Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements

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Transcript of Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements

  • Slide 1
  • Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements...
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  • From traditional botanical medicine to Western pharmaceutical: Medicinal Plant Traditional Medicine Preparation Standardized Extract of Medicinal Plant Purified Active Compound
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  • From traditional botanical medicine to Western pharmaceutical: The following slides are only intended to give you an idea of the extent and rigor of the FDAs drug development standards you do NOT need to memorize all these steps just know that this is a very demanding and costly process.
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical: Documentation and structural elucidation of API (active pharmaceutical ingredient) through NMR, mass spectroscopy, and crystallography Develop methods for manufacturing the purified API (e.g., extraction and purification; DNA recombinant technology; chemical synthesis Accelerated stability studies (API maintains stability in chamber with high temp and humidity for at least one month Analytical methods for standardizing API as a drug Formulation of API into product to be administered to humans Mode of administration (e.g., oral, IV, IM, topical)
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Efficacy/Activity: Demonstration of bioactivity with therapeutic potential in in vitro assays Determination of specific mechanism of action is desired, but not required: Physiological mechanism Specific receptor site of action Specific molecular site of action Demonstration of efficacy in in vivo (animal) model(s)
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. In Vitro/Ex-Vivo Toxicology: Pharmacological screening in a variety of tissue and organ systems Ex-vivo animal tissues of a variety of target organs Test for mutagenicity and carcinogenicity Changes in levels of cytochrome p450 enzymes
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Animal Toxicity & Safety: Single dose escalation studies in two animal species (dog & rat) three animals in each dose group each group receives a progressively larger dose escalate single dose to lethal level, if possible, to establish LD50 laboratory and pathology measure blood levels of API measure liver enzymes, renal function, blood glucose, CBC & UA harvest organs for histopathological evaluation
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Animal Toxicity & Safety: Repeat multiple dosing studies for 7-14 days in two animal species (dog & rat) includes spectrum of doses equivalent to proposed human dose range Acute toxicology 30-day studies in dog & rat dose is given comparable to dose size and interval planned for humans evaluates safety of drugs to be used acutely (1-21 days)
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Animal Toxicity & Safety: Chronic toxicology 9-12 month studies in dog and rat evaluates safety of drugs to be used chronically (>30 d) dose given comparable to amount and interval planned for humans give higher dose levels to establish toxic dose record manifestations / adverse events with toxic dose periodically measure blood drug levels, liver enzyme levels, renal function, blood glucose, CBC and UA histopathology on multiple organs at end of study
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Animal Toxicity & Safety: Carcinogenicity 12-18 month study in rat and mouse Reproduction/teratology studies in rabbit and rat must be performed before any studies on women of child-bearing potential fertility assessments (sperm count, ovulation, pregnancy, delivery) teratology assessments (dose through pregnancy and assess babies, follow through at least two generations, histopathology on multiple body parts)
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  • From traditional botanical medicine to Western pharmaceutical: Pre-clinical, cont. Pharmacokinetics in Animals: ADME (Absorption, Distribution, Metabolism, and Excretion) radiolabeled API is traced through metabolism in animals isolate and characterize metabolites develop assay methods to recover API and metabolites from animal blood and urine Spike and recovery of API from human blood develop recovery assay for human blood spiked with API
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  • From traditional botanical medicine to Western pharmaceutical: IND (Investigational New Drug) Filing pre-IND filing with the FDA IND filing all pre-clinical in-vitro and in-vivo studies completed all pre-clinical results and information presented proposed study protocol for Phase 1 study
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  • From traditional botanical medicine to Western pharmaceutical: Phase 1 Clinical Trial (Human Safety Studies) Institutional Review Board (IRB) must first approve clinical study design IRB contains an M.D., lay person, ethicist, and a lawyer
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  • From traditional botanical medicine to Western pharmaceutical: Phase 1 Clinical Trial (Human Safety Studies) Single dose escalation studies in humans: Inpatient study for 24 hours eight people in each study group (6 study drug, 2 placebo) first study in healthy men and women with no child bearing potential second study may be in patients with target disease subjective signs/symptoms, PE and labs on study patients (week before, morning of study before drug is given, and day after drug is given) Initial study dose is below proposed human dose, then progressively larger doses are given to as high as 10X the proposed therapeutic dose
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  • From traditional botanical medicine to Western pharmaceutical: Phase 1 Clinical Trial (Human Safety Studies) Pharmacokinetics (PK) and absorption, distribution, metabolism, and excretion (ADME) studies inpatient single-dose PK study for 24-48 hours 8 healthy people (no placebo), four dose groups from below proposed dose to up to 2X proposed human dose serial blood levels measured at 15, 30, 60, 90 min; 2, 3, 4, 6, 8, 12, 24, and 48 hours
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  • From traditional botanical medicine to Western pharmaceutical: Phase 1 Clinical Trial (Human Safety Studies) Pharmacokinetics (PK) and absorption, distribution, metabolism, and excretion (ADME) studies Inpatient multiple dose PK study for 5-7 days 12 healthy people (no placebo) proposed dose size and interval is used Inpatient multiple dose PK study in special patient subgroups hepatic impairment, renal impairment, elderly Drug formulation bioavailability and bioequivalence (BABE) done for formulations: any change in drug formulation requires a new BABE study
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  • From traditional botanical medicine to Western pharmaceutical: Phase 2 Clinical Trial (Human Efficacy Studies) Human Efficacy Studies patients with target disease are treated with drug 2 10 studies are completed each study has a minimum of 50 patients double-blind placebo controlled multiple dose sizes and formulations are assessed signs/symptoms, PE, and safety labs are evaluated throughout study
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  • From traditional botanical medicine to Western pharmaceutical: Phase 2 Clinical Trial (Human Efficacy Studies) Drug Interaction Studies e.g., coumadin, antibiotics, protease inhibitors eight patients placebo-controlled patients take drug with and without additional drug PK studies Food Interaction Studies e.g., milk eight patients placebo-controlled patients take drug with and without food PK studies
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  • From traditional botanical medicine to Western pharmaceutical: Phase 2 Clinical Trial (Human Efficacy Studies) End of Phase 2 meeting with FDA present findings from Phase 1 and 2 studies propose final dose size and formulation present proposed study protocol for Phase 3
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  • From traditional botanical medicine to Western pharmaceutical: Phase 3 Clinical Trial (Human Efficacy Studies) final formulation and dose size is used often two large, well controlled studies on efficacy one large, open-label safety study to achieve safety data on 1000 patients for drugs that will be taken chronically, a safety study of 100-200 patients taking the drug for at least one year
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  • From traditional botanical medicine to Western pharmaceutical: Phase 4 Clinical Trial (Human Efficacy Studies) additional studies that may be done include: comparison of efficacy with competing drug assessment of efficacy in additional therapeutic indications
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  • From traditional botanical medicine to Western pharmaceutical: New Drug Approval (NDA) Filing: Pre-NDA meeting with FDA NDA filing file with assigned FDA division and medical reviewer present findings from Phases 1-4 takes 6-18 months to get approval from FDA Advisory Committee fast-track approval in 6 months for AIDS and cancer drugs upon approval, drug may be marketed
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  • History of Herbal Medicine Use in the U.S. in the mid-nineteenth century, herbs dominated the American pharmacopoeias, and the majority of medicines in the US were plant based
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  • History of Herbal Medicine Use in the U.S. United States Pharmacopoeia (