WO2012077775A1 - Composition pour le traitement d'une douleur cancéreuse et son utilisation - Google Patents

Composition pour le traitement d'une douleur cancéreuse et son utilisation Download PDF

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WO2012077775A1
WO2012077775A1 PCT/JP2011/078508 JP2011078508W WO2012077775A1 WO 2012077775 A1 WO2012077775 A1 WO 2012077775A1 JP 2011078508 W JP2011078508 W JP 2011078508W WO 2012077775 A1 WO2012077775 A1 WO 2012077775A1
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pain
paf
cancer
administration
factor
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PCT/JP2011/078508
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English (en)
Japanese (ja)
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克也 森田
敏博 土肥
直世 本山
友也 北山
隆 兼松
成二 白石
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国立大学法人広島大学
独立行政法人国立がん研究センター
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Priority to JP2012547918A priority Critical patent/JP5954790B2/ja
Publication of WO2012077775A1 publication Critical patent/WO2012077775A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for treating cancer pain and use thereof.
  • Platelet-activating factor is a phospholipid discovered as a basophil-derived platelet aggregation factor.
  • PAF produced by various cells such as neutrophils, monocytes, basophils, and vascular endothelial cells in response to stimulation activates immune system cells (leukocyte infiltration, eosinophil migration, neutrophils) Migratory action, etc.), strong vascular permeability enhancing action and bronchoconstriction action.
  • immune system cells leukocyte infiltration, eosinophil migration, neutrophils
  • Migratory action etc.
  • strong vascular permeability enhancing action and bronchoconstriction action.
  • analysis of PAF receptor gene-modified mice revealed that PAF is important for pulmonary edema and bronchial asthma in systemic anaphylactic shock, acute lung injury (acute lung injury), acute respiratory distress syndrome (acute respiratory distress syndrome; ARDS) It is considered as a mediator.
  • the present inventors have conducted research on the physiological function and pathophysiology of PAF for many years.
  • a very small amount (0.1 pg) of PAF administered into the spinal cavity induces hyperalgesia and tactile pain (allodynia) symptoms, which are indicators of neuropathic pain, and this action is 3-bromo- 5- (N-phenyl-N- (2-((2- (1,2,3,4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl) carbamoyl) ethyl) carbamoyl) -1-propylpyridinium nitrate (Hereinafter also referred to as TCV-309) and other PAF receptor antagonists have been clarified (see Non-Patent Document 1).
  • PAF PAF may cause neuropathic pain at the time of spinal cord injury.
  • PAF receptor stimulation downstream of this PAF receptor stimulation, the mechanism that suppression of inhibitory glycine nerve activity via glutamic acid or NO / cGMP enhances pain was clarified (see Non-Patent Document 2).
  • PAF is considered to be neuropathic pain, chronic inflammatory pain, acute inflammatory pain, thermal stimulation or mechanical stimulation, etc. based on pharmacological studies using PAF antagonists.
  • Non-Patent Document 3 the analgesic action of PAF antagonists has been shown in a spinal cord injury model (see Non-Patent Document 4). Furthermore, since neuropathic pain is also suppressed by spinal PAF receptor knockdown due to RNA interference, the analgesic action of the PAF antagonist is not due to any nonspecific action of the PAF antagonist, but to a specific PAF receptor. It is confirmed that it is expressed based on inhibition.
  • the transmission of pain to the center is controlled by the descending pain suppression system at the relay point at the dorsal horn of the secondary sensory nerve from the primary sensory nerve.
  • the descending pain suppression pathway consists of central brain gray matter (PAG) and medullary rostral ventral medial (RVM) neurons that extend descending fibers to the dorsal horn of the spinal cord, and mediators such as endogenous opioids, noradrenaline and serotonin , And directly or indirectly suppress the nerve.
  • the indirect inhibitory system is mediated by inhibitory neurons such as opioids, GABA, and glycine, and suppresses the excitement of the primary sensory nerve and the secondary sensory nerve.
  • Opioid analgesics eg, narcotic analgesics such as morphine, oxycodone, fuentanyl, and pethidine; non-narcotic analgesics such as bentazosin, tramazole, buprenorphine, eptazosin, butorphanol
  • tricyclic antidepressants selective serotonin
  • the mechanism for activating these descending pain suppression systems is important for the analgesic action of reuptake inhibitors (SSRI) and serotonin / noradrenaline reuptake inhibitors (SNRI). It is known that the function of the inhibitory neurotransmission system is reduced during neuropathy. It is considered that the PAF antagonist antagonizes the attenuation by glycine-suppressed PAF and activates the descending pain suppression system, which can show a broad analgesic spectrum for pains having different causes as described above.
  • SSRI reuptake inhibitors
  • SNRI serotonin
  • the purpose is to find out further functions of PAF antagonists that are effective in the treatment of neuropathic pain.
  • the first composition of the present invention is characterized by containing a PAF antagonist in order to treat cancer pain.
  • the first composition of the present invention may further contain a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • factors that enhance the function of the descending pain suppression pathway in the spinal cord for example, opioid analgesics such as morphine, SSRI (selective serotonin reuptake inhibitor), SNRI (selective serotonin / noradrenaline reuptake inhibitor)
  • opioid analgesics such as morphine, SSRI (selective serotonin reuptake inhibitor), SNRI (selective serotonin / noradrenaline reuptake inhibitor)
  • the function of the drug and the like
  • the second composition of the present invention contains a PAF antagonist to treat pain, and is used to be used in combination with a factor that enhances the function of the descending pain suppression system pathway in the spinal cord. It is preferable that the above-mentioned factors are further contained.
  • the pain is preferably cancer pain.
  • the function of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord can be enhanced, so that the amount of the factor used can be reduced and the side effects of the factor can be suppressed. it can.
  • the first kit of the present invention is characterized by comprising a PAF antagonist and optionally a factor that enhances the function of the descending pain suppression pathway in the spinal cord to treat pain, It is preferred to further comprise instructions describing the use procedures for treating pain.
  • the pain is preferably cancer pain, and more preferably further provided with instructions describing the use procedure for treating cancer pain.
  • the function of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord can be enhanced, so that the amount of the factor used can be reduced and the side effects of the factor can be suppressed. it can.
  • the PAF antagonist provided in the first kit is preferably applied to the subject before applying a factor that enhances the function of the descending pain suppression pathway in the spinal cord, and may be repeatedly administered. preferable.
  • the second kit of the present invention comprises a PAF antagonist and, optionally, a factor that enhances the function of the descending pain suppression system pathway in the spinal cord in order to prepare the above-described composition. It is preferable to further include instructions describing the use procedures for preparing the above-described composition.
  • the method of the invention includes the step of administering to a subject an effective amount of a PAF antagonist to treat pain.
  • the PAF antagonist used in the method of the present invention may be provided as a compound, in the form of the composition described above, or may be provided as a material provided in the kit described above.
  • the PAF antagonist can enhance the function of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord, the amount of the factor used can be reduced and the side effect of the factor can be reduced. Can be suppressed. That is, the method of the present invention may be performed to enhance the action of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord, or may be performed to suppress the side effects of the factor.
  • the screening method of the present invention is characterized by including a step of examining whether a candidate compound inhibits the action of PAF in order to screen for a compound capable of treating cancer pain.
  • analgesic effect can be obtained with a small amount for cancer pain, and the effect can be maintained for a long time and there are few side effects. Furthermore, if this invention is used, the analgesic effect of morphine can fully be improved, and there exists an effect of reducing the dosage amount of morphine and reducing a side effect.
  • cancer pain Pain resulting from cancer (cancer pain) is found in 30-50% of patients undergoing treatment for cancerous lesions and in 70-90% of patients with advanced cancer. In recent years, not only cancer treatment but also symptom control of cancer patients has been demanded, and the need for palliative care has been attracting attention.
  • opioid analgesics such as morphine
  • non-opioid analgesics nonsteroidal anti-inflammatory drugs, acetaminophen, etc.
  • analgesics has been tried.
  • Increasing the amount of opioid analgesics produces strong side effects such as constipation, drowsiness, nausea / vomiting, and undesirable side effects such as drug resistance, drug dependence, and epilepsy when administered for long periods of time.
  • Anti-convulsants antiepileptics
  • psychotropic drugs anxiolytics
  • NMDA receptor antagonists muscle relaxants
  • antidepressants corticosteroids
  • antiarrhythmic drugs Drugs, bisphosphonate preparations, cannabinoids and the like.
  • drugs do not provide sufficient analgesic effect for opioid analgesics, their side effects must always be considered.
  • the most common side effects of analgesics are constipation, nausea / vomiting, sedation and somnolence. Many cancer patients are elderly, and when the sedation is significantly sustained, many functions necessary for daily life are at risk of degeneration. In addition, if the treatment requires administration of multiple drugs, patient compliance is significantly reduced.
  • Drug duration is also an important factor in treating cancer pain. Prolonging the duration of the drug has a positive impact on the whole of the life because it can lead to improvements in depression, insomnia, and other factors for patients with pain, especially at night. Recent studies have shown that patients with depression and insomnia at the same time as chronic pain complain of the highest level of pain-related disorders, and that insomnia is associated with increased pain and distress. Conventional analgesics require administration more than once a night (eg, every 4 hours for morphine), thus disturbing sleep and resulting in worsening of the patient's QOL. Prolonging the duration of sufficient analgesic effect during bedtime is important for pain relief.
  • Cancer pain is composed of various factors, and various factors such as nociceptive pain, inflammatory pain, neuropathic pain, emotion, and emotion affect the cancer pain. And since these change complicatedly with the progress of a medical condition, cancer pain cannot be relieved only by suppressing each element. Treatment for alleviating such cancer pain is limited only by applying existing analgesics and analgesics. No absolute cure for cancer pain has yet been found.
  • cancer pain In the generation and maintenance of cancer pain, especially bone cancer pain, the factors causing the pain change as the cancer develops and progresses, which is one of the major characteristics of cancer pain.
  • Various inflammatory and analgesic mediators are released from cancer cells, causing nociceptive pain.
  • pain is caused by pressing nerve tissue as the cancer tissue grows.
  • the primary sensory nerves abundantly present in the periosteum are subjected to stronger physical damage, resulting in strong pain.
  • nerve demyelination occurs and neuropathy occurs.
  • opioid analgesics such as morphine. If analgesia is not sufficient, opioid analgesics can be increased until analgesia is obtained as much as possible, but side effects such as central depression become apparent. The effectiveness of analgesics is limited due to the relationship between efficacy and side effects.
  • a drug having a short duration such as morphine needs to be administered frequently. Even when a sustained-release agent is used, administration once a day or more is necessary.
  • analgesic for cancer pain (1) it has a new mechanism of action, (2) sufficient analgesic effect can be obtained with a small amount and less side effects, and (3) analgesic effect of morphine when used in combination with morphine It is very preferable to satisfy the conditions such as (4) the dose of morphine can be reduced, side effects can be reduced, and (5) the action can be sustained for a long time.
  • the present invention provides a new technique for treating cancer pain.
  • the present inventors administer PAF antagonist (systemic administration and intrathecal administration) to a standard cancer pain model animal (femoral cancer model prepared by transplanting NCTC2472 tumor cells into mouse femur).
  • PAF antagonists have been associated with cancer pain-related symptoms over 5-6 days by systemic administration (0.01-0.3 mg / kg intravenous administration, 0.3 mg / kg oral administration) or intraspinal administration (10 pg). was found to significantly relax.
  • This femoral cancer model includes opioids (Pain 99, 397 (2002); J Pharmacol Sci. 111, 60, (2009)), bisphosphonate (Pain 111,169, (2004)), anti-NGF (nerve growth factor) Antibody Tanezumab (Pain 115, 128, (2005)), TRPV1 (transient receptor potential vanilloid 1) antagonist (J Neurosci. 25, 3126 (2005)), Gapavenin (Exp Neurol.
  • PAF antagonists can be an effective treatment for cancer pain-related conditions that are insensitive to existing therapeutic agents.
  • any PAF or PAF analog antagonist ie, a substance that antagonistically inhibits the action of a PAF agonist
  • any PAF or PAF analog antagonist is a compound derived from a natural product or a derivative thereof.
  • PAF or PAF analog antagonist ie, a substance that antagonistically inhibits the action of a PAF agonist
  • any PAF or PAF analog antagonist is a compound derived from a natural product or a derivative thereof.
  • Lipid Mediators 2: 123-158, 1990, Bet a1., Platelet-activating factor antagonists.
  • Current Organic Chemistry 1 (4) 345-360, 1997, Hironori Sagara, etc.
  • plant extracts containing them for example, Ginkgo biloba leaf extract containing ginkgolides (Braquet, PG. Et al. Blood Vessels, 16, 558 (1985)), lignans ( lignans) kadsurenone (Kazurenone) stalk extract (Shen, TY. et al. Proc. Natl. Acad. Sci. USA, 82, 672 (1985)), other lignans Burdock containing cows (Cow lion, Arctii Fructus) and forsythia (Forsythiae ⁇ Fructus), stone pepper containing arnicolides (Centipeda minima) (Iwakami, S. et al.
  • xanthorrhiza Curium turmeric, Java turmeric
  • berum ⁇ bet. Ha ginger, white turmeric
  • other extracts as well as natural substances with anti-inflammatory effects related to PAF (see Bohlin L et al., Current Organic Chemistry, 1 (4), 345-360, 1997) It can be preferably used.
  • gingolides such as gingolide A, gingolide B, gingolide C, gingolide J or BN-52063 and derivatives thereof; BN5211, AKS-168, CV-3388, CV-6209, E5880, R74719, R74654, ABT- Pyridinium derivatives such as 299, SDZ 64619, TCV-309, UR-10324, UR-11353, KO-286011; triazolo such as BU50739, E6123, Ro24-47364, STY-21084, WEB2086, WEB-2170, WEB-2347 1,4-diazepine-based compounds are preferred, and in particular, gingolide derivatives Gingolide A, Gingolide B, Gingolide C, pyridinium derivatives TCV309, BU50739 of Riazoro diazepin-based compounds, WEB 2086 are preferred.
  • the basic treatment for cancer pain is as follows: [1] Take preventive measures if possible; [2] Start treatment early; [3] Improve or restore function with analgesia Evaluate; [4] Care for emotional and mental problems (understanding and aggressiveness of the patient and those around them is important).
  • the PAF antagonist can be protected from the onset of cancer pain by being administered before the onset of pain. This suggests that the PAF antagonist has an action mechanism different from that of known analgesics and is effective as a prior analgesic that can prevent the onset of cancer pain.
  • sedation is known as a major side effect of existing opioid analgesics and many analgesics, but since PAF antagonists do not exhibit such a central action, the present invention is not limited to conventionally known cancerous properties. It is much more advantageous than pain treatment.
  • non-opioid analgesics non-steroidal anti-inflammatory drugs (eg loxoprofen, diclofenac, indomethacin, etodolac, piroxicam, celecoxib, acetaminophen)) or analgesics that are effective in treating cancer pain
  • non-steroidal anti-inflammatory drugs eg loxoprofen, diclofenac, indomethacin, etodolac, piroxicam, celecoxib, acetaminophen
  • an analgesic adjuvant having a mechanism of action different from that of the PAF antagonist is preferable, and one that does not exhibit the above-described central action is more preferable.
  • Analgesic adjuvants that have a mechanism of action different from that of PAF antagonists include, for example, antiepileptic drugs (carbamazepine, phenytoin, sodium parproate, clonazepam, gabapentin, pregabalin, lamotrigine; lidocaine, an antiarrhythmic drug, Mexiletine, flecainide; lidocaine and mexiletine as local anesthetics; risperidone, chlorpromazine, haloberidol, hydroxyzine, polochlorparadine as psychotropic drugs; diazepam, chlordiazepoxide as anti-anxiety drugs; ketamine as an NMDA receptor antagonist Ifenprodil; muscle relaxant tizanidine, baclofen; antidepressants amitriptyline, nortriptyline, milnacipran, maprotiline; corticosteroid and hydrocortisone Not but cannabinoids like limitation; pre
  • Preferred administration methods for PAF antagonists include systemic administration and local administration (eg, direct delivery to the spinal cord and trigeminal spinal tract nucleus).
  • the routes applied for these administrations include, but are not limited to, oral, intraarterial, intrathecal, intrathecal, intramuscular, intraperitoneal, intravenous, intranasal, and inhalation routes. It is appropriately selected by a clinician in consideration of the condition of the subject, age, other diseases being treated, pharmaceuticals used, and the like.
  • PAF antagonists act on the dorsal horn of the spinal cord or the trigeminal spinal tract nucleus to protect against GlyR ⁇ 3 function inhibition and provide analgesia.
  • the dose can be much reduced compared to systemic administration, and thus it can be suppressed to a level that does not require consideration of systemic toxicity.
  • the most preferable mode of administration is intrathecal administration (administration into the cerebrospinal fluid surrounding the spinal cord).
  • the drug concentration can be controlled by the injection amount and the injection speed.
  • the effective amount of the PAF antagonist is appropriately determined in consideration of the condition of the subject (patient) (age, weight, health condition, etc.), judgment of a medical professional, the effect and toxicity of each active agent contained in the composition. Can be determined.
  • the duration of action of the PAF antagonist is remarkably long, which reduces the burden on the patient in the treatment of pain and is advantageous from the viewpoint of reducing medical costs. Moreover, it has been clarified that the mechanism of action is due to internalization of the PAF receptor (data not shown), and there is little possibility of side effects such as tolerance and accumulation action. This is another advantage over existing analgesics.
  • the PAF antagonist may be used as a compound or in the form of a composition or kit described later.
  • the present invention provides a composition containing a PAF antagonist.
  • the composition of the present invention may be a pharmaceutical composition for treating pain or a composition for preparing such a pharmaceutical composition.
  • treatment is intended to alleviate (ameliorate) or eliminate symptoms and can be performed therapeutically (after onset), as well as prophylactic (pre-onset). Also included are those that can be performed.
  • the treatment of pain with the composition of the present invention is due to the effect of enhancing the action of a factor that enhances the function of the descending pain suppression system pathway or the pain relieving action by the PAF antagonist.
  • the pain to be treated is preferably cancer pain, most preferably bone cancer pain, but is not particularly limited as long as it is cancer pain, neuropathic pain, acute inflammatory pain, chronic Inflammatory pain, nociceptive pain caused by short-term noxious stimulation (for example, thermal stimulation or mechanical stimulation), and the like can be mentioned.
  • the present invention which has been demonstrated using bone cancer model animals in the examples described later, that treatment of bone cancer pain that develops through a complicated mechanism can be treated, is not easily conceived by those skilled in the art. It can be said that it shows a remarkable effect beyond the scope of the contractor's prediction.
  • morphine is a factor that enhances the function of the descending pain suppression pathway in the spinal cord. That is, the composition of the present invention may further contain a factor that enhances the function of the descending pain suppression system pathway in the spinal cord. Moreover, although it may further contain an analgesic aid effective for treating pain as described above, in this case, those having an action mechanism different from that of the PAF antagonist are preferable, and those that do not exhibit the above-mentioned central action More preferred.
  • the carrier and excipient used in the composition of the present invention are not particularly limited as long as they are pharmaceutically acceptable.
  • pharmaceutically acceptable carrier intends any carrier that does not itself induce the production of harmful antibodies in an individual receiving the composition. Such carriers are well known to those skilled in the art.
  • pharmaceutically acceptable excipients are known in the art and are well described in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES (Merck Pub. Co., NJ 1991).
  • the composition of the present invention may further comprise one or more components such as water, saline, glycerol, or ethanol.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances, stabilizers, antioxidants and the like may be present in the compositions of the invention.
  • composition of the present invention can be prepared in the form of powder, granules, tablets, capsules and the like preferable for oral administration.
  • the compositions of the present invention may also be prepared as a liquid solution or suspension, or a solid form suitable for solution or suspension in a liquid vehicle for injection, or as a topically applied cream. obtain.
  • direct delivery of the compositions of the invention is generally oral, injection (subcutaneous, intradermal, intraperitoneal, intraluminal, intrathecal, intragastric, intestinal, intravenous, intramuscular or intramedullary), Or achieved by coating.
  • the composition of the present invention can be in an orally ingestible form such as powder, tablet, granule, capsule, liquid, etc., and contains an amount of PAF antagonist that exhibits the desired effect. If it is, the shape is not particularly limited.
  • the composition of the present invention can be produced by a known method in the pharmaceutical field.
  • the content of the PAF antagonist in the composition of the present invention is not particularly limited as long as the PAF antagonist can be administered using the composition in consideration of the administration form, administration method and the like.
  • the dosage of the composition of the present invention is appropriately set depending on the preparation form, administration method, purpose of use, and age, weight, and symptoms of the patient to be administered. Administration may be performed in a single dose or divided into several doses within a desired dose range.
  • the present invention provides a kit comprising a PAF antagonist.
  • the kit of the present invention may be a kit for preparing a composition for treating pain.
  • the kit of the present invention may further comprise a factor that enhances the function of the descending pain suppression pathway in the spinal cord.
  • an analgesic adjuvant effective for treating pain as described above may be further provided, but in this case, those having a mechanism of action different from that of the PAF antagonist are preferable, and those that do not exhibit the above-mentioned central action. More preferred.
  • the term “kit” is intended to include a package comprising a particular material contained in a container (eg, bottle, plate, tube, dish, etc.).
  • a container eg, bottle, plate, tube, dish, etc.
  • instructions are provided for using the above materials, and instructions describing the procedures for obtaining the effect according to the present invention (for example, procedures for treating pain, in particular cancer pain) are provided.
  • kits comprising is intended to mean being contained within any of the individual containers that make up the kit.
  • the kit of the present invention may be a package in which a plurality of different compositions are packed together, or may be a solution in a form of a solution contained in a container.
  • the kit of the present invention may be prepared by mixing two or more different substances in the same container or in separate containers. “Instructions” may be written on paper or other media, printed, or attached to electronic media.
  • the kit of the present invention may be used to constitute the above-described composition, and may comprise the substances contained in the above-described composition separately, or may comprise the above-described composition and additional components separately. May be.
  • the present invention provides a method for treating pain.
  • the methods of the invention include the step of administering to a subject an effective amount of a PAF antagonist.
  • a PAF antagonist shows a sustained effect of pain relief.
  • administration of an effective amount of TCV-309 is at least 12 hours or more, preferably 24 hours or more, 1 day, 2 days, 3 days, 4 days, 5-6 days, or longer (7-30 days) Can sustain pain relief over a long period of time. This is in contrast to many neuropathic pain drugs currently on the market.
  • the method of the present invention may further include a step of administering to the subject a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • the step of administering the factor may be performed simultaneously with the step of administering the PAF antagonist, may be performed before administering the PAF antagonist, or may be performed after administering the PAF antagonist.
  • the method may further include the step of administering an analgesic adjuvant effective for treating pain, as described above, to the subject. In this case, it preferably has a mechanism of action different from that of the PAF antagonist, Those that do not exhibit central effects are more preferred.
  • the method of the present invention may further include a step of examining the degree of pain in the subject. By performing this step before and after the step of administering the PAF antagonist, it is possible not only to know whether or not the pain experienced by the subject has been treated, but also whether or not the occurrence of pain has been prevented. I can know.
  • the present invention is also preferably used in combination with pain in which a factor that enhances the function of the descending pain suppression pathway in the spinal cord is used.
  • the present invention provides a new technique suitable for use in combination with factors that enhance the function of the descending pain suppression pathway in the spinal cord.
  • information transmission of pain stimulation is strongly suppressed by the descending pain suppression system pathway of the spinal cord.
  • the descending pain suppression pathway also projects to glycinergic nerves, and the promotion of glycine release from nerve endings is part of the mechanism.
  • PAF antagonists enhance this system by inhibiting the modulation (deinhibition) of inhibitory glycine neuronal activity by PAF.
  • the amount of opioid analgesic used in combination can be reduced by using a PAF antagonist.
  • a PAF antagonist (1 to 10 ⁇ g / kg intravenously 24 hours before morphine administration) in combination with subcutaneous administration of morphine 0.3 mg / kg, which hardly shows analgesic action alone. Pain suppression was shown. When combined with 10 ⁇ g / kg of a PAF antagonist in combination with 10 mg / kg of morphine having a mild analgesic effect, almost complete pain suppression is shown, and this effect is similarly shown when the dose of morphine is reduced to 10 ⁇ g / kg. It was done. In addition, a remarkable analgesic effect was shown by subcutaneous administration of 0.3 mg / kg of morphine 7 days after administration of 30 to 300 ⁇ g / kg of the PAF antagonist.
  • concomitant use with a PAF antagonist can significantly reduce the dose of morphine.
  • Such an action of the PAF antagonist can be expected to be similarly exerted even when used in combination with an opioid analgesic having the same mechanism of action as morphine. This is no longer a problem of “constipation”, which is most concerned as a side effect of opioid analgesics.
  • the combined use with factors that enhance the function of the descending pain suppression pathway in the spinal cord suggests a synergistic effect and a reduced risk of side effects.
  • opioid analgesics such as morphine
  • morphine The most annoying side effect of opioid analgesics such as morphine is to cause constipation, even at smaller doses than the analgesic effect, and to suffer from strong constipation during opioid therapy.
  • Defecation suppression caused by subcutaneous administration of morphine 1-50 mg / kg was not affected at all by the combined use of 10 ⁇ g / kg of PAF antagonist. This indicates that the PAF antagonist does not enhance the defecation-inhibiting action despite significantly enhancing the analgesic action of morphine, and that constipation can be reduced by reducing the amount of morphine.
  • the PAF antagonist may be used as a compound or in the form of the composition or kit described above.
  • a composition it contains a PAF antagonist to treat pain and is used to be used in combination with factors that enhance the function of the descending pain suppression pathway in the spinal cord, Preferably, it is applied to the subject prior to applying a factor that enhances the function of the descending pain suppression pathway, and repeated administration is also preferred.
  • a kit it is characterized by comprising a PAF antagonist and a factor that enhances the function of the descending pain suppression system pathway in the spinal cord to treat pain. Preferably, it is applied to the subject prior to applying a factor that enhances the function of the descending pain suppression system pathway, and repeated administration is also preferred.
  • kits may be used in order to prepare the composition mentioned above.
  • a method comprising administering an effective amount of a PAF antagonist to a subject intended for treatment with a factor that enhances the function of the descending pain suppression pathway in the spinal cord is also of the present invention. Within range. In the present method, the above steps may be repeated multiple times.
  • composition, kit and method in this section should be referred to the description in the above-mentioned section “Treatment of cancer pain with a PAF antagonist”.
  • the present invention is based on the discovery of a novel function of a PAF antagonist. This indicates that it is possible to obtain a compound capable of treating cancer pain by knowing whether or not it is a PAF antagonist. That is, the present invention provides a method for screening a compound capable of treating cancer pain.
  • the screening method of the present invention comprises a step of examining whether or not a candidate compound inhibits the action of PAF in order to screen for a compound capable of treating cancer pain, wherein the candidate compound is PAF.
  • a step of examining whether or not to competitively inhibit the binding to the PAF receptor may be further included.
  • the screening method of the present invention further includes a step of selecting a candidate compound having a pain suppressing action on a cancer pain model animal.
  • the screening method of the present invention is used for screening a compound that suppresses a side effect of the above factor even if it is used for screening a compound that enhances the function of a factor that enhances the function of the descending pain suppression pathway in the spinal cord. May be used.
  • the screening method of the present invention comprises a step of examining whether a candidate compound inhibits the action of PAF in order to screen for a compound capable of treating cancer pain.
  • a step of examining whether the candidate compound competitively inhibits binding to the PAF receptor may be further included.
  • the screening method of the present invention preferably further includes a step of examining whether or not the candidate compound has a pain suppressing action in the pain model animal.
  • the screening method of the present invention may be used to screen for a compound that enhances the function of a factor that enhances the function of the descending pain suppression pathway in the spinal cord.
  • a known bioassay may be used, and the action of PAF used as a screening index includes, but is not limited to, the following: Platelet aggregation; Leukocyte elastase secretion in polymorphonuclear leukocytes (PMNs); Leukocyte ⁇ -D-glucuronidase secretion in PMNs; Reactive oxygen production in PMNs.
  • PMNs polymorphonuclear leukocytes
  • PMNs polymorphonuclear leukocytes
  • Leukocyte ⁇ -D-glucuronidase secretion in PMNs Reactive oxygen production in PMNs.
  • HL-60 cells differentiated into PMNs and neutrophils and cell lines overexpressing PAF receptors, whether or not the enhancement of cell migration ability by PAF is inhibited is investigated. Whether or not inhibits the action of PAF.
  • cells expressing the PAF receptor are labeled with a fluorescently or radiolabeled PAF, and the candidate compound. And then in the presence / absence of a cell membrane, a cell membrane fraction is prepared, and the presence or absence of radioactivity in the fraction may be examined.
  • the platelet aggregation action can be measured by preparing a washed platelet suspension obtained by collecting and separating blood and measuring the platelet aggregation by adding PAF with an aggregometer.
  • the measurement of leukocyte elastase secretion in PMNs may be performed by measuring elastase activity in a medium obtained by adding PAF to a leukocyte suspension obtained by collecting and separating blood and then centrifuging.
  • Leukocyte ⁇ -D-glucuronidase secretion in PMNs is measured by adding ⁇ -D-glucuronidase activity in the medium obtained by adding PAF to the leukocyte suspension obtained by collecting and separating blood and then centrifuging it. That's fine.
  • superoxide (O 2 ⁇ ) which is a kind of produced active oxygen, is reduced by cytochrome C
  • Measurement may be performed using a chemiluminescence method using superoxide dismutase (SOD), a fluorescence method using a flow cytometer, or an NBT reduction method.
  • Measurement of cell migration using PMNs and neutrophil-like differentiated HL-60 cells and cell lines overexpressing the PAF receptor was performed by setting the cell suspension and PAF solution with a filter in between. What is necessary is just to measure the cell number which passed the small diameter of the filter according to the concentration gradient.
  • the pain model animal that can be used in the screening method of the present invention is not particularly limited as long as it is a known cancer pain model animal, but NCTC2472 tumor cells used in Examples described later are transplanted into a mouse femur.
  • the prepared femur cancer model is most preferable. That is, the screening method of the present invention can be a method for screening a compound capable of treating bone cancerous cancer pain.
  • BN 50739 was dissolved in 45% 2-hydroxypropyl- ⁇ -cyclodextrin (Sigma / RBI, Natick, MA), adjusted to pH 6.0 with 1M NaOH (5 mg / mL), and then artificial cerebrospinal fluid (ACSF) or Dilute with saline. Other reagents were dissolved in ACSF or saline.
  • the composition of ACSF was NaCl 142 mM, KCl 5 mM, CaCl 2 ⁇ 2H 2 O 2 mM, MgCl 2 ⁇ 6H 2 O 2 mM, NaH 2 PO 4 1.25 mM, D-glucose 10 mM, HEPES 10 mM, and adjusted to pH 7.4. .
  • Reagents were administered intravenously, orally or intrathecally.
  • intravenous administration various reagents (5 mL / kg body weight) were administered from the mouse tail vein.
  • oral administration various reagents (5 mL / kg body weight) were directly administered into the stomach cavity using an oral needle for mice.
  • intrathecal administration administration of the spinal cord, various reagents (5 mL / kg body weight) dissolved in 5 ⁇ L of ACSF were used with a Hamilton micro syringe (27 gauge 1/2 injection needle) for the fifth and sixth lumbar intervertebral Was administered slowly.
  • the needle was inserted into the spinal subarachnoid space and confirmed by “flick”, a fast reflex movement of the mouse tail. It has been shown that the distribution of drugs administered intrathecally is limited to the lumbar portion of the spinal cord due to the distribution of malachit green or commassie brilliant blue by intraspinal administration.
  • mice [1.2. animal ⁇ In the experiment, 6-30 weeks old, 25-30 g C3H / HeN male mice were used. The animals were housed in an environment of a room temperature of 22 ⁇ 1 ° C., a humidity of 55 ⁇ 10%, and a 12 hour light / dark cycle (light period: 8 am to 8 pm) with 5 animals per cage. Feed and water were available ad libitum. Experiment. Performed during the light cycle. All animals were handled according to the Japanese Pharmacological Society Animal Handling Guidelines and the Hiroshima University Animal Handling Guidelines. Mice that were significantly debilitated in a short period of time (20% or more), or that were debilitated due to difficulty in drinking or feeding, were treated with euthanasia in order to reduce pain.
  • a mouse femoral cancer model (FBC mouse) was prepared by transplanting osteolytic sarcoma cells NCTC2472 into the left femur bone marrow of C3H / HeN mice. C3H / HeN mice were subjected to skin incision under sodium pentobarbital (50 mg / kg, intraperitoneal administration) anesthesia to expose the femur. An injection port was created in the distal part of the femur using a dental reamer (No. 25). The cell suspension adjusted to 2 ⁇ 10 7 cells / mL (HBSS) was injected from the injection port using 5 ⁇ L, 30 G injection needle and microsyringe. The injection port was closed with dental cement (Caviton), and the skin was sutured. Sham mice were prepared by injecting 5 ⁇ L of HBSS instead of cells. Randomization and drug administration to the various treatment groups was performed on the 11th postoperative day.
  • NCTC2472 cells were cultured at 37 ° C. in an environment of 5% CO 2 and 95% air using Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 100 units / mL penicillin, 100 ⁇ g / mL streptomycin. .
  • DMEM Dulbecco's Modified Eagle's Medium
  • Evaluation was performed before administration of the drug and at a predetermined time after administration. The study was conducted in an environment where the observer could not discriminate between treatment groups.
  • RNA interference In vivo knockdown of the target gene by RNA interference, a PAF receptor-specific double-stranded RNA (siRNA) is prepared from a sequence specific to the mouse PAF receptor gene, and hemagglutinating virus of Japan envelope After encapsulating in a vector system (HVJ-Envelope Vector Kit GenomeONE; Ishihara Sangyo Kaisha, Ltd., Osaka, Japan), it was administered by intrathecal administration from the fifth and sixth lumbar vertebrae of mice. Target protein expression was confirmed by immunoblotting and immunohistochemical analysis. A control group was administered with only the same amounts of mutant siRNA and HVJ-Envelope Vector.
  • siRNA PAF receptor-specific double-stranded RNA
  • Constipation due to morphine administration was assessed by a decrease in defecation volume and an increase in the tail reaction of mice, which is attributed to contraction of the anal and bladder sphincters.
  • Mice were acclimated to the environment by raising them in a test cage (filter paper in a grid-like acrylic cage with floors) starting 24 hours before drug administration. Feed and water were available ad libitum. After subcutaneous administration of morphine (0.1-10 mg / kg), the amount of defecation and the presence or absence of a tail reaction were observed for 1 hour. No sample or water was given during the observation. The amount of defecation for 1 hour was corrected by the weight of the mouse. The tail reaction was evaluated by the percentage of mice that raised their tails to 45 ° or more during the experiment. Mice were used for only one experiment.
  • the behavior (Guarding ⁇ ⁇ ⁇ behavior) in which a mouse after transplantation of cancer cells lifts the affected limb at rest is considered as one index of pain.
  • the Guarding behavior time was shortened in a dose-dependent manner (0.01 mg / kg to 0.3 mg / kg) by intravenous administration of TCV-309, and almost no Guarding behavior was observed until 3 days after the administration. This effect was observed until 7 days after administration, and recovered after 10 days (FIG. 2C).
  • the Limb-use abnormality score with the abnormal gait in mice was also suppressed in a dose-dependent manner (0.01 mg / kg to 0.3 mg / kg; FIG. 2D).
  • the PAF antagonist TCV-309 exerts a pain relieving action that lasts for a long time even in a very small amount.
  • WEB2086 0.1 mg / kg
  • BN50739 0.1 mg / kg
  • TCV-309 In order to clarify the action point of the PAF antagonist, the effect when TCV-309 was administered intrathecally was examined (FIGS. 6A to 6D). When a very small amount of TCV-309 (10 pg / mouse) was administered intrathecally, a powerful pain relieving action lasting 3 to 4 days was induced. Therefore, it was suggested that the action point of TCV-309 includes at least the spinal cord.
  • TCV-309 enhanced the effect of morphine within the original duration of action of morphine, or the presence of morphine enhanced the effect of TCV-309.
  • the pain alleviation observed 4 hours after morphine administration was similar to that observed with TCV-309 alone (without morphine) (FIG. 8A right to 8D right). This indicates that the analgesic effect of morphine disappears 4 hours after administration, and that TCV-309 does not prolong the duration of action of morphine.
  • Morphine (0.3 mg / kg) was administered to FBC mice 7 days after administration of various concentrations of TCV-309 (0.01 mg / kg to 0.3 mg / kg), and the pain alleviation effect 20 minutes later was examined. did. The pain alleviating effect of TCV-309 alone was almost disappeared 7 days after administration (FIG. 9A).
  • TCV-309 (0.01 mg / kg) was combined with morphine (0.3 mg / kg), no antiallodynic effect was observed, but TCV-309 (0.03 mg / kg to 0.3 mg / kg)
  • morphine (0.3 mg / kg) was used in combination with TCV-309, a strong antiallodynic effect was observed in a dose-dependent manner (FIG. 9A).
  • FIG. 11 shows the change over time in the pain relieving action of morphine alone in FBC mice.
  • Morphine showed an analgesic effect when administered subcutaneously at 10 mg / kg or more, and the duration of the analgesic effect was 2-3 hours.
  • no dose dependency of morphine was observed except for von Frey test (B). This is presumed to be because when the morphine dose was 10 mg / kg or more, the locomotor activity was significantly increased in a dose-dependent manner, so that the pain intensity could not be properly evaluated.
  • FIG. 14 shows the change over time in the pain relieving effect in FBC mice when TCV-309 is used in combination with morphine. Similar to the high dose morphine (10 mg / kg or more) administered alone (FIG. 11), the duration of analgesic effect was 2-3 hours. This has been found that the combined use of TCV-309 with morphine strongly enhances the analgesic action of morphine but does not affect the duration.
  • Morphine (0.01-10 mg / kg) was subcutaneously administered to FBC mice 3 hours after intravenous administration of TCV-309 (10 ⁇ g / kg), and the defecation amount and tail reaction were examined (FIG. 16).
  • TCV-309 did not affect the tail response of morphine (FIG. 16B).
  • TCV-309 (0.3 mg / kg) was intravenously administered to FBC mice at intervals of 4 days immediately after transplantation of NCTC2472 cells.
  • physiological saline was administered every 4 days from 1 day to 16 days after transplantation.
  • FIGS. 16C and 16D show the life-prolonging effect of the PAF antagonist in FBC mice.
  • the vertical axis shows the mortality rate (including cancer death and euthanasia).
  • mice began to appear to be difficult to feed / feed after 17 days after transplantation, and more than 50% of mice reached 26 days after transplantation, and all mice reached 60 days after transplantation.
  • TCV-309 anti-allodynia action was pretreated for 20 minutes by intravenous administration of TCV-309 (0.1 mg / kg) against the strength of allodynia caused by administration of various concentrations of PAF into the spinal cavity. And from the effect of pretreatment for 3 days.
  • the anti-allodynia effect when TCV-309 (0.1 mg / kg) was intravenously administered 30 minutes after the onset of allodynia by intrathecal administration of PAF (10 pg, 0.1 ng, 1 ng) in untreated mice was examined.
  • the allodynia score decreases immediately after administration of TCV-309, and the antiallodynia effect reaches its maximum value after 10 to 20 minutes.
  • the effect depends on the dose of PAF, and the effect on 10 pg, 0.1 ng and 1 ng of PAF. 97%, 37% and 10% inhibition, respectively.
  • the antiallodynic effect of TCV-309 was constant in intensity until 6 hours thereafter, but rapidly increased between 6 and 12 hours, and completely antagonized the effect of PAF after 12 hours.
  • the PAF allodynia intensity remained constant until 6 hours after administration, but showed a slight decrease after 6 hours (FIG. 17A).
  • TCV-309 (0.1 mg / kg) pretreated for 20 minutes translated the dose-effect curve of PAF-induced allodynia response to the right (competitive antagonistic inhibition).
  • Pretreatment of TCV-309 for 3 days shifted the PAF dose-effect curve to the right and markedly suppressed (noncompetitive competitive inhibition) its maximum response (FIG. 17B). It was revealed that the PAF antagonist inhibits the PAF receptor in a mode of competitive antagonism with PAF in a short time after administration in vivo, but transitions to an irreversible inhibition mode after a long time.
  • the possibility that the inhibition mode of the PAF antagonist may change from competitive competitive inhibition to non-competitive competitive inhibition over time, as it may change to an irreversible inhibition mode by acting for a long time, and There is a possibility that the intracellular movement (internalization) of the PAF receptor is promoted.
  • the PAF receptor is a 7-transmembrane G protein-coupled receptor, and it is known that receptor internalization occurs when an agonist acts. Therefore, the effect of a PAF antagonist on PAF receptor internalization was examined.
  • the PAF receptor is expressed in nerve cells, microglia and dorsal horn ganglion cells in the spinal cord, but its expression level is small. Therefore, it was difficult to analyze the amount of PAF receptor expressed on the cell membrane by Western blot. Microglia highly expresses a PAF receptor, and is strongly activated by PAF stimulation, and various cell functions are enhanced. The present inventors have also shown that microglia activation is involved in the PAF-induced allodynia reaction in the spinal cord. From these viewpoints, the effect of the PAF antagonist on the internalization of the PAF receptor was examined using microglia isolated and cultured from the spinal cord.
  • Microglia isolated and cultured from the newborn mouse spinal cord were cultured with TCV-309 (0.15 ⁇ M), and then proteins on the cell membrane surface were labeled with biotin. In addition, cell surface proteins were recovered with streptavidin after cell lysis. The amount of PAF receptor expressed on the cell membrane surface was analyzed by Western blotting, and the effect of TCV-309 on receptor internalization was evaluated based on the decrease in the amount of PAF receptor expressed on the cell membrane.
  • Mouse spinal cord microglia were obtained from primary cultured cells in the spinal cord of newborn mice (1-2 days after birth) (Motoyoshi et al., Neurochem Int 52 (6): 1290-1296). , 2008). The purity of microglia was 98% or more in CD11b (OX-42) immunocytochemical staining.
  • the amount of PAF receptor contained in the biotinylated cell membrane fraction was measured by Western blotting as the amount of PAF receptor expressed on the cell surface.
  • TCV-309 0.15 ⁇ M
  • the amount of receptors expressed on the cell membrane surface was 60% and 41%, respectively, in the control group, which was marked over time. It decreased clearly (FIG. 17C). There was no change in the amount of PAF receptor in the whole cell fraction (data not shown).
  • PAF antagonists promote internalization of PAF receptors. This suggests that enhanced internalization of the PAF receptor by the PAF antagonist may be involved in the long duration of action of the inhibitor.
  • PAF receptor is expressed in microglia and astrocytes, and cells activated by PAF receptor stimulation produce / release cytokine / reactive oxygen species and other substances related to inflammation / pain and produce PAF / Liberate. It was shown that the PAF antagonist exerts analgesic action in all stages from the early stage to the late stage of onset of cancer pain. It is suggested that the production and release of PAF may be enhanced during these pains. Microglia and astrocytes are possible candidates for the source of PAF during pain. Therefore, the possibility of causing pain by spinal cord transplantation of activated astrocytes and the involvement of PAF in the onset of pain were examined.
  • Astrocyte culture method Primary culture of mouse spinal cord astrocytes was performed using the spinal cord of ddY newborn mice (0-3 days after birth) (Takano et al., Neurochem Int 57 (7): 812- 818, 2010). The purity of the cells subjected to the experiment using astrocytes was 96% or more by immunocytochemical staining using GFAP.
  • the culture medium was collected, and the cell supernatant was separated by centrifugation to obtain an astrocyte conditioned medium. This was administered into the spinal cavity of normal mice, and the allodynia score and the allodynia threshold were evaluated over time.
  • FIG. 20 shows the pain relieving action when continuous frequent intravenous administration of TCV-309 is performed at various timings in cancer pain model mice.
  • the figure shows that the increase in allodynia score was suppressed until around 30 days regardless of the administration time, and then a slow increase in score was observed, and the decrease in the allodynia threshold was suppressed until around 30 days regardless of the administration time, Thereafter, a slow decrease in threshold was observed, the onset of resting pain was suppressed until about 30 days regardless of the administration time, and then the slow onset of pain was observed, and regardless of the administration time. It shows that the onset of body movement pain was suppressed until around 30 days, and then the onset of slow pain was observed. Specifically, it is as follows.
  • a PAF antagonist (TCV-309, 0.3 mg / kg iv) was administered immediately after cancer cell transplantation (ie, 3 hours later) and once a day for 6 consecutive days, so that allodynia and guarding behavior, Limb -Onset of use abnormality was not observed until around 30 days after transplantation, and then a slow pain response was observed.
  • TCV-309 continuous administration disappeared the pain response immediately after administration, and the pain response could be suppressed until about 30 days after transplantation (FIG. 20A-D).
  • the analgesic mechanism of the PAF antagonist may include at least specific inhibition of the PAF receptor in the spinal cord.
  • the present invention can be in the following aspects: [1] A composition for treating cancer pain, comprising a PAF antagonist. [2] The composition according to 1, further comprising a factor that enhances the function of the descending pain suppression pathway in the spinal cord. [3] The composition according to 1-2, which is used to enhance the action of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord. [4] The composition according to 1-2, which is used to suppress a side effect of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord. [5] A composition for treating pain, Contains a PAF antagonist, A composition for use in combination with a factor that enhances the function of the descending pain suppression pathway in the spinal cord.
  • composition according to 5 wherein the pain is cancer pain.
  • the composition according to 5 to 6 which is applied to a subject before applying a factor that enhances the function of the descending pain suppression pathway in the spinal cord.
  • the composition according to 5 to 7, which is used for enhancing the action of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • the composition according to 5 to 7, which is used for suppressing a side effect of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • a kit comprising a PAF antagonist and, optionally, a factor that enhances the function of the descending pain suppression pathway in the spinal cord.
  • the kit according to 11 comprising an instruction sheet describing a use procedure for treating pain.
  • the kit according to 12, wherein the pain is cancer pain.
  • the kit according to 11, comprising an instruction describing a use procedure for enhancing an action of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • the kit according to 11 comprising an instruction sheet describing a use procedure for suppressing a side effect of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord.
  • kits according to 11, wherein the procedure for preparing the composition according to 1 to 10 is described.
  • a method of treating pain comprising administering an effective amount of a PAF antagonist to a subject.
  • a method of enhancing the action of a factor that enhances the function of the descending pain suppression pathway in the spinal cord comprising administering an effective amount of a PAF antagonist to a subject.
  • a method for suppressing a side effect of a factor that enhances the function of a descending pain suppression system pathway in the spinal cord comprising a step of administering an effective amount of a PAF antagonist to a subject.
  • a method for screening for a compound that suppresses a side effect of a factor that enhances the function of the descending pain suppression system pathway in the spinal cord comprising the step of examining whether the candidate compound inhibits the action of PAF. [25] The method according to 22 to 24, further comprising examining whether the candidate compound competitively inhibits binding of PAF or a PAF analog to the PAF receptor. [26] The method according to 22 to 25, further comprising the step of selecting a candidate compound having a pain suppressing action on a pain model animal.
  • PAF antagonist for example, compounds listed in the section [2: Treatment of cancer pain by PAF antagonist] are preferably used.
  • Specific effects of the present invention include the following: (1) Cancer pain (especially bone cancer pain) can be strongly suppressed over a long period of time. (2) Since a life-prolonging effect on bone cancer transplanted animals has been shown, a life-prolonging effect on primary bone cancer patients or bone metastatic cancer patients can also be expected. (3) frequent continuous administration once a day for 6 to 7 days, regardless of the stage of cancer (ie, immediately after cancer cell transplantation or after pain becomes prominent) Since no pain reaction was developed even after 30 days from the end, the onset of cancer pain can be prevented and the pain relieving effect can be sustained over a long period (12 hours, 24 hours, 1 to 30 days) it can.
  • the analgesic action of the above factor can be remarkably enhanced by the combined use with a factor that enhances the function of the descending pain suppression pathway in the spinal cord such as morphine.
  • the combined use of a PAF antagonist and the above factor can alleviate cancer pain at a dose lower than the dose that provides a pain relieving effect with the PAF antagonist alone or the above factor alone.
  • Tactile stimulation-induced pain response (allodynia) was induced by activated astrocyte transplantation, and allodynia disappeared when a PAF antagonist (TCV-309, 0.3 mg / kg, iv) was administered.
  • TCV-309 is administered continuously immediately after cancer cell transplantation and 1 to 6 days after surgery (once daily), and allodynia expression is delayed until after 30 days even if drug administration is interrupted thereafter. I was able to.
  • continuous and frequent administration of PAF antagonists disrupts the formation of a sustained “PAF” activation pathway (PAF receptor stimulation-feedback loop through induction of PAF release) via astrocytes. Permanent palliative treatment of chronic pain in cancer may be possible.
  • a PAF antagonist By using whether or not it is a PAF antagonist as an index, a compound capable of treating cancer pain (particularly bone cancer pain) can be easily obtained.
  • the present invention Using the present invention, pain can be effectively treated, and particularly refractory cancer pain can be dramatically relieved.
  • the present invention providing such an excellent tool can be used in the fields of medicine and pharmacy and can greatly contribute to the development of pharmaceuticals and biochemical reagents.

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Abstract

L'invention concerne une composition qui contient un antagoniste de PAF qui est utilisée pour le traitement d'une douleur cancéreuse. La composition peut de plus contenir un facteur qui stimule la fonction d'une voie descendante d'un système inhibiteur de la douleur dans la moelle épinière, ou la composition peut être utilisée en combinaison à un facteur qui stimule la fonction d'une voie descendante d'un système inhibiteur de la douleur dans la moelle épinière.
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JP2015534491A (ja) * 2012-10-09 2015-12-03 イーユー・ソル・バイオテック・カンパニー・リミテッドＥＵ Ｓｏｌ Ｂｉｏｔｅｃｈ Ｃｏ．， Ｌｔｄ． 脳損傷または脳卒中の治療用キット
WO2016144995A1 (fr) * 2015-03-09 2016-09-15 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions et méthodes de traitement du glioblastome
US12070463B2 (en) 2015-03-09 2024-08-27 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions and methods for the treatment of seizure caused by brain tumor

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