WO2019043679A1 – March 7, 2019 – METHOD FOR SENSITIVITY TESTING OF CANNABINOIDS ON PATIENT-DERIVED TUMOR BIOPSIES AND CTCS

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Inventors :

BALLAN, Eyal - 9 Harimon street, Ramat Hasharon; GRINBERG, Moran - Rehovot

Owner :

CANNABICS PHARMACEUTICALS INC. BALLAN, Eyal

Application Number :

WOIL18050004

Document Number :

WO2019043679A1

Priority Date :

September 4, 2017

Filing Date :

January 2, 2018

Date of Grant/ Publication :

March 7, 2019

Class :

G01N33 / 574

Abstract

The present invention discloses a method useful for selecting a personalized cannabinoid- based therapy for a mammalian subject diagnosed with cancer. The method comprises steps of: in vitro contacting (i) genetically identifiable non-cancerous biological specimens from said mammalian subject; (ii) genetically identifiable cancerous biopsy specimens from said mammalian subject; and (iii) genetically identifiable circulating tumor cells (CTCs) with a plurality of cannabinoid analytes; recording data on the outcome of said in vitro contact; selecting a first cycle personalized cannabinoid therapy for said mammalian subject; monitoring therapeutic response of said mammalian subject to said selected therapy; detecting signals derived from said CTCs at n time points, wherein n is an integer equal or higher than 2, comprising of at least one time point before start of said personalized therapy and at least a second time point at a time during said first cycle; and processing said detected signals with said therapeutic response of said first cycle and selecting a second cycle of clinical personalized therapy for said mammalian subject. The present invention further discloses a system thereof and a method useful for selecting a personalized cannabinoid- based regime for cancer prevention in sub clinical individuals.

Claim(s)

1. A method useful for selecting a personalized cannabinoid- based therapy for a mammalian subject diagnosed with cancer, wherein the method comprises steps of: a. in vitro contacting i. genetically identifiable non-cancerous biological specimens from said mammalian subject; ii. genetically identifiable cancerous biopsy specimens from said mammalian subject; and iii. genetically identifiable circulating tumor cells (CTCs) with a plurality of cannabinoid analytes b. recording data on the outcome of said in vitro contact; c. selecting a first cycle personalized cannabinoid therapy for said mammalian subject; d. monitoring therapeutic response of said mammalian subject to said selected therapy; e. detecting signals derived from said CTCs at n time points, wherein n is an integer equal or higher than 2, comprising of at least one time point before start of said personalized therapy and at least a second time point at a time during said first cycle; and f. processing said detected signals with said therapeutic response of said first cycle and selecting a second cycle of clinical personalized therapy for said mammalian subject.;
2. The method of claim 1, wherein said mammalian subject is a human patient.;
3. The method according to claim 2, wherein said human patient is selected from a group consisting of patient not diagnosed with cancer, patient diagnosed with cancer and patient diagnosed with cancer resistant to conventional chemotherapies.;
4. The method of claim 1, wherein said cancerous biopsy specimens are selected from the group consisting of fine needle aspirate, a tumor tissue biopsy and a tumor cell.;
5. The method of claim 1, wherein the non- cancerous biological specimens is selected from the group consisting of: tissues, extracts, cell cultures, cell lysates, lavage fluid, or physiological fluids and any combination thereof.;
6. The method according to claim 1, wherein said cancerous specimens are selected from the group consisting of: breast, ovarian, colon/ rectum, prostate, melanoma, head and neck, osteosarcoma, gastric, glioma, glioblastoma, neuroblastoma, leukemia, adenocarcinoma, adrenal, anal, bile duct, bladder, bone, brain/CNS, cervical, endometrial, esophagus, eye, gastrointestinal, kidney, leukemia, liver, lung , lymphoma, multiple myeloma, nasal cavity and paranasal sinus, nasopharyngeal, non- hodgkin’s lymphoma, oral cavity, oropharyngeal, osteosarcoma, ovarian, pancreatic, penile, pituitary, prostate , pancreas, retinoblastoma, rhabdomyosarcoma, salivary gland, sarcoma, skin, small intestine, stomach, testicular, thymus, thyroid, uterine sarcoma, vaginal and vulvar and any combination thereof.;
7. The method according to claim 1, wherein the genetic identification in non-cancerous tissue is selected from the group of cell markers consisting of: ALK gene, Alpha- fetoprotein (AFP), Beta-2-microglobulin (B2M), Beta-human chorionic gonadotropin (Beta-hCG), BCR-ABL fusion gene, BRAF mutation V600E, CA15- 3/CA27.29, CA19-9, CA-125, Calcitonin, Carcinoembryonic antigen (CEA), CD20, Chromogranin A (CgA), Chromosomes 3, 7, 17, and 9p21, Cytokeratin fragments 21- 1, EGFR mutation, Estrogen receptor (ER)/progesterone receptor (PR), Fibrin/fibrinogen, HE4, HER2/neu, Immunoglobulins, KIT, KRAS mutation, Lactate dehydrogenase, Nuclear matrix protein 22, Prostate-specific antigen (PSA), Thyroglobulin, Urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI-1), 5-Protein signature (Oval), 21-Gene signature (Oncotype DX), 70- Gene signature (Mammaprint) and any combination thereof.;
8. The method according to claim 1, wherein the genetic identification further comprises gene expression profiling.;
9. The method of claim 1 wherein the outcome of in vitro contacting is selected form the group consisting of: anti-proliferative, regenerative, anti-inflammatory, anti-mitotic, differentiative, anti-metastatic, anti-angiogenic, apoptotic, cytotoxic, cytopathic and any combination thereof.;
10. The method of claim 1, wherein said measurable effect on cells is an effect on a biological parameter selected from the group consisting of: proliferation, migration, absorbance, adherence, apoptosis, necrosis, autophagy, cytotoxicity, cell size, motility, cell cycle and any combination thereof.;
11. The method of claim 1 wherein the step of recording data on the outcome of in vitro contacting comprises steps selected from the group consisting of isolation, enumeration, sensitization with a plurality of cannabinoid analytes and any combination thereof.;
12. The method of claim 1, wherein the step of recording data on the outcome of in vitro contacting is selected from the group of means consisting of: optic, luminescent, fluorescent, immunological, cell count, radioactive, non-radioactive isotopic, electrical and any combination thereof.;
13. The method of claim 1, wherein said step of recording data and selecting a personalized cannabinoid therapy is operable by High Through output Screening (HTS).;
14. The method of claim 1, wherein therapeutic response is selected from the group consisting of: cancer markers level, tumor size monitoring, metastasis monitoring, survival, quality of life measured according to one or more scales, and any combination thereof.;
15. The method of claim 1, wherein the therapeutic response is selected from the group consisting of inhibited cancer cell proliferation, inhibited cancer cell growth, inhibited angiogenesis in a tumor, inhibited cancer cell invasion, inhibited cancer cell mobility, inhibited cancer cell differentiation, promoted cancer cell death, inhibited cancer progression, inhibited cancer metastasis, or improved animal survival, or a combination thereof.;
16. The method of claim 1 , further comprising enumerating said CTCs at t time points, wherein n is an integer equal or higher than 2, comprising one time point before start of personalized therapy and a second time point at a later time over life of said mammalian subject, further detecting the signals of a measurable effect of said CTCs with personalized therapy, further selecting a new personalized therapy and recommending the administration of the new selected personalized therapy to said mammalian subject.;
17. A method for measuring the therapeutic response of said subject to said personalized treatments according to claim 1, at n time points, wherein n is an integer equal or higher than 2, comprising first time point before start of personalized treatment and a second time point at a later time over life of said mammalian subject; comprising: a. enumerating said CTCs of said mammalian subject at t time points, b. measuring dimensions of tumor of said mammalian subject at n time points, further recommending the administration of the personalized therapy be continued if both CTC enumerating values and tumor dimensions values at second time point are lower than value at said first time point.;
18. The method according to claim 16, wherein if both CTC enumerating values and tumor dimensions values at the second time point are higher than the values obtained at said first time point, comprising steps of: e. dis-continuation the administration of the personalized therapy; f. contacting said CTCs specimen of said second time point with new personalized therapy; g. detecting a signal indicative of a measurable effect on said cancerous biological specimens with said targeted therapies, wherein alteration of said signal over time measured on said biological specimen relative to a control sample, is indicative of said measurable effect of said targeted therapy on said cell sample; h. recommending the administration of the selected personalized therapy to said mammalian subject.;
19. The method according to claim 1, repeating the detecting the signals of a measurable effects of said CTCs at plurality of time points , determining whether the subject is responsive; and recommending the administration of the selected personalized therapy be continued if the subject is responsive or to be discontinued is the subject is non responsive, i.e. resistant.;
20. The method of claim 1, wherein resistance to a drug is detected when there is uninhibited cancer cell proliferation, uninhibited cancer cell growth, uninhibited angiogenesis in a tumor, uninhibited cancer cell invasion, uninhibited cancer cell mobility, uninhibited cancer cell differentiation, diminished cancer cell death, uninhibited cancer progression, uninhibited cancer metastasis, a decline in animal survival, or a combination thereof.;
claim 21: 21. The method according to claim 1 wherein said conventional chemotherapy is selected from the group consisting of chemotherapy, surgery, radiotherapy, hormonotherapy, and/or immunotherapy.;
claim 22: 22. The method according to claim 1 further selecting a personalized cannabinoid therapy for treating an individual who has cancer with cells that are multiple drug resistant.;
claim 23: 23. The method according to claim 1, wherein detection signals of said CTCs comprises steps selected from a group of isolation, enumeration, sensitization with a plurality of cannabinoid analytes and any combination thereof.;
claim 24: 24. The method according to claim 1 , wherein said measurable effect on cells is selected from the group consisting of: anti-proliferative, regenerative, anti-inflammatory, antimitotic, differentiative, anti-metastatic, anti-angiogenic, apoptotic, cytotoxic, cytopathic and any combination thereof.;
claim 25: 25. The method according to claim 1, wherein said measurable effect on cells is an effect on a biological parameter selected from the group consisting of: proliferation, migration, absorbance, adherence, apoptosis, necrosis, autophagy, cytotoxicity, cell size, motility, cell cycle and any combination thereof.;
claim 26: 26. The method according to claim 1 , wherein said measurable effect on cells is selected from the group consisting of physiological, genetic, biochemical, structural and any combination thereof.;
claim 27: 27. The method according to claim 1 wherein detection signals of said CTCs is operable by MAINTRAC blood test protocol for circulating tumor cells.;
claim 28: 28. The method according to claim 1, wherein said processing of detected signals comprises steps selected from the group consisting of: correlating, normalizing, calibrating, factorizing, calculating, statistically analyzing and any combination thereof.;
claim 29: 29. The method according to claim 1, wherein said analyte is selected from the group consisting of cannabinoid-type, cannabinoid derivative, cannabis extract or fraction thereof, non-cannabinoid-type constituent, product, compound, molecule or substance and any combination thereof;
claim 30: 30. The method according to claim 1, wherein said analyte is extracted from cannabis; said cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.;
claim 31: 31. The method of claim 1, wherein said cannabinoid anlaytes are selected from the group consisting of: Cannabigerol (CBG) type, Cannabichromene (CBC) type, Cannabidiol (CBD) type, ?9 -Tetrahydrocannabinol (THC) type, ?8 -THC type, Cannabicyclol (CBL) type, Cannabielsoin (CBE) type, Cannabinol (CBN) and Cannabinodiol (CBND) types, Cannabitriol (CBT) type, cannabinoids with miscellaneous types and any combination thereof.;
claim 32: 32. The method of claim 21, wherein the THC or a derivative thereof is selected from the group consisting of THC, THCV, THCA, THCVA, Delta-9-tetrahydrocannabinol (A9-THC) and delta-8-tetrahydrocannabinol (A8-THC) and any combination thereof.;
claim 33: 33. The method of claim 21, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, CBDV, CBDA and any combination thereof.;
claim 34: 34. The method of claim 1, wherein said selection of personalized cannabinoid therapy comprising (a) adjuncting cannabinoid- based therapy to conventional chemotherapy or (b) using cannabinoid- based therapy as mono-therapy.;
claim 35: 35. A system useful for selecting a personalized cannabinoid- based therapy for a mammalian subject diagnosed with cancer, wherein the system comprises a. in vitro contacting module configured to contact i. genetically identifiable non-cancerous biological specimens from said mammalian subject ii. genetically identifiable cancerous biopsy specimens from said mammalian subject iii. genetically identifiable circulating tumor cells (CTCs) with a plurality of cannabinoid analytes b. module for recording data on the outcome of said in vitro contacting c. module for selecting a first cycle personalized cannabinoid therapy for said mammalian subject d. module for monitoring therapeutic response of said mammalian subject to said selected therapy e. module for detecting signals derived from said CTCs at n time points, wherein n is an integer equal or higher than 2, comprising of at least one time point before start of said personalized therapy and at least a second time point at a time during said first cycle and f. module for processing said detected signals with said therapeutic response of said first cycle and selecting a second cycle of clinical personalized therapy for said mammalian subject.;
claim 36: 36. The system of claim 35 wherein said modules comprises a. at least one measurement appliance configured to interconnect to said modules, said measurement appliance for generating a plurality of output signals indicating information related to the (i) recorded data on the outcome of said in vitro contacting (ii) monitored therapeutic response of said mammalian subject (iii) detected signals derived of said CTCc (iv) processed detected signals with therapeutic response (selected personalized therapy, b. an analysis module operable to perform analysis of said output signals, said module interconnected to a processor , c. a processor operable to execute computer program modules, said program modules comprise a genomic module, an in vitro module and a diagnosis module, d. a memory associated with the processor, e. a database associated with said processor and said memory, f. a computer system comprising a processor and means for controlling the processor to carry out the method of claim 1 and a computer program executable by the processor and stored on a computer readable medium, g. a central device further comprised a computer-readable medium storing instructions that, when executed by a computer, cause it to perform a specified method.;
claim 37: 37. The system of claim 35, wherein said mammalian subject is human patient.;
claim 38: 38. The system according to claim 37, wherein said human patient selected from a group of patients not diagnosed with cancer, patient diagnosed with cancer and patient diagnosed with cancer resistant to conventional chemotherapies.;
claim 39: 39. The system of claim 35, said cancerous biopsy specimens are one of the members of a group containing fine needle aspirate, a tumor tissue biopsy and a tumor cell.;
claim 40: 40. The system of claim 35, wherein the non- cancerous biological specimens is selected from the group consisting of: tissues, extracts, cell cultures, cell lysates, lavage fluid, or physiological fluids and any combination thereof.;
claim 41: 41. The system according to claim 35, wherein said cancerous specimens are selected from the group consisting of: breast, ovarian, colon/ rectum, prostate, melanoma, head and neck, osteosarcoma, gastric, glioma, glioblastoma, neuroblastoma, leukemia, adenocarcinoma, adrenal, anal, bile duct, bladder, bone, brain/CNS, cervical, endometrial, esophagus, eye, gastrointestinal, kidney, leukemia, liver, lung , lymphoma, multiple myeloma, nasal cavity and paranasal sinus, nasopharyngeal, non- hodgkin lymphoma, oral cavity, oropharyngeal, osteosarcoma, ovarian, pancreatic, penile, pituitary, prostate , pancreas, retinoblastoma, rhabdomyosarcoma, salivary gland, sarcoma, skin, small intestine, stomach, testicular, thymus, thyroid, uterine sarcoma, vaginal and vulvar and any combination thereof.;
claim 42: 42. The system according to claim 35, configured to genetic identification in noncancerous tissue are selected from the group of cell markers consisting of: ALK gene, Alpha-fetoprotein (AFP), Beta-2-microglobulin (B2M), Beta-human chorionic gonadotropin (Beta-hCG), BCR-ABL fusion gene, BRAF mutation V600E, CA15- 3/CA27.29, CA19-9, CA-125, Calcitonin, Carcinoembryonic antigen (CEA), CD20, Chromogranin A (CgA), Chromosomes 3, 7, 17, and 9p21, Cytokeratin fragments 21- 1, EGFR mutation, Estrogen receptor (ER)/progesterone receptor (PR), Fibrin/fibrinogen, HE4, HER2/neu, Immunoglobulins, KIT, KRAS mutation, Lactate dehydrogenase, Nuclear matrix protein 22, Prostate-specific antigen (PSA), Thyroglobulin, Urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI-1), 5-Protein signature (Oval), 21-Gene signature (Oncotype DX), 70- Gene signature (Mammaprint) and any combination thereof.;
claim 43: 43. The system according to claim 35, configured to genetic identification further configured to gene expression profiling .;
claim 44: 44. The system of claim 35 wherein the outcome of in vitro contacting is selected form the group consisting of: anti-proliferative, regenerative, anti-inflammatory, antimitotic, differentiative, anti-metastatic, anti-angiogenic, apoptotic, cytotoxic, cytopathic and any combination thereof.;
claim 45: 45. The system according to claim 35, wherein said measurable effect on cells is an effect on a biological parameter selected from the group consisting of: proliferation, migration, absorbance, adherence, apoptosis, necrosis, autophagy, cytotoxicity, cell size, motility, cell cycle and any combination thereof.;
claim 46: 46. The system of claim 35 wherein said outcome of in vitro contacting is selected from a group consisting of isolation, enumeration, , sensitization with a plurality of cannabinoid analytes and any combination thereof.;
claim 47: 47. The system according to claim 35, wherein the module configured to record data on the outcome of in vitro contacting are selected from the group of: optic, luminescent, fluorescent, immunological, cell count, radioactive, non-radioactive isotopic, electrical and any combination thereof.;
claim 48: 48. The system according to claim 35, wherein said module to select a personalized cannabinoid therapy is operable by High Through output Screening (HTS).;
claim 49: 49. The system of claim 1, wherein therapeutic response is selected from the group consisting of: cancer markers level, tumor size monitoring, metastasis monitoring, survival, quality of life measured according to one or more scales, and any combination thereof.;
claim 50: 50. The system of claim 1, wherein the therapeutic response is selected from the group consisting of inhibited cancer cell proliferation, inhibited cancer cell growth, inhibited angiogenesis in a tumor, inhibited cancer cell invasion, inhibited cancer cell mobility, inhibited cancer cell differentiation, promoted cancer cell death, inhibited cancer progression, inhibited cancer metastasis, or improved animal survival, or a combination thereof.;
claim 51: 51. The system of claim 35, further comprising modules to enumerate said CTCs at t time points, wherein n is an integer equal of higher than 2, comprising of one time point before start of personalized therapy and a second time point at a later time over life of said mammalian subject, further comprising module to detect the signals of a measurable effect of said CTCs with personalized therapy, further comprising module to select a new personalized therapy to recommend the administration of the new selected personalized therapy to said mammalian subject.;
claim 52: 52. A system configured to measure the therapeutic response of said subject to said personalized treatments according to claim 35, at n time points , wherein n is an integer equal of higher than 2, comprising of first time point before start of personalized treatment and a second time point at a later time over life of said mammalian subject; comprising: a. module configured to enumerate said CTCs of mammalian subject at t time points, b. module configured to measure dimensions of tumor of said mammalian subject at n time points further configured to recommend the administration of the personalized therapy be continued if both CTC enumerating values and tumor dimensions values at second time point are lower than value at said first time point i.e. subject is responsive.;
claim 53: 53. The system according to claim 51, if both CTC enumerating values and tumor dimensions values at the second time point are higher than the values obtained at said first time point i.e. subject is not- responsive, comprising : a. dis-continuation the administration of the personalized therapy b. module to contact said CTCs specimen of said second time point with new personalized therapy , c. module to detect a signal indicative of a measurable effect on said cancerous biological specimens with said targeted therapies, wherein alteration of said signal over time measured on said biological specimen relative to a control sample, is indicative of said measurable effect of said targeted therapy on said cell sample d. module to recommend the administration of the selected personalized therapy to said mammalian subject;
claim 54: 54. The system according to claim 35, configured to repeat the detection of a measurable effects of said CTCs at plurality of time points , to determine whether the subject is responsive; and to recommend the administration of the selected personalized therapy be continued if the subject is responsive or to be discontinued is the subject is non responsive, i.e. resistant.;
claim 55: 55. The system of claim 35, wherein resistance to a drug is configured to detect when there is uninhibited cancer cell proliferation, uninhibited cancer cell growth, uninhibited angiogenesis in a tumor, uninhibited cancer cell invasion, uninhibited cancer cell mobility, uninhibited cancer cell differentiation, diminished cancer cell death, uninhibited cancer progression, uninhibited cancer metastasis, a decline in animal survival, or a combination thereof.;
claim 56: 56. The system according to claim 35 wherein said conventional chemotherapy is selected from the group consisting of chemotherapy, surgery, radiotherapy, hormonotherapy, and/or immunotherapy.;
claim 57: 57. The system according to claim 35 further configured to select a personalized cannabinoid therapy for treating an individual who has cancer with cells that are multiple drug resistant.;
claim 58: 58. The system according to claim 35, wherein detection signals of said CTCs comprises a group of isolation, enumeration, sensitization with a plurality of cannabinoid analytes and any combination thereof.;
claim 59: 59. The system according to claim 35, wherein said measurable effect on cells is selected from the group consisting of: anti-proliferative, regenerative, anti-inflammatory, antimitotic, differentiative, anti-metastatic, anti angiogenic, apoptotic, cytotoxic, cytopathic and any combination thereof.;
claim 60: 60. The system according to claim 35, wherein said measurable effect on cells is an effect on a biological parameter selected from the group consisting of: proliferation, migration, absorbance, adherence, apoptosis, necrosis, autophagy, cytotoxicity, cell size, motility, cell cycle and any combination thereof.;
claim 61: 61. The system according to claim 35, wherein said measurable effect on cells is selected from the group consisting of physiological, genetic, biochemical, structural and any combination thereof.;
claim 62: 62. The system according to claim 35 wherein detection signals of said CTCs are configured to operate by MAINTRAC blood test protocol for circulating tumor cells.;
claim 63: 63. The system according to claim 35, configured to process detected signals, selected from the group consisting of: to correlate, normalize, calibrate, factorizing, calculate, statistically analyze and any combination thereof.;
claim 64: 64. The system according to claim 35, wherein said analyte is selected from the group consisting of cannabinoid-type, cannabinoid derivative, cannabis extract or fraction thereof, non-cannabinoid-type constituent, product, compound, molecule or substance and any combination thereof;
claim 65: 65. The system according to claim 35, wherein said analyte is extracted from cannabis; said cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.;
claim 66: 66. The system according to claim 35, wherein said cannabinoid anlaytes are selected from the group consisting of: Cannabigerol (CBG) type, Cannabichromene (CBC) type, Cannabidiol (CBD) type, ?9 -Tetrahydrocannabinol (THC) type, ?8 -THC type, Cannabicyclol (CBL) type, Cannabielsoin (CBE) type, Cannabinol (CBN) and Cannabinodiol (CBND) types, Cannabitriol (CBT) type, cannabinoids with miscellaneous types and any combination thereof.;
claim 67: 67. The system according to claim 65, wherein the THC or a derivative thereof is selected from the group consisting of THC, THCV, THCA, THCVA, Delta-9- tetrahydrocannabinol (A9-THC) and delta-8-tetrahydrocannabinol (A8-THC) and any combination thereof.;
claim 68: 68. The system according to claim 65, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, CBDV, CBDA and any combination thereof.;
claim 69: 69. The system according to claim 35, wherein said selection of personalized cannabinoid therapy configured cannabinoid- based therapy adjunct to conventional chemotherapy or cannabinoid- based therapy as mono-therapy.;
claim 70: 70. A method useful for selecting a personalized cannabinoid- based regime for cancer prevention in sub clinical individuals, wherein the method comprises steps of: g. in vitro contacting i. genetically identifiable non-cancerous biological specimens from said mammalian subject; ii. genetically identifiable circulating tumor cells (CTCs) with a plurality of cannabinoid analytes h. recording data on the outcome of said in vitro contact; i. selecting a first cycle personalized cannabinoid administration for said mammalian subject; j. monitoring CTC levels of said mammalian subject response to said cannabinoid administration; k. detecting signals derived from said CTCs at n time points, wherein n is an integer equal or higher than 2, comprising of at least one time point before start of said personalized administration and at least a second time point at a time during said first cycle; and 1. processing said detected signals with said CTC signals of said first cycle and selecting a second cycle of cannabinoid administration; for said mammalian subject. 71. The method of claim 1, wherein said mammalian subject is a human patient.

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