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Page 1: Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements...

Botanical Substances in Western Medicine

from herbs to pharmaceuticals to dietary supplements...

Page 2: Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements...

From traditional botanical medicine to Western pharmaceutical:

• Medicinal Plant

• Traditional Medicine Preparation

• Standardized Extract of Medicinal Plant

• Purified Active Compound

Page 3: Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements...

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 FDA’s 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 (USP) is a reference of all pharmaceutical substances in use in the US, along with standards for composition, labeling, etc.

• the USP is a non-profit, non-governmental effort relying on volunteer experts

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History of Herbal Medicine Use in the U.S.

• first convention to compile the USP met in Washington D.C. in 1820 – before that time, drug standards were basically in chaos

• USP convention met every 10 years thereafter until 1940, when it began to meet every 5 years

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History of Herbal Medicine Use in the U.S.

• The pharmaceutical products in the USPs reflect the drugs used in orthodox medical practice at the times that the USPs were created

• The types and numbers of botanical substances in the USPs should reflect the status of these drugs in orthodox US medicine at the times when the USPs were created

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History of Herbal Medicine Use in the U.S.

• The 1870 USP contained the most botanical substances (636)

• The 1840 USP contained the highest total percentage of botanical substances (70%)

• By 1930, nearly 2/3 of the botanical medicines present in the 1870 USP were gone

• The use of other types of drugs had also declined by 1930, but in 1940, new synthetic drugs and powerful antibiotics began to fill the USP

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History of Herbal Medicine Use in the U.S.

• The decline in botanical substances in the USP didn’t reflect any new empirical data on the (lack of) effectiveness of herbal drugs, rather it represented a shift in attitude towards these drugs

• Increased demand for powerful and fast-acting medicines

• Emphasis on inorganic compounds and powerful isolated plant compounds

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History of Herbal Medicine Use in the U.S.

• Putative sociological factors that may have contributed to the demise of herbal drugs in the US:– American sense of individualism, man against

nature, distrust of natural products unless isolated / purified / synthesized

– Emphasis on technology– Tendency towards geographic mobility (not

enough time to learn local flora) » traditionally, herbal medicine use much

stronger in rural communities

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History of Herbal Medicine Use in the U.S.

• Putative sociological factors that may have contributed to the demise of herbal drugs in the US:– Shifting emphasis on reductionist science:

demanded that molecular structure of active substance, exact mechanism of action be defined

– Regulation of drug marketing in the US came to enforce this standard (herbal drugs must have proven efficacy through rigorous human clinical trials, just like synthetic drugs)

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History of Herbal Medicine Use in the U.S.

• Economic factors contributed to the demise of herbal drugs in the US:– Herbal drugs were seldom the focus of research

and development by pharmaceutical companies, because they typically represented little opportunity for financial gain» often difficult to characterize mechanism of

action / molecular structure» affect multiple points in a biochemical

pathway» pure plant extracts typically not patentable

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History of Herbal Medicine Use in the U.S.

• In 1994, congress passed the Dietary Supplement Health and Education Act (DSHEA), which essentially de-regulated the sale of herbal medicines in the US by recasting them as “dietary supplements”

• Removes herbs from strict FDA regulations placed on drugs, as long as they do not claim any medically relevant therapeutic effects (i.e., as long as they’re not sold as drugs)

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History of Herbal Medicine Use in the U.S.

• According to the DHEA, as long as a product is not harmful, it can be sold as a “dietary supplement” and it does not have to undergo human efficacy trials

• This de-regulation removed many of the financial barriers preventing herbal drugs from being brought to market, making botanicals much more profitable

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History of Herbal Medicine Use in the U.S.

• the DHEA was co-written by Democratic Sen. Tom Harkin, founder of the US Office of Alternative Medicine, and Republican Sen. Orin Hatch of Utah

– Mormon society traditionally embraces herbal medicine

– Since the passing of the DHEA, Utah has been dubbed the “Silicon Valley of dietary supplements”

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• Today, many herbal “dietary supplements” are available

• Problems stemming from the DHEA– standardization of dose– standardization of amount of active compound

present in supplements• Lack of standardization has been a major

obstacle for establishing efficacy / comparing clinical trial results

Herbal Medicines Today

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• From Krochmal et al. 2004

Herbal Medicines Today

Page 38: Botanical Substances in Western Medicine from herbs to pharmaceuticals to dietary supplements...

• From Krochmal et al. 2004

Herbal Medicines Today

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Herbal Medicines Today• Future of herbal

medicine will most likely emphasize standardization and validation of composition

• Responsibility for this work will most likely continue to fall upon non-profit organizations such as the USP

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• Ginkgo biloba – Ginkgo– demonstrated effective in the

treatment of dementia and alzheimer’s

– has multiple cardiovascular effects (anti-platelet, anti-oxidant, anti-hypoxic), which may work together to protect tissues from damage

Common Herbal Supplements

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• Hypericum perforatum– St. John’s Wort– demonstrated effective in the

treatment of mild to moderate depression

– most likely works through serotonin uptake inhibition

– Should not be used concurrently with other medications, as it modifies levels of certain cytochrome P450s (induces CYP3A4, but also inhibits CYP1A1, CYP1B1, CYP2D6, and CYP3A4)

Common Herbal Supplements

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• Panax ginseng - Ginseng– CNS stimulant, but clinical

trials have failed to demonstrate efficacy as an antidepressant, diuretic, aphrodisiac, antidiabetic, immune system modulator, cognitive aid, or any other claimed therapeutic use

Common Herbal Supplements

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Echinacea sp. (especially purpurea) – Echinacea• effective in treatment of

upper respiratory infections: immune system stimulant, antifungal, anti-inflammatory

Common Herbal Supplements

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• Serenoa repens – Saw Palmetto– effective treatment for benign

prostatic hyperplasia– ripe berries contain

compounds that inhibit testosterone metabolism and have anti-inflammatory effects

Common Herbal Supplements

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• Piper methysticum - Kava– effective mild sedative

and anti-anxiety drug– Central muscle relaxing

and anti-convulsant, and has been used experimentally to reduce severity of seizures

Common Herbal Supplements