Artemisinin- an innovative cornerstone for anti-

malaria therapy

성균관대학교 약학대학천연물약품화학연구실석박통합 7 기 김충섭

About malaria

Market development through supply chain en-largement of A. annua

Ⅰ

III

Contents

From Artemisia annua to artemisinin and Coartem®Ⅱ

Market development through supply chain en-largement of artemisininⅣ

About malariaⅠ

1. Symptoms & Infections

2. Epidemiology & Economic ef-

fects

3. Research

4. Prevention

5. Treatment

센터의 필요성 Ⅰ. About malariaAbout malaria

Malaria

Symptoms- Flu-like symptoms- High-fever, intermittent fever- Coma, death Infections- Blood parasite Plasmod-ium- Anopheles mosquitoes

Epidemiology- Often in Africa- 500 million infection/year- 1 children/30 sec dies

Economic effects- USD 12 billion/year- No economic develop-ment- No tourism

Research- About infection cy-cle and vector control- Four Nobel prizes (1902, 04, 27, 48)

Prevention- Insecticide-treated bed nets- Indoor Residual Spray-ing- 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)

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

Ⅱ. From Artemisia annua to

artemisinin and Coartem1. Antimalarial activity of Qinghao (A. annua L.)

(1950s)Drug resis-

tanceto chloro-

quine

(1960s)Malariaout of control

(Vietnam War)Soldiers in-

fected

(1970s)40,000 com-

pounds and ex-tracts screened

in China

Drug resis-tance

Screening Qinghao (Artemisia annua L., 개똥쑥 )

Hemorrhoids(168 BC)

Intermittentfever

(1596 AD)

Fever(300s AD)

Remedies

forQinghao (Yin)

+Internal heat

(Yang)

Sulphadox-ine-

pyrimethamine,

Mefloquine developed

Artemisinin

Arteannuin

Qinghaosu

Ⅱ. From Artemisia annua to

artemisinin and Coartem2. Artemisinin from A. annua L.

Amounts- ↑Leaves, small green stems,

buds, flowers and seeds

- ↓Stems, roots

Sesquiter-penes

Artemisia annua L.

Structure elucidation- NMR, MS and IR

- Sesquiterpene lactone

- C15H22O5

- X-ray crystallography

- 1,2,4-trioxane ring (activity)

Essential oils

Clinical trials- Parasite decreased 95% in 16h

(chloroquine: 40h)

- Effective in resistant spp. and

cerebral form

Ⅱ. From Artemisia annua to

artemisinin and Coartem2. Artemisinin from A. annua L.

SERCA: sarco-endoplasmic reticulum Ca2+-ATPase

Nat. Chem. Biol. 3, 408-414 (2007)

(from hemoglobin)

3. Congeners of artemisinin

Total syntheses- First reported in 1983- Not commercially viable

Characteristics- Thermally stable (~150℃)- Poorly soluble in water and oil- Peroxide: essential for ac-tivity

Dihy-

droartemisinin- More potent- Solubility in water ↓- Stability ↓

Artemether- Soluble in oil- Available by I.M.- Short t1/2

Arteether- Soluble in oil- Available by I.M.

Sodium arte-

sunate- Soluble in wa-ter- 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

artemisinin and Coartem®

3. Congeners of artemisinin

Total syntheses- First reported in 1983- Not commercially viable

Characteristics- Thermally stable (~150℃)- Poorly soluble in water and oil- Peroxide: essential for ac-tivity

OZ277(RBx11160)

- More potent- Long lasting- Structurally simple- Scale-up- Reach market in 2009 (with piperaquine)

Artemether- Soluble in oil- Available by I.M.- Short t1/2

Sodium arte-

sunate- Soluble in wa-ter- Available by I.V.- Short t1/2

- Approved as new malarial drugs in China (1986-1987)

- Added to Essential Medicines List(1997, 2000)

Ⅱ. From Artemisia annua to

artemisinin and Coartem®

Ⅱ. From Artemisia annua to

artemisinin and Coartem®4. Development of ACT – Coartem®

Drug resistance to available

agents

Combination therapy- Successful cure rates in

other cases

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/lume-fantrine)

Artemether Lume-fantrine

- Only pre-qualified & fixed dose ACT- Cure rates 95 %- Effective on multidrug resis-tance- Registered in 81 countries- 100 million treatments

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

Ⅲ

Ⅲ. Market development through supply chain enlargement of A. annua1. Major challenge in establishing a supply chain

Market develop-ment

• Time needed for season

- Planting

- Cultivating

- Harvesting

Major challenge

• Weather conditions

- Meteorological impacts

• Damage by insects

• Supply and demand

- Oversupply → price ↓

→ business less attractive

→ production reduced

Ⅲ. Market development through supply chain enlargement of A. annua2. Market situation for A. annua

In 2004Unexpected demand for artemisinin

In 2001 Coartem®

launched

Until 2003Sufficient

amounts of A. annua

Whole sup-ply chain

had to built up

Market complexity↑- Harvest earlier → artemisinin content↓- Unsuitable storage → loss of biomass- Extraction, purification x → poor quality

• African countries needed ACTs• Exceed supply capac-ity

Ⅲ. Market development through supply chain enlargement of A. annua3. Plantation efforts to meet market demands

Year

Coartem

Artemisinin required

[kg]

Artemisinin planned for

[kg]

Amount of

biomass [kg]

Required area

[hectares]

Re-marks

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. mar-ket 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

Table 1. Demand planning for A. annua and artemisinin in 2004

Local governments

Communities

Mutual agreement

Farmers

Planning – hardly possible- How many kg of biomass may be har-

vested per hectare?

- What would be the artemisinin content

achieved with high yield seeds on larger

plantations?

- No experience of how the huge volumes of

biomass may be dried and processed

Ⅲ. Market development through supply chain enlargement of A. annua3. Plantation efforts to meet market demands

Farmers

Novartis

Extrac-tion company

Communities

Contract

Timely delivery

SeedsSeminars

Economic effects

Biomass man-agers

Meet market de-mands

Ⅲ. Market development through supply chain enlargement of A. annua4. Geographical split of the supply market

Novartis

중국

베트남- Tanzania, Kenya, Uganda- Long experience with culti-vation- Larger areas up to 200 hectares were planted- Irrigation on a large scale

동아프리카

Reduced agricul-

tural risks

Ⅲ. Market development through supply chain enlargement of A. annua5. Efforts to improve A. annua biomass

High yield seeds(being investi-

gated)

Artemisinin content ↑

Planta-tion area

↓

Drying efforts ↓

Trans-port-ation

Storage

Reduced time & cost

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

Ⅳ

1. Capacity for extraction and purification: in 2003Ⅳ. Market development through supply chain enlargement of artemisinin

Dried leaves

Hexane or Petroleum ether

Reflux several times

Lipophilic sub-stances (waxes)

EtOAc

Charcoal&

recrystallization

Artemisinin

Solvent – recoveredSilica gel – partially regenerateWithout automation

2. Major side products (Waxes)Ⅳ. Market development through supply chain enlargement of artemisinin

Waxes

- Mixture of long-chain apolar lipids

- Form a protec-tive coating on plant leaves and fruits

- In animals, al-gae, fungi and bacteria

- Not chemically homogeneous group

- Water-resistant

- In crude artemisinin: aliphatic alcohols and hydrocarbons

Identification

- Microscope: difference between the samples with or without waxes can be observed

- IR spectroscopy: quantification by calibration

- GC-FID: quatification

3. Other side productsⅣ. Market development through supply chain enlargement of artemisinin

More than 150 natural products

A. annua

HPLC-UV-MS HPLC-UV

-Extinction coefficients (흡광계수 )

4. Extraction and purification 2004 onwards Ⅳ. Market development through supply chain enlargement of artemisinin

Analytical method (TLC-FID)

- Accurate- Quickly- Results with and auto-mated evaluation

Purification method- Chromatography → crystal-lization . Waxes co-precipitating . Plugging during filtrations . With major related sub-stance (dehydro-artemisinin)

Synthetic production- Semi-synthesis (artemisinic acid → artemisinnin)- Cost non-competitive