Download Botanical Substances in Western Medicine

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
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.
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)
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)
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
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
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)
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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)
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
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”
Herbal Medicines Today
• 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
• From Krochmal et al. 2004
Herbal Medicines Today
• From Krochmal et al. 2004
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
Common Herbal Supplements
• Ginkgo biloba – Ginkgo
– demonstrated effective in the
treatment of dementia and
alzheimer’s
– has multiple cardiovascular effects
(anti-platelet, anti-oxidant, antihypoxic), which may work together
to protect tissues from damage
Common Herbal Supplements
• 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
• 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
Echinacea sp. (especially
purpurea) – Echinacea
• effective in treatment of
upper respiratory
infections: immune system
stimulant, antifungal, antiinflammatory
Common Herbal Supplements
• 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
• 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