US20150051299A1 - Treatment of schizophrenia using beta-caryophyllene and cb2 receptor agonists - Google Patents

Treatment of schizophrenia using beta-caryophyllene and cb2 receptor agonists Download PDF

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US20150051299A1
US20150051299A1 US14/385,739 US201314385739A US2015051299A1 US 20150051299 A1 US20150051299 A1 US 20150051299A1 US 201314385739 A US201314385739 A US 201314385739A US 2015051299 A1 US2015051299 A1 US 2015051299A1
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bcp
schizophrenia
pcp
pnd
treatment
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Sharon Anavi-Goffer
Juerg Gertsch
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Ariel University Research and Development Co Ltd
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NAPROMED BIOPHARMACEUTICALS GmbH
Ariel University Research and Development Co Ltd
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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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • 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
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • 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 invention in some embodiments, relates to the field of therapy and more particularly, but not exclusively, to compositions comprising beta-caryophyllene (BCP), methods of making the compositions and methods using BCP, for the treatment of schizophrenia.
  • BCP beta-caryophyllene
  • the invention in some embodiments, relates to the field of therapy and more particularly, but not exclusively, to compositions comprising Cannabinoid Receptor Type 2 (CB2) receptor agonists, methods of making the compositions and methods using CB2 receptor agonists for the treatment of schizophrenia.
  • CBD2 Cannabinoid Receptor Type 2
  • Schizophrenia affects about 1% of the population (Lewis & Lieberman, 2000), and genetic and environmental factors underlie the eventual eruption of the disease (Ross, 2006). Schizophrenia is often chronic, characterized by deterioration of social contact, cognitive deficits, anxiety and depression, resulting in suicide in about 10% of the schizophrenic population (Lewis & Lieberman, 2000).
  • compositions comprising beta-caryophyllene (BCP), methods of making the compositions and methods using BCP for the treatment of schizophrenia.
  • BCP beta-caryophyllene
  • CB2 Cannabinoid Receptor Type 2
  • a therapeutic composition comprising beta-caryophyllene (BCP) and a pharmaceutically effective carrier for use in treating schizophrenia.
  • BCP beta-caryophyllene
  • the composition is for use in the treatment of a human subject. In some embodiments, the composition is for use in the treatment of a non-human subject.
  • the schizophrenia is selected from the group consisting of paranoid schizophrenia; disorganized schizophrenia; undifferentiated schizophrenia; catatonic schizophrenia; and residual schizophrenia.
  • the treating comprises treating at least one symptom of schizophrenia selected from the group consisting of a negative symptom of schizophrenia and a positive symptom of schizophrenia.
  • the pharmaceutically effective carrier comprises dimethyl sulfoxide (DMSO). In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL. In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • DMSO dimethyl sulfoxide
  • the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • a single discrete unit e.g., a single tablet, capsule, metered liquid
  • the composition comprises BCP at a weight in the range of from about 25 to about 100 mg.
  • the composition is formulated as an injectable solution dosage form.
  • the injectable solution is configured to be administered by a route selected from the group consisting of intravenous injection, intramuscular injection, intradermal injection, intraperitoneal injection, intrathecal injection and subcutaneous injection.
  • the composition is formulated as an orally-administrable dosage form.
  • the composition is formulated in a dosage form selected from the group consisting of a tablet, a capsule, a dragee, a powder, granules, and an ingestible solution, especially a tablet or capsule.
  • the composition further comprises at least one additional antipsychotic agent.
  • at least one additional antipsychotic agent is selected from the group consisting of chlorpromazine, haloperidol, perphenazine, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone, or combinations thereof.
  • beta-caryophyllene BCP
  • a pharmaceutically effective carrier in the manufacture of a composition (also known as a medicament) for treating schizophrenia in a subject in need thereof.
  • the composition is configured for use in the treatment of a human subject.
  • the composition is configured for use in the treatment of a non-human subject.
  • the schizophrenia is selected from the group consisting of paranoid schizophrenia; disorganized schizophrenia; undifferentiated schizophrenia; catatonic schizophrenia; and residual schizophrenia.
  • the treating comprises treating at least one symptom of schizophrenia selected from the group consisting of a negative symptom of schizophrenia and a positive symptom of schizophrenia.
  • the pharmaceutically effective carrier comprises dimethyl sulfoxide (DMSO). In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL. In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • DMSO dimethyl sulfoxide
  • the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • a single discrete unit e.g., a single tablet, capsule, metered liquid of the composition that is manufactured comprises BCP at a weight in the range of from about 25 to about 100 mg.
  • the composition is made as an injectable solution dosage form.
  • the injectable solution is configured to be administered by a route selected from the group consisting of intravenous injection, intramuscular injection, intradermal injection, intraperitoneal injection, intrathecal injection and subcutaneous injection.
  • the composition is made as an orally-administrable dosage form.
  • the dosage form selected from the group consisting of a tablet, a capsule, a dragee, a powder, granules, and an ingestible solution, especially a tablet or capsule.
  • the composition further comprises at least one additional antipsychotic agent.
  • at least one additional antipsychotic agent is selected from the group consisting of chlorpromazine, haloperidol, perphenazine, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone, or combinations thereof.
  • a method for treating schizophrenia in a subject in need thereof comprising administering a therapeutic composition comprising beta-caryophyllene (BCP) and a pharmaceutically effective carrier.
  • BCP beta-caryophyllene
  • the subject is a human subject.
  • the subject is a non-human subject.
  • the schizophrenia is selected from the group consisting of paranoid schizophrenia; disorganized schizophrenia; undifferentiated schizophrenia; catatonic schizophrenia; and residual schizophrenia.
  • the treating comprises treating at least one symptom of schizophrenia selected from the group consisting of a negative symptom of schizophrenia and a positive symptom of schizophrenia.
  • the average daily amount of the BCP administered to the subject is from about 0.4 mg/kg to about 2 mg/kg.
  • the pharmaceutically effective carrier comprises dimethyl sulfoxide (DMSO). In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL. In some such embodiments, the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • DMSO dimethyl sulfoxide
  • the pharmaceutically effective carrier comprises DMSO, saline and Cremophor EL at a ratio of 1:0.6:18 Cremophor EL:DMSO:saline.
  • the administering comprises injecting the composition to the subject.
  • the injecting comprises injecting by a route selected from the group consisting of intravenous injection, intramuscular injection, intradermal injection, intraperitoneal injection, intrathecal injection and subcutaneous injection.
  • the administering comprises orally administering the composition to the subject.
  • the method further comprises co-administering at least one additional antipsychotic agent.
  • the at least one additional antipsychotic agent is selected from the group consisting of chlorpromazine, haloperidol, perphenazine, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone, or combinations thereof.
  • the at least one additional antipsychotic agent is co-administered in a single dosage form together with the BCP. In some such embodiments, the at least one additional antipsychotic agent is co-administered in a dosage form separate from the BCP. In some such embodiments, the co-administration comprises sequential or simultaneous administration. In some such embodiments, the sequential administration comprises administration of the at least one additional antipsychotic agent prior to administration of the BCP. In some such embodiments, the sequential administration comprises administration of the at least one additional antipsychotic agent subsequent to administration of the BCP.
  • BCP beta-caryophyllene
  • E-BCP pharmaceutically-active isomers
  • Z-BCP substantially inactive sesquiterpenes
  • BCP oxide substantially inactive sesquiterpenes
  • natural sources include a greater proportion of E-BCP than Z-BCP.
  • the BCP includes both E-BCP and Z-BCP, alone or in combination.
  • the BCP used for implementing the teachings herein is at least 65%, at least 75%, at least 85% and even at least 95% by weight E-BCP. In some embodiments, the BCP is substantially pure (at least 99% by weight) E-BCP.
  • the BCP used for implementing the teachings herein is at least 65%, at least 75%, at least 85% and even at least 95% by weight Z-BCP. In some embodiments, the BCP is substantially pure (at least 99% by weight) Z-BCP.
  • the BCP used for implementing the teachings herein is at least 65%, at least 75%, at least 85% and even at least 95% by weight E-BCP and/or Z-BCP. In some embodiments, the BCP is substantially pure (at least 99% by weight) E-BCP and/or Z-BCP.
  • the BCP used for implementing the teachings herein comprises 45-49% E-BCP, 45-49% Z-BCP, 1-5% BCP oxide and 1-5% alpha humulene.
  • BCP used for implementing the teachings herein comprises 45-90% E-BCP, 5-30% Z-BCP, 1-5% BCP oxide and traces alpha humulene.
  • composition comprising a CB2 receptor agonist and a pharmaceutically effective carrier for use in treating schizophrenia.
  • compositions comprising a CB2 receptor agonist and a pharmaceutically effective carrier in the manufacture of a composition for treating schizophrenia in a subject in need thereof.
  • a method for the treating schizophrenia in a subject in need thereof comprising administering a therapeutic composition comprising a CB2 receptor agonist and a pharmaceutically effective carrier.
  • Any suitable CB2 receptor agonist may be used in implementing the composition, the use or the method of treating, in some embodiments BCP and/or HU308.
  • BCP BCP and/or HU308.
  • the various features, options and embodiments are as explicitly discussed with reference to BCP.
  • teachings herein are applied to the treatment of human subjects, for example, humans suffering from schizophrenia.
  • teachings herein are applied to the treatment of non-human animal subjects suffering from schizophrenia.
  • treating includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition
  • a “therapeutic composition” refers to a preparation of one or more of the active ingredients with other components such as pharmaceutically-acceptable carriers and excipients.
  • the purpose of a therapeutic composition is to facilitate administration of an active ingredient to a subject.
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to a subject and does not substantially abrogate the activity and properties of the administered active ingredients. An adjuvant is included under these phrases.
  • excipient refers to an inert substance added to a therapeutic composition to further facilitate administration of an active ingredient.
  • compositions used in implementing the teachings herein may be formulated using techniques with which one of average skill in the art is familiar in a conventional manner using one or more pharmaceutically-acceptable carriers comprising excipients and adjuvants, which facilitate processing of the active ingredients into a pharmaceutical composition and generally includes mixing an amount of the active ingredients with the other components. Suitable techniques are described in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition, which is incorporated herein by reference.
  • compositions useful in implementing the teachings herein may be manufactured by one or more processes that are well known in the art, e.g., mixing, blending, homogenizing, dissolving, granulating, emulsifying, encapsulating, entrapping and lyophilizing processes.
  • compositions suitable for implementing the teachings herein include compositions comprising active ingredients in an amount effective to achieve the intended purpose (a therapeutically effective amount). Determination of a therapeutically effective amount is well within the capability of those skilled in the art, for example, is initially estimated from animal models such as monkey or pigs.
  • FIGS. 1A and 1B relate to mouse body weight at PND 16-17:
  • FIG. 1A is a line graph showing changes in body weight at postnatal days 3 to 17 in mice treated with phencyclidine (PCP), PCP+BCP or control (vehicle) and
  • FIG. 1B is a bar graph showing body weight for the 3 groups at postnatal day 17;
  • FIGS. 2A-2C relate to open field test at PND 16-17:
  • FIGS. 2A and 2B are line graphs showing ambulation ( 2 A) and rearing ( 2 B) at PND 16-17 and
  • FIG. 2C is a bar graph showing body weight at PND 17;
  • FIGS. 3A-3F relate to open field test at PND 16-17:
  • FIGS. 3A and 3D are bar graphs showing body weight for males ( 3 A) and females ( 3 D)
  • FIGS. 3B and 3E are line graphs showing ambulation in males ( 3 E) and females ( 3 F)
  • FIGS. 3C and 3F are line graphs showing rearing in males ( 3 C) and females ( 3 F);
  • FIGS. 4A-4F relate to open field test at PND 35-37:
  • FIGS. 4A and 4D are bar graphs showing body weight for males ( 4 A) and females ( 4 D)
  • FIGS. 4B and 4E are line graphs showing rearing in males ( 4 B) and females ( 4 E)
  • FIGS. 4C and 4F are line graphs showing ambulation in males ( 4 C) and females ( 4 F);
  • FIGS. 5A-5D relate to pre-pulse inhibition at age 8 weeks: FIGS. 5A and 5C are bar graphs showing response to startle for 8 week old males ( 5 A) and females ( 5 C); FIGS. 5B and 5D are line graphs showing percentage inhibition of prepulse inhibition for males ( 5 B) and females ( 5 D);
  • FIGS. 6A-6H relate to elevated plus maze test at age 13 weeks: female duration closed ( 6 A), male duration closed ( 6 B), female duration open ( 6 C), male duration open ( 6 D), female duration distal open ( 6 E), male duration distal open ( 6 F), female open/close duration ( 6 G) and male open/close duration ( 6 H);
  • FIGS. 7A-7I are bar graphs showing mRNA expression of cannabinoid receptors in 9 day old mice for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the left cortex ( 7 A), right cortex ( 7 B) and brain stem ( 7 G); for Cannabinoid Receptor Type 1 (CB1) in the left cortex ( 7 C), right cortex ( 7 D) and brain stem ( 7 H); and for CB2 in the left cortex ( 7 E), right cortex ( 7 F), and brain stem ( 7 I) for control mice and mice treated with PCP;
  • GPDH glyceraldehyde 3-phosphate dehydrogenase
  • FIG. 8 is a Table detailing the percentage change (%) relative to control animals of protein expression of cannabinoid receptors in 2 week old mice;
  • FIGS. 9A-9C are bar graphs showing protein expression of 67 kDa glutamic acid decarboxylase (GAD67)/actin in the left cortex ( 9 A), right cortex ( 9 B) and brain stem ( 9 C) of 2-week old mice treated with saline or PCP;
  • GID67 glutamic acid decarboxylase
  • FIGS. 9D-9F are bar graphs showing protein expression of 67 kDa glutamic acid decarboxylase (GAD67)/actin in the left cortex ( 9 D), right cortex ( 9 E) and brain stem ( 9 F) of 9-day old mice treated with saline or PCP;
  • FIGS. 10A-10C relate to monoacylglycerol lipase (MGL) expression in 2 week old mice treated with saline or PCP: bar graph relating to the left cortex ( 10 A), bar graph relating to the right cortex ( 10 B) and Western blot ( 10 C);
  • FIGS. 11A and 11B are schematic representations of the endocannabinoid synthesizing and degrading pathways as described in Anavi-Goffer, ChemBioChem 2009;
  • FIGS. 12A-12C relate to PND17 using a DMSO-based vehicle: line-graph showing male ambulation ( 12 A), line-graph showing male rearing ( 12 B) and line graph showing male body weight ( 12 C);
  • FIGS. 13A-13C relate to PND16: line-graph showing body weight over PND 3-17 ( 13 A), line-graph showing male and female ambulation ( 13 B) and line-graph showing male and female rearing ( 13 C);
  • FIGS. 14A-14E show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on ambulation but did not affect body weight: line graph of body weight at PND 40-68 ( 14 A), bar graph of female and male body weight at PND63 ( 14 B), line graph of male ambulation at PND 63 ( 14 D), line graph of female ambulation at PND 63 and line graph of male and female ambulation at PND 63;
  • FIGS. 15A-15C show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on rearing: line graph of male and female rearing at PND63 ( 15 A), line graph of male rearing at PND63 ( 15 B) and line graph of female rearing at PND63 ( 15 C);
  • FIGS. 16A-16C show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on PPI: line graph of % PPI at PND68 ( 16 A); bar graph of female startle response at PND68 ( 16 B) and bar graph of male startle response at PND68 ( 16 C);
  • FIGS. 17A-17C show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on the response to tone (PPI test): line graph of response to tone at PND68 ( 17 A); line graph of female response to tone at PND68 ( 17 B) and line graph of male response to tone at PND68 ( 17 C);
  • FIGS. 18A-18C show results demonstrating that BCP treatment at adolesence did not affect the startle response at the end of the PPI test: female startle response at PND 68 ( 18 A), male startle response at PND 68 ( 18 B) and all-mice startle response at PND68 ( 18 C);
  • FIGS. 19A-19F show results demonstrating that BCP treatment at adolesence did not reverse the effects of PCP in plus maze test: open/close duration at PND 64 ( 19 A), open/(close+open) duration at PND 64 ( 19 B), distal open/(close+open) duration at PND 64 ( 19 C), open/close frequency at PND 64 ( 19 D), open/(open+close) frequency at PND 64 ( 19 E) and distal open/(open+close) frequency at PND 64 ( 19 F);
  • FIGS. 20A-20E show results demonstrating that BCP treatment at adolesence reversed the effects of PCP on the time spent in the hidden zone (behavior in the Phenotyper cage): bar graph of female hidden zone duration at PND 91 ( 20 A), bar graph of male hidden zone duration at PND 91 ( 20 B), bar graph of male and female hidden zone duration at PND 91 ( 20 C), bar graph of male hidden zone frequency at PND 91 ( 20 D) and bar graph of female hidden zone frequency at PND 91 ( 20 E);
  • FIGS. 21A-21C show results demonstrating that BCP treatment at adolesence reversed the effects of PCP on frequency of entries to the wheel (motor behavior in the Phenotyper cage: bar graph of female wheel zone frequency at PND 91 ( 21 A), bar graph of male wheel zone frequency at PND 91 ( 21 B) and bar graph of male and female wheel zone frequency at PND 91 ( 21 C);
  • FIGS. 22A-22F show results demonstrating that BCP treatment at adolesence on the time spent at drinking and food zones (Phenotyper cage): bar graph showing male food zone duration at PND91 ( 22 A), bar graph showing female food zone duration at PND91 ( 22 B), bar graph showing male and female food zone duration at PND91 ( 22 C), bar graph showing male drink zone duration at PND91 ( 22 D), bar graph showing female drink zone duration at PND91 ( 22 E) and bar graph showing male and female drink zone duration at PND91 ( 22 F);
  • FIGS. 23A-23E show results demonstrating that BCP treatment at adolesence improved exploration and rearing behaviors of male PCP treated mice at PND 104: line graph of female ambulation at PND 104 ( 23 A), line graph of male ambulation at PND 104 ( 23 B), line graph of female rearing at PND 104 ( 23 C), line graph of male rearing at PND 104 ( 23 D) and bar graph of male and female body weight at PND 104 ( 23 E);
  • FIGS. 24A-24C show results demonstrating that BCP treatment at adolesence did not reverse the effect of PCT on grooming at PND104: bar graph of female grooming at PND 104 ( 24 A), bar graph of male grooming at PND 104 ( 24 B) and bar graph of male and female grooming at PND 104 ( 24 C);
  • FIGS. 25A-25I show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on attention at PND106 (PPI test): bar graph of female startle at PND 106 ( 25 A), bar graph of male startle at PND 106 ( 25 B), bar graph of male and female startle at PND 106 ( 25 C), line graph of female response to tone of varying intensity ( 25 D), line graph of female response to tone of varying intensity ( 25 E), line graph of female response to tone of varying intensity ( 25 F), line graph of % prepulse inhibition for females at PND 106 ( 25 G), line graph of % prepulse inhibition for males at PND 106 ( 25 H) and line graph of % prepulse inhibition for males and females at PND 106 ( 25 I);
  • FIGS. 26A-26F show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on frequency of entries to hidden zone (Phenotyper cage) at PND 105: bar graph of male hidden zone frequency at PND 105 ( 26 A), bar graph of female hidden zone frequency at PND 105 ( 26 B), bar graph of male and female hidden zone frequency at PND 105 ( 26 C), bar graph of male wheel zone frequency at PND 105 ( 26 D), bar graph of female wheel zone frequency at PND 105 ( 26 E) and bar graph of male and female wheel zone frequency at PND 105 ( 26 F);
  • FIGS. 27A-27E show results demonstrating that BCP treatment at adolesence reversed the effect of PCP on time spent at the hidden zone but not the time spent in the wheel zone (Phenotyper cage) at PND 105: bar graph of male hidden zone duration at PND 105 ( 27 A), bar graph of female hidden zone duration at PND 105 ( 27 B), bar graph of male wheel zone duration at PND 105 ( 27 C), bar graph of female wheel zone duration at PND 105 ( 27 D) and bar graph of male and female wheel zone duration at PND 105 ( 27 E); and
  • FIGS. 28A-28B show results demonstrating that AM630 reversed the effect of BCP on PCP-induced inhibition of ambulation and rearing: line graph of male ambulation at 17 days ( 28 A) and line graph of male rearing at 17 days ( 28 B).
  • compositions comprising beta-caryophyllene (BCP), methods of making the compositions and methods using BCP for the treatment of schizophrenia.
  • BCP beta-caryophyllene
  • CB2 Cannabinoid Receptor Type 2
  • the Cannabinoid Receptor Type 2 (CB2) is a guanine nucleotide-binding protein (G protein)-coupled receptor that in humans is encoded by the CNR2 gene.
  • Beta-caryophyllene (BCP, CAS 87-44-5) is a CB2-receptor agonist (Gertsch et al. 2008, Anavi-Goffer et al., 2012). The fact that orally-administered BCP is absorbed by the digestive tract and becomes systemically available and apparent substantial non-toxicity makes BCP attractive as a potential active pharmaceutical ingredient.
  • the Inventors have studied the effect of BCP in a murine model of schizophrenia, produced by administration of the N-methyl-D-aspartic acid (NMDA) antagonist, phenylcyclidine (PCP).
  • NMDA N-methyl-D-aspartic acid
  • PCP phenylcyclidine
  • Administration of phencyclidine to rats e.g. Josselyn and Vaccarino, 1998; Wang & Johnson, 2005; Ballmaier, 2007; Takahashi, 2006
  • mice e.g. Long, 2006; Hashimoto 2005
  • Phencyclidine may be administered acutely or chronically, during adulthood or during postnatal development, using different dose ranges (2.5 mg/kg to 20 mg/kg).
  • the Inventors In order to induce chronic, long lasting schizophrenic-like behaviors and neurochemical changes in the endocannabinoid system, the Inventors have now developed a neonatal mouse model, based on a neonatal phencyclidine model previously described for rats (Takahashi, 2006). As the Inventors have extensively studied the endocannabinoid system in Sabra strain mice (Harlan, Israel), see for example Fride 2005 and Fride 2007, these mice have been used in the present study.
  • the Inventors have found that following administration of PCP, the CB2 receptor expression level is selectively down-regulated in different brain areas. Furthermore, up-regulation of putative CB2 receptor expression has been detected in the right cortex and basal ganglia/diencephalon of mice which were neonatally treated with phencyclidine. These results support some aspects of the teachings herein, where putative CB2 receptors are up-regulated in specific brain areas in schizophrenia.
  • composition comprising beta-caryophyllene (BCP) and a pharmaceutically effective carrier for use in treating schizophrenia.
  • beta-caryophyllene BCP
  • a pharmaceutically effective carrier in the manufacture of a medicament for treating schizophrenia in a subject in need thereof.
  • such a composition is configured for administration to a human subject. In some embodiments, such a composition is configured for administration to a non-human animal subject.
  • a method for treating schizophrenia in a subject in need thereof comprising administering a pharmaceutically-effective amount of beta-caryophyllene (BCP) to the subject.
  • BCP beta-caryophyllene
  • the subject is a human subject.
  • the subject is a non-human animal.
  • compositions and methods of treatments disclosed herein are useful for treating one or more of paranoid schizophrenia; disorganized schizophrenia; undifferentiated schizophrenia; catatonic schizophrenia; and residual schizophrenia.
  • compositions and methods of treatments disclosed herein are useful in the treatment of a negative symptom of schizophrenia.
  • compositions and methods of treatments disclosed herein are useful in the treatment of a positive symptom of schizophrenia.
  • the duration of treatment according to the method of treating schizophrenia according to the teachings is any suitable duration as determined by a treating health-care professional, typically a psychiatric doctor.
  • the average daily dose of BCP administered to a human subject is from about 0.4 mg/kg to about 2 mg/kg, such as, for example, from about 0.4 mg/kg to about 1.5 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1.6 mg/kg, from about 0.4 mg/kg to about 1.4 mg/kg, from about 0.4 mg/kg to about 1.2 mg/kg, from about 0.4 mg/kg to about 1 mg/kg, from about 0.4 mg/kg to about 0.8 mg/kg, from about 0.4 mg/kg to about 0.6 mg/kg or from about 0.4 mg/kg to about 0.5 mg/kg.
  • the average daily dose for a human subject is in the range of from about 25 mg to about 100 mg, such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.
  • the average daily dose is administered with a frequency of between about once a week to about 3 times per day, for example once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, 6 times per week, once per day, twice per day or 3 times per day.
  • a composition according to the teachings herein is provided as or made as a dosage form including a plurality of discrete units (e.g., discrete solids or metered liquids), especially discrete solid units such as pills (including tablets and caplets) and capsules (including gelcaps), where each unit includes BCP in the range of from about 25 mg to about 100 mg, such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.
  • such a dosage form is exceptionally useful for the once-daily administration of the desired average daily dosage.
  • composition disclosed herein may be administered by any suitable route of administration, including but not limited to oral administration, parenteral administration (including intravenous injection, intramuscular injection, intradermal injection, intraperitoneal injection, intrathecal injection and subcutaneous injection), and rectal administration. That said, in some embodiments, oral administration is preferred due to the proven oral availability and substantial-non toxicity of BCP.
  • the composition disclosed herein may comprise a pill, a capsule, a dragee, a powder, granules, an ingestible solution (such as a liquid, a gel, a syrup, or a suspension) and the like, for oral ingestion by a subject.
  • a composition for oral administration comprises a pill or a capsule.
  • the composition is a gastroresistant orally-administrable dosage form, that is to say, an orally-administrable dosage form configured to carry the BCP through the stomach to be released into contact with the digestive tract only after passage through the duodenum.
  • the composition is in the form of a gastroresitant soft gel capsule, comprising between 25 mg and about 100 mg BCP in a carrier comprising vegetable oil.
  • Some embodiments of the method when implemented with an adult human subject, comprise orally ingesting a single such capsule twice a day for at least one month, so that the average daily dose is between about 50 mg and about 200 mg BCP.
  • the composition described herein further comprises at least one additional antipsychotic agent, such as, for example, a typical antipsychotic agent (including, but not limited to, one or more of chlorpromazine, haloperidol, perphenazine, or fluphenazine), and/or an atypical antipsychotic agent (including, but not limited to, one or more of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone), or combinations thereof.
  • a typical antipsychotic agent including, but not limited to, one or more of chlorpromazine, haloperidol, perphenazine, or fluphenazine
  • an atypical antipsychotic agent including, but not limited to, one or more of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone
  • the BCP is administered together with at least one additional antipsychotic agent, such as, for example, a typical antipsychotic agent (including, but not limited to, one or more of chlorpromazine, haloperidol, perphenazine, or fluphenazine), and/or an atypical antipsychotic agent (including, but not limited to, one or more of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone), or combinations thereof.
  • a typical antipsychotic agent including, but not limited to, one or more of chlorpromazine, haloperidol, perphenazine, or fluphenazine
  • an atypical antipsychotic agent including, but not limited to, one or more of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone
  • BCP and an antipsychotic agent are administered together, BCP and the additional antipsychotic agent are co-administered in a single dosage form.
  • BCP and the additional antipsychotic agent are co-administered in separate dosage forms, either sequentially or simultaneously.
  • the additional antipsychotic agent may be administered prior to administration of BCP, or the additional antipsychotic agent may be administered subsequent to administration of BCP.
  • composition comprising a CB2 receptor agonist and a pharmaceutically effective carrier for use in treating schizophrenia.
  • a CB2 receptor agonist and a pharmaceutically effective carrier in the manufacture of a medicament for treating schizophrenia in a subject in need thereof.
  • a method for treating schizophrenia in a subject in need thereof comprising administering a pharmaceutically-effective amount of a CB2 receptor agonist to the subject.
  • BCP was obtained from Sigma-Aldrich (St. Louis, Mo., USA), catalogue Nr. W225207 and further purified using preparative HPLC (HP1090 series; column, PEGASIL ODS (Senshu Sci. i.d. 10 ⁇ 250 mm); solvent, 70% CH3OH; flow rate, 2.0 mL/min; detection, UV 220 nm] to remove other sesquiterpenes.
  • GC-MS analysis showed that the BCP used in the below included 95% E-BCP, 3% Z-BCP, 1% BCP Oxide and traces of alpha humulene.
  • AM630 was obtained from Cayman Chemical Company (Ann Arbor, Mich., USA).
  • PCP, Cremophor EL and DMSO were obtained from Sigma-Aldrich (St. Louis, Mo., USA).
  • Phencyclidine an NMDA antagonist which induces schizophrenia and psychotic effects in humans
  • PCP Phencyclidine
  • This treatment induces long-lasting schizophrenic-like effects in mice that lasted into adulthood.
  • the therapeutic effects of beta-caryophyllene, a dietary cannabinoid and CB2 receptor agonist, in accordance with the teachings herein were evaluated.
  • BCP final dose 10 mg/kg in 1:0.6:18 Cremophor EL:DMSO:saline was administered by injection 1 hour after PCP. Results were obtained from one litter which was divided into the three groups.
  • mice were assessed for hyperactivity behavior on postnatal day 16 ( FIG. 2 ). Mice were placed in the center of a transparent glass cube cage 30 ⁇ 40 ⁇ 31 cm divided into squares of 7.5 ⁇ 7.5 cm. The number of squares and rearing activity were counted for 8 min. Positive Symptoms. Prepulse Inhibition (PPI) of the Startle Reflex
  • mice were placed in a startle chamber and allowed to acclimate for 5 min.
  • a loudspeaker produced a 65 dB background white noise or the various acoustic pre-pulse stimuli (dB): 74, 78, 82, 86, and 90 (20 ms).
  • a 120 dB (40 ms) stimulus was given first to induce a response to startle.
  • the response of the mouse was transduced and stored by a computer.
  • Each test session lasted for 11 min and consisted of 5 presentations of each of the trial types presented in random order and separated by 15 second intervals.
  • Anxiety as measured by the paucity of time spent on the two, anxiety-provoking, open arms (as opposed to the two enclosed arms) of an “Elevated Plus Maze” was used as a parameter of negative symptoms of schizophrenia (Josselyn and Vaccarino, 1998).
  • the plus maze was elevated 50 cm above the table top.
  • Behavior of each mouse was recorded for 5 min by a video camera and scored using the “EthoVision” software (Noldus Information Technology, Wageningen, The Netherlands), measuring the number of entries as well as the amount of time spent in each arm, open or closed. Increased time spent in the closed arms indicated increased anxiety. Increased time spent in the opened arms indicated anxiolytic behavior (reduced stress).
  • FIGS. 2A , 2 B At PND 17, at the end of treatment with BCP, locomotor activity, hyperactivity, and exploratory behaviors were tested with the open-field test ( FIGS. 2A , 2 B).
  • PCP significantly inhibited both ambulation and rearing behaviors.
  • Treatment with BCP reversed the effects of PCP on rearing and exploration.
  • the effect of BCP is not dependent on ethanol as its solvent.
  • a DMSO-based carrier completely reversed the effects of PCP on ambulation ( FIG. 12A ) and rearing behavior ( FIG. 12B ).
  • mice were re-evaluated in the open-field test at PND 35-37. Results of body weight, rearing and ambulation were separated according to the sex of mice ( FIGS. 4A-F ). Treatment with BCP significantly reversed the effect of PCP on female body weight ( FIG. 4D ). At this age there was no significant difference in male body weight between the groups ( FIG. 4A ).
  • FIGS. 4E , 4 F In females, no differences in rearing and exploration behaviors were seen between the different groups ( FIGS. 4E , 4 F, respectively).
  • mice were Tested at Age 8 Weeks in the Pre-Pulse Inhibition Test ( FIGS. 5A-D ).
  • mice were tested in the Elevated-Plus Maze test which indicates the level of anxiety ( FIGS. 6A-H ).
  • Phencyclidine alters the level of anxiety. However its effect is dependent on the strain of mice, sex and possibly age (Turgeon, 2011; Wily, 1995).
  • FIGS. 6A , 6 B, 6 C, 6 D There was no significant change in the time spent in the closed arm or open arm (all length of arm), for either females or males.
  • PCP reduced the time spent in the distal end of the opened arm (the very far end of the arm from the center) for females, and BCP reversed this effect ( FIGS. 6E , 6 G).
  • FIGS. 6F , 6 H PCP increased the time spent in the distal end of the opened arm (the very far end of the arm from the center) for males, and BCP reversed this effect.
  • FIGS. 7A-I Brain tissue of control mice (saline treated) and mice treated with PCP were analyzed in the left and right cortex and brain stem ( FIGS. 7A-I ; FIG. 8 . Results from the cortex and brain stem were reported by the Inventors in 2011 (Anavi-Goffer et al).
  • FIGS. 7A-7C No difference in GAPDH was seen in the left cortex, right cortex or brain stem ( FIGS. 7A-7C , respectively).
  • FIG. 7G A significant increase in mRNA expression of CB2 receptor was found in the left cortex of the PCP-treated mice ( FIG. 7G ) but in the right cortex there was no difference between control and PCP-treated mice ( FIG. 7H ).
  • FIG. 7I A significant increase in mRNA expression of CB2 receptor was found in the brain stem of the PCP-treated mice ( FIG. 7I ).
  • GAD67 a neurochemical marker for schizophrenia
  • FIG. 9A-F Brain tissue of control mice and mice treated with PCP were analyzed for GAD67, a neurochemical marker for schizophrenia.
  • GAD67 protein level was significantly decreased ( FIG. 9A ) but no change was found at the mRNA level FIG. 9D ).
  • FIG. 9B the right cortex, the reduction in protein level of GAD67 did not reach a significant level and no change was seen in the mRNA level ( FIG. 9B , FIG. 9E ).
  • FIG. 9F the results of Western blotting showed a non-significant reduction in GAD67 protein level
  • FIG. 9C This suggests that there might be a common mechanism which links the changes in GAD67 to those of CB 1 and CB2, and this mechanism may be related to the function of GABAergic neurons.
  • FIGS. 10A-C , FIG. 11B Brain tissues were analyzed for MGL, an enzyme which degrades 2-AG an endocannabinoid ( FIGS. 10A-C , FIG. 11B ) in control mice and mice treated with PCP.
  • mRNA levels of MGL decreased in the left cortex of the PCP-treated group ( FIG. 10A ), but not in the right cortex ( FIG. 10B ). The direction of these results was correlated with the reduction in protein level of MGL as analyzed with Western blotting ( FIG. 10C ).
  • FIG. 11A A scheme of synthesis and degradative enzymes of the endocannabinoid system is shown in FIG. 11A ( FIGS. 11A and 11B were published by Anavi-Goffer & Mulder, Chembiochem. 2009 10:1591-8).
  • PCP 5 mg/kg was administered by injection on PND 3, 5, 7, 10, 12, 13, 15 and 17. Body weight was measured at every injection between PND 3-17. The open field test was conducted on PND 16.
  • mice When the mice were adolescent (PND 43-61), BCP (5 mg/kg in a mixture of DMSO:Cremophor EL:saline 0.6:1:18.4) was injected twice a week (on Sunday and Wednesday) for 3 weeks, a total of 6 injections. After the final BCP injection, mice were tested in the open field test (PND 63), Elevated Plus Maze test (PND 64), PPI test (PND 68) and behavior at the Phenotyper cage (PND 91). Mice were re-tested at adulthood on PND 104 (open field), PND 105 (Phenotyper) PND 106 (PPI).
  • PND 43-61 When the mice were adolescent (PND 43-61), BCP (5 mg/kg in a mixture of DMSO:Cremophor EL:saline 0.6:1:18.4) was injected twice a week (on Sunday and Wednesday) for 3 weeks, a total of 6 injection
  • PCP significantly reduced body weight in male and female mice as measured on days 3, 5, 7, 10, 12, 15 and 17.
  • BCP treatment during adolescence significantly reversed the effect of PCP on ambulation in male and female mice at PND 63 ( FIGS. 14C-14E ).
  • BCP treatment in adolescence significantly inhibited the exploration of mice compared with saline-treated mice.
  • BCP reversed the effect of PCP on rearing in both females and males ( FIGS. 15A-15C ).
  • BCP treatment in adolescence significantly reversed the effect of PCP on pre-pulse inhibition ( FIG. 16A ).
  • BCP had no substantial effect on saline-treated mice.
  • BCP treatment at adolescent significantly reversed the effect of PCP on startle response in females ( FIG. 16B ). In males, there was no difference in the response to the startle stimuli between groups ( FIG. 16C ).
  • FIGS. 25A-25C there was no difference in the response to the startle stimuli (120 dB) between groups ( FIGS. 25A-25C ).
  • BCP reversed the effect of PCP on the response to tones ( FIGS. 25D-25F ).
  • BCP treatment at adolescence reversed the effect of PCP on the % pre-pulse inhibition (PPI) ( FIGS. 25G-25I ).
  • PCP increased the time spend at the Hidden Zone, indicating the PCP-treated mice had higher level of anxiety of mice at the PhenoTyper cage compared with vehicle-treated mice.
  • BCP treatment at adolescence reversed the effects of PCP on the time spend in the Hidden Zone of PhenoTyper cage in females and males, respectively ( FIGS. 20A , 20 B).
  • FIG. 20C shows combined results, suggesting that BCP reversed the effect of PCP on anxiety level.
  • PCP appeared to reduce the frequency of entries to the Hidden Zone in males ( FIG. 20D ) but not in females ( FIG. 20E ).
  • BCP reversed the effect of PCP in males ( FIG. 20D ).
  • FIGS. 21A , 21 B shows combined results of both sex.
  • PCP increased the frequency of entries to the Hidden Zone, indicating an increased level of anxiety.
  • BCP treatment at adolescence reversed the effects of PCP on the frequency of entries to the hidden zone ( FIGS. 26A , 26 B, 26 C). These results suggest that treatment with BCP reduced the level of stress and anxiety. BCP treatment appeared to reduce the effect of PCP on the frequency of entries to the Wheel Zone FIG. 26 . This effect was prominent in males than in females ( FIGS. 26D , 26 E).
  • BCP treatment at adolescence reversed the effects of PCP on the time spend at the hidden zone ( FIGS. 27A , 27 B). These results suggest that treatment with BCP reduced the level of stress and anxiety. BCP treatment at adolescence showed a trend to reverse the effect of PCP on the time spend in the wheel ( FIGS. 27C , 27 D, 27 E).
  • AM630 (6-Iodopravadoline, CAS 164178-33-0) is a molecule that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165 ⁇ selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses.
  • mice were injected with PCP (5 mg/kg in saline) at postnatal days PND 4, 6, 8, 11, 13, 15, and 18 to provide a murine model of schizophrenia.
  • a control group was injected with vehicle (0.6:1:18.4 DMSO:Cremophor EL:saline) alone. Each experiment was repeated twice. In each experiment, male mice were divided into 4 groups:
  • mice were injected with vehicle or BCP (final dose 10 mg/kg in 1:0.6:18 Cremophor EL:DMSO:saline) or BCP+AM630 (equal parts of 20 mg/kg BCP in DMSO and 20 mg/kg AM630 in DMSO, providing a final concentration of 10 mg/kg each of BCP and AM630, mixed together).
  • BCP final dose 10 mg/kg in 1:0.6:18 Cremophor EL:DMSO:saline
  • BCP+AM630 equal parts of 20 mg/kg BCP in DMSO and 20 mg/kg AM630 in DMSO, providing a final concentration of 10 mg/kg each of BCP and AM630, mixed together.

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