocaine, phencyclidine, and methylenedioxymethamphetamine.
- narcotic analgesics comprise opioids and include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, diazepam, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, cocaine, heroinandthebaine.
- opioids include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, diazepam, dihydrocodeine, diphenoxylate, ethylmorph
- Addictive drugs also include hypnotics and sedatives, such as barbiturates, chlordiazepoxide, amylobarbitone, butobarbitone, pentobarbitone, choral hydrate, chlormethiazole, hydroxyzine and meprobamate, and alcohols, such as ethanol, methanol and isopropyl alcohol.
- hypnotics and sedatives such as barbiturates, chlordiazepoxide, amylobarbitone, butobarbitone, pentobarbitone, choral hydrate, chlormethiazole, hydroxyzine and meprobamate
- alcohols such as ethanol, methanol and isopropyl alcohol.
- psychostimulants include amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, diethylpropion, methylphenidate, cocaine, phencyclidine, and methylenedioxymethamphetamine .
- Addictive drugs may further comprise antianxiety agents such as the benzodiazepines, alprazolam, bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam, and neuroleptic and antipsychotic drugs, such as the phenothiazines, chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine, thiopropazate, Attorney Docket No.
- antianxiety agents such as the benzodiazepines, alprazolam, bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, o
- thioridazine and trifluoperazine and the butyrophenones such as pimozide, thiothixene and lithium.
- CNS stimulants such as caffeine, may also be included.
- withdrawal symptoms include irritability, anxiety, restlessness, lack of concentration, lightheadedness, insomnia, tremors, increased hunger and weight gain, and of course, an intense craving for tobacco.
- Withdrawal symptoms from the cessation of opioid use include craving, anxiety, dysphoria, yawning, perspiration, lacrimation, rhinorrhoea, restless and broken sleep, irritability, dilated pupils, aching of bones, back and muscles, piloerection, hot and cold flashes, nausea, vomiting, diarrhea, weight loss, fever, increased blood pressure, pulse and respiratory rate, twitching of muscles and kicking movements of the lower extremities.
- Medical complications associated with injection of opioids include a variety of pathological changes in the CNS including degenerative changes in globus pallidus, necrosis of spinal gray matter, transverse myelitis, amblyopia, plexitis, peripheral neuropathy, Parkinsonian syndromes, intellectual impairment, personality changes, and pathological changes in muscles and peripheral nerves.
- Infections of skin and systemic organs are also quite common including staphylococcal pneumonitis, tuberculosis, endocarditis, septicemia, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus and osteomyelitis.
- compositions used in treating opioid dependence including methadone, naloxone, naltrexone, and clonidine, are not without their drawbacks, frequently causing their own set of side-effects.
- the present invention of combining the CNS active agent, in this embodiment, addictive drugs, with the neuromodulators of the present invention can be used to reduce dosages of addictive drugs during the period of therapy for withdrawal.
- CNS active agents of the present invention may also comprise analgesics, including opioids and opiates, such as oral anileridine (Leritine®- analogs of meperidine), Meperidine (Demerol®), Normeperidine, Morphine and congeners, codeine, Tylenol, antiinflammatory agents, narcotics, antipyretics including the opioid analgesics-such as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine.
- opioids and opiates such as oral anileridine (Leritine®- analogs of meperidine), Meperidine (Demerol®), Normeperidine, Morphine and congeners, codeine, Tylenol, antiinflammatory agents,
- acetylsalicylic acid aspirin
- paracetamol aspirin
- phenazone acetylsalicylic acid
- Analgesics have wide-ranging side-effects from mild to severe, including sedation, psychic slowing, dysphoria, mood changes, psychosis, convulsions, Attorney Docket No. 26737.013 constipation, nausea, mental clouding and delirium.
- the conventionally accepted effective dosage of codeine ranges from doses of 15-30 mg, 1-3 times daily.
- the CNS active agent of the present invention also includes antipsychotics.
- Conventional antipsychotics are antagonists of dopamine (02) receptors; atypical antipsychotics also have 02 antagonistic properties, but with different binding kinetics, as well as, and activity at other receptors, particularly 5-HT2A, 5-HT2c and 5-HT1 D.
- Examples of antipsychotics for use in the present invention are clozapine (Clozaril®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), sertindole, amisuipride and aripiprazole (Abilify®).
- Antipsychotics also include medical cannabis and its components, such as cannabidiol.
- olanzapine (2-methyl-4-(4- methyl-1 -piperazinyl)-l OH-thieno[2,3-bJ ii ,5]benzo) is used to treat schizophrenia and biopolar mania, but has the significant side-effects of increased appetite and subsequent weight gain and sedation.
- SEROQUEL® sustained release formulation (quetiapine fumarate sustained release) and SEROQUEL® (original formulation quetiapine) are used to treat schizophrenia, bipolar disorder, major depressive disorder, dementia, and generalized anxiety disorder, in conventionally accepted therapeutic doses of 400-700 mg daily. While less likely to induce extra-pyramidal symptoms and long term tardive dyskinesia, one of SEROQUEL®'s prominent side-effects is sedation. Other side-effects include headache and dry mouth.
- SEROQUEL XR is supplied for oral administration as 200 mg (yellow), 300 mg (pale yellow), and 400 mg (white). Each 200mg tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400mg tablet contains 461 mg of quetiapine fumarate equivalent to 400mg quetiapine. All tablets are capsule shaped and film coated. Inactive ingredients for SEROQUEL XR are lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all SEROQUEL XR tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (200 and 300 mg tablets) are included in the film coating of specific strengths.
- Ganaxolone (3a-hydroxy-3b-methyl-5a-pregnan-20-one) is the 3b-methylated synthetic analog of the neurosteroid allopregnanolone (3a,5a-P), a metabolite of Attorney Docket No. 26737.013 progesterone, and used to treat epilepsy in adults and children.
- ganaxolone does not have significant classical nuclear steroid hormone activity and, unlike 3a,5a-P, cannot be converted to metabolites with such activity.
- Ganaxolone potentiation of the GABAA receptor occurs at a site distinct from the benzodiazepine site. Acute ganaxolone treatment is associated with reversible, dose-related sedation.
- Asenapine is described in U.S. Patent No. 4,145,434.Clozapine, 8-chloro-l I -(4- methyl-i-piperazinyl)-5H-dibenzo[be][l,4]diazepine, is used to treat schizophrenia.
- Risperidone 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9 - tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, is used to treat various psychotic diseases.
- Sertindole I-[2-[4-[5-chloro- 1 -(4-fluorophenyl)- lH-indol-3-yI 1-1-10 piperidinyl] ethyl] imidazolidin-2-one, is also used to treat schizophrenia.
- Quetiapine 5-[2-(4-dibenzo[bfI[l ,4]thiazepin- 1 I -yl -1 -piperazinyl) ethoxy]ethanol,is used to treat and its activity in assays which demonstrate utility in the treatment of schizophrenia are describedin U.S. Pat. No. 4,879,288.
- Quetiapine is typically administered as its (E)-2-butenedioate (2: 1) salt.
- Aripiprazole, 7- ⁇ 4-[4-(2,3-dichlorophenyl)-l -piperazinyl]-butoxy ⁇ -3,4-dihydro carbostyril or 7- ⁇ 4-[4-(2,3-dichlorophenyl)-l -piperazinylj-butoxy ⁇ -3,4-dihydro -2(1 H)- quinolinone is an atypical antipsychotic agent used for the treatment of schizophrenia.
- Amisulpride a selective dopamine antagonist, is an atypical antipsychotic agent, higher doses of which block the postsynaptic dopamine receptors resulting in an improvement in psychoses. Amisulpride is not approved by the Food and Drug Administration for use in the United States. Amisulpride (in 50mg doses) is marketed as a treatment for dysthymia in Italy (as Deniban).
- Antidepressants may be used as analgesics at low doses to manage chronic back pain.
- Tricyclic antidepressants such as amitriptyline, nortriptyline, and imipramine, and selected tetracyclic agents are believed to control pain, due to the blockade of neurotransmitters, norepinephrine and serotonin.
- Side-effects of tricyclic antidepressants include anticholinergic side-effects (dry mouth, cardiac arrhythmias, orthostatic hypotension), sedation, and a lowered seizure threshold.
- Methotrimeprazine (Nozinan®) is a phenothiazine with analgesic properties, but it also has prominent sedative, anticholinergic, and hypotensive effects, which may preclude its use in most long-term therapy.
- Carbamazepine is widely used for chronic neuropathic pain, such as trigeminal neuralgia, but has adverse effects (mainly drowsiness, dizziness and gait disturbance) over two weeks. Conventially accepted effected doses have been mostly 400-1000 mg/day. Carbamazepine Attorney Docket No.
- 26737.013 risks many interactions and toxicities of particular significance in the elderly (sedation, ataxia, hyponatremia, leukopenia). Its elimination half-life is about 12 hours.
- Gabapentin Gabapentin (Neurontin®) a well-known alpha-2-delta ligand, l-(aminomethyl)- cyclohexylacetic acid, is an antiepileptic agent that is also approved to help alleviate neuropathic pain. Its mechanism of action is unknown.
- Conventionally accepted effective Gabapentin dosing should be initiated low and titrated 100 to 300 mg every three to five days until pain relief is achieved or side-effects, such as dizziness or somnolence, become intolerable.
- Suitable CNS active agents of the present invention also include muscle relaxants (MRs) such as nonbenzodiazepines generally and baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, orphenadrine and quinine.
- MRs muscle relaxants
- Nonbenzodiazepines include a variety of drugs that can act at the brain stem or spinal cord level.
- Cyclobenzaprine is structurally related to the tricycle antidepressant amitriptyline but is not clinically used as an antidepressant. Cyclobenzaprine relieves muscle spasms, but is not effective for the treatment of muscle spasms due to CNS diseases, such as cerebral palsy or spinal cord disease. Cyclobenzaprine possesses anticholinergic activity unlike that of carisoprodol, due to the structural similarity to amitriptyline. A 5 mg dose has been found to be as effective as a 10 mg dose and has the advantage of less sedation.
- Cyclobenzaprine should be initiated with the lowest dose (5 mg) and titrated up slowly. Elimination half-life is 1-3 days, and hence it can be given as a single bedtime dose. Possible side-effects include drowsiness, dizziness, and anticholinergic effects.
- Carisoprodol and metaxalone have moderate antispasmodic effects and are mildly sedative. Similar to Carisoprodol, most of Metaxalone 's beneficial effects are thought to be due to its sedative properties. Principal advantages over other commonly used MRs include lack of abuse, limited accumulation due to relatively short elimination half-life, and relatively low degree of sedation. A disadvantage of metaxalone may be its duration of four to six hours. The conventionally accepted effective dose of metaxalone is 400 to 800 mg, three to four times daily. In some cases, metaxalone should be avoided in elderly patients, due to its anticholinergic and sedative side-effects. Attorney Docket No. 26737.013
- Methocarbamol including various formulations combined with acetaminophen, ASA, and codeine (e.g. Robaxacet-8®, Robaxisal-C®) has long been available to treat non-neuropathic pain. It also has a sedative effect.
- Carisoprodol 350 mg, 4 times daily
- Baclofen and tizanidine are indicated for spasticity and muscle spasms associated with multiple sclerosis and spinal cord trauma. All agents in this drug class appear to have a similar onset of action but vary in their elimination half-lives, duration of activity, pharmacokinetics, and pharmacodynamics.
- CNS active agents also include sedating antihistamines.
- Diphenhydramine and doxylamine are oral, sedating antihistamines that may be used for insomnia and nocturnal pain.
- CNS active agents also comprise zaleplon, Zolpidem, eszopiclone and trazodone, which induce sleep.
- Drugs for treatment of Neurodegenerative diseases will now be described. Many of the drugs used to treat agitation accompanying neurodegenerative diseases, such as antiparkinsonian (anti-PD) and anti-Alzheimer disease (anti-AD) drugs like Arricept, Exelon, Memantine, and tacrine illicit does-dependent, psychiatric side-effects, specifically sedation, particularly in the elderly.
- anti-PD antiparkinsonian
- anti-AD anti-Alzheimer disease
- Arricept Arricept
- Exelon Exelon
- Memantine Memantine
- tacrine illicit does-dependent, psychiatric side-effects, specifically sedation, particularly in the elderly.
- CNS active agents include: Antiparkinson agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S(-)-2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin (N-0923); anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam, medical cannabis, and cannabidiol; antiemetics and antinauseants such as the phenothiazines, prochloperazine, thiethylperazine, medical cannabis, cannabidio
- CNS agents generally are prescribed according to their conventionally accepted effective dosage. Conventionally accepted effective dosages for some CNS agents are listed below:
- o Clozapine Adults Initial: 12.5mg qd-bid. Titrate: Increase by 25- 50mg/day, up to 300-450mg/day by end of 2nd week, then increase weekly or bi-weekly by up to lOOmg. Usual: 100-900mg/day given tid. Max: 900mg/day o Olanzapine- Usual Dose— Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days.
- Bipolar Mania Monotherapy/Adjunctive: Give bid. Initial: lOOmg/day on Day 1. Titrate: Increase to 400mg/day on Day 4 in increments of up to lOOmg/day in bid divided doses. Adjust doses up to 800mg/day by Day 6 in increments ⁇ 200mg/day. Max: 800mg/day. Maintenance for Bipolar I Disorder: Give bid. 400-800mg/day.
- Schizophrenia Initial: 25mg bid. Titrate: Increase by 25-50mg bid-tid on the 2nd and 3rd day to 300-400mg/day Attorney Docket No. 26737.013 given bid-tid by the 4th day. Adjust doses by 25-50mg bid at intervals of at least 2 days. Maint: Lowest effective dose. Max: 800mg/day.
- ABILIFY o Aripiprazole-The recommended starting and target dose for ABILIFY is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation
- o Depakote -Initial 10-15mg/kg/day. Titrate: Increase by 5-10mg/kg/week.
- Tegretol -Initial (Immediate- or Extended-Release Tabs) 200mg bid or (Sus) lOOmg qid
- itrate (Immediate-Release Tabs/Sus) Increase weekly by 200mg/day given tid-qid.
- Extended-Release Tabs Increase weekly by 200mg/day given bid.
- Maint 800-1200mg/day.
- Max 1200mg/day.
- Trileptal-Monotherapy Initial: 4-5mg/kg bid. Titrate: Increase by 5mg/kg/day every 3rd day.
- Adjunct Therapy Initial: 4-5mg/kg bid. Max: 600mg/day. Titrate: Increase over 2 weeks.
- Nozinan® o Methotrimeprazine (Nozinan®) -Minor conditions in which Nozinan may be given in low doses as a tranquilizer, anxiolytic, analgesic or sedative: begin treatment with 6 to 25 mg/day in 3 divided doses at mealtimes. Increase the dosage until the optimum level has been reached. As a sedative, a single night Attorney Docket No. 26737.013 time dose of 10 to 25 mg is usually sufficient. Severe conditions: Such as psychoses or intense pain in which Nozinan is employed at higher doses: Begin treatment with 50 to 75 mg/day divided into 2 or 3 daily doses; increase the dosage until the desired effect is obtained. In certain psychotics, doses may reach 1 g or more/day. If it is necessary to start therapy with higher doses, i.e., 100 to 200 mg/day, administer the drug in divided daily doses and keep the patient in bed for the first few days.
- Baclofen -Initial: 5mg tid for 3 days. Titrate: May increase dose by 5mg tid every 3 days. Usual: 40-80mg/day. Max: 80 mg/day (20mg qid).
- o Apomorphine-2mg SC closely monitor BP. Titrate: Increase by lmg every few days; assess efficacy/tolerability. Max: 6mg/day.
- o Ropinirole-The recommended starting dose for Parkinson's disease is 0.25 mg 3 times daily; based on individual patient response, dosage should then be titrated with weekly increments as described in Table 5. After week 4, if necessary, daily dosage may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total dose of 24 mg/day.
- o Benzatropine-Initial 0.5-lmg PO/IV/IM qhs. Titrate: May increase every 5-6 days by 0.5mg. Usual: l-2mg PO/IV/IM qhs. Max: 6mg/day. Attorney Docket No. 26737.013
- o Elavil (Amitriptyline)-Initial (Outpatient) 75mg/day in divided doses or 50- lOOmg qhs. (Inpatient) lOOmg/day. Titrate: (Outpatient) Increase by 25-50mg qhs. (Inpatient) Increase to 200mg/day. Maint: 50-100mg qhs. Max:
- o Tofranil(Imipramine)-Depression Initial: (Inpatient) lOOmg/day in divided doses. Titrate: Increase to 200mg/day; up to 250-300mg/day after 2 weeks if needed. (Outpatient) 75mg/day. Titrate: Increase to 150mg/day. Maint: 50-
- Moderate Severity Initial: 75mg/day. Usual: 75-150mg/day. Severely 111: May increase up to 300mg/day.
- NMS neuromodulators
- Neuromodulators modulate sensory receptors.
- enteric neurons including mechanoreceptors, chemoreceptors, thermal receptors, and possibly nociceptors (pain receptors).
- Low- and high-threshold mechanoreceptors are also present.
- the low-threshold receptors process normal input from the gut.
- the high-threshold receptors only respond to higher pressures and distention and may be important in mediating pain in patients with irritable bowel syndrome (IBS).
- IBS irritable bowel syndrome
- Psychological factors are also important in the patient who develops IBS.
- Serotonin, cholecystokinin (CCK), neurokinins, and other chemicals stimulate chemoreceptors.
- Mechanoreceptors also contain chemoreceptors. As a result, serotonin and other chemoreceptor stimulators serve a paracrine function and modify the response of mechanoreceptors in the gut.
- modulate means the ability to regulate positively or negatively neuronal activity, preferably the activity of vagal nerve. These terms can be used to refer to an increase, decrease, masking, altering, overriding or restoring neuronal activity. Modulation, neuromodulation, or stimulation of neuronal activity affects psychological and/or psychiatric activity of a subject.
- Neuromodulator(s) or “stimulating”, or “potentiating” agents comprise medications, neurotransmitters and/or mimetics thereof, synthetic or natural peptides or hormones, neurotransmitters, cytokines and other intracellular and intercellular chemical signals and messengers, and the like.
- certain neurotransmitters, hormones, and other drugs are excitatory for some tissues, yet are inhibitory to other tissues.
- NM may be endogenous, natural or pharmaceutical agents that exert central nervous system (CNS) effects by interfering with one or more of neurotransmitter systems.
- CNS central nervous system
- the neuromodulator agent is referred to as an "excitatory” drug, this means that the drug is acting in an excitatory manner, although it may act in an inhibitory manner in other circumstances and/or locations.
- this drug is acting in an Attorney Docket No. 26737.013 inhibitory manner, although in other circumstances and/or locations, it may be an "excitatory” drug.
- stimulation of an area herein includes stimulation of cell bodies and axons in the area, especially receptors of said neuromodulators localized on afferent or efferent vagal nerve fibers.
- Combination of or "In combination with” a neuromodulator of the present invention refers to co-administration of the two agents. Co-administration may occur either concurrently or sequentially.
- neuromodulation of centrally active agents refers to pharmaceutical stimulation of vagal afferent and/or vagal efferent receptors by the administration of combinations of neuromodulators in the formulations provided below.
- the vagal neuromodulator of the present invention stimulates the vagal afferent and/or vaagal efferent receptors when administered as part of the pharmaceutical composition.
- the vagal neuromodulator comprises mechanoreceptor stimulators, chemoreceptor stimulators, a vagal efferent stimulator, a vagal afferent stimulator and a nociceptor stimulator. Neuromodulators may also be used in combination with electrical stimulation.
- Mechanoreceptors sense mechanical events in the mucosa, musculature, serosal surface, and mesentery. They supply both the enteric minibrain and the CNS with information on stretch-related tension and muscle length in the wall and on the movement of luminal contents as they brush the mucosal surface. Whether the neuronal cell bodies of intramuscular and mucosal mechanoreceptors belong to dorsal root ganglia, enteric ganglia, or both, is uncertain. Mechanoreceptor stimulator(s) of the present invention stimulate the mechanoreceptors and comprise mucomodulators, surfactants and vasoactive agents.
- Preferable mechanoreceptors stimulators comprise mucomodulators and vasoactive agents.
- Mucomodulators include N-acetyl-cysteine are thiols with a free-sulfhydryl group. They are assumed to break disulfide bonds between gel-forming mucins and thus reduce mucus viscosity. Mucokinetic agents are thiols with a blocked sulfhydryl group. Expectorants such as guaifenesin (GUA) increase mucus secretion. They may act as irritants to gastric vagal receptors, and recruit efferent parasympathetic reflexes that cause glandular exocytosis of a less viscous mucus mixture.
- GUI guaifenesin
- the pharmaceutical compositions may comprise mucomodulators that reduce the viscosity of the gastric mucosa, thereby accelerating the exposure of gastric Attorney Docket No. 26737.013 mucosa to chemoreceptor neuromodulator, such as vasoactive agent or neurotransmitter.
- mucomodulators are, for example, reducing agents such as N-acetyl cysteine, dithiothreitol, GUA, citric acid or mannitol.
- Suitable mucomodulators also comprise expectorants, including ambroxol, ammonium bicarbonate, ammonium carbonate, bromhexine, calcium iodide, carbocysteine, guaiacol, guaiacol benzoate, guaiacolcarbonate, guaiacol phosphate, guaifenesin, guaithylline, hydriodic acid, iodinated glycerol, potassium guaiacolsulfonate, potassium iodide, sodium citrate, sodium iodide, storax, terebene, terpin, and trifolium.
- expectorants including ambroxol, ammonium bicarbonate, ammonium carbonate, bromhexine, calcium iodide, carbocysteine, guaiacol, guaiacol benzoate, guaiacolcarbonate, guaiacol phosphate,
- Additional mechanoreceptor modulators are surfactants.
- Surfactants modulate surface tension providing hypotension wherein the surface tension is less than 10; or hypertension (the surface tension of about 10 to 70 dynes/cm).
- Surfactants in this invention may be selected from the following groups: PEGS (Polyethylene glycols); Sodium Lauryl Sulfates; Sorbitan esters; Polysorbates and Benzalkonium Chlorides.
- Polysorbate is selected from the group consisting of: Polysorbate 20 (polyoxethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxethylene (20) sorbitan monopalmitate), and Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate).
- Other surfactants can be selected from such groups as dispersing agents, solubilizing agents, emulsifying agents, thickening and spreading agents.
- Neuromodulators of the present invention also comprise chemoreceptor stimulators which will now be described.
- Chemoreceptor stimulators may be pH modulators, secretagouges, adrinomimetics, xanthines, cholecystokinins, and gastric agonists.
- Chemoreceptors are sensitive to biochemical neurotransmitters, hormones, ATP-receptor modulators and pH and generator information on nutrient concentration, osmolality and pH in the luminal contents.
- the actions of extracellular ATP are known to be mediated by specific cell surface receptors, P2-purinoceptors. These receptors are subdivided into two families: P2x and P2y.
- Chemoreceptor stimulators of the present invention are neurotransmitters, neuropeptides and other agents that stimulate chemoreceptors localized in afferent nerves.
- Chemoreceptor stimulators of the present invention comprise adrenomimetics (ADR), (e.g. adrenaline, noradrenaline, adrianol, phenylephrine/metazone (PHE), ephedrine, ethylephrine, etc.) and polypeptides (e.g. glucogon, angiotensin, octapressin, etc.) that are Attorney Docket No. 26737.013 most often used to affect arterial blood pressure by either stimulating alpha-adrenergic receptors or directly on the visceral muscles of the vascular wall.
- ADR adrenomimetics
- PHE phenylephrine/metazone
- polypeptides e.g. glucogon, angiotensin, octapressin, etc.
- PHE may be classified functionally as: "Vasoactive” or “Vasoconstricting” agent and/or "Hypertensive agent” (refers to any of a class of pharmacological agents which increase blood pressure), examples of appropriate hypertensive agents include, without limitation, phenylephrine and sodium chloride (NaCl).
- “Bronchodilators” include salbutamol (albuterol), phenylephrine, isoproterenol, and propranolol. Most adrenomimetics are vaso-active agents and selectively stimulate adrenoreceptors, causing arterial constriction and increase in systolic and diastolic pressure.
- PHE practically does not have any cardio stimulating effect.
- Other vasoactive agents such as Neuropeptide Y (NPY), vasodilators (Papaverin, PGE2; Drovatravin, phentolamine) and vasoconstrictors (PHE, NPY derivatives and analogs and Toxins) may potentially modulate vagal afferents as well.
- NPY Neuropeptide Y
- vasodilators Papaverin, PGE2; Drovatravin, phentolamine
- PHE vasoconstrictors
- PHE bran-Mezaton
- Adrenomimetics among them PHE, have some common shortcomings, as they increase tissue oxygen consumption, cause metabolic acidosis, may cause arrhythmia (especially during general anesthesia), and exert an exciting influence on the CNS.
- chemoreceptor stimulators is xanthines which include ephedrine, caffeine, theophylline and theobromine.
- the potency of these compounds has generally been ranked according to the ephedrine, caffeine, and theobromine series; however, they are not identical.
- Heptapeptide, octapeptide and nonapeptide analogs of CCK-8 act as CCK agonists for stimulating gallbladder contractions, arresting the secretion of gastric acid, and treating convulsions.
- Hepta- and octapeptides with sulfate ester groups which are useful for treating obesity.
- Pentagastrin (PG) ⁇ -alanyl-L-tryptophyl-L-methionyl-L-aspartyl-L-phenyl-alanyl amide; SEQ ID NO:2
- PG ⁇ -alanyl-L-tryptophyl-L-methionyl-L-aspartyl-L-phenyl-alanyl amide
- Additional chemoreceptor stimulators are pH modulators.
- Selected pH modulators are anti-acid drugs and parietal cells activators.
- the preferred anti-acid drugs are histamine antagonists.
- Proton pump inhibitors are Attorney Docket No. 26737.013 compounds that inhibit the activity of the H+/K+-adenosine triphosphatase (ATPase) proton pump in the gastric parietal cells. In its pro-drug form, PPI is non-ionized and, therefore, is capable of passing through the cellular membrane of the parietal cells.
- the non-ionized PPI moves into the acid-secreting portion of activated parietal cells, the secretory canaliculus.
- the PPI trapped in the canaliculus becomes protonated, and is thus converted into the active sulfenamide form that can form disulfide covalent bonds with cysteine residues in the alpha subunit of the proton pump, thereby irreversibly inhibiting the proton pump.
- 6,489,346; 6,645,988; and 6,699,885 include, for example, chocolate, sodium bicarbonate, calcium, peppermint oil, spearmint oil, coffee, tea and colas, caffeine, theophylline, theobromine and amino acids residues.
- all of these proposed parietal cell activators induce the release of endogenous gastrin that exerts both inhibitory and stimulatory effects on acid secretion by activating both CCK-A and CCK-B receptors.
- pH modulators of the present invention include for example: sodium or potassium bicarbonate, magnesium oxide, hydroxide or carbonate, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate, di-sodium carbonate, disodium hydrogen phosphate, a mixture of aluminum glycinate and a buffer, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. It is noted that while sodium bicarbonate dissolves easily in water, calcium carbonate is water-insoluble and is slowly soluble only in acidic environment.
- Chemoreceptor stimulators of the present invention also include the following pH modulators, which may be used alone or in combination: alumina, calcium carbonate, and sodium bicarbonate; alumina and magnesia; alumina, magnesia, calcium carbonate, and simethicone; alumina, magnesia, and magnesium carbonate; alumina, magnesia, magnesium carbonate, and simethicone; alumina, magnesia, and simethicone; alumina, magnesium alginate, and magnesium carbonate; alumina and magnesium carbonate; alumina, magnesium carbonate, and simethicone; alumina, magnesium carbonate, and sodium bicarbonate; alumina and magnesium trisilicate; alumina, magnesium trisilicate, and sodium bicarbonate; alumina and simethicone; alumina and sodium bicarbonate; aluminum carbonate, basic; aluminum carbonate, basic, and simethicone; aluminum hydroxide; calcium carbonate and magnesia; calcium carbonate, and
- gastric acid stimulant refers to any agent that is capable of stimulating gastric acid secretion via direct or indirect effect on parietal cells.
- Preferred gastric acid stimulants to be used in combination with PG or a PG analogue are small dicarboxylic and tricarboxylic acids such as succinic acid, succinic acid salts and esters, maleic acid, citric acid and fumaric acid, or the salt thereof.
- Additional secretagouges comprise etyron (S-ethylisothiouronium bromide), S-alkylisothiouronium derivatives, and S-ethylisothiouronium diethylphosphate, variously for treatment of high blood pressure, hyperoxia and acute hypotension, (e.g., shock conditions and chronic hypotension or oxygen poisoning).
- etyron S-ethylisothiouronium bromide
- S-alkylisothiouronium derivatives S-alkylisothiouronium derivatives
- S-ethylisothiouronium diethylphosphate variously for treatment of high blood pressure, hyperoxia and acute hypotension, (e.g., shock conditions and chronic hypotension or oxygen poisoning).
- Osmoreceptor stimulators are additional stimulants of chemoreceptors.
- osmolality is defined as hypotonic or hypertonic when diluted in gastric fluid is lower or higher respectively than isotonic composition.
- the pharmaceutical composition of the present invention stimulates the vagal gastric afferents when lower than 190 mOsm or higher than 270 mOsm.
- the isotonic nature of the composition when diluted in gastic fluid ( ⁇ 500mL) has 190 mOsm - to 270 mOsm.
- the composition further comprises:osmotic pressure of the composition between about 300 mOsm/kg to 880 mOsm/kg (NaCl equivalency of the solution is between about 0.9% NaCl to 3.0% NaCl). If hypo-osmotic, the composition further comprises: osmotic pressure of the compositionless than 300 mOsm/kg (NaCl equivalency of the solution is less than 0.9% NaCl).
- the osmoreceptor stimulator may be salts, sorbitol, sucrose; carbohydrates may comprise maltodextrins, glucose syrups, hydrolyzed starches, soluble starches, monosaccharides like glucose, fructose, galactose, mannose, etc. and disaccharides like sucrose and lactose. Mixtures may also be used, but the osmotic value of the final product should outside of isotonic range 250-380 mOsm/1.
- Neuromodulators further comprise vagal efferent stimulators.
- Neuromodulators cross the blood brain barrier and directly or indirectly affect the release of neurotransmitters, or exhibit excitatory or inhibitory action potential by themselves.
- Preferable vagal efferent neuromodulators in this invention are secretagouoges, such as: CCK, pilocarpine, succinic acid, secretin, TRH, sympatheticomimetics and analogues thereof.
- secretagouoges such as: CCK, pilocarpine, succinic acid, secretin, TRH, sympatheticomimetics and analogues thereof.
- sympatheticomimetics include theophylline, ephedrine, pseudoephedrine, and synephrine.
- GABA modulators are also suitable for use in the present invention as a vagal neuromodulator.
- GABA modulators include GVG, GHB, muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin), vigabatrin, tiagabine(Gabitril®), lamotrigine (Lamictal®), pregabalin, topiramate (Topamax), a prodrug thereof or a pharmaceutically acceptable salt of the GABA modulator or prodrug thereof.
- GABA modulators include GVG, GHB, muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin), vigabatrin, tiagabine(Gabitril®), lamotrigine (Lamictal®), pregabalin, topiramate (Topamax), a prodrug thereof or a pharmaceutically acceptable salt of the GABA modulator or prodrug thereof.
- GABA agonists
- vagal efferent modulators are CNS stimulants, such as caffeine or other botanical stimulating extracts.
- the neuromodulators of the present invention include nociceptor stimulators, which include opioids.
- opioids interact with the .mu. -opioid receptor, the .kappa. -opioid receptor, or both.
- opioids are opioid-receptor agonists, including morphine, loperamide and loperamide derivatives.
- Suitable opioids for use with the invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, nor-binaltorphimine, bremazocine, buprenorphine, butorphanol, clonitazene, codeine, CTOP, DAMGO, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodeine enol acetate, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprenorphine, DPDPE, eptazocine, ethoheptazine, ethylketocyclazocine, ethylmethylthiambutene, etonitazene, etorphine, fentanyl, hydrocodon
- opioids include (1) opium alkaloids, such as morphine (Kadian®, Avinza®), codeine, and thebaine; (2) semisynthetic opioid derivatives, such as Attorney Docket No. 26737.013 diamorphine (heroin), oxycodone (OxyContin®, Percodan®, Percocet®), hydrocodone, dihydrocodeine, hydromorphine, oxymorphone, and nicomo ⁇ hine; (3) synthetic opioids, such as (a) pheylheptylamines, including methadone and levo-alphacetylmethadol (LAAM), (b) phenylpiperidines, including pethidine (meperidine), fentanyl, alfentanil, sufentanil, remifentanil, ketobemidone, and carfentanyl, (c) diphenylpropylamine derivatives, such as propoxyphene, dextropropoxyphene, de
- Nociceptor stimulators of the present invention comprise analgesics, including aceclofenac, acetaminophen, acetaminosalol, acetanilide, acetylsalicylsalicylic acid, alclofenac, alminoprofen, aloxiprin, aluminum bis(acetylsalicylate), aminochlorthenoxazin, 2-amino-4-picoline, aminopropylon, aminopyrine, ammonium salicylate, amtohnetin guacil, antipyrine, antipyrine salicylate, antrafenine, apazone, aspirin, benorylate, benoxaprofen, benzpiperylon, benzydamine, bermoprofen, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bucetin, bufexamac, bumadizon, butacetin, calcium acetylsalicy
- Additional nociceptor stimulators are antitussive agents including alloclamide, amicibone, benproperine, benzonatate, bibenzonium bromide, bromoform, butamirate, butethamate, caramiphen ethanedisulfonate, carbetapentane, chlophedianol, clobutinol, cloperastine, codeine, codeine methyl bromide, codeine n-oxide, codeine phosphate, codeine sulfate, cyclexanone, dimethoxanate, dropropizine, drotebanol, eprazinone, ethyl dibunate, ethylmorphine, fominoben, guaiapate, hydrocodone, isoaminile, levopropoxyphene, morclofone, narceine, mormethadone, noscapine, oxeladin, oxolamine, p
- TRH thyrotropin-releasing hormone
- Ps4 and 5-HT thyrotropin-releasing hormone
- Brainstem TRH is believed to play a physiological role in the central vagal stimulation of gastric myenteric cholinergic neurons in response to several vagal dependent stimuli.
- neurosteroids such as dehydroepiandrosterone and its salts, that interact with the GABAA receptor complex.
- Cytokines such as TNF-a, interleukin (IL)-lbeta, IL-6 and IL-18 - were also reported to modulate vagal nerve-related activity.
- Narcotic and non-narcotic analgesics such as Metamizol (sodium N-(l,5- dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino-methylsulphonate;
- Narcotic anagetics such as morphine and other opioids, are known vagal afferent stimulators.
- Dopram, doxapram hydrochloride, or chlorobutanol are known to potentiate hexobarbital induced narcosis.
- Hypertensive agents such as clonidine, a hypertensive drug, and Pirbuterol, treatment for congestive heart failure.
- Excitatory neurotransmitter modulators i.e., norepinephrine, epinephrine, glutamate, acetylcholine, serotonin, dopamine, ginseng
- agonists thereof and agents that act to increase levels of an excitatory neurotransmitter(s) (i.e., edrophonium; Mestinon; trazodone; SSRIs (i.e., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine);
- SSRIs i.e., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine
- tricyclic antidepressants i.e., imipramine, amitriptyline, doxepin, desipramine, trimipramine and nortriptyline
- monoamine oxidase inhibitors i.e., phenelzine, tranylcypromine, isocarboxasid
- inhibitory neurotransmitters i.e., dopamine, glycine, and gamma-aminobutyric acid (GABA)
- GABA gamma-aminobutyric acid
- Dopamine acts as an excitatory neurotransmitter in some locations and circumstances, and as an inhibitory neurotransmitter in other locations and circumstances.
- Antagonists of inhibitory neurotransmitters i.e., bicuculline
- agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
- Excitatory neurotransmitter antagonists such as prazosin, and metoprolol
- agents that decrease levels of excitatory neurotransmitters may inhibit neural activity.
- Carbidopa/levodopa or dopamine agonists include ropinirole, pramipexole and cabergoline, bromocriptine mesylate (Parlodel®), pergolide mesylate (Permax®), pramipexole dihydrochloride (Mirapex®), and ropinirole hydrochloride (RequipTM).
- Anesthetics include enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, etomidate, ketamine, methohexital, propofol, and thiopental.
- Spasmolytics or antispasmodics include methocarbamol, guaifenesin, diazepam, dantrolene, phenyloin, tolterodine, oxybutynin, flavoxate, and emepronium.
- Antiemetics or antinauseants include, but are not limited to, promethazine (Phenergan®), metoclopramide (Reglan®), cyclizine (Merezine®), diphenhydramine (Benadryl®), meclizine (Antivert®, Bonine®), chlorpromazine (Thorazine®), droperidol (Inapsine®), hydroxyzine (Atarax®, Vistaril®), prochlorperazine (Compazine®), trimethobenzamide (Tigan®), cisapride; h2-receptor antagonists, such as nizatidine, ondansetron (Zofran®), corticosteriods, 5-Hydroxytryptamine antagonists, such as dolasetron (Anzemet®), granisetron (Kytril®), ondansetron (Zofran®), tropisetron; dopamine antagonists, such as domperidone (Mot
- “Pharmaceutically acceptable salts” includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
- pharmaceutically-acceptable cationic salts is intended to define but is not limited to suchsalts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N ,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l ,3 -propanediol) andprocaine.
- alkali metal salts e.g., sodium and potassium
- alkaline earth metal salts e.g., calcium and magnesium
- pharmaceutically-acceptable acid addition salts is intended to define, but is not limited to, such salts as hydrochloride, hydrobromide, sulfate, hydrogensulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methane sulfonate (mesylate) and p-toluenesulfonate (tosylate) salts .
- CNS active agents, neuromodulators or any other compounds are described herein, they also include pharmaceutically acceptable salts and prodrugs thereof.
- compositions of the present invention may also comprise other excipients and pharmaceuticals.
- Excipients for topical applications may comprise antibiotics, analgesics, antifungal agents, non-steroidal anti-inflammatory agents, anti-tussive agents, expectorants, glucocorticoids, vitamins, anti-oxidants, flavoring agents, sweetening agents, osmotic agents, moisturizers, emollients, buffering agents, solubilizing agents, penetration agents, protectants, surfactants, and propellants, thinking agents, parietal cells activators and other conventional systemic or topical pain relief therapies, analgesics, and pharmaceuticals.
- Anti-oxidants may include ascorbic acid, sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxy quinoline, and N-acetyl cysteine.
- Suitable flavoring agents include oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate.
- Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), and saccharine.
- Suitable preservatives include quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric Attorney Docket No. 26737.013 acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of para-hydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, and polymyxin.
- quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride
- mercurial agents such as phenylmercuric nitrate, phenyl
- “Therapeutically effective amount” is used herein with respect to a drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,”, administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those of ordinary skill in the art. “Therapeutically effective amount” also includes an amount that is effective for prophylaxis. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
- compositions and methods of the present invention modulate the vagal tone of the autonomic nervous system, by modulating CNS activity through activation/stimulation of afferent inputs from the gastric vagal nerves innervating the upper gastrointestinal tract.
- This invention therefore permits the conventionally accepted effective dose of the CNS active agent to be reduced to a lower, yet therapeutically effective amount, by combining administration of the CNS active agent with at least two vagal neuromodulators such that the neuromodulators are released when the CNS active agent is present in systemic circulation, typically reductions of about 20 to about 95% may be obtained using the pharmaceutical composition and method of the present invention.
- the reduction in CNS active agent is preferably at least about 40% and more preferably at least about 50%, or at least 60% of the conventionally accepted effective dose.
- the present invention offers the ability to affect neuronal function by delivering the neuromodulator to vagal nerve -afferent or -efferent receptors in order to treat the CNS- related disorder.
- the invention provides a novel pharmaceutical approach to modulate the vagal tone of the autonomic nervous system, wherein the CNS activity is modulated by activation of the afferent inputs from the gastric vagal nerves innervating the upper gastrointestinal tract.
- the invention is based on the novel concept of PV AN. This technology will allow a) the reduction of CNS drug side effects at current dosages, and b) Attorney Docket No. 26737.013 achieving comparable drug efficacy using markedly lower levels of CNS drugs, resulting in effective therapy as well as reduced drug side effects.
- the disclosed compositions promise to increase quality of life of patients by reducing the side- effects characteristic of CNS-based therapy, while promising equivalent efficacy.
- the disclosed compositions may consist of two pharmaceutical compartments: (i) the first containing a CNS centrally acting agent, for example, benzodiazepines; and (ii) vagal nerve afferents' neuromodulators (NM).
- the combination of the CNS active agent, along with at least two vagal neuromodulators, one of which is a mechanoreceptor allows the conventionally accepted effective dose to be used without interfering with efficacy, but with reduced side-effects associated with use of the CNS active agent, including sedation, somnolence, sleepiness, memory impairment, amnesia, impairment of cognitive and learning function, ataxia; impaired night sleep/day alertness, impaired memory, impaired concentration, impaired appetite, drowsiness, hypotension, fatigue, kinetic disorders, catalepsy, movement disorders, bowel irritation and impaired reaction, and such other side- effects as are discussed herein.
- the conventionally accepted effective dose ranges of CNS active agents may be reduced about 20-95%, preferably about 20 to about 40% and more preferably about 20 to about 50%.
- the term "in conjunction with” means that when the CNS and the neuromodulators are administered in separate dosage forms, there is at least some chronological overlap in their physiological activity.
- the CNS and NM can be administered simultaneously and/or sequentially. Sequential release would be used if it is required to synchronize the release of the CNS agent with the action of the neuromodulators by delaying the release of neuromodulator in the stomach (ex. by using polymeric coated neuromodulator particles).
- the pharmaceutical combinations may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and ideally once to twice a day.
- Synchronization means timing the release of the CNS active agent in relation to the release of the vagal neuromodulators so that there is some chronological overlap in physiological activity. Synchronization may be defined by reference to the Tmax of both the CNS active agent and the vagal neuromodulator(s) in relation to one another.
- the delay in the release of the NM is within 30 minutes, more preferably within about 20 minutes, and most preferably within about 10 minutes of the difference of the TmaxCNS and TmaxNM.
- the administration of the NM may be delayed in relation to the administration of the CNS active agent by at least 10 minutes, at 15 minutes, at least 20 minutes, at least 30 minutes, about 15 to about 30 minutes, or about 15 minutes.
- "about” typically means within one or two minutes, more preferably within a minute of the stated time.
- compositions and combinations of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection, or through an implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated with pharmaceutically acceptable carriers, vehicles, or diluents to provide dosage forms appropriate for each route of administration.
- parenteral e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection, or through an implant
- nasal, vaginal, rectal, sublingual, or topical routes of administration can be formulated with pharmaceutically acceptable carriers, vehicles, or diluents to provide dosage forms appropriate for each route of administration.
- compositions of the present invention are preferably formulated in a single oral dosage form containing all active ingredients.
- the compositions of the present invention may be formulated in either solid or liquid form. Embodiments of the form of the pharmaceutical composition of the present invention are set forth below:
- Hard gelatin capsules comprising morphine hydrochloride, pilocarpine, sorbitol and lactose monohydrate Attorney Docket No. 26737.013
- Orodispersible tablets morphine sulfate, carbachol and sorbitol,crosspovidone, mannitol, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, flavoring agent
- CNS active agent particles, and particles from at least two vagal neuromodulators are formulated in a single solid dosage form, such as multi-layered tablets, suspension tablets, effervescent tablets, powder, pellets, granules or capsules comprising multiple beads.
- the CNS active agent and neuromodulators are formulated in a single liquid dose, such as a suspension containing all active ingredients or dry suspension to be reconstituted prior to use.
- the CNS active agent particles and neuromodulator particles may be coated with either enteric pH-dependent release polymer or non-enteric, time-dependent release polymer in order to synchronize the local biological activity of the vagal neuromodulator (ex. GUA or/and PHE in the GI lumen) and the systemic effect of the CNS active agent on the CNS target.
- the neuromodulator particles are coated as well, in order to delay neuromodulator release.
- the CNS active agent particles are coated with a thick non-enteric layer so as the release of the CNS active agent is delayed between about 20 to 80 minutes (preferably, about 25-75 min/ or about 30-60 min), and the neuromodulator particles are coated with a thin non-enteric polymer layer so as to delay the release of the neuromodulators by about 5-60 min (preferably, about 8-45 min/or about 10-30 min).
- the preferred NM is GUA (guaifenesin, a mechanoreceptor stimulator), PHE (chemoreceptor stimulator), SA (succinic acid, vagal efferent stimulant), morphine (nociceptor stimulator) or a combination thereof.
- Non-enteric time-dependent release polymers include, for example, one or more polymers that swell in the stomach with the absorption of water from the gastric fluid, thereby increasing the size of the particles to create a thick coating layer.
- the time-dependent release coating generally possesses erosion and/or diffusion properties that are independent of the pH of the external aqueous medium.
- the active ingredient is slowly released from the particles by diffusion or following slow erosion of the particles in the stomach.
- the erosion properties of the polymer in the stomach resulting from the interaction of fluid with the surface of the dosage form are determined mainly by the polymer molecular weight and the drug/polymer ratio.
- the molecular weight of the polymer be in the range of -105 to -107 gram/mol.
- the CNS active agent or neuromodulator/polymer ratio be in the range of -2:3 to -9: 1, preferably -3:2 to 9: 1, and ideally -4: 1 to 9: 1.
- Suitable non-enteric time-dependent release coatings are for example: film- forming compounds such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non- enteric forms of the Eudragit brand polymers.
- film-forming materials may be used alone or in combination with each other or with the ones listed above.
- These other film forming materials generally include poly(vinylpyrrolidone), Zein, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinyl acetate), and ethyl cellulose, as well as other pharmaceutically acceptable hydrophilic and hydrophobic film-forming materials.
- These film-forming materials may be applied to the substrate cores using water as the vehicle or, alternatively, a solvent system. Hydro-alcoholic systems may also be employed to serve as a vehicle for film formation.
- Other materials suitable for making the time -dependent release coating of the invention include water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; Attorney Docket No.
- 26737.013 synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives, such one of the following group including hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose; other cellulose polymers such as sodium carboxymethylcellulose; and other materials known to those of ordinary skill in the art.
- lamina forming materials that can be used for this purpose include poly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend of gelatin and polyvinyl-pyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer.
- Delaying the release of vagal neuromodulators in the stomach may be achieved by the use of floating particles with lower density than gastric fluid.
- floating particles result from the release of carbon dioxide within ethylcellulose-coated sodium bicarbonate beads upon contact with gastric fluids. The release of carbon dioxide from the ethylcellulose-coated sodium bicarbonate core causes particle buoyancy, thereby delaying the release of vagal neuromodulators from the particles.
- vagal neuromodulator(s) it may be desirable to prolong the retention time of vagal neuromodulator(s) in the stomach by using forms that unfold rapidly within the stomach to a size that resists gastric emptying.
- Such systems retain their integrity for an extended period of time and are not emptied from the stomach until breakdown into small pieces occurs.
- a cross-shaped device made of erodible polymer and loaded with drug which is folded and inserted into a hard gelatin capsule has been used in other applications. Following oral administration, the gelatin shell disintegrates and the folded device opens out. With a size of 1.6-5 cm, it cannot pass from the stomach through the pylorus until the polymer is sufficiently eroded.
- Prolonging the retention time of vagal neuromodulators in the stomach may be achieved by using a hydrophilic erodible polymer system such as Polyethylene oxide (Polyox) and Hydroxypropyl-methylcellulose (HPMC) at a size convenient for administration to humans.
- a hydrophilic erodible polymer system such as Polyethylene oxide (Polyox) and Hydroxypropyl-methylcellulose (HPMC)
- the system Upon imbibing fluid, the system rapidly swells to a size that will encourage prolonged gastric retention, allowing sustained delivery of the contained drug to absorption Attorney Docket No. 26737.013 sites in the upper gastrointestinal tract. Since these systems are made of an erodible, hydrophilic polymer(s), they readily erode over a reasonable time and pass out of the stomach.
- the time period of expansion is such that this will not occur in the esophagus and, if the system passes into the intestine in a partially swollen state, the erodibility and elastic nature of the hydrated polymer will eliminate the chance of intestinal obstruction by the device.
- the pharmaceutical composition of the present invention is formulated as a single dosage form comprising multiple beads contained in hard or soft gelatin capsules.
- the capsules contain a mixed population of beads selected from: beads containing Immediate Release (IR) of CNS active agent, or beads comprised of the CNS active agent coated with time -dependent release polymer, beads comprised of calcium carbonate, beads comprised of ethylcellulose, sodium bicarbonate beads coated with vagal neuromodulator(s) and calcium carbonate and hydroxypropyl methylcellulose.
- IR Immediate Release
- beads comprised of the CNS active agent coated with time -dependent release polymer
- beads comprised of calcium carbonate
- the cellulose- based polymer in the composition permits the vagal neuromodulator beads to float, thus delaying the release of vagal neuromodulators from the beads.
- the gelatin capsules contain mixed population of beads selected from: beads comprised of IR-coated CNS active agent or beads comprised of CNS active agent coated with time -dependent release coating, beads comprising calcium carbonate and beads comprising alginate coated with vagal neuromodulator(s), calcium carbonate and hydroxypropyl methylcellulose.
- the gelatin capsules contain mixed population of beads selected from: beads comprised of IR-coated or non-coated CNS active agent, or beads comprised of CNS active agent coated with time-dependent release polymer, beads comprised of one type of vagal neuromodulators (such as GUA) and particles in the form of mini-tabs comprised of a second type of vagal neuromodulator (such as PHE), other excipients and hydroxypropyl methylcellulose.
- compositions of the present invention are formulated as press-coat or double -layered tablets comprised of IR CNS active agent in one layer, with a second layer comprised of the vagal neuromodulators PHE and GUA, and hydroxypropyl methylcellulose.
- the pharmaceutical composition of the present invention may be formulated as a two layer non-aqueous semi-solid packed into hard gelatin capsules in which the CNS active agent is solubilized in a lipid base (non-aqueous, quick release).
- the lipid base is liquid above room temperature but forms a semi-solid upon cooling, thus allowing its encapsulation.
- a lipid soluble mucomodulator such as GUA
- GUA lipid soluble mucomodulator
- PHE sorbitol
- combination of at least two thereof may be included as well.
- the single dosage form of the pharmaceutical is comprised of non-coated CNS active agent particles or immediate release (IR)-coated particles.
- IR coated, or non-coated CNS active agents in the duodenum and upper jejunum or ileum is faster than the absorption of coated CNS active agents. Therefore, the use of non-coated CNS active agents in the composition permits a more precise synchronization between the biological activity of vagal neuromodulators and the time in which the CNS active agent is active, without the need for delayed neuromodulator release.
- compositions of the present invention are formulated as double-layered tablets, press-coat tablets, effervescent tablets or suspension tablets and are comprised of NMs, such as osmoreceptor stimulator (potassium chloride), or/and pH modulator, or secretagogues (succinic acid, caffeine, or pilocarpine) non-coated, or IR -coated particles of CNS active agents and one or more excipients.
- NMs such as osmoreceptor stimulator (potassium chloride), or/and pH modulator, or secretagogues (succinic acid, caffeine, or pilocarpine) non-coated, or IR -coated particles of CNS active agents and one or more excipients.
- the active ingredients of the pharmaceutical composition of the present invention may be formulated in multiple oral dosage forms in which one or more mechanoreceptor stimulators are administered in a separate dosage form but in conjunction with the CNS active agent.
- the one or more mechanoreceptor stimulators may be formulated as an oral suspension or as a solid dosage form (such as capsules, tablets, suspension tablets, or effervescent tablets), while the CNS agent may be formulated in a separate solid dosage form, such as IR-coated beads or time -dependent release beads contained in capsules or tablets.
- the vagal neuromodulators in the separate dosage form are formulated as suspension tablet, effervescent tablet, chewable tablet or powder for suspension for compliance of neuropsychotic or addicted patients.
- tablets or capsules are also possible as a dosage form for the buffering agents.
- vagal neuromodulator(s) can be administered before, simultaneously, or after the CNS active agent. In sequential administration, there may be some substantial delay (e.g., minutes or even few hours) Attorney Docket No. 26737.013 between the administration of the vagal neuromodulator(s) and the CNS active agent, as long as the NMs exert a physiological effect when the CNS active agent becomes active.
- the CNS active agent administered is in a time -dependent release form, preferably before the vagal neuromodulator's administration in order to ensure that the CNS active agent (already absorbed into the blood from the intestines) will be available for modulation of vagal afferent or efferent receptors while the neuromodulators are active in the stomach.
- the active ingredients of the pharmaceutical composition may be incorporated within inert pharmaceutically acceptable beads.
- the CNS active agent and vagal neuromodulators may be mixed with additional ingredients prior to being coated onto the beads.
- Ingredients include binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures.
- Binders include, for example, celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties.
- Suitable surfactants include pharmaceutically acceptable non-ionic or ionic surfactants, such as sodium lauryl sulfate.
- the particles may be formed into a packed mass for ingestion by conventional techniques.
- Particles may be encapsulated as a "hard-filled capsule" using known encapsulating procedures and materials.
- the encapsulating material should be highly soluble in gastric fluid so that the particles are rapidly dispersed in the stomach after the capsule is ingested.
- the active ingredients of the present invention are packaged in compressed tablets.
- compressed tablet generally refers to a plain, uncoated tablet for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression. Such solid forms can be manufactured using methods well known in the art.
- Tablet forms can include, for example, one or more of lactose, mannitol, cornstarch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.
- the manufacturing processes may employ one, or a combination of, four established methods: (1) dry mixing; (2) direct compression; Attorney Docket No. 26737.013
- Such tablets may also comprise film coatings, which preferably dissolve upon oral ingestion or upon contact with diluents.
- the pharmaceutical compositions of the present invention are formulated in compressed forms, such as suspension tablets and effervescent tablets, such that an aqueous form of the pharmaceutical composition is produced upon reaction with water or other diluents upon oral administration.
- compressed forms such as suspension tablets and effervescent tablets
- an aqueous form of the pharmaceutical composition is produced upon reaction with water or other diluents upon oral administration.
- the present pharmaceutical composition tablets or other solid dosage forms disintegrate the pH modulator with minimal shaking or agitation.
- suspension tablets refers to compressed tablets which rapidly disintegrate after they are placed in water, and are readily dispersible to form a suspension containing a precise dosage of the CNS active agent, PHE and GUA.
- the suspension tablets may be comprised of CNS active agent at about 1/2 to 1/10 of the conventionally accepted effective dosage (for example less 4 mg of morphine), 10-200 mg PHE (Phenylephrine hydrochloride) and about 100-1200 mg of GUA (Guaifenesin).
- a disintegrant such as Croscarmellose sodium may be added to the formulation.
- the disintegrant may be blended in compressed tablet formulations either alone or in combination with microcrystalline cellulose (Avicel®). Microcrystalline cellulose, alone or co-processed with other ingredients, is well known for its ability to improve compressibility of difficult to compress tablet materials.
- the suspension tablet composition may, in addition to the ingredients described above, contain other ingredients often used in pharmaceutical tablets, including flavoring agents, sweetening agents, flow aids, lubricants or other common tablet adjuvants, as will be apparent to those skilled in the art.
- Other disintegrants such as crospividone and sodium starch glycolate may be employed, although croscarmellose sodium is preferred.
- the oral dosage forms described above may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art and will vary to provide the desired effect to the desired formulation.
- suitable quantities of other materials e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art and will vary to provide the desired effect to the desired formulation.
- the pharmaceutical composition of the present invention may comprise a kit.
- the kit comprises directions for the administration of the separate components.
- the kit form may be desirable when the separate components are preferably Attorney Docket No. 26737.013 administered in different dosage forms (e.g., oral and parenteral) or at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
- the neuromodulator or combination of neuromodulators may be provided in one dosage form and the CNS active agent may be provided in a separate dosage form.
- the neuromodulator composition is administered in conjunction with the CNS active agent so that there is at least some chronological overlap in their physiological activity.
- the CNS active agent and neuromodulator can be administered simultaneously and/or sequentially.
- a blister pack is well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs contain a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. Tablets or capsules are placed in individual packets formed in the plastic foil and sealed. Tablets or capsules can be removed from the blister pack by manually applying pressure on a desired individual packet to open it and remove the table or capsule.
- kit e.g., aid is a calendar printed on the card as follows "First Week, Monday, Tuesday, ... etc. * . Second Week, Monday, Tuesday, ! etc.).
- a “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
- a daily dose of a neuromodulator composition can consist of one tablet or capsule, while a daily dose of the CNS active agent can consist of several tablets or capsules and vice versa.
- the memory aid should reflect this.
- the pharmaceutical composition kit form reduces the side-effect of hypotension induce by the CNS active agents (i.e. opiate, barbiturate, benzodiazepine, sodium oxybate, atypical neuroleptics).
- the kit comprises: (a) CNS active agent in pharmaceutical compatible excipient; (b) hypertensive agent in pharmaceutical compatible excipient; and (c) instructions (e.g. an insert) describing timing/schedule of administration of (a) and (b) components.
- CNS active agent(s) are selected from the following groups: benzodiazepines, atypical neuroleptics, barbiturates, sodium oxybate, opiates, or combinations thereof;
- hypertensive agent is a selective alpha ADR receptor agonist Phenylephrine (vagal afferent neuromodulator);
- CNS central nervous system stimulants for example caffeine or dexedrine can be included.
- pseudoephedrine as a neuromodulator (NM)-agent may be added to the kit.
- PSE exhibits dual action: (i) not selective antagonist of Attorney Docket No. 26737.013
- kits including vagal afferent chemo- and mechano-receptors; and (ii) CNS stimulant.
- effective of CNS active agent in the kit may be at least two times lower than the same CNS active agent when used as a stand alone medication. Instructions describing the sequence of use of kit ingredients are also provided.
- Olanzapine from -0.25 to -100 mg, once/day; preferred, from -0.2 to -30 mg, once/day; ideally from -0.1 to -25 mg once/day;
- Clozapine from -12.5 to -900 mg daily; preferred, from -4 to - 450 mg daily;
- Risperidone from -0.25 to -16 mg daily; preferred from -0.2-8 mg daily;
- Sertindole from -0.0001 to -1.0 mg/kg daily; preferred 0.0001 to -0.5 mg/kg daily
- Quetiapine from -1.0 to -40 mg/kg given once daily or in divided doses; preferred 0.5 to -30 mg/kg daily
- Risperidone from -0.25 to -16 mg daily; preferred from -0.1-8 mg daily;
- Asenapine from -0.005 to -60 mg total per day, given as a single dose or 25 in divided doses; preferred from -0.0025-30 mg daily
- Carbamezepine from -200 to -1200 mg/day; preferably -100-400 mg/day;
- Valproic Acid from -250 to -2500 mg/day; preferably -100 -1000 mg/day;
- Lamotrigine from -50 to -600 mg/day in I to 2 doses; preferably -25 to -400 mg; most preferably -200 mg;
- Gabapentin from -300 to -3600 mg/day in 2 to 3 divided doses; preferably300 to -1800 mg/day; most preferably -900 mg/day;
- Tiagabine from -2 to -56 mg/day in 2 to 4 divided doses; preferably - 1 to -30 mg/day; most preferably -20 mg/day.
- Topiramate from -200 to -600 mg/day divided in 2 doses; most preferably 35 -400 mg/day.
- Kionopin from: 0.25 mg; to: 20mg preferably -0.1 to 10 mg
- Neurontin(Gabapentin) from: 100 mg; to: 2400 mg preferably ⁇ 50 to 1000 mg
- Carbatrol Capsules ER (Carbamazepine): from: 200 mg; to: 1200 preferably -100 to 600 mg
- Felbatol(Felbamate) from: 1200 mg;to: 3600 mg preferably -600 to 1200 mg
- Keppra(Levetiracetam) Minimum : 1000 mg; to : 3000 preferably -1000 to 3000 mg
- Tegretol(Carbamazepine) from: 200 mg; to: 1200 mg preferably -100 to 600 mg
- Topamax(Topiramate) from: 25 mg; to: 400 mg preferably -15 to 200 mg
- Zonegran from: 100 mg;to: 600 mg preferably -50 to 300 mg
- Zarontin Capsules(Ethosuximide) from: 250 mg;to: 1500 mg preferably -150 to 750 mg
- composition of the present invention also may be administered parenterally.
- Neuropeptides, hormones, such as CCK and secretin are preferable vagal neuromodulators for parenteral delivery in conjunction with CNS active agents.
- the pharmaceutical composition is formulated into a solution that can be administered intravenously in a concentrated hypertonic form or subcutaneously in a more dilute isotonic or, at most, slightly hypotonic form.
- the method of treatment varies with the condition of the patient, the critically ill one being given both the I.V. treatment with the solution of higher osmolality and the subcutaneous treatment with the more dilute isotonic solution at the same time in preference to either one alone, whereas, the less critical patient can be treated with either one and, under most circumstances, just the isotonic solution administered subcutaneously.
- the pharmaceutical composition comprises a bolus injection of a combination of CNS active agent(s) with a vagostimulator or another neuromodulator with one continuous fast injection, rather than a slow infusion of the drug.
- CNS active agent(s) can be Attorney Docket No. 26737.013 determined empirically and can be employed in pure form or, in pharmaceutically acceptable salt, ester, or prodrug form.
- compositions of the invention may be very useful in mitigating and/or preventing acute inflammatory response.
- the pharmaceutical compositions of the invention may be very useful in mitigating and/or preventing acute inflammatory response.
- the bulk of the sodium cation should come from sodium chloride.
- the bicarbonate ion in the form of sodium bicarbonate and the same amount of the chloride ion as sodium chloride, one falls within the upper limits of the 100-130 meq./L. of sodium ion concentration.
- bicarbonate ion concentration is approximately 50-200 meq./L., considerably more than 80 meq./L. of bicarbonate anionin the form of sodium bicarbonate can be used. Additional buffering action, therefore, can be achieved with potassium bicarbonate where up to twelve times the normal plasma potassium concentration level of about 5 meq./L. has been employed successfully.
- this hyperkalemic condition is unexpectedly alleviated by introducing even more potassium into the system. As was the case with the previously-mentioned ingredients, every little bit helps and there is, therefore, no minimum effective concentration although the preferred range is between approximately 15 and 60 meq./L.
- Glucose is an important ingredient, as well. In addition to nurturing weakened cells, glucose reacts with the cell components to enhance movement into the cells of excessive potassium ions already present in the blood, thus alleviating the hyperkalemic condition and replacing the potassium lost from the cells during diarrhea.
- the proper amount of glucose is about 5% to about 8% glucose, or approximately that which is required to supply the patient's metabolic energy needs.
- An upper limit of glucose concentration may be defined as something less than that required to exceed the desire osmolarity of the hypertonic I.V. solution and still leave room for the other necessary ingredients. Even with I.V. administration, the glucose concentration necessary to stay below the osmolarity limits in the hypertonic solution are such as to fall well below that at which the renal threshold is exceeded and further dehydration might take place.
- the I.V. solution is preferably hypertonic although it could be isotonic if it were not for certain practical considerations.
- An osmolarity of between approximately 500-1000 mosm./L. is the preferred range and good results have Attorney Docket No. 26737.013 been achieved on a limited basis with a hypertonic solution having an osmolarity of 1000 mosm./L. brought about by the addition of hydroxyl ions to the already basic solution.
- the osmolarity of the hypertonic solution for I.V. use might even be made higher without ill effect depending upon which of the ingredients had its relative concentration increased.
- the glucose concentration could probably be increased some more without ill effect.
- the osmolality of the I.V. solution should be kept compatible with that of the more dilute subcutaneous solution which must be isotonic or nearly so.
- the osmolarity of the hypertonic solution must be about 2 times that of the isotonic solution means about 600 mosm./L.
- the hypertonic solution has a high osmolality of up around 1000 mosm./L.
- One such composition that satisfies the hypertonic conditions by adding to CNS active agents follows ions: Potassium 23 meq./L;Bicarbonate 80 meq./L;Sodium 115 meq./L; Chloride 64 meq./L; Glucose 6.8%.
- Hard gelatin capsules may contain a mixed granules population of Phenylephrine tannate (PHE) and CNS active agent(s).
- PHE granules are in IR or delayed release formulation;
- CNS active agent(s) is formulated as time-dependent release coating (immediate or slow release).
- Granules may be packed into a hard gelatin capsule in an amount corresponding to 1 mg CNS active agent(s) and 30 mg PHE per capsule.
- the IR layer comprises:40 mg of time -dependent release coated (HPMC); CNS active agent(s) granules; Attorney Docket No.
- the delayed release layer comprises: 100 mg of granules 30 mg PHE; granules (HPMC coated); and diluent.
- a PHE solution is sprayed on inert beads in a fluid bed apparatus. After drying, the PHE beads are further coated with hydroxypropyl methylcellulose (HPMC) to form the final granules.
- HPMC hydroxypropyl methylcellulose
- the rate of PHE release is determined by the thickness and erosion rate of the HPMC layer. PHE is aimed to be released from the coated beads 10-20 min following administration.
- Examples of powder for oral suspension or effervescent (sache) formulation are comprised of vagal nerve afferent neuromodulators (PHE/GUA) and vagal nerve efferent neuromodulators (succinic acid-SA or/and derivative of SA/or and/or caffeine) granules mixed in the multi-components formulations.
- PHE/GUA/SA granules are coated with think HPMC layer IR.They are added to a glass of water, for example, just prior to administration of the CNS active agent(s) granules (IR).
- PHE/GUA Neuromodulators
- CNS active agent(s) granules mixed in the multi-components formulations.
- the double layer tablet formulation comprises PHE/GUA granules are coated with thin HPMC layer (delayed release- 15 min) and form the top layer.
- CNS active agent(s) granules immediate or slow release.
- Barbiturate and succinic acid liquid solution is prepared by dissolving succinic acid in hypertonic phosphate-buffered saline.
- a hypertonic saline solution for the dissolution of the barbiturate and succinic acid, a concentrated (20 times) solution of hypertonic phosphate buffered saline (PBS) is diluted to obtain a 1» solution.
- PBS solution is prepared by dissolving the following reagents in sufficient water to make 1,000 ml of solution: 160g sodium chloride; 4.0g potassium chloride; 23g sodium hydrogen phosphate,; 4.0g potassium dihydrogen phosphate; and, optionally, 0.4g of phenol red powder.
- the hypertonic PBS solution is then sterilized by autoclaving at 15 pounds of pressure for 15 minutes and is diluted with additional sterile water to a 1 times concentration prior to dissolution of the barbiturate and succinic acid.
- barbiturate and succinic acid are dissolved in 1 times hypertonic PBS at concentrations of 0.2 mg and 1 mg/ml, respectively, and the resulting solution (200 ml) is dispensed into sealable translucent plastic bags for use in intravenous administration of the compounds. These steps are performed under sterile conditions.
- Injectable CNS active agent formulations comprises:CNS active agent(s) 5-25%; CCK 5-25%; Surfactant polymer (as a mechanoreceptor stimulator-mucomodulator 0.1-50%; preservatives 0.05-0.25%; pH adjusting agent pH about 6 to about 7; and water for injection q.s.
- the pharmaceutical composition comprises respective amounts of olazepine and the neuromodulator composition to be delivered on a daily basis between ⁇ 1 mg to -160 mg olazepine and between ⁇ 1 to -1000 mg of the neuromodulator composition.
- the composition is administered to a patient for the treatment of schizophrenia on a once, twice, thrice, or four times per day basis.
- Controlled release delivery systems are designed to allow pharmacodynamic synchronization between CNS active agents and vagal neuromodulators without interfering with pharmacokinetic parameters (see Table 4 below) and metabolism of CNS active agents.
- the sequence of the CNS active agent andPhenylephrine, or other Neuromodulator(s) is delayed at least 15-30 minutes so that Phenylephrine is administered after the CNS active agent to address hypertension while reducing the conventionally accepted effective dose of the CNS active agent by at least twice.
- the insertion of guidance timing which would be measurable or a timer-signaling device is also possible.
- At least two dosage form compartments may be present in a dosage form unit.
- CNS active agents preferably will be incorporated in an immediate release compartment, but may also be incorporated in a sustained release compartment or enteric coated release (designed for immediate release in the intestine) compartment.
- Neuromodulator (NM) cocktails may be contained in the delayed layer compartments.
- the release of the (NM) contained in delayed-release (second) dosage form compartment initiated meaning of "form compartment initiated” not clear) at least one hour after the first CNS active agent contained dosage form initiates release, with the initiation of the release generally occurring no more than six hours after initiation of release of CNS active agent from the first dosage form.
- the first dosage form produces a Cmax for the CNS agent released from the immediate release compartment within approximately 0.2 to 6 hours after initiation of release, with the neuromodulators released from delayed dosage form in no more than approximately 0.5-4 hours after initiation of the release from the first dosage form.
- the first dosage form initiates release of NM agent(s) at a time later as compared to when the CNS active agents would be released from an immediate release dosage form.
- the first dosage form compartment would initiate release within 1 to four hours after administration of the product.
- the immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the CNS active agent, and Attorney Docket No. 26737.013 neuromodulator, such as PHE.
- This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
- the materials to be added to the CNS active agent for example, flunitrazepam, diazepam, clozapine or olanzapine, or other antidepressant, anti-psychotic or anxiolytic or other CNS active agent
- the materials to be added to the CNS active agent include microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc
- WAV 1.0 to 60%
- other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration.
- These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above.
- surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic sur
- the components in this composition are the same immediate release embodiment, but with additional polymers integrated into the composition or as coatings over the pellet or granule.
- Materials that can be used to obtain a delay in release suitable for this embodiment of the invention include polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose. These materials may be present in the preferable range of 0.5-25% (WAV) of this component.
- the components may be the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- the materials useful for this purpose include cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives, present in concentrations from about 4-20% (WAV).
- the pharmaceutical composition may be formulated by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. The product is then cooled and may be sieved or granulated and compressed using a suitable tablet press, such as a rotary tablet press.
- a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
- a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
- the product is then cooled and may be sieved or granulated and compressed using a suitable tablet press, such as a rotary tablet press.
- PSE pseudoephedrine 75% (WAV); Polyox 10% (WAV); Hydroxypropylcellulose 5% (WAV); and Croscarmellose sodium 10% (WAV)
- WAV Hydroxypropylcellulose 5%
- WAV Croscarmellose sodium 10%
- WAV Hydroxypropylcellulose 5%
- Croscarmellose sodium 10% 5%
- components in this composition are the same as the immediate release, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- Materials useful for this purpose include cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives, which may be present in concentrations from 4-20% (WAV).
- the components are the same as the immediate release embodiment (as above), but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- Materials useful for this purpose include ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons, which may be present in concentrations from 4-20% (WAV).
- the CNS active agent-NM cocktail pharmaceutical composition of the present invention may comprise of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.
- Phenylephrine is one neuromodulator of the present invention.PHE examples to achieve various delays of PHE described release (as provided by various coating procefures of PHE pellets) are described.
- composition of excipients for preparation of PHE-50 mg pellets provided below.
- composition of the aqueous AQOAT AS-LF aqueous coating dispersion applied to the PHE pellets is provided below:
- Pellet Formulation pellets prepared as in Example A
- Preparation Procedure of PHE 50 mg
- Delayed Pulse Release Such coating allows an -one hour delayed release rate (as tested by in vitro dissolution in USP gastric fluids test).
- composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the Anti-fungal pellets is provided below :
- Coat Anti-fungal pellets with AQOAT AS-HF film coating dispersion such that 30% coat weight gain is applied to the pellets.
- composition of the aqueous Eudragit.RTM. FS 30D dispersion applied to the PHE pellets(as described in Example A) is provided below:
- Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30%-60% coat weight gain to the pellets.
- composition of Anti -fungal Tablets Component Percentage:
- the fill weight should be adjusted to achieve the desired dose.
- Pellets are filled into hard gelatin capsules at a ratio of 33.4%:66.6%:CNS agent granules and PHE Pellets respectively.
- the components are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- Materials useful for this purpose include ethylcellulose, hydroxyl- propylmethylcellulose, hydroxypropylcellulose, hydroxyl-ethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons, which Attorney Docket No. 26737.013 may be present in concentrations from 4-20% (WAV).
- the CNS active agent-NM cocktail (including GUA) of the present invention may take in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.
- composition of excipients for preparation of GUA-500 mg pellets provided below.
- composition of the aqueous AQOAT AS-LF aqueous coating dispersion applied to the Phe pellets is provided below:
- Example-Pellet Formulation pellets prepared as above and Preparation Procedure of PHE (50 mg) with Delayed Pulse Release. Such coating allows about one hour delayed release rate (as tested by in vitro dissolution in USP gastric fluids test).
- composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the pellets is provided below:
- composition of the aqueous methacrylate copolymer Eudragit S (Rohm Pharma, Germany)FS 30D dispersion applied to the GUA pellets is provided below:
- composition of the aqueous Eudragit.RTM. FS 30D dispersion applied to the GUA pellets is provided below:
- composition of CNS agent-PVN Tablets Component Percentage:
- Pellets are filled into hard gelatin capsules at a ratio of 33.4%:66.6%:CNS agent granules and Phe pellets respectively.
- the capsule is filled with the three different pellets to achieve the desired dose.
- the method of administering the pharmaceutical composition of the present invention may be used to treat a variety of diseases, illnesses and conditions for which the CNS active agents of the present invention might be prescribed when used alone, or in combination with other therapies. Categories of these diseases, illnesses and conditions include depression; anxiety; psychotic, delusional, mood and personality disorders; memory disorders and dementia; phobias; sexual dysfunction; chemical dependencies to addictive CNS active agents, including alcohol; eating disorders; alcohol addition; Parkinson's diseases; endocrine disorders; vasospasm; gastrointestinal tract disorders; cancer; headache; osteoporosis or frailty associated with aging or obesity; and cardiovascular or heart related disease.
- composition of the present invention may aid in accelerating bone fracture repair; attenuating protein catabolic response after a major operation; reducing cachexia and protein loss due to chronic illness; accelerating wound healing and accelerating the recovery of burn patients or of patients having undergone major surgery.
- a method for reducing depending of an addictive CNS active agent comprises administering to a patient between about 20 to about 80 percent of the conventionally accepted effective dosage of the addictive CNS active agent; administering to the patient at least one mechanoreceptor stimulator and at least one chemoreceptor stimulator, the mechanoreceptor stimulator, the mechanoreceptor stimulator and the chemoreceptor stimulator being administered for synchronization of the Tmax of the addictive CNS active agent and the Tmax of the mechanoreceptor stimulator.
- the delay time in administration as a function of Tmax of the Attorney Docket No. 26737.013 mechanoreceptor stimulator (NM) and the CNS active agent are described in more detail above.
- the method for administering the pharmaceutical composition of the present invention comprises co-administering the CNS active agent and the mechanoreceptor stimulator, and the vagal neuromodulator sequentially or in time- released form thereby ameliorating CNS active agent side-effects without reducing the conventionally accepted effective dosage of the CNS active agent.
- the method comprises co-administering the CNS active agent and the mechanoreceptor stimulator at a level sufficient to maintain the pharmacokinetic effectiveness of the CNS active agent while reducing associated side-effects.
- Yet another method comprises the step of administering to a subject a therapeutically effective amount of CNS active agent-neuromodulator formulation of the present invention.
- the CNS active agent-neuromodulator formulation is an injectable.
- the CNS active agent-neuromodulator formulation is an aerosol formulation.
- the pharmaceutical composition of the invention does not require a high CNS active agent concentration that may lead to dose -dependent side-effects. Using lower CNS active agent dosages will allow patient recovery and reduced inpatient care.
- a general protocol for oral administration comprises IR formulation of CNS active agent followed by a combination of vagostimulators or other neuromodulator(s) in IR formulation (preferably as an effervescent formulation) with a delay of between administrating of CNS active agent benzodiazepine and neuromodulator cocktail at least 50% of a known Tmaxof CNS active agent benzodiazepine in blood in order to obtain optimal synchronization between onset of neuromodulation and availability of CNS active agent benzodiazepine in circulation and CNS target site.
- the methods of this invention also encompass treating the diseases or conditions described herein by the co-administration of two separate pharmaceutical compositions and by administrating to a patient single dosage form as described above.
- the methods and pharmaceutical compositions of the invention are directed to the treatment and prevention of stress conditions and nervous dysfunctions such as convulsions, seizure, muscle stiffness, Attorney Docket No. 26737.013 psychotic disorders, depression, anxiety-related disorders, substance addiction, memory impairment, neuro-gastroenterological disorders and pain.
- the present invention reduces or prevents the side-effects of depression, dizziness, drowsiness, lethargy, weakness in the extremities, difficulty in being mobile, and orthostatic hypotension and other blood pressure effects associated with therapeutic CNS acting agents without compromising the positive clinical effects of those same therapeutic agents.
- the present invention also decreases the risk of injury to patients and liability to healthcare personnel treating such patient populations.
- the present invention increases the opportunity for out-patient treatment settings, which in turn decreases overall healthcare costs.
- incidences of relapse are reduced or prevented.
- Soma Carisoprodol
- Pseudoephedine 60 mg
- Pseudoephedine 60 mg
- Pseudoephedine At 11 : 10 a.m. - 600 mg of Guaifenesin.
- a 40-year old healthy female volunteer was prescribed 250 mg Soma two times a day for reduction of lower back pain.
- the volunteer suffered from the sedative side-effect of Soma.lt was suggested to the volunteer that she try taking the Soma in conjunction with the synchronized vagal neuromodulation treatment of the present invention over two days but not before sleep time.
- Seroquel is primarily used to treat psychotic symptoms in doses of 400-700 mg daily, with side-effects of headache, dry mouth, as well as other side-effects. To establish that the administration with neurmodulators reduces the sedative side-effects of CNS active agents, a non-blind clinical trial with 5 volunteers was carried out using Seroquel. Attorney Docket No. 26737.013
- Dosage 400mg Seroquel; 60 mg Pseudoephedrine (PED- sinufed); 600 mg Guaifenesin (GUA- Mucinex) in the manner outlined below:
- Control Treatment At time t: 400mg Seroquel;
- Double Cocktail Treatment At time t: Seroquel + Pseudoephedrine (PSD);
- Double Cocktail Treatment At time t: Seroquel. At time t+30min: Guaifenesin (GUA);
- TCT Triple Cocktail Treatment
- PSD Pseudoephedrine
- GAA Guaifenesin
- TCT-ND Triple Cocktail Treatment, No Delay
- Results were tabulated following a brief interview, consisting of a number of simple questions . While more qualitative than quantitative, the results provide a good preliminary indication of the efficacy of the proposed formulations.
- TCT triple cocktail treatment
- the result of the study was that the triple cocktail treatment (TCT) had a better side-effects profile as measured by the level of sedation when compared to either the control treatment (CT), or the double cocktail treatments (DCT-PSE; DCT-GUA), or the No Delay Triple Cocktail (TCT-ND).
- Volunteer A a 34 year old healthy male (1.83 cm, 95 Kg), was prescribed lmg Lorazepam (BDR) by his family doctor for anxiety and anxiety related insomnia. Volunteer A took Lorazepam in conjunction with the neuromodulators to reduce Lorazepam's associated sedative side-effects. Volunteer A, who felt his anxiety peak particularly on weekends, agreed to take Lorazepam during the day together with the neuromodulators. When taking Lorazepam alone, Volunteer A reported that his anxiety was ameliorated, but he was severely sedated, sleeping over 3 hours in an afternoon. When taking Lorazepam together with pseudoephedrine, Volunteer A reported being as sedated as with Lorazepam alone, yet upon waking felt much less anxious than without treatment.
- BDR Lorazepam
- the study was a single blind trial in which a panel of 8 patients suffering from GAD were administered alprazolam (1 mg), pseudoephedrine (60 mg), and guaifenesin ER (600 mg). Subjects underwent an initial screening and then two weeks of testing with the medications of the study (see FIG. 7 for an illustration of the study scheme). Fourteen days prior to the first treatment session, subjects were screened with a standard medical/psychiatric history and physical exam (Screening Visit, Visit 1).
- Standard laboratory tests were performed at Screening Visit 1 including those of chemistry, hematology and urinalysis, urine test for drugs of abuse, HIV and hepatitis B and C serology tests, 12-lead resting electrocardiogram, and serum pregnancy test for females.
- Subjects were given a placebo medication that mimics the two neuromodulators for 7 days and underwent another series of tests at the end of this 7-day period (Visit 3).
- the subjects were asked to rate their sleepiness on the SSS two hours and four hours after each dose of alprazolam (data not shown). Thereafter, the subjects were given the active neuromodulators and told to start with them on the next day following ingestion of their regular alprazolam medication.
- the subjects took pseudoephedrine with alprazolam and Mucinex 15 minutes later (neuromodulators were given no more than twice a day and not Attorney Docket No. 26737.013 after 6 PM). Three hours after each dose, patients were asked to rate their sleepiness on the SSS.
- the research study was performed on four healthy volunteers, ages 25-41 years old and 60-75 kg. The study was carried out in two sessions with one week in between. During the study volunteers completed a test to measure sleepiness by Stanford Sleepiness Scale (SSS). This SSS test was done before doses of the compositions being evaluated and 2, 4 and 6 hours after such doses.
- SSS Stanford Sleepiness Scale
- 6 hour time point test SSS scores were 1, 3, 2.
- the fourth subject woke up for the 6 hour time point test and his SSS score was 3.
- the purpose of this study was to determine if the co-administration of pseudoephedrine and guaifenesin with lorazepam is effective in reducing the sedation commonly seen with the administration of lorazepam alone.
- the research study was performed on four healthy volunteers ages 25-41 years old and 60-75 kg. The study was carry out by two sessions with interval for one week between. During the study volunteers completed a set of a test to measure sleepiness by Stanford Sleepiness Scale (SSS). This test was done before doses of study drug and 2, 4 and 6 hours after doses of study drug.
- SSS Stanford Sleepiness Scale
- the total sleep time for each subject during first session was 3-3.5 hours for 2 patients and about 2 hours for one patient and about 1 hour for one patient.
- second session Liazepam administrated with neuromodulators
- total sleep time for one subject was hour and half, 30 minutes for two subjects and one subject did not slept at all.
- Cognitive battery tests were also conducted on the subjects treated with lorazepam by CNS Vital Signs Inc.. These tests are based on venerable neuropsychology tests that have been in the literature for years (e.g. Gualtieri TC & Johnson LG. Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Archives of Clinical Neuropschology 2006; 21 :623-643.), allowing for greater ease in interpretation and integration.
- the cognitive battery measures the speed and accuracy of six clinically relevant mental functions or clinical domains that are indicators of the health and integrity of the brain's higher function: Processing Speed, Executive Function, Psychomotor Speed, Reaction Time, Complex Attention, and Cognitive Flexibility. The subtest are:
- Finger tapping test Measures motor speed and fine motor control. There are three rounds of tapping with each hand. Low scores indicate motor slowing.
- SDC Digit Coding
- Stroop test Measures processing speed, cognitive flexibility, and inhibition/disinhibition. Prolonged reaction times indicate cognitive slowing or impairment. Errors may be due to impulsive responding, misperception or confusion. Reading disabilities may be apparent in this test. The ST generates simple and complex reaction times.
- Shifting Attention test measures executive control and set shifting. Subjects have to adjust their responses to randomly changing rules. The best scores have a high number of correct responses, few errors, and a short reaction time. Normal subjects may be slow but accurate or fast but not so accurate.
- CPT Continuous Performance Test
- the domain scores are presented as "Subject Scores" which are computed from raw score calculations using the data values of individual subtests and are simply the number Attorney Docket No. 26737.013 of correct responses, incorrect responses and reaction times. Stroop Test, CPT, and SAT contribute to the Complex Attention domain. All three are tests of attention.
- a score of 0 in the complex attention domain represents "above average” performance (e.g. no errors) while a score of 50 represents “below average” performance (e.g. many errors).
- Complex attention evaluates the subject's ability to maintain focus, track information over brief or lengthy periods of time and to perform mental tasks quickly and accurately.
- subjects were treated with lorazepam combined with PSE and GUA, they exhibited a normal performance in the complex attention domain at 4 and 6 h post-dose, similar to that of the baseline pre-dose.
- subjects were treated with lorazepam combined with placebo they showed an increase of 200% in errors at 4 and even 6 h post- dose compared to baseline pre-dose.
- the improvement in complex attention following combined treatment of lorazepam with NMs versus placebo suggests that NMs are beneficial for prevention of benzodiazepine-induced neurocognitive malfunction.
- the purpose of the study was to determine the efficacy of Pseudoephedrine (PED) and Guaifenesin (GUA) given in conjunction with 1-1.5 mg Lorazepam in reducing Lorazepam's sedative side-effects.
- PED Pseudoephedrine
- GUI Guaifenesin
- the study design has: Non-blinded, cross-over efficacy study (volunteers 2, 3, 4); and Single blinded cross-over efficacy study (volunteers 1 & 5).
- Control Treatment At time t: 0 mg (no. 2,4, & 5) /1.5 (no. 1 & 3) Lorazepam
- Double Cocktail Treatment (DCT-PSE): At time t: Lorazepam + Pseudoephedrine (PSD)
- Double Cocktail Treatment At time t: Lorazepam; at time t+ 30min: Guaifenesin (GUA-Mucinex)
- TCT Triple Cocktail Treatment
- Results were tabulated following a brief interview, consisting of a number of simple questions. While more qualitative than quantitative, the results provide a good preliminary indication of the efficacy of the proposed formulations.
- the results indicate that: Compared to the control treatment (CT), the triple cocktail treatment (TCT) showed comparable efficacy in terms of stress and anxiety reduction (Q 3, 4, 5). Compared to the control treatment (CT), the PSE double cocktail treatment (DCT-PSE) exhibited reduced efficacy in terms of stress and anxiety reduction (Q 3, 4, 5).
- the GUA double cocktail treatment (DCT-GUA) and the undelayed triple cocktail treatment (TCT-ND) exhibited comparable efficacy to the control treatment in terms of stress and anxiety reduction.
- the triple cocktail treatment had a better side-effects profile as measured by the level of sedation Attorney Docket No. 26737.013
- PSE as a chemoreceptor stimulator and GUA were used to reduce the sedative side-effects of Lorazepam, a commonly used anxyolytic agent with sedative properties, Quetiapine (Seroquel) an atypical antipsychotic commonly prescribed for the treatment of schizophrenia and bi-polar disorder, and SOMA a muscle relaxant commonly used for the treatment of acute muscle pains.
- N 6
- N 6
- Each study had a number of arms: 1. drug alone, 2. drug with NM1 (PSE), 3. drug with NM2 (GUA), 4. drug with both NM's, taken without synchronization, and finally the experimental arm, and 5. drug with both NM's synchronized with the t-max of the drug.
- the combined CNS active agent comprising both chemoreceptor stimulator (PSE) and mechanoreceptor stimulator (GUA) was effective in reduction of the sedation outcome without disturbing anti-stress action of the drugs.
- delayed administration of GUA (at least for 10-30 minutes, preferably 15-20 minutes) was significant to synchronize between PK and PD of CNS active agent and neuromodulators .
- Clozaril The benzodiazepine-based atypical antipsychotic, Clozaril (clozapine, a dibenzodiazepine) is the most potent atypical neuroleptic agent currently available. Clozapine is the only atypical anti-psychotic approved by the FDA for the treatment of resistant schizophrenia disorders. Due to its severe side effect profile, much of this highly potent drug's market share remains unexploited. Reformulated clozapine with a superior safety and side effect profile may capture a significant share of the schizophrenia market. In fact, a recent study has indicated that schizophrenia associated mortality rates are consistently lower among patients treated with clozapine as compared to patients treated with second generation anti-psychotics such as Zyprexa and Seroquel. (See, e.g., Tiihonen et al., The Lancet 374(9690):620-627 (2009); and Dunner, et al, J Clin Psychiatry. 67(5):688-95 (2006))
- MK-801 (dizocilpine) is a non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor and is used in research to create animal models of schizophrenia.
- MK801 was successful in modeling both the positive and negative symptoms of schizophrenia (Rung et al., Prog. Neuropsychopharmacol. Biol. Psychiatry 29(5): 827-32 (2005)).
- Ataxia levels were used as a measurement of the antipsychotic effect of CLZ in conjunction with GUA and PSE (see FIG. 9A).
- the conventional effective dose of CLZ (known from the scientific literature) that completely prevents the development of MK- toxicity was tested in parallel with the sedation-inducing effect of CLZ.
- the anticonvulsive effects of the drug diazepam (DZP) in parallel with the diazepam- induced sedation-side effects were studied in the animal model of korazol (corazolum)- induced seizures.
- the korazol model used is also relevant for epilepsy and anxiety.
- Pentylenetetrazol has been used experimentally to study the seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. See, e.g., Squires et al, Life Sci. 35(14): 1439-1444 (1984).
- Pentylenetetrazol is also a prototypical anxiogenic drug and has been extensively utilized in animal models of anxiety. See Jung et al., Neurosci Biobehav Rev 26(4): 429-39 (2002). Attorney Docket No. 26737.013
- vagal afferent mechanism of action for reducing locomotor activity side effects was shown by local inhibition of vagal afferent neuronal potentials by intragastric administration of lidocaine. This eliminated the effect of the neuromodulators, PSE and GUA. In addition, the synergistic effects of PSE and GUA were evaluated.As shown in Table 16, a synergistic effect was observed in the animal model of epilepsy and anxiety when the antispasmodic, diazepam, was co-administered with pseudoephedrine and guaifenesin.
- the Porsolt forced swimming test is a commonly used test to measure the effectiveness of antidepressants (see Petit-Demouliere et al, Psychopharmacology (Berl) 177(3): 245-255 (2005)). It is a behavioural despair test centered around a rodent's response to the threat of drowning, and its result has been interpreted as measuring susceptibility to negative mood (Porsolt et al, Archives Internationales de Pharmacodynamic et de Therapie 229(2):327-336 (1977)).
- the cataleptic effect was induced by lmg/kg haloperidol (time of rat immobilization on an inclined grid reduced to under 40 seconds).
- the phenylephrine and guaifenesin (PVAN) mediated attenuation of major side effects of typical antipsychotics (e.g., neuroleptics) was investigated with haloperidol.
- haloperidol Various side effects accompany treatment with haloperidol.
- typical antipsychotic agents such as haloperidol and chlorpromazine
- EPS extrapyramidal side effects
- Haloperidol may cause akathisia, an inability to sit still or remain motionless.
- haloperidol may cause catalepsy, a side effect characterized by fixity of posture.
- Drug -induced catalepsy i.e., the impairment of movement initiation
- rodents is an animal model of EPS and is mainly caused by blockade of the Attorney Docket No. 26737.013 dopamine D2 receptor (D2-R) (See Crocker and Hemsley Prog. Neuropsychopharmacol. Biol. Psychiatry 25:573-590 (2001); and Wadenberg et al. Neuropsychopharmacology 25:633-641 (2001)).
- haloperidol and its compositions to prevent psychosis at a conventionally effective dose was measured as a marker of haloperidol efficacy.
- Antipsychotic action of the substances was evaluated by a decrease in the MK-801 -induced ataxia score in the schizophrenia model in rats compared to the control (see FIG. 12A).
- Two glaucoma patients tread by medical cannabis prescribed to reduce glaucoma symptoms.
- patients suffer from temporary loss of mental acuity, lowered reaction time, poor coordination of movement.
- patient B suffers from anxiety and increased heartbeat.
- PVN 60 mg pseudoephedrine and 600 mg guaifenesin.
- Patient B heartbeat was normal and no anxiety symptoms appeared. There was no evidence of described or any other negative side effects neither after short nor long time after co-administration of cannabis and PVN.
- Cannabinoids are found to have particular application as neuroprotectants in stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and dementia. Compared with THC, cannabinoids are not psychoactive in healthy individuals. Cannabidiol (“CBD”) is one of at least 85 cannabinoids found in cannabis. It is a major constituent of the plant, second to THC, and represents up to 40% in its extracts considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder, schizophrenia, nausea, convulsion and inflammation, as well as inhibiting cancer cell growth.
- CBD Cannabidiol
- Nonpsychoactive cannabinoids such as cannabidoil
- cannabidoil is particularly advantageous to use as neuroprotectants and antipsychotic agents because they avoid toxicity that is encountered with psychoactive cannabinoids.
- CNS-related side effects such as sedation were reported in seven clinical trials of CBD in healthy volunteers as reviewed in http://www.mdpi.eom/1424-8247/5/5/529.
- PVAN vagal afferent neuromodulation
- Levodopa is the most effective anti -Parkinsonian agent permitted in the clinic for the treatment of Parkinson's disease. Levodopa significantly enhances dopamine synthesis and inhibits the degeneration of dopaminergic neurons in the striatum. The combined mechanism of anti-Parkinsonian action allows levodopa to equally and effectively address both extrapyramidal disorders (catalepsy, rigidity, tremor) and motor deficits (oligokinesia) in patients with Parkinson's, as well as in animal models of Parkinson's disease. Consequently, levodopa is a standard of anti-Parkinsonian action, which is used to compare antiparkinsonian effects of new drugs. However, a serious drawback of long-term use of levodopa is the development of severe dyskinesia in patients with Parkinson's due to the excitatory action of the compound on the central nervous system.
- Levodopa at 20 mg/kg has not sufficiently reliable nonspecific neuroprotective activity as it reduces the lethality from 10% to 0%, but it only slightly reduced the weight loss in rats compared to the control on day 19 of the experiment.
- Table 21 Average antiparkinsonian and neuroprotective activity of the compounds in the rotenone induced model of Parkinson's disease in rats from 5th to 19th day of the experiment.
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US10624936B2 (en) | 2017-09-26 | 2020-04-21 | Cynthia Denapoli | Method of reducing stress and anxiety in equines |
WO2023044086A1 (en) * | 2021-09-20 | 2023-03-23 | Rutgers, The State University Of New Jersey | Pharmaceutical compositions for the treatment of cancers |
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