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WO2025037252A1 - Compositions et méthodes pour le traitement de la douleur chronique et de la dépression - Google Patents

Compositions et méthodes pour le traitement de la douleur chronique et de la dépression Download PDF

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WO2025037252A1
WO2025037252A1 PCT/IB2024/057892 IB2024057892W WO2025037252A1 WO 2025037252 A1 WO2025037252 A1 WO 2025037252A1 IB 2024057892 W IB2024057892 W IB 2024057892W WO 2025037252 A1 WO2025037252 A1 WO 2025037252A1
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ketamine
naoh
composition
depression
tas2r
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Daniel C. Javitt
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • composition that includes an N-methyl-D-aspartate receptor (NMDAR) antagonist and a TAS2R receptor functional agonist for treating neuropathic pain and depression.
  • NMDAR N-methyl-D-aspartate receptor
  • TAS2R receptor functional agonist for treating neuropathic pain and depression.
  • Acute pain may be considered a normal sensation triggered in the nervous system that serves to alert the individual to possible injury.
  • chronic (neuropathic) pain is a persistent discomfort in which pain signals persist for prolonged periods of time (e.g., weeks, months, or years).
  • Neuropathic pain may be initiated by any of a number of instigating events, including trauma, infection, nerve injury or other physical events.
  • neuropathic pain can occur even in the absence of an inciting event.
  • Chronic (neuropathic) pain is also highly co-morbid with depression and may be both a cause and consequence. Both acute and persistent neuropathic pain are major public health problems that are associated with reduced quality of life, neuropsychiatric disorders such as depression, and increased opioid abuse. Current treatments for both acute and neuropathic pain are only partially effective.
  • Both acute and neuropathic pain may be modeled in rodents using the formalin test, in which formalin is injected into the hind paw of a rodent and the amount of subsequent licking behavior is used as an index of pain response.
  • TRPA1 transient receptor potential ankyrin 1
  • NMDAR N-methyl-D-aspartate receptor
  • ketamine has been shown to block only the acute stages of formalin-induced pain following systemic administration, whereas it selectively blocks the late phase of the response following intrathecal administration (e.g. Bulutcu et al., Life Sci. 71:841- 53, 2002).
  • Other NMDAR antagonists that may have a ketamine-like effect include dextromethorphan, D-methadone, phencyclidine, S-ketamine and R-ketamine.
  • NMDAR Protein kinase C
  • Ketamine has also been proposed as a treatment for chronic pain.
  • findings have been mixed, and ketamine is not currently approved by the FDA for this purpose.
  • compositions that can treat chronic pain, including chronic pain related to or resulting from neuropsychiatric conditions such as depression.
  • Described herein is a pharmaceutical formulation that includes ketamine, including racemic ketamine and its enantiomers S-ketamine and R-ketamine, and a bitter taste receptor (TAS2R) response mediating agent, such as NaOH and denatonium, wherein the ketamine is provided at a concentration of between 100 pM and 100 mM, inclusive, and wherein the molar ratio of ketamine to TAS2R response mediating agent is between 10:1 and 1:5. These ratios may also be expressed as molar ratios of NaOH:ketamine or denatonium:ketamine.
  • TAS2R bitter taste receptor
  • the TAS2R response mediating agent is NaOH, and the molar ratio of ketamine to NaOH is 2:1.
  • the TAS2R response mediating agent is denatonium, and the molar ratio of ketamine to denatonium is 1:5.
  • the described formulation includes 100 pM ketamine and 0.5 mM denatonium.
  • the formulation is formulated for parenteral administration, such as for subcutaneous, intramuscular, intravenous, intraarticular, intraperitoneal, or intrathecal administration.
  • parenteral administration such as for subcutaneous, intramuscular, intravenous, intraarticular, intraperitoneal, or intrathecal administration.
  • methods of treatment which are inclusive of uses of the described composition for treatment, of neuropathic (chronic) pain and/or depression associated with or developing from the chronic pain.
  • the methods of treatment of chronic pain and/or depression include administering to a subject in need thereof, an effective amount of any one of the described pharmaceutical formulations, thereby treating the chronic pain or chronic pain associated with depression.
  • the formulation is administered parenterally, such as subcutaneously, intramuscularly, intravenously, intraarticularly, intraperitoneally, or intrathecally.
  • the formulation is administered as a single bolus. In other particular embodiments, the formulation is administered as a gradual infusion over a series of minutes or even hours.
  • the depression is major depression. In other embodiments, the depression is bipolar depression.
  • the present invention will be effective not only in treatment of neuropathic pain, but also depressive disorders specifically, and neuropsychiatric disorders more generally.
  • Fig. 1 shows the effects of increasing concentrations of ketamine or ketamine plus NaOH on the acute (top panel) or chronic (bottom panel) pain response. As indicated, NaOH was provided at an equimolar concentration as ketamine.
  • Fig. 2 shows a graphical analysis to confirm the optimal dose range of the effect of equimolar ketamine: NaOH combination on the delayed pain response.
  • Fig. 3 shows the effect of different ratios of Ketamine (Ket):NaOH ratios ⁇ s.e.m. on delayed paw lick time. * p ⁇ .05 vs. 10:1 ratio.
  • Fig. 4 shows the increase in acute pain sensitivity following spinal ligation (SNL) surgery in rodents. Animals before (Pre- OP) and after (Post-OP) surgery were tested. In all experimental conditions examined (saline, ketamine, 2:1 ketamine:NaOH), Post-OP animals demonstrated the expected induced increased chronic pain sensitivity as reflected in a significantly reduced paw withdrawal threshold. **p ⁇ 0.05, compared to sham group.
  • Fig. 5 compares the results of SNL animals in the forced swim test. The same test groups as In Fig. 4 are shown. Immobility, climbing, and swimming are shown. Decreased immobility and increased swimming are indicative of an antidepressant effect. *p ⁇ 0.05 compared to Sham-Saline; #p ⁇ 0.05 compared to SNL-Saline. DETAILED DESCRIPTION
  • compositions means “includes.”
  • consist essentially of” or “consisting essentially of” indicates that the active ingredient or step of the described composition or method includes only the expressly recited ingredient or step. It is to be understood that compositions that "comprise” a given ingredient can also in other embodiments “consist essentially of” that ingredient. Similarly, methods that "comprise” a given set of steps can also in other embodiments “consist essentially of” the expressly indicated set of steps.
  • the abbreviation, "e.g.,” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.,” is synonymous with the term “for example.”
  • Administration The introduction of a composition into a subject by a chosen route.
  • Administration of an active compound or composition, including pharmaceutical formulations can be by any route known to one of skill in the art for providing the composition to a patient.
  • Local administration of the described compositions includes direct administration to a target area. Examples of local administration also include, but are not limited to, topical administration, subcutaneous administration, intramuscular administration, intrathecal administration.
  • local administration includes routes of administration typically used for systemic administration, for example by directing intravascular administration to the arterial supply for a particular organ.
  • Systemic administration includes any route of administration designed to distribute an active compound or composition widely throughout the body via the circulatory system, including typical parenteral routes of administration.
  • systemic administration includes, but is not limited to intraarterial and intravenous administration.
  • Systemic administration also includes, but is not limited to, topical administration, subcutaneous administration, intramuscular administration, or administration by inhalation, when such administration is directed at absorption and distribution throughout the body by the circulatory system.
  • Animal Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds.
  • mammal includes both human and non-human mammals.
  • subject or patient includes both human and veterinary subjects or patients, who are in need of treatment for a particular condition, such as chronic pain and/or chronic pain associated with depression.
  • Effective amount of a compound, therapeutically effective amount of a compound A quantity of compound sufficient to achieve a desired effect in a subject being treated.
  • An effective amount of a compound can be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount of the compound will be dependent on the compound applied, the subject being treated, and particularly factors such as subject weight and metabolism, the severity and type of the affliction, and the manner of administration of the compound. It will be understood that the pharmaceutical formulations described herein are provided to patients in need of treatment at therapeutically effective amounts.
  • an "effective amount" of one component of the combination is the amount of that compound that is effective to provide the desired effect when used in combination with the other components of the combination.
  • Injectable composition A pharmaceutically acceptable fluid composition comprising at least one active ingredient, although the compositions described herein comprise more than one active ingredient (i.e., and NMDAR antagonist and a TAS2R response mediating agent).
  • the active ingredients are usually dissolved or suspended in a physiologically acceptable carrier, and the composition can additionally comprise minor amounts of one or more non-toxic auxiliary substances, such as emulsifying agents, preservatives, pH buffering agents and the like.
  • compositions and salts are conventional. Remington (The Science and Practice of Pharmacology, 22nd Edition (2012)), describes compositions and formulations suitable for pharmaceutical delivery of the compounds described herein. In general, the nature of the carrier and/or salt will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like.
  • Pharmaceutical agent A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject.
  • pharmaceutical composition is understood to be synonymous with “pharmaceutical formulation.”
  • Treating a disease refers to a therapeutic intervention that ameliorates or reduces a sign or symptom of a disease or pathological condition after it has begun to develop, such as chronic pain.
  • N-methyl-D-aspartate receptor (NMDAR) antagonists have previously been implicated in the maintenance of neuropathic pain. However, differences in the type of analgesia provided were observed to be dependent on the mode of administration. Although intraperitoneal administration of the NMDAR antagonist ketamine selectively blocked the acute stages of formalin-induced pain following systemic administration, it was observed to block the late (chronic) phase of the response following only intrathecal administration (e.g. Bulutcu et al., Life Sci. 71:841-53, 2002).
  • Ketamine produces its molecular effects by blocking Ca 2+ flow through NMDAR.
  • compounds that regulate intracellular Ca levels through bitter taste receptors (TAS2R) can act synergistically with ketamine or other NMDAR antagonists for treatment of chronic pain.
  • compositions, and specifically pharmaceutical formulations that include a combination of an NMDAR antagonist and a TAS2R response mediating agent, which can treat chronic pain and chronic pain associated with depression.
  • NMDAR antagonists for use in the described composition include, but are not limited to ketamine, and NMDAR antagonist compounds having ketamine-like activity. Particular embodiments of such compounds include ketamine in its racemic form, its enantiomers S-ketamine and R-ketamine, dextromethorphan, and D-methadone.
  • Ketamine is typically formulated as Ketamine HCI (CAS Number 1867-66-9), and is marketed as a general anesthetic under the trade name Ketalar.
  • the ketamine referred to in the examples provided herein is Ketamine HCI, it will be appreciated that Ketamine (CAS Number 6740-88-1) as well as other pharmaceutical forms of the compound, are encompassed by this disclosure.
  • Ketamine also termed R,S ketamine
  • Ketamine is a racemic mixture of S- and R-ketamine. Ketamine as referred to in this application consists of the racemic mixture unless otherwise specified. Ketamine, S-ketamine, and R-ketamine are all reported to have anti-depressant effects either in humans or animal models.
  • Ketamine may be administered orally, intranasally, or parenterally, and the described combinations can be formulated for such routes of administration.
  • Parenteral routes include without limitation intravenous, intramuscular, subdermal, intrathecal, or subdural.
  • Ketamine is currently available for medical use at concentrations of 10, 50 and 100 mg/mL, corresponding to molar concentration of 42, 210 and 420 mM, based on a molecular weight of 237.7 g/mol (see e.g., pfizermedicalinformation.com/en-us/ketamine/storage-handling).
  • concentration of ketamine in the described formulations necessary for treatment of chronic pain is significantly lower than that commonly administered.
  • the formulations described herein include ketamine provided at a concentration from 100 pM to 100 mM (corresponding approximately to mass-based concentrations of .01 to 24 mg/mL), such as from 250 pM to 4 mM (corresponding to approximately .05 to 1 mg/mL).
  • the formulations described herein include ketamine provided at a concentration from 30 pM to 100 mM, including 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25, mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM or 100 mM. Intermediate doses are possible as well.
  • the described compositions include ketamine provided at a concentration from 30 pM to 30 mM.
  • compositions described herein include as a second component a response mediating agent of at least one TAS2R.
  • Bitter taste receptors are an additional type of receptor that regulate intracellular Ca levels. Although these receptors were once thought to be localized only to the oral cavity and to be involved only in taste perception, the importance of extraoral TAS2Rs has been increasingly appreciated including receptors located within the central nervous system (e.g. Lu et a., J Gen Physiol, 149:181-197, 2017, DOI: 10.1085/jgp.201611637).
  • TAS2R For example, in bronchial smooth muscle, activation of TAS2R leads to dissociation of gustducin into y subunits, which, in turn, inhibits L-type voltage-dependent Ca2+ channels, leading to smooth muscle relaxation.
  • Neurons in multiple regions of the rat brain have been shown to express TAS2Rs and downstream signaling molecules a-gustducin, PLCb2 and TRPM5 (e.g.Dehkordi et al., Brain Res 1475:1- 10, 2012; DOI: 10.1016/j.brainres.2012.07.038), including regions potentially involved in pain perception and mood regulation.
  • TAS2R4 which are expressed in rat neuronal cells (e.g. Singh et al., BBRC 406:146-151, 2011; D0l:10.1016/j.bbrc.2011.02.016).
  • TAS2R response mediating agent binds to multiple TAS2R.
  • Canonical ligands for TAS2R include compounds such as denatonium, quinine and quinidine. Quinidine and denatonium are among the most promiscuous compounds and activate 9 and 8 TAS2Rs, respectively.
  • receptors include TASR4, 7, 10, 14, 39, 40, 43, 44, and 46.
  • receptors include TAS2R4,8, 10, 11, 13, 24, 39, 43, 46 and 47 may mediate the response to denatonium.
  • the order of potency is TAS2R47>10>13/46>39>24/43>8.
  • alkali compounds have bitter taste and likely bind to
  • TAS2R Inorganic bases such as NaOH, KOH, or MgOHz may also have a bitter taste with presumed mediation through TAS2R. The cation may also contribute to the response (e.g. St. John & Boughter, Chem Senses 34:487-498, 2009). The identity of the TAS2R receptor that transduces the hydroxide effect has not been determined. Cations such as Na + , when combined with a hydroxyl may also increase signaling through the TAS2R-linked TRMP5 channel. Interactions with other bitterness related proteins including but not limited to a-gustducin and PLCb2 could also be combined with an NMDAR antagonist as described.
  • the formulations described herein include at least one TAS2R response mediating agent.
  • the TAS2R response mediating agent compound is a hydroxyl containing compound, combined with a cation.
  • the cation is sodium (Na + ).
  • the cation is calcium (Ca 2+ ).
  • the cation is combined with chloride to form a salt.
  • Particular examples of the hydroxyl containing compound for use in the described combination formulations include NaOH, KOH, and Ca(OH)2.
  • the TAS2R response mediating compound is denatonium.
  • bitter taste compounds for use in the described combination compositions can be identified from sources such as the BitterDB (available online at bitterdb.agri.huji.ac.il/dbbitter.php).
  • the NMDAR antagonist is ketamine, including its S- and R- ketamine
  • the TAS2R response mediating compound is NaOH.
  • ketamine can be provided in the concentrations noted above, and NaOH is combined with ketamine at a molar ratio in the range of 1:10 to 1:1 NaOH to ketamine.
  • Non-limiting examples include 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, and 1:1.
  • Exemplary non-integer ratios of NaOH to ketamine that can be used in the described formulations include 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, and 1:2.9.
  • the range of NaOH to ketamine is between 1:5 and 1:1.
  • the ratio is NaOH to ketamine in the pharmaceutical formulation is 1:5.
  • the ratio of NaOH to ketamine is 1:2.
  • the NMDAR antagonist is ketamine and the TAS2R response mediating compound is denatonium.
  • ketamine can be provided in the concentrations noted above, and denatonium is combined with ketamine at a molar ratio in the range of 10:1 to 1:1 ketamine to denatonium.
  • Nonlimiting examples include 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1.
  • Exemplary non-integer ratios of ketamine to denatonium that can be used in the described formulations include 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, and 1:5.9.
  • the range of ketamine to denatonium is between 1:5 and 1:1.
  • the ratio is ketamine to denatonium in the pharmaceutical formulation is 1:5.
  • the described pharmaceutical formulations are in particular embodiments formulated for parental administration to a patient.
  • Such formulations include pharmaceutically acceptable salts, buffers, solvents, excipients, and diluents common to the art.
  • the solution may be rendered partially or fully isotonic by addition of a NaCI solution.
  • NaCI solutions that can be added to render the solution formulation of the described compositions include 1/3 normal, 1/2 normal, or 2/3 normal.
  • An isotonic solution is defined as containing .9% NaCI.
  • ketamine-TAS2R combinations such as ketamine-NaOH and ketamine-denatonium were observed to be effective in treating the associated depressive symptoms.
  • Many psychic factors may contribute to the risk for depression including childhood loss, bereavement, life change, stress, physical or sexual abuse, relationship difficulties or financial loss. These collectively are termed psychic pain.
  • Manifestations of depression include sadness, tension, reduced sleep and appetite, difficulties in concentration, difficulty in starting activities, reduced interest, and pessimistic and suicidal thoughts. Treatment of chronic pain and associated depression can therefore also help ameliorate the long term effects of psychic pain.
  • compositions described herein can be used in methods for treating chronic pain in a subject in need of such treatment.
  • the methods include administering to a subject any one of the compositions (pharmaceutical formulations) described herein, thereby treating the chronic pain, and in particular embodiments the chronic pain and associated depression or depressive symptoms as noted above.
  • the described pharmaceutical formulation is administered parenterally, and so the formulation is adapted to the particular parental administration used.
  • the pharmaceutical formulation is administered subcutaneously, intramuscularly, intravenously, intraarticularly, intraperitoneally, or intrathecally.
  • the described pharmaceutical formulation can, in particular embodiments, be administered by a systemic method of administration, and can, in other particular embodiments, be administered by a local method of administration.
  • the described combination can be formulated as needed for a particular mode of administration, though the appropriate formulation for one type of administration can, in particular embodiments also be used for another type of administration.
  • the provided pharmaceutical formulation is administered as a single bolus to the subject. In other embodiments, it is infused gradually over time periods of several minutes or hours. Non-limiting examples include 5, 10, 15, 20, 30, 40, 60, 90, 120 minutes or longer. Intermediate administration periods are contemplated as well.
  • the pharmaceutical formulation is provided within a treatment regimen that includes periodic administration of the pharmaceutical formulation of days, weeks, months, and periods in between,
  • the formulation is provided over the course of regular periods, for example every five days or every two weeks.
  • the formulation is provided in a staggered manner.
  • a non-limiting illustrative example of such staggered treatment is treatment every day for a week, followed by two weeks without treatment, followed by treatment every day for a week.
  • the described methods can treat neuropathic (chronic) pain, but also depression associated with or stemming from neuropathic pain.
  • the depression is major depression.
  • the depression is bipolar depression.
  • Example 1 Modulation of analgesic efficacy of ketamine by NaOH in the rat formalin test
  • This example demonstrates the use of the formalin test to determine the potential analgesic effects of compounds for pain.
  • effects are measured on both acute and delayed formalin-induced pain, as reflected in paw licking behavior.
  • Rats were returned to the observation chamber and immediately observed for behavior. The total time spent licking, flinching or biting the treated hind-paw over the next 35 min was recorded and videos were scored by a trained observer blinded to the treatment group. The acute response was evaluated in 5 min intervals for 0-10 min, and the delayed response was evaluated from 10-35 or 10-40 min.
  • Ketamine NaOH reduced delayed paw licking activity over the interval of 2.1-3.6 log- pM ketamine, corresponding to concentrations of between 125 pM and 4.0 mM.
  • Example 2 Effects of different ratios of Ketamine vs. NaOH on analgesic effects
  • Results are shown in Table 4. No significant effects were observed across conditions for either acute or delayed paw lick responses. As in earlier experiments, ketamine 100 pM did not significantly reduce delayed responses in the absence of NaOH. Neither Ca(OH)2 or KOH enhanced the effects of ketamine 100 pM. S-Ketamine 100 pM induced numeric decreases in delayed paw licking vs. control, but the differences were not statistically significant.
  • Chronic pain may also lead to depressive symptoms that cause additional disability and may reflect an independent treatment target.
  • Anti-depression effects may be modeled in rodents using behavioral measures including the forced swim test, which measures the time that rodents remain immobile when placed in water.
  • chronic pain Is created by spinal nerve ligation (SNL) in which a ligation is placed around the left L5 nerve, which leads to hypersensitivity of the paw withdrawal threshold.
  • SNL spinal nerve ligation
  • L6 The transverse process of L6 was removed and nearby connective tissue cleaned to expose L5 and L6 spinal nerves. After the nerves were isolated and clearly visualized, 4-0 silk threads were used to ligate the left L5. The muscles were then sutured with 4-0 silk threads and the wound closed by staples. All rats received an analgesic (buprenorphine, 0.05 mg/kg, s.c.) immediately before and 6 hours after surgery. Each rat was monitored until awake and moving freely around the recovery chamber. Animals were then single-housed for the duration of the study.
  • an analgesic buprenorphine, 0.05 mg/kg, s.c.
  • Paw withdrawal test Paw withdrawal from a mechanical stimulus was measured by applying VF filaments of ascending bending force to the plantar surface of the hind paws (ipsilateral and contralateral). Baseline and post-treatment withdrawal threshold values for non-noxious mechanical sensitivity were evaluated using von Frey filaments (Semmes-Weinstein filaments, Stoelting) of varying stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 10, 15, 26g) starting with the middle filament (3.6 g). Each filament was presented perpendicular to the plantar surface with sufficient force to cause slight buckling against the paw, then held for approximately 6 seconds or until a positive response was noted. A positive response was defined as withdrawal from the von Frey filament.
  • This preadministration swim test consisted of one 15 min session in individual cylinders containing 23 ⁇ 1°C water; this was followed 24 h later by the experimental test of 5 min.
  • the water level was 16 cm deep during habituation and 30 cm deep during testing. Immobility, climbing, and swimming behaviors were recorded every 5 sec for a total of 60 counts per subject. In the event that an animal was unable to maintain a posture with its nose above water, it was removed immediately from the water and therefore eliminated from the study.

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Abstract

L'invention concerne une composition qui comprend un antagoniste du récepteur N-méthyl-D-aspartate (NMDAR) et un agent médiant la réponse au récepteur TAS2R pour traiter la douleur neuropathique et la dépression. L'invention concerne également des méthodes de traitement de la douleur chronique avec la composition décrite.
PCT/IB2024/057892 2023-08-14 2024-08-14 Compositions et méthodes pour le traitement de la douleur chronique et de la dépression Pending WO2025037252A1 (fr)

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US18/448,990 2023-08-14
US18/448,990 US12005035B1 (en) 2023-08-14 2023-08-14 Compositions and methods for treatment of chronic pain and depression
US18/736,572 US20250057788A1 (en) 2023-08-14 2024-06-07 Compositions and methods for treatment of chronic pain and depression
US18/736,572 2024-06-07

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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2014143646A1 (fr) * 2013-03-15 2014-09-18 Janssen Pharmaceutica Nv Composition pharmaceutique d'hydrochlorure de kétamine s
WO2017003935A1 (fr) * 2015-06-27 2017-01-05 Shenox Pharmaceuticals, Llc Système d'administration transdermique de la kétamine

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DEHKORDI ET AL., BRAIN RES, vol. 1475, 2012, pages 1 - 10
DONCHEVA ET AL., ADVANCES IN CLINICAL AND EXPERIMENTAL MEDICINE., vol. 28, 2018
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