Artemisininan innovative cornerstone for antimalaria therapy
성균관대학교 약학대학
천연물약품화학연구실
석박통합7기 김충섭
Contents
Ⅰ
About malaria
Ⅱ
From Artemisia annua to artemisinin and Coartem®
III
Market development through supply chain
enlargement of A. annua
Ⅳ
Market development through supply chain
enlargement of artemisinin
Ⅰ
About malaria
1. Symptoms & Infections
2. Epidemiology & Economic effects
3. Research
4. Prevention
5. Treatment
센터의 필요성
About malaria
Ⅰ. About malaria
Epidemiology
Symptoms
- Often in Africa
- 500 million infection/year
- 1 children/30 sec dies
- Flu-like symptoms
- High-fever, intermittent fever
- Coma, death
Economic effects
Infections
- USD 12 billion/year
- No economic development
- No tourism
- Blood parasite Plasmodium
- Anopheles mosquitoes
Prevention
Research
- About infection cycle
and vector control
- Four Nobel prizes
(1902, 04, 27, 48)
Malaria
- Insecticide-treated bed nets
- Indoor Residual Spraying
- Treat mosquitoes’ breeding
areas with insecticides
Treatment
- Artemisinin-based Combination Therapies (ACT)
- ‘Roll Back Malaria’ (RBM) by WHO, IRBD, UNDP, and UNICEF
- Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)
Ⅱ
From Artemisia annua to
artemisinin and Coartem®
1. Antimalarial activity of Qinghao (A. annua L.)
2. Artemisinin from A. annua L.
3. Congeners of artemisinin
4. Development of ACT – Coartem®
Ⅱ. From Artemisia annua to
1. Antimalarial activity of Qinghao (A. annua L.)
Drug
resistance
Screening
(1970s)
40,000 compounds
and extracts
screened in China
Sulphadoxinepyrimethamine,
Mefloquine
developed
(1950s)
Drug resistance
to chloroquine
(Vietnam War)
Soldiers infected
(1960s)
Malaria
out of
control
artemisinin and Coartem
Qinghao (Artemisia annua L., 개똥쑥)
Hemorrhoids
(168 BC)
Fever
(300s AD)
Remedies
Qinghao (Yin)
+
Internal heat
(Yang)
for
Intermittent
fever
(1596 AD)
Ⅱ. From Artemisia annua to
2. Artemisinin from A. annua L.
artemisinin and Coartem
Structure elucidation
- NMR, MS and IR
- Sesquiterpene lactone
- C15H22O5
- X-ray crystallography
- 1,2,4-trioxane ring (activity)
Artemisia annua L.
Amounts
- ↑Leaves, small green stems,
Essential oils
Artemisinin
Arteannuin
Qinghaosu
buds, flowers and seeds
- ↓Stems, roots
Clinical trials
- Parasite decreased 95% in 16h
(chloroquine: 40h)
Sesquiterpenes
- Effective in resistant spp. and
cerebral form
2. Artemisinin from A. annua L.
Ⅱ. From Artemisia annua to
artemisinin and Coartem
(from hemoglobin)
SERCA: sarco-endoplasmic reticulum Ca2+-ATPase
Nat. Chem. Biol. 3, 408-414 (2007)
Ⅱ. From Artemisia annua to
3. Congeners of artemisinin
artemisinin and Coartem®
Total syntheses
- First reported in 1983
- Not commercially viable
Characteristics
- Thermally stable (~150℃)
- Poorly soluble in water and oil
- Peroxide: essential for activity
Dihydroartemisinin
- More potent
- Solubility in
water ↓
- Stability ↓
Arteether
- Soluble in oil
- Available by I.M.
Artemether
- Soluble in oil
- Available by I.M.
- Short t1/2
Sodium artesunate
- Soluble in water
- Available by I.V.
- Short t1/2
OZ277
(RBx11160)
-
More potent
Long lasting
Structurally simple
Scale-up
Reach market in 2009
(with piperaquine)
Ⅱ. From Artemisia annua to
3. Congeners of artemisinin
artemisinin and Coartem®
Total syntheses
- First reported in 1983
- Not commercially viable
Characteristics
- Thermally stable (~150℃)
- Poorly soluble in water and oil
- Peroxide: essential for activity
- Approved as
new malarial
drugs in China
(1986-1987)
- Added to
Essential
Medicines List
(1997, 2000)
Artemether
- Soluble in oil
- Available by I.M.
- Short t1/2
Sodium artesunate
- Soluble in water
- Available by I.V.
- Short t1/2
OZ277
(RBx11160)
-
More potent
Long lasting
Structurally simple
Scale-up
Reach market in 2009
(with piperaquine)
4. Development of ACT –
Drug resistance to
available agents
Combination therapy
- Successful cure rates in
other cases
Ⅱ. From Artemisia annua to
Coartem®
artemisinin and Coartem®
Combination in antimalaria therapy
-
Chlorproguanil-dapsone (LapDap)
Dihydroartemisinin/piperaquine (DHA/PPQ)
Artesunate-amodiaquine (AS-AQ)
Artesunate-mefloquine (AS-S/P)
Artesunate/ayronaridine (AS/PRN)
Coartem® (Artemether/lumefantrine)
- Only pre-qualified & fixed
dose ACT
- Cure rates 95 %
- Effective on multidrug resistance
- Registered in 81 countries
- 100 million treatments
Artemether
Lumefantrine
Ⅲ
Market development through supply
chain enlargement of A. annua
1. Major challenge in establishing
a supply chain
2. Market situation for A. Annua
3. Plantation efforts to meet market
demands
4. Geographical split of the supply market
5. Efforts to improve A. annua biomass
1. Major challenge in establishing a supply chain
Ⅲ. Market development
through supply chain
enlargement of A. annua
Market development
Major challenge
•
Time needed for season • Weather conditions
- Planting
- Cultivating
- Harvesting
- Meteorological impacts
•
Damage by insects
• Supply and demand
- Oversupply → price ↓
→ business less attractive
→ production reduced
Ⅲ. Market development
through supply chain
enlargement of A. annua
2. Market situation for A. annua
In 2001
• African countries
needed ACTs
• Exceed supply capacity
Coartem®
launched
Until 2003
Sufficient amounts
of A. annua
Market complexity↑
In 2004
Unexpected
demand for
artemisinin
- Harvest earlier
→ artemisinin content↓
- Unsuitable storage
→ loss of biomass
- Extraction, purification x
→ poor quality
Whole supply
chain had to
built up
Ⅲ. Market development
through supply chain
enlargement of A. annua
3. Plantation efforts to meet market demands
Local
governments
Planning – hardly possible
- How
Communities
many
kg
of
biomass
may
be
harvested per hectare?
- What would be the artemisinin content
Mutual agreement
achieved with high yield seeds on larger
plantations?
- No experience of how the huge volumes
Farmers
of biomass may be dried and processed
Table 1. Demand planning for A. annua and artemisinin in 2004
Year
Coartem
Artemisinin
required [kg]
Artemisinin
Amount of
planned for [kg] biomass [kg]
Required area
[hectares]
Remarks
2003
1.3
750
750
147,000
53
oversupply
2004
4.4
2,500
2,500
496,000
180
oversupply
2005
30
17,000
17,000
3,382,000
1,230
Max. market
could supply
2006
120
68,000
124,000
25,000,000
9,000
2007
200
113,000
150,000
30,100,000
11,000
2008
200
113,000
150,000
30,100,000
11,000
Ⅲ. Market development
through supply chain
enlargement of A. annua
3. Plantation efforts to meet market demands
Novartis
Contract
Extraction
company
Communities
Economic
effects
Timely delivery
Seeds
Seminars
Biomass managers
Meet market demands
Farmers
Ⅲ. Market development
through supply chain
enlargement of A. annua
4. Geographical split of the supply market
Novartis
중국
Reduced
agricultural
risks
동아프리카
베트남
- Tanzania, Kenya, Uganda
- Long experience with cultivation
- Larger areas up to 200 hectares
were planted
- Irrigation on a large scale
Ⅲ. Market development
through supply chain
enlargement of A. annua
5. Efforts to improve A. annua biomass
High yield seeds
(being investigated)
Plantation
area ↓
Drying
efforts ↓
Artemisinin content ↑
Transportation
Reduced time & cost
Storage
Ⅳ
Market development through supply
chain enlargement of artemisinin
1. Capacity for extraction and
purification: in 2003
2. Major side products (Waxes)
3. Other side products
4. Extraction and purification 2004
onwards
1. Capacity for extraction and purification: in 2003
Ⅳ. Market development through
supply chain enlargement of
artemisinin
Reflux
several times
Dried leaves
Hexane or
Petroleum ether
Solvent – recovered
Silica gel – partially regenerate
Without automation
EtOAc
Artemisinin
Charcoal
&
recrystallization
Lipophilic
substances (waxes)
Ⅳ. Market development through
supply chain enlargement of
artemisinin
2. Major side products (Waxes)
Waxes
Identification
- Mixture of longchain apolar lipids
- Microscope: difference between the samples with or
without waxes can be observed
- Form a protective
coating on plant
leaves and fruits
- IR spectroscopy: quantification by calibration
- In animals, algae,
fungi and bacteria
- Not chemically
homogeneous group
- Water-resistant
- In crude
artemisinin: aliphatic
alcohols and
hydrocarbons
- GC-FID: quatification
Ⅳ. Market development through
supply chain enlargement of
artemisinin
3. Other side products
A. annua
HPLC-UV-MS
More than 150 natural
products
HPLC-UV
-Extinction coefficients
(흡광계수)
4. Extraction and purification 2004 onwards
Analytical method (TLC-FID)
- Accurate
- Quickly
- Results with and automated
evaluation
Ⅳ. Market development through
supply chain enlargement of
artemisinin
Purification method
- Chromatography → crystallization
. Waxes co-precipitating
. Plugging during filtrations
. With major related substance
(dehydro-artemisinin)
Synthetic production
- Semi-synthesis
(artemisinic acid → artemisinnin)
- Cost non-competitive