Chinese Medicine
اسلاید 1: www.tabaye.ir
اسلاید 2: “West Meets East” Chinese Medicine Could be a Cornerstone for Developing Future MedicineYung-Chi ChengHenry Bronson Professor of PharmacologyYale School of Medicine
اسلاید 3: Cancer & Viral Chemotherapy Scope of ActivityMolecular and Biochemical Pharmacology of Anticancer and Antiviral CompoundsDrug DiscoveryClinic Protocol Design Drug Entity of Current InterestNucleoside AnalogsNatural ProductsChinese Medicine
اسلاید 4: Chemical(s)IndicationClinical StageDHPG (Gancyclovir)*CMVApproved3TC (Lamivudine)*HBVApprovedL-FTC (Emtricitabine)HBVPhase III (completed)L-FMAU (Clevudine)HBVApprovedL-OddC (Troxacitabine)Solid TumorPhase I/IIL-Fd4C (Elvucitabine)HIVHBVPhase IIPhase I/IID-IPdR (Ropidoxuridine)Radiosensitizer For solid tumorPhase I/IIOrphan Drug StatusD-4’Ed4THIVPreclinicalPHY-906CancerPhase II * Do Not Hold Patent * Do Not Hold Patent * Do Not Hold PatentChemicals Discovered in this Laboratory (In Collaboration with Others) Under Different Stages of Clinical Development
اسلاید 5: Nature Product Analogs Under Current InvestigationCamptothecin and VP-16 conjugates CancerTylophorine analogsCancer and autoimmune diseasesHelioxanthin analogsHepatitis B VirusFalvanoid analogsFacilitator of oral uptake of drug
اسلاید 6: Scope of Medicine-For treatment of disease-For improving use of other medicine-For prevention of disease-For enhancement of “quality of life” of patients and “healthy” individuals
اسلاید 7: The Current Paradigm of Mainstream Pharmaceutical DiscoveryReductionist approachTo identify a target associated with diseaseTo identify a single compound that can regulate a given target associated with a disease. Such compounds are expected to have potency and selectivity for the treatment of the disease targeted.
اسلاید 8: Challenges of Current Mainstream Drug Discovery ApproachFor a given disease, it can be caused by multiple reasons, it will be difficult to find one chemical with defined target related to diseases- To treat the majority of patients- To prevent a majority of the population contracting the diseaseFor a given treatment, multiple side effects could occur, it will be difficult to find one drug to relieve all the side effectsFor different patients with the same disease caused by the same etiological factor, the response to a given treatment could be different. Host factors need to be taken into considerationMany of potent drugs for the treatment or prevention of chronic diseases may require long-term use, delayed toxicity may occur
اسلاید 9: New Paradigm for Future MedicineMultiple targetsPolychemical medicine instead of one chemical medicine with system biology approach in mind
اسلاید 10: Two Approaches to Polychemical MedicineConventional “Step by step”Revisiting history as the basis of reinventing medicineTraditional Chinese medicine and other Folk medicine
اسلاید 11: Chinese herbal medicine has many chemicals which could target on multiple sites or act on a single site additively or synergistically through direct or indirect interaction.Chinese Medicine has multiple medical usage for the treatment of complicated diseases or multiple symptoms as well as disease prevention and improving quality of life.Chinese Medicine takes a holistic approach and is an early form of “system biology” and “integrated medicine”.Chinese Medicine is prescribed on an individual basis to optimize its usage. It is “individualized medicine”.Chinese Medicine Could Meet Some of the Current Unmet Medical Needs and Serve as the Basis for Future Medicine”
اسلاید 12: Botanical Drugs: A new area for the US FDAGuidelines for the Botanical Drug Industry: (June 2004)Waive the combination ruleMay enter Phase I,II clinical studies with a documented history of useRequirements for approval will include:SafetyEfficacyProduct Consistency“Botanical drug” and drug interactionMechanism(s) of Action(s) & Active Ingredients
اسلاید 13: How to Make Preparations of Herbal Medicine with ConsistencyAuthentication of herbGood agricultural practices (GAP)Good manufacturing practices (GMP)
اسلاید 14: Authentication of HerbMicro-morphological analysisGene sequence analysisChemical analysisIn vitro (solution state)In situ (solid state)
اسلاید 15: Stem TissueCoated Stem TissueA schematic Diagram Showing the determination a chemical image of herbal tissue by Matrix-Assisted Laser Desorption / Ionization Mass Spectrometry (MALD-MS)
اسلاید 16: Direct Desorption / Ionization of Morphinane Alkaloids from the Stem Tissue of Sinomenium acutum by MALDI By: K.M. Ng (HKU) Z. Zhao (BU) et al.
اسلاید 17: ◊ 0311007 and □ 0311008 are two different samples from Shaanxi province ▲ 0311011 and ●0312032 are from Anhui province and Chongqin city, respectively. K.M. Ng et al. (Unpublished Results)Spatial distribution of two metabolites from within stem tissue of Sinomenium acutum collected from different growing areas
اسلاید 18: Good Agricultural Practices consistency of raw ingredientsBotanical authenticationMacro and micro histologyAgricultural contaminantsHeavy metals, pesticides, fungicides, herbicides …Bacterial, plant, fungal contaminantsHarvest time“Raw Plant” fingerprintsGood Manufacturing Practice consistency of drug substance and productPhytomicsQCChemical AnalysisBiological AnalysisInformatics / Data miningBotanical Quality Control
اسلاید 19: Quality Control for Complex MixturesRegulatory and Scientific ChallengeWhat do you measure?How do you measure it?How do you compare it?A NOVEL APPROACH IS REQUIRED!! What can be done now Multiple parameters InclusiveComprehensive Quality Control Measures
اسلاید 20: Two Tier Approach to Botanical QCTier One: Individual AnalysisSpecific, Absolute QuantitationIndividual Chemical Marker CompoundsSpecific Enzyme/Receptor Target ActivitiesTier Two: Fingerprint AnalysisGlobal, Relative QuantitationChemical FingerprintBioresponse Fingerprint
اسلاید 21: Criteria for PhytomicsQCInformation-intensive fingerprintsMolecular resolutionQuantitative analysisRobust, integrated technologiesCentralized informaticsValidated platform with SOPsChemical and biological metrics
اسلاید 22: PhytomicsQCTMDNAProtein“blueprint”RNA“messenger”“executioner”BioResponse fingerprintChemical fingerprintMr. Mouse / PharmacologyProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 23: CPT-11 Capecitabine, 5-FU CPT-11/5-FU/LV VP-16 L-OddC Gemcitabine Oxaliplatin Colorectal Cancer Liver Cancer Colorectal Cancer Lung Cancer Leukemia, Pancreatic Pancreatic Cancer Colorectal CancerChemotherapeutic Agent IndicationPHY906 *Composition Spray dried aqueous extract of four botanicals Traditional use (since 300 A.D.)Diarrhea, vomiting, nausea, intestinal crampingModern use (2000 A.D.) : An adjuvant for cancer chemotherapy* U.S. Patent 7,025,993 B2 ; IND: 62,627
اسلاید 24: PHY906: Identification using LC/MS DataIn collaboration with PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 25: PSI Ratio vs. IntensityIntensityPSI Provided by PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 26: PSI Distribution of 15 Sources of same FormulaProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 27: Biological Response for Quality Control of Herbal MedicineEnzyme or Receptor AssaysCell-Based AssaysCell growth or behaviorsFunctional genomicsProteomicsPhytomicsIn Vivo Assays
اسلاید 28: PhytomicsQCTMDNAProtein“blueprint”RNA“messenger”“executioner”BioResponse fingerprintChemical fingerprintMr. Mouse / PharmacologyProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 29: 18%4%35%7%4%2%26%4%Pathway Analysis of Regulated GenesPHY906-6 in HepG2 cells (regulated genes > 1.2 fold in dChip analysis)
اسلاید 30: Batch 6Batch 7Batch 8Batch 9Batch FBatch 6 1.000.990.990.920.32Batch 71.000.990.930.36Batch 81.000.950.42Batch 91.000.45Batch F1.00PSI Calculations (based on 20 genes)Genomic BioResponse Fingerprint Comparison of PHY906 Batches Batch 6, 7, 8 : clinical batches (GMP)Batch 9: non-clinical batch (manufactured unde GMP protocol) Batch F: non-clinical batch (non-GMP protocol)
اسلاید 31: Herb 1Herb 2G. LucidiumPHY 906524 “union” gene set in HepG2WhiteRedAmericanGinsengBioResponse Gene Expression ProfilesIso-IC50 drug treatment doseDifferent BioResponse patterns observed for different herbalsCan distinguish different herbal preparations, herbal variants and herbal speciesConclusion:Genomic Expression provides a sensitive, global bio-fingerprint as a unique response pattern to the herbal chemical compositionPHY906G. LucidiumGinsengHerb 1Herb 2
اسلاید 32: Issues of TCM Clinical TrialBe sure that a consistent preparation of clinical trial material can be made.Double blind and Placebo design is preferable. Other alternative designs could be considered.A clear clinical endpoint which is acceptable worldwide should be used for efficacy. Toxicity should be closely monitored.Statistical consideration is critical in the design.
اسلاید 33: PHY906 in Advanced Colorectal Cancer Phase I/IIA Randomized, Double-Blind, Placebo-Controlled, Cross-over Dose Escalation Study SitesShivani Kummar, M.D., Oncologist Yale Univ/Veterans Administration CT Cancer Center, West Haven, CTScott Wadler, M.D., Oncologist, Weill Cornell Medical Center, New York, NY Mark O’Rouke, M.D., Oncologist Cancer Centers of the Carolinas, Greenville, SCLeslie R. Laufman, M.D. Hematology/Oncology Consultants, Inc., Columbus, OHStudy DesignResults:Safe at two doses (NO SAEs) Reduced diarrhea/nausea by one gradeNo effect on metabolism of CPT-11, 5FUOut of 17 patients, 15 patients showed either partial response or stable disease after 2 courses of treatmentProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)
اسلاید 34: PHY906 in Hepatocellular CarcinomaPhase I/II Open Label, Dose-Escalation, Safety, and Efficacy StudyClinical Study Sites Yun Yen, M.D., Ph.D. City of Hope National Medical Center Michal Rose, M.D. Yale University/ Veterans Administration CT Cancer Center, West Haven, CT Samuel So, M.D. Stanford University Medical Center, Stanford, CAPhase II ObjectivesPrimary: Overall survival time (OS)SecondaryTime to disease progression (TTP)Quality of patient life Safety and tolerability Phase I Objectives Primary Tolerability of PHY906 plus capecitabine Safety of 2 consecutive courses Evaluation of PHY906 toxicity and adverse effectsProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)Results and aboveNo grade 3 drug related toxicity
اسلاید 35: Are All Four Botanicals Necessary?PHY906:BDF-1 Mice Bearing Colon 38 Tumor CPT-11 Treatment
اسلاید 36: Principles of Combined Usage of Herbs in TCM Formula Imperial Herb ( 君 )The chief herb (main ingredient) of a formula; toxic and nontoxic Ministerial Herb ( 臣 ) Ancillary to the imperial herb, augments and promotes the action of the main ingredient Assistant Herb ( 左 )Reduces side effects of the chief herb Servant Herb ( 使 ) Harmonizes or coordinates the actions of the other herbs
اسلاید 37: Mechanisms of Herb Interaction of PHY906 for Absorption of Phytochemicals into Blood Stream Inhibition of multiple drug resistant protein which could decrease the uptake of certain chemicals in the GI tract, leading to the increase of oral uptake of certain chemicals. Inhibition of CYP3A4, a predominant drug metabolic enzyme in the intestine, leading to the increase of oral uptake of certain chemicals. Inhibition of microfloral β-glucuronidase & glucosidase Stabilization and/or improvement of modification of solubility of certain chemicals.
اسلاید 38: INTERACTIONS OF INDIVIDIUAL HERBSInteraction of different ingredients of Chinese formula (described by Tao Hongjing 451-526)ChineseChineseEnglish translationExplanation1相使 Help or reinforce each otherAdditive or synergistic enhancement of pharmacologic action by two or more substances with similar properties.2相須 Need each otherPotentiation or synergism; enhancement of therapeutic action by substances with different properties.3相畏Mutual respect or restraintInhibition or reduction of pharmacologic effects by two or more substances with properties in common.4相惡Mutual dislikeInhibition or reduction of an effect of one drug by another with an opposing action. 5相殺Kill each otherThe specific nullification of the effect of one compound by another agent through competitive antagonism, such as between agonist and antagonist compounds.6相反Oppose each otherIncompatibility, not suitable for combination due to severe adverse effects.
اسلاید 39: Botanical Data Mining: The Next StepWHY?Identification of active phytocompoundsDefining a biologically relevant chemical fingerprintDevelopment of second generation drugsHOW?Correlation of biological response and chemical fingerprint
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اسلاید 42: What will it take to globalize Chinese medicine?Experience-based claims → Evidence-based claimsSubjective quality control → Objective quality controlUser unfriendly → User friendlyPreparation and PrescriptionComplex formula →Simplified formulaClarification of dosage and toxicityShort term vs long termClarification of interaction with current medicineMechanism(s) of its action(s) and active compounds involved.New usage of traditional Chinese medicine or its Derivatives.
اسلاید 43: INDUSTRYACADEMIC INSTITUTEGOVERNMENTINTRA-REGIONAL COLLABORATIONINTER-REGIONAL COLLABORATIONTo globalize Chinese medicine, close collaboration among academia, industry and Government is needed. Given the limitation of resource (human, technology and financial) international collaboration is critical for the advancement.“Collaboration is Critical”
اسلاید 44: Consortium for Globalization of Chinese Medicine (CGCM) GlobalNon-profitNon-discriminatoryNon-political www.tcmedicine.orgIn pursuit of advancing the field of Chinese herbal medicine to benefitHuman kind through joint efforts of the academic institutions, industriesAnd regulatory agencies around the world. MISSION OF CONSORTIUM
اسلاید 45: Working GroupsQuality ControlChinese Medicine DatabaseHerbal ResourceClinical TrialsCurrently we have 61 members and 7 affiliate industrial members7 Regional Consortiums: Australia, Beijing, Canada, Guangdong, Hong Kong, Shanghai, and Taiwan.www.tcmedicine.org
اسلاید 46: Traditional Chinese Medicine (TCM) Modern Chinese Medicine (MCM) (China, Japan, Korea, etc) Globalized Chinese Medicine (GCM) Future New Medicine (NM) Other Folk Medicine (FM) (Tibet, India, Europe, etc) Current Mainstream Medicine (CMM) Western Medicine (WM)The Evolution of Medicine
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