(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date (10) International Publication Number

20 September 2007 (20.09.2007) PCT W O 2007/106049 Al
(51) International Patent Classification: Paris (FR). PICARD, DAVID [FRISG]; 52 DUCHESS
A61K36/481 (2006.01) A61K35/62 (2006.01) WALK, Singapore 268956 (SG).
A61K 36/236 (2006.01) A6JK36/65 (2006.01)
A61K 36/88 (2006.01) A6JP 25/28 (2006.01) (74) Agent: ELLA CHEONG SPRUSON & FERGUSON
A61K35/56 (2006.01) A61K35164 (2006.01) (SINGAPORE) PTE LTD; P.O. BOX 1531, ROBINSON
A61K36/537 (2006.01) A61K36/69 (2006.01) ROAD POST OFFCE, Singapore 903031 (SG).
A61P 9/04 (2006.01) A61P 43/00 (2006.01) (81) Designated States (unless otherwise indicated, for every
kind of nationalprotection available): AE, AG, AL, AM,
(21) International Application Number: AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CI, CN,
PCT/SG2007/000072 CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, H,
GB, GD, GE, GIL GM, GI, TIN, HR, HU, ID, IL, IN, IS,
(22) International Filing Date: 15 March 2007 (15.03.2007) JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
L, LU, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ,
(25) Filing Language: English NA, NG, M, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU,
SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, R,
(26) Publication Language: English IT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(30) Priority Data: (84) Designated States (unless otherwise indicated,for every
60/782,798 16 March 2006 (16.03.2006) US kind of regional protection available): ARIPO (BW, GI,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
(71) Applicant (for all designated States except US): ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
MOLEAC PTE LTD [SG/SGG; 11 BIOPOLIS WAY, European (AT, BE, BG, CI, CY, CZ, DE, DK, EE, ES, IS,
HELIOS #09-08, Singapore 138667 (SG). FR, GB, GR, KU, I, IS, IT, IK,LU, LV, MC, MI, NL, PL,
PT, RO, SE, SI, SK, R), OAPI (BE, BJ, C CG,
, CL CM,
GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
(75) Inventors/Applicants (for US only): SUIA,XUEMINUPZblisAedW
[CN/CN]; FIRST TEACHING HOSPITAL OF TIAN-
=JIN
-

UNIVERSITY OF TRADITIONAL CHINESE

MEDICINE, 314 ANSHANXI ROAD, NANKAI DIS-
- with internationalsearch report

Fortwo-letter codes and otherabbreviations, refer to the "Guid

TRICT, Tianjin 300193 (CN). BOUSSER, MARIE dance Notes on Codes andAbbreviations" appearingat the begin
GERMAINE [FR/FR]; 54 AVE RENE COTY, F-75004 ning of each regular issue of the PCT Gazette.

Title: COMBINATION
0(54) THERAPY FOR TREATMENT OF PATENTS WITH NEUROLOGICAL DISORDERS AND
-CEREBRAL INFARCTION

(57) Abstract: The present invention provides compositions and methods of treating a patient having a condition selected from the
group of cerebral stroke, heart stroke, neurodegenerative diseases, brain or nervous system trauma, or neuroplasticity wherein the
Composition comprises: (i) at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of Radix Astragali (milkvetch root or Huang Qi); Rhizoma
Salviae Miltiorrhizae root (red sage or Dan Shen); Radix Paeoniae Rubra (red peony or chi shao); Ligusticum Chuanxiong (Chuan
Xiong); Rhizoma Notoginseng (Sanqi); Odoriferous Rosewood (Jiang Xiang); Scorpion (Quan Xie); Radix Polygalae (Yuan Zhi);
TGrassleaf
sweetfag (Shi Changpu); Leech (Hirudo or Shuizhi); Ground beetle (Tu Bie Chong); Cow bezoar (calculus Bovis artifacts
or Rengong Niuhuang); Gambirplant (ramulus uncariae cum uncis or Gou teng); and (ii) an agent used in Western medicine
WO 2007/106049 PCT/SG2007/000072
COMBINATION THERAPY FOR TREATMENT OF PATIENTS WITH NEUROLOGICAL
DISORDERS AND CEREBRAL INFARCTION

FIELD OF THE INVENTION

The present invention provides methods and compositions for the treatment of stroke and
neurological disorders. The methods and compositions of the present invention bring together
aspects of Traditional Chinese Medicine (TCM) and Western medicine.

BACKGROUND
Stroke is a major cause of death and disability. Primary stroke prevention focuses on lifestyle
modifications of risk factors while secondary stroke prevention aims to reduce the overall risk
of recurrence in persons who have had a stroke.

There is currently a lack of treatment methods for stroke recovery in Western medicine, these
being frequently limited to the following options:
a) Intra-arterial thrombolysis with intravenous tissue plasminogen activator (rt-PA),
which is applicable only to 3 to 5% of stroke patients (as it has to be- applied only for
acute ischemic forms, only if patients do not present any contra-indication, and only
within 3 to 6 hours after the onset of symptoms), can restore blood perfusion and
prevent neurological and functional damage to some degree;
b) administration of aspirin / other antiplatelets / or sometimes anticoagulant to most of
the cerebral stroke patients for secondary stroke prevention, which gives an
improvement effect of about 1% (The International Stroke Trial (IST) a randomised
trial of aspirin, subcutaneous heparin, both or neither among 19435 patients with
acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997
May 31; 349(9065):1569-81);
c) medications such as analgesics may be needed to-control associated symptoms
d) rehabilitation includes physical therapy such as physiotherapy, massage, speech
therapy, or occupational therapy.

One known TCM product is NeuroAid*. Clinical studies performed in China on compositions
the same as NeuroAid* have shown that this natural product combination increases stroke
patients' neurological disability recovery and functional outcomes with extremely few side
effects or other adverse effects. The composition of NeuroAid* has been approved by and
registered with the State Food and Drug Administration (SFDA) and is administered for the
treatment of cerebral infarct patients during their recovery at an early or late stage, and the
indications in Traditional Chinese Medicine are: to supplement qi and activate blood
circulation. It is applied to treat those patients who are suffering from ischemic or hemorrhagic
(for the latter, it is at present indicated in late phase only) cerebral infarction of qi deficiency

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WO 2007/106049 PCT/SG2007/000072
and blood stasis with manifestations of hemiplegia, hemianesthesia, wry mouth, aphasia
(inarticulateness) and etc during their channel and collateral convalescent period of ischemia
apoplexy, and its efficacy is supported by clinical trial data.

It may be useful for treating other types of stroke than cerebro-vascular stroke such as cardio
vascular disease (heart stroke mainly due to coronary artery stroke) as well as other
neurological disorders. Neurological disorders are disorders that affect the central nervous
system, the peripheral nervous system and the autonomic nervous system such as
neurodegenerative diseases (for example, Alzheimer's disease and Parkinson's disease),
epilepsy, seizure, demyelinating diseases (for example, multiple sclerosis), cerebral palsy,
traumatic injuries to or tumours in the brain, spinal cord and peripheral nerves.

NeuroAid* is capable of use as a Western medicine or a dietary supplement to provide nutrition

to healthy individuals as well as patients afflicted with stroke or neurological disorders.

NeuroAid* is typically administered orally (per os) as such or by diluting the capsules in water
or via a gastric tube, 3 times each day and 4 capsules each time for a 4-week course of
treatment. The duration of treatment is typically 3 months/3 courses, adaptable with regard to
the patient's condition.

The use of TCM is, however, particularly challenging for European clinicians because of the
lack of guidelines, clinical data and the small number of studies conducted under Western
guidelines. Potential interactions between TCM and Western medicine that may lead to
adverse side effects are also a major concern among both practitioners of TCM and Western
medicine. Of particular concern are the increase or decrease in the effects of a blood thinner
such as Warfarin that may lead to either a bleeding episode or formation of a blood clot, and
the decrease in the effect of a blood pressure medication that may lead to high blood
pressure and a stroke. For example, the potential interaction of the Chinese herb salvia with
the Western drug Warfarin leading to excessive blood thinning with bleeding has been well
documented with confirmatory laboratory studies. Non-steroidal anti-inflammatory drugs
(NSAIDS), in particular aspirin, also have the potential to interact with Chinese herbs and
increase bleeding risks. For these, and other reasons, TCM is generally not used in
conjunction with Western medicines.

As current treatment options do not address the needs of difficult-to-treat patients with
important stroke disabilities, such as hemiparalysis or aphasia, the present invention seeks to
combine TCM with established agents for the treatment of stroke patients to present a new
therapeutic treatment option for stroke patients.

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WO 2007/106049 PCT/SG2007/000072
SUMMARY OF INVENTION
According to a first aspect, there is provided a method of treating a patient having a condition
selected from the group of cerebral stroke, heart stroke, neurodegenerative diseases, brain
trauma, nervous system trauma and conditions related to neuroplasticity, the method
comprising administering to the patient, (i) a composition which comprises at least 4, 5, 6, 7,
8, 9, 10, 11, 12, 13 or 14 of the following ingredients: Radix Astragali root (Membranous
Milkvetch root or Huang Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red Sage root or
Dan Shen), Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum
Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony
or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried body of Scorpion (Quan
Xie), Radix Polygalae root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi Changpu), Leeches
(Hirudo or Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar
(calculus Bovis artifactus or Rengong Niuhuang), Gambirplant stem with hooks (Ramulus
uncariae cum uncis or Gou Teng); and (ii) an agent used in Western medicine for the
treatment of cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous
system trauma or conditions related to neuroplasticity.

According to a second aspect, there is provided the use of: (i) a composition which comprises
at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following ingredients: Radix Astragali root
(Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red
Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome
of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex
moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried body of
Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi
Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial
Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang), Gambirplant stem with hooks
(Ramulus uncariae cum uncis or Gou Teng); and (ii) an agent used in Western medicine for
the treatment of stroke, in the manufacture of a medicament for use in treating patients with
cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system
trauma or conditions related to neuroplasticity.

According to a third aspect, there is provided the use of: a composition which comprises at
least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following ingredients: Radix Astragali root
(Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red
Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome
of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex
moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried body of
Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi
Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial
Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang), Gambirplant stem with hooks

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WO 2007/106049 PCT/SG2007/000072

(Ramulus uncariae cum uncis or Gou Teng), in the manufacture of a medicament for treating
a patient having a condition selected from the group consisting of cerebral stroke, heart
stroke, neurodegenerative diseases, brain trauma, nervous system trauma and conditions
related to neuroplasticity, where the patient also receives an agent used inWestern medicine
for the treatment of patients with cerebral stroke, heart stroke, neurodegenerative diseases,
brain trauma, nervous system trauma or conditions related to neuroplasticity.

According to a fourth aspect, there is provided the use of an agent used inWestern medicine
for the treatment of cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma,
nervous system trauma or conditions related to neuroplasticity in the manufacture of a
medicament for treating a patient having a condition selected from the group consisting of
cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system
trauma and conditions related to neuroplasticity where the patient also receives a composition
which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following ingredients:
Radix Astragali root (Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae
Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root
or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma
Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood
(Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf
sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie
Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang),
Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou Teng).

According to a fifth aspect, there is provided a product comprising as a combined preparation:

(i) a composition which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following
ingredients: Radix Astragali root (Membranous Milkvetch root or Huang Qi),'Radix et Rhizoma
Salviae Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae Rubra root (Red
Peony root or Chi Shao), -rhizome of Ligusticum Chuanxiong (Chuan Xiong), Radix et
Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of Odoriferous
Rosewood (Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae root (Yuan
Zhi), Grassleaf sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground
Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or
Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou
Teng); and (ii) an agent used in Western medicine for the treatment of stroke, for
simultaneous, separate or sequential use in the treatment of patient with a cerebral stroke,
heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma or conditions
related to neuroplasticity, and optionally instructions for use.

According to a sixth aspect, there is provided a method of treating a patient having a condition
selected from the group of cerebral stroke, heart stroke, neurodegenerative diseases, brain

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WO 2007/106049 PCT/SG2007/000072
trauma, nervous system trauma and conditions related to neuroplasticity, the method
comprising administering to the patient, (i) NeuroAid*; and (ii) an agent used in Western
medicine for the treatment of cerebral stroke, heart stroke, neurodegenerative diseases, brain
trauma, nervous system trauma or conditions related to neuroplasticity.

According to a seventh aspect, there is provided a product comprising as a combined

preparation (i) NeuroAid*; and (ii) an agent used in Western medicine for the treatment of
stroke, for simultaneous, separate or sequential use as a medicament for the treatment of a
patient having a condition selected from the group of cerebral stroke, heart stroke,
neurodegenerative diseases, brain trauma, nervous system trauma and conditions related to
neuroplasticity, and optionally instructions for use.

According to an eight aspect, there is provided a method of identifying at least one compound
for treating at least one of cerebral stroke, heart stroke, neurodegenerative diseases, brain
trauma, nervous system trauma or conditions related to neuroplasticity, the method
comprising the step of selecting one or more isolated compounds from one or more herbs
selected from the group consisting of Radix Astragali root (Membranous Milkvetch root or
Huang Qi), Radix et Rhiizoma Salviae Miltiorrhizae root (Red Sage root or Dan Shen), Radix
Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum Chuanxiong
(Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi),
Wood of Odoriferous Rosewood (Jiang Xiang), dried body of Scorpion (Quan Xie), Radix
Polygalae root (Yuan Zhi), Grassleaf sweefflag rhizome (Shi Changpu), Leeches (Hirudo or
Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis
artifactus or Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis
or Gou Teng).

According to a ninth aspect, there is provided a compound, or selected combination of

compounds, identifiable by the method of the eighth aspect.

According to a tenth aspect, there is provided a compound, or selected combination of

compounds, identifiable by the method of the eighth aspect, said compound, or selected
combination of- compounds, selected from the group consisting of gamma-muurolene;
cyperene; alpha-elemene; gamma-cadinene; delta-cadinene; alpha-gurjunene; alpha
guaiene; alpha-copaene; beta-cuabebene; caryophyllene; delta-guaiene; alpha-cedrene;
1,9,9-trimethyl-4,7-dimethano-2,3,5,6,7,8-hexahydroazulene; 1,1,5,5-tetramethyl-4-methano
2,3,4,6,7,10-hexahydronaphthalene; cuparene; beta-elemene; gamma-elemene; alpha
muurolene; beta-guaiene; 2,6-ditert-butyl-4-methyl phenol; 2,8-dimethyl-5-acetyl-bicylo[5,3,o]
decadiene-1,8; methyl palmitate; ethyl palmitate; methyl heptadecadienoate; methyl
octadecadienoate; ethyl octadecadienoate; a-ditertbutyl phthalate; dicapryl phthalate;

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WO 2007/106049 PCT/SG2007/000072
diisocapryl phthalate; acetic acid; heptanoic acid; octanoic acid; nonanoic acid; palmitic acid;
isoallyl-benzene; phenylethanone; octadecadienoic acid; 3-ene-nonanone-2;
cyclododecanone; trans-nonenal-2; tridecene; 1-methyl-4-dioximethylthino
bicycle[2,2,2]octane; tetradecane; pentadecane; hexadecane; heptadecane; octadecane;
nonadecane; eicosane; heneicosane; docosane; alpha, alpha-dimethyl-benzenemethanol; 1
methoxthyl-benzene; 2,2,2-tri-ethoxyl-ethanol; I -methyl-4-isoallyl-cyclohexane[1,2];
ginsenoside Rbl; ginsenoside Rd; ginsenoside Re; ginsenoside Rg; ginsenoside Rg2;
ginsenoside Rh1; gypenoside XV 11; notoginsenoside RI; notoginsenoside R2;
notoginsenoside R3; notoginsenoside R4; notoginsenoside R6; dencichine; beta-N-oxalo-L
alpha, beta-diaminopropionic acid; quercetin; beta-sitosterol; stigmasterol; daucostgerol;
sanchinan A; dextrose aldehyde acide; picrates; choline; betaine; folic acid (2', 4'
Dihydroxy-5, 6-dimethoxyis of lavane); kumatakenin; tanshinone I; cryptotanshinone;
hydroxytanshinone; methyltanshinonate; methylene tanshiquinone; przewatanshinquinone A,
przewatanshinquinone B; miltirone; dihydrotanshinone I;tanshinol A; tanshinol B; tanshinol C;
3-a-hydroxy tanshinone 11; nortanshinone; 1,2,15,16-tetrahydrotanshiquinone; tanshinone i A;
tanshinone 11B; cryptotanshinone; isotanshinone I; isotanshinone 11; isocryptotanshinone;
miltirone; isotanshinone; isocryptotanshinone; tanshiquinone A; tanshiquinone B;
tanshiquinone C; saloilenone; danshenspiroketallactone; tanshilactone; salviol;
tanshialdehyde; danshensuan A; danshensuan B; danshensuan C; protocatechuic acid;
protocatechuic aldehyde; baicalin; P-sitosterol; ursolic acid; daucosterol; isoferulic acid;
dihydroisotanshinone I; paeoniflorin; paeonol; paeonin; albiflorin; triterpenoids; sistosterol;
oxypaeoniflorin; benzoylpaeoniflorin; benzoic acid; P-sitosterol; gallotannin; pedunculagin; 1
0-galloylpedunculagin; eugeniin; tannin acid; resin; naphtha; cnidiumlactone; chuanxingo; 4
hyroxy-3-butylidene-phthalide; 4,5-dihydro-3-butylidene-phthalide; 3-butyl-phthalide; 7
hydroxy-3-butylidenephthalide; 3-butyl-4,5-dihydrophthalide; (Z)-4,5-dihydro-6,7-trans
dihydroxy-3-butylidene-phthalide; (Z)-4,5-dihydro-6,7-cis-dihydroxy-3-butylidene-phthalide;
senkyunolide K; senkyunolide L; senkyunolide M; (Z)-6,7-epoxy-ligustilide; 3,6,7-trihydroxy
4,5,6,7-tetrahydro-3-butyl-phthalide; neocnidilide; 3-n-butyl-3-hydroxyl-4,5,6,7-tetrahydro-6,7
dihydroxyphthalide; (Z,Z')-diligustilide; (Z)-6,8',7,3'-diligustilide; wallichilide; (Z')-3,8-dihydro
6,6',7,3' a-diligustilide; chuanxingzine; tetramethyl-pyrazine; L-isoleucine-L-valine anhydride;
adenine; L-valine-L-valine anhydride; trimethylamine; perlolyrine; ferulic acid; sedanonic acid;
vanillic acid; caffeic acid; protocatechuic acid; linolenic acid; chrysophanol; methyl
phenylacetate; sedanoic acid lactone; methyl pentadecanoate; ethyl p entadecanoate; ethyl
heptadecanoate; ethyl isohepta-decanoate; ethyl octadecanoate; ethyl isoctadecanoate;
methyl linolenate; lactone; asafetida acid; vanillin; bis-5,5'-formylfurperye ether; 5
hydroxymethyl-6-endo-3'-methoxy-4'-hydroxyphenyl-8-oxa-abicyclo(3,2,1)-oct-3-en-2-one;
spathulenol; P-sitosterol; vitamin A; arasaponin A; paeonol; paeonoside; apiopaeonoside;
paeconol; paeonolide (paeconol, arabian sugar and paeoniflorin); paeoniflorin;
ozypaeoniflorin; benzoylpaeoniflorin; benzoyl-oxypaeoniflorin; gallic acid; 1,2,3,4,6
pentagalloylglucose; hirudin, heparin; rhynchophylline; isorhynchophylline; corynoxeine;

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WO 2007/106049 PCT/SG2007/000072

isocorynoxeine; corynantheine; dihydrocorynantheine; hirsutine; hirsuteine; heter-Gouteng

alkali; katsutoxin; secaline; lycine; cow sulfonic acid; cetylic acid; octadecanoic acid;
cholesterin; lecithin; p-Asarone (cis-form); asaryl-aether; Caryophyllene; a-Humulene;
Sekishone; 1-allyl-2,4,5-trimethyl-oxy-benzene; p-Asarone; asarone; cis-methylisoengenol;
trans-methylisoeugenol; shyobunone; isoshyobuncne; epishyobunone; linalool; calamenene;
p-gurjunene; 6-cadinene; calamendiol; isocalamendiol; preisocalamendiol; acoronene;
acorone; acoragermacrone; acolamone; isoacolamone; caryophyllene; cis-metylisoeugenol;
onjisaponin A, onjisaponin B, onjisaponin C, onjisaponin D, onjisaponin E, onjisaponin F,
onjisaponin G; tenuifolin; 2-beta-2,7-dihydroxy-2,3-carboxyoleanolic acid 3-beta-O-glucoside;
tenuigenin A; tenuigenin B; Saponin; onjixanthone; 1,6-dihydroxy-3,7-dimethoxy xanthone; 1
hydroxy-3, 6,7-trimethoxy xanthone; 5-anhydro-D-sorbitol; N-acetyl-D-glucosamine; 3,4,5
trimethoxy-cinnamic acid; polygalitol; tenuidine; bilirubin; biliverdin; cholic acid;
chenodeoxycholic acid; lithocholic acid; stero-cholic acid; conjugated bile acid; cholestrol;
mucigen; carotin; SMC-S; SMC-F; cow cholalic powder; cholalin; pig deoxygenated cholalin;
cow sulfonic acid; cholesterin; Dalbergin; Nordalbergin; Isodalbergin; o-Methyldalbergin;
Dalbergenone and Dalbergichromene, analogues of said selected compounds and any
pharmaceutically acceptable salts thereof.

GLOSSARY OF TERMS
This section is intended to provide guidance on the interpretation of the words and phrases
set forth below (and where appropriate grammatical variants thereof).

As used herein, the term "about" as used in relation to a numerical value means, for example,
+50% or +30% of the numerical value, preferably ±20%, more preferably +10%, more
preferably still +5%, and most preferably ±1%. Where necessary, the word "about" may be
omitted from the definition of the invention.

The term "comprising" means "including" or "consisting". Thus, for example, a composition
"comprising" X may consist exclusively of X or may include one or more additional
components.

The term "treatment" includes any and all uses which remedy a disease state or symptoms,
prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the
progression of disease or other undesirable symptoms in any way whatsoever. Hence,
"treatment" includes prophylactic and therapeutic treatment.

By "a cerebral stroke patient" we include a patient who has suffered an ischemic or
haemorrhagic cerebral stroke. A cerebral stroke is a sudden and permanent death of brain
cells that occurs when the flow of blood is blocked and oxygen cannot be delivered to the

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brain. lschaemic stroke most commonly occurs when the flow of blood is prevented by clotting
(known as 'thrombosis' of the artery) or by a detached clot that lodges in an artery (referred to
as an 'embolic stroke'). Haemorrhagic stroke results from rupture of an artery wall, and from
blood leaking into the surrounding brain. Haemorrhagic stroke, like ischemic stroke, causes
the death of tissue by depriving the brain of blood and oxygen, and results in a number of
neurological disabilities (motor, speech) as well as functional disabilities.

The term "stroke" refers to the sudden death of tissue cells due to a lack of oxygen when the
blood flow is impaired by blockage or rupture of an artery. Stroke is a vascular accident that
can occur in the brain or in the cardiac system. The latter condition is medically known as
"myocardial infarction" and more commonly known as a "heart attack". Because of the
similarity of both stroke mechanisms, it may be useful to use NeuroAid* to help patients with
a heart stroke recovering better from their disability.

DETAILED DESCRIPTION
The present invention provides a new combination treatment for patients having one or more
of the following conditions: cerebral stroke, heart stroke, neurodegenerative diseases, brain
trauma, nervous system trauma or conditions related to neuroplasticity.

The present invention provides methods and compositions for treating patients having a
condition selected from the group consisting of cerebral stroke, heart stroke,
neurodegenerative diseases, brain trauma, nervous system trauma and conditions related to
neuroplasticity. The patients are administered with:
(i) a composition which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the
following ingredients: Radix Astragali root (Membranous Milkvetch root or Huang
Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red Sage root or Dan Shen),
Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum
Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex
moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried
body of Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf
sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle
(or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or
Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis
or Gou Teng); and
(ii) an agent used inWestern medicine for the treatment of stroke.

This invention is based on the discovery that NeuroAid* is not only efficacious in treating
stroke patients but that it may be safely used in combination with treatments commonly used

8
WO 2007/106049 PCT/SG2007/000072
in Western medicine for treating stroke patients without adverse side effects such as
haemostasis disorders or high blood pressure as described above.

As chronic forms of neurodegeneration such as Alzheimer's and Parkinson's disease

(associated with cognitive dysfunction) share common mechanisms of neuronal death with
acute forms of neurodegeneration which accompanies stroke, head trauma, cardiac arrest
and subarachnoid hemorrhage, NeuroAid@ may be useful to improve or treat these brain
disorders as it is believed to have potential activity on neuroprotection or on plasticity.
Neuroplasticity (also referred to as brain plasticity or cortical plasticity) refers to changes that
occur in the organization of the brain and its circuits of neurons, in particular changes that
occur to the location of specific information processing functions. This process supports the
learning of new functions as the result of experience during development as mature animals
and the creation of new information with healthy neurons by-passing damaged neurons
affected by trauma or a medical condition.

Hence, in addition to treating cerebral stroke patients it is envisaged that NeuroAid* or a

NeuroAid*-like composition (e.g. a composition according to (i) above), optionally in
combination with available agents used inWestern medicine, may be useful for the treatment
of such neurodegenerative diseases. Typically, the Western medicine used in combination
with NeuroAid* or a NeuroAid*-like composition is one that targets a different mechanism
from NeuroAid* or a NeuroAid*-like composition. For example, the Western medicine may
be antiplatelets and anticoagulants typically used in secondary stroke prevention, and
neuroprotectants typically used in improving recovery potential in the acute phase of stroke
via mechanisms described below.

NeuroAide and similar compositions

The ingredients set forth in (i) above may be present in the composition in a relatively crude
form (e.g. unprocessed or crushed herbs) or in a more refined form (e.g. purified extracts).

In one embodiment, NeuroAid* is used. NeuroAid* is a TCM product in capsule form

comprising 9 herbal components and 5 animal components. NeuroAid* comprises Radix
Astragali root (Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae
Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root
or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma
Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood
(Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf
sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie
Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang),
Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou Teng).

9
WO 2007/106049 PCT/SG2007/000072
NeuroAid*, which may be registered under different names in different countries (e.g. in
South Africa it is marketed as Strocaid* or Danqi Piantan Jiaonang") is manufactured by and
available commercially in the People's Republic of China from Tianjin Shitian Pharmaceutical
Group Co., Ltd (located in the Jianxin Industrial area, Wangwenzhuang town, Xiqing district,
Tianjin City, China; Postal Code 300381;). It is also available from Moleac Pte Ltd (formerly
Molecular Acupuncture Pte Ltd), the main licensee outside of the People's Republic of China
(11 Biopolis Way, Helios #09-08 Singapore 138667; Tel: 65 64789430; Fax: 6564789435).

For the avoidance of doubt, NeuroAid* not only includes NeuroAid* in the form inwhich it is
currently marketed but also includes future formulations of NeuroAid* which may, for
example, be marketed by Tianjin Shitian Pharmaceutical Group Co., Ltd or Moleac Pte Ltd.
Such future formulations may, for example, vary in dosage amounts or the concentration of its
active ingredients etc.

Combination therapy with NeuroAid*

In the present invention, NeuroAid* can be used in combination with one or more agents
used in Western medicine for the treatment of stroke. By "an agent used in Western
medicine", we include any form of mainstream medicine or Western medicine, including
dietary supplements. For the avoidance of doubt, by "an agent used inWestern medicine", we
do not include medicaments used inTCM medicaments or the like.

Examples of suitable agents include antiplatelets, anticoagulants and neuroprotectants. One,

two, three or more of such further agents may, for instance, be used in combination with
NeuroAid*. Thus, the following are envisaged as suitable examples for use as combination
partner (ii): an antiplatelet; an anticoagulant; a neuroprotectant; an antiplatelet in combination
with an anticoagulant; an antiplatelet in combination with a neuroprotectant; an anticoagulant
in combination with a neuroprotectant; and, an antiplatelet in combination with an
anticoagulant and a neuroprotectant.

Antiplatelet agents
Antiplatelet agents are medications that block the formation of blood clots by preventing the
clumping of platelets. Examples of antiplatelet agents include without limitations: Aspirin, the
thienopyridine derivatives such as ticlopodine (Ticlid) and clopidogrel (Plavix), the
Phosphodiesterase IlI inhibitors such as Cilostazol (Pletal), Adenosine re-uptake inhibitors
such as Dipyridamole (Persantine or Aggrenox (in combination with aspirin)), and the
glycoprotein lib/Illa inhibitors such as Abciximab (ReoPro), Eptifibatide (Integrilin) and
Tirofiban (Aggrastat) and orally active RGD mimetic prodrugs such as Orbofiban, Sibrafiban,
SR121566, or Roxifiban.

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WO 2007/106049 PCT/SG2007/000072
These agents differ in the way in which they prevent platelets from clumping: for example,
Aspirin (Cyclo-oxygenase inhibitor) blocks thromboxan A-2 by inhibiting the enzyme cyclo
oxygenase-1 (COX-1), the thienopyridine derivatives (ADP inhibitors) block the adenosine
diphosphate (ADP) receptor on the surface of platelets membrane, and glycoprotein IIB/Ila
inhibitors prevent platelet aggregation by inhibiting a different receptor at the surface of
platelets (the attachment of glycoprotein lib/Illa to its receptor is the final step in all pathways
that cause platelets aggregation).

One or more antiplatelet agents can be employed in the present invention, for instance, a
combination of, for example, 2 or 3 or more antiplatelet agents may be employed.

Anticoagulant therapies
Antiplatelet agents are part of anticoagulation therapies. There are two other groups of
anticoagulant agents which may also be employed inthe present invention:
" Inhibitors of clotting factor synthesis such as without limitation, vitamin K antagonists
like coumarins or indanedione derivatives (Warfarin or Coumadin).
* Inhibitors of thrombin that include several products such as, but not limited to Heparin
(Standard Unfractionated Heparin (UFH), Low Molecular Weight Heparin (LMWH)
such as Enoxaparin, Tinzaparin) or to recombinant forms of hirudin such as desirudin
and lepirudin (Refludan).

Neuroprotectants
Using various mechanisms, neuroprotectants are compounds that preserve neuronal tissue at
risk of dying during stroke and in the aftermath of stroke. Some neuroprotectant agents are
sometimes used to treat human stroke patients and include antioxidants (e.g. selenium, 30
vitamin E, vitamin C, glutathione, cysteine, flavinoids, quinolines, enzymes with; reducing
activity, etc), N-methyl-D-aspartate Receptor Antagonists (Dextrorphan, Selfotel,
Magnesium), Narcotic Receptor antagonist (Nalmefene (Cervene), Ca-channel blockers, Na
channel modulators (Lubeluzole), Alpha-aminobutyric acid agonist (Clomethiazole), glutamate
receptor modulators, serotonin receptor agonists (repinotan), phospholipids, free-radical
scavenger (Tirilazad, and NXY-059), astrocyte activation inhobitor (ONO 2506), monoclonal
antibodies such as anti-ICAM-1 (Enlimomab), Human anti-leukocytic antibody, Hu23F2G,
membrane stabilization agent CDP-choline (Citicholine), Fibroblast growth factor (Fiblast),
unsaturated- and polyunsaturated fatty acids, estrogens and selective estrogen receptor
modulators (SEAMS), progestins, thyroid hormone and thyroid hormone- mimicking
compounds, cyclosporin A and derivatives, thalidomide and derivatives, methylxanthines,
Mono-Amine-Oxydase inhibitors (IMAO), serotonin-, noradrenaline and dopamine uptake

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WO 2007/106049 PCT/SG2007/000072
blockers, dopamine I agonists, L-DOPA, nicotine and derivatives, and NO synthase
modulators.

Modes of Administration
The combination partners (i) and (ii) may be present in a single formulation or may be present
as separate formulations. In one embodiment there may be a synergistic effect. As mentioned
above, combination partner (ii) may comprise more than one agent, for example, two
antiplatelet agents, or an antiplatelet agent and a neuroprotectant may be used.

The combination partners (i) and (ii) may be administered to the patient at the same time (e.g.
simultaneously) or at different times (e.g. sequentially) and over different periods of time,
which may be separate from one another or overlapping. The combination partners (i) and (ii)
may be administered in any order.

The combination partner (ii) utilized and the appropriate administration route and dose level
will be known to those in the art or could be readily determined by one skilled in the art.
Typically, as is well known in the medical art, dosage regimens may depend on various
factors including the patient's size, body surface area, age, the particular compound to be
administered, sex, time and route of administration, general health, and other drugs being
administered concurrently. While individual needs vary, determination of optimal ranges of
effective amounts of each component is within the skill of the art. The dosage would be
similar to that administered when the agent is used without NeuroAid*.

Dosage amounts for ticlopidine and for dipyridamole are described in the Physicians' Desk
Reference, as are dosage amounts for other antiplatelet and neuroprotectant agents. Dosage
amounts of aspirin for the indicated effects are known to those skilled in the medical arts, and
generally range from about 20mg to about 325 mg per day. For example, a formulation may
contain about 20mg, 30mg, 80 mg, 160 mg, 250 mg, 300 mg, 325 mg or 350 mg of aspirin.

NeuroAid* may be administered orally as such, typically with four 0.4g capsules being taken
3 times a day. For patients with swallowing difficulties, capsules may be opened and powder
diluted in water that can be drunk as such or injected via a gastric tube. Hence, a daily dose
of about 4.8g is envisaged. In one embodiment, the patient's daily dose of NeuroAid* (or
other composition according to (i) above) is about 2g to 8g; 3g to 7g; 4g to 6g; 4.25g to 5.75g;
4.5g to 5.25g; 4.5g to 5g; 4.6g to 4.10g; or 4.7g to 4.9g. A "daily dose" can be a single tablet
or capsule etc. or multiple tablets or capsules etc. to be taken on a given day. Suitably, the
composition according to (i) is taken orally.

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WO 2007/106049 PCT/SG2007/000072
In one embodiment, each course of NeuroAid* treatment lasts about 4 weeks. Typically 3
courses are administered, most commonly back to back. No therapeutic window is required
but additional courses can be added even after a few days of treatment cessation. Hence, in
one embodiment, each NeuroAid* treatment lasts about 12 weeks. In another embodiment,
the treatment course of NeuroAid* (or other composition according to (i) above) is about 4 to
24 weeks; 7 to 16 weeks; 9 to 15 weeks; 10 to 14 weeks; or 11 to 13 weeks.

In instances of ischemic stroke, treatment with anti-platelet drugs usually commences as soon
as possible after onset of stroke symptoms while in instances of haemorrhagic stroke,
anticoagulation treatments such as Coumadin or Heparin, are highly contra-indicated and
discontinued immediately if they were part of patient's usual treatment. Protamine and vitamin
K may be given to reduce bleeding in patients with anticoagulant-induced bleeding.

In addition to combination partners (i) and (ii), other compounds may be administered, for
example, proton pump inhibitors such as Nexium, Protonix and Aciphex. Daily doses of
proton pump inhibitors are typically administered to reduce the risk of ulcer development and
bleeding in patients under long-term low-dose aspirin or antiplatelet therapy.

BRIEF DESCRIPTION OF DRAWINGS

* Figure 1 Phase I clinical trial results on use of NeuroAid* versus BNJ (a)Neurological deficit
improvement (DTER scores) before and after treatment with NeuroAid* or BNJ (b) Functional
outcomes before and after treatment with NeuroAid* or BNJ.

* Figure 2 Phase III clinical trial results on use of NeuroAid* versus BNJ (a)Neurological deficit
improvement (DTER scores) before and after treatment with NeuroAid* or BNJ (b) Functional
outcomes before and after treatment with NeuroAid* or BNJ.

Figure 3 Clinical study results on the interaction between NeuroAid* and aspirin in healthy
volunteers and its effect on blood pressure. (a) systolic blood pressure (b) diastolic blood
pressure.

* For Figures 1 and 2:

Level of severity of stroke (DTER scores) = LOW, MILD, COMMON, SEVERE
Functional outcomes: 0 pts = able to take care of oneself and speak freely; 2 pts = able to live
independently and to do some simple work with some incomplete functions; 4 pts = able to walk
and take care of oneself but must be helped partially; 6 pts = able to stand and take a step but
must be taken care of at all times; 8 pts = confined to bed.

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WO 2007/106049 PCT/SG2007/000072

EXAMPLES
In the following examples, tables and drawings, the term "NeuroAid*" refers to a composition
that is the same as NeuroAid*.

EXAMPLE I
Phase |1 trial: NeuroAid* versus Buchang Naoxintong Jioanang (BNJ)
A randomized, double-blinded, stratified, control design was adopted for the clinical trial on the
efficacy of NeuroAid* in treating patients suffering from apoplexy compared to BNJ which is
known for its effectiveness intreating patients suffering from apoplexy (see Example 3). A total of
200 subjects were involved; 100 cases were treated with NeuroAid* while 100 cases were
treated with BNJ (control). BNJ is produced and provided by Xianyang Buchang Pharmaceutical
Co., Ltd. Four capsules of each drug were administered 3 times daily, with each course of
treatment lasting 4 weeks.

The evaluation criteria for neurological and functional recovery from apoplexy (DTER scoring
diagnostic standard) and TCM symptom therapeutic effects (TCM diagnostic symptom scoring
standard) were assessed in accordance with the Clinical Guiding Principles for the Treatment of
Apoplexy with New Chinese Herbs promulgated by the Ministry of Health of the PRC in 1993.
Severity of symptoms in the DTER scoring standard was classified according to 4 levels
(SEVERE, COMMON, MILD and LOW) while functional outcomes were classified in points from
0 to 8.

The data (Figure 1) demonstrated NeuroAid*'s clinical efficacy and superiority in improving
patients' neurological deficit and functional (autonomy/dependency post-stroke) outcomes versus
that of the control treatment BNJ.

EXAMPLE 2
Phase Ill trial: NeuroAid* versus BNJ
A randomized, double-blinded, stratified, control design was adopted. A total of 405 subjects
were involved, where 300 cases were treated NeuroAid* while 105 cases were treated with the
control drug BNJ produced and provided by Xianyang Buchang Pharmaceutical Co., Ltd. Four
capsules of each drug were administered 3 times daily, with each course of treatment lasting 4
weeks.

The evaluation criteria for neurological and functional recovery from apoplexy (DTER scoring
diagnostic standard) and TCM symptom therapeutic effects (TCM diagnostic symptom scoring
standard) were assessed as inthe Phase 11trial.

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WO 2007/106049 PCT/SG2007/000072

The data (Figure 2)demonstrated that NeuroAid* was superior to BNJ in improving the patients'
neurological deficit particularly in helping patients recover from their hemi-paralysis. With regard
to functional outcomes, even if NeuroAid* failed to demonstrate any superiority to BNJ, both
treatments had comparable effect and about 50% of the stroke patients included in the study
returned to a functionality dependent state after 4 weeks of treatment (comprehensive function
score similar to Rankin score used inthe West equal to 0 or 2).

No adverse effects of treatment with NeuroAid* were observed in the Phase Il or Phase Ill trials.
The finding of a broad therapeutic window (>14 days after stroke onset) inboth trials also gives a
huge advantage over fibrinolytic agents, which have to be given within the first 3 to 6 hours.

EXAMPLE 3
Comparative study on efficacy of BNJ versus Citicoline and aspirin
A randomized, double-blinded, stratified, control design was adopted for the comparative study
on the efficacy of BNJ and Citicoline in treating patients with apoplexy. Citicoline is the only
putative neuro-protectant that has shown results in Western randomized, double-blinded trials
given within 24 hours after symptom onset. Davalos et al. (Oral Citicoline in Acute Ischemic
Stroke. An Individual Patient Data Pooling Analysis of Clinical Trials (2002) Stroke 33:2850)
documents the ability of Citicoline to improve complete recovery at 3 months.

A first comparative study performed in the PRC involved 150 subjects treated with Citicoline
(0.5g IV)for 15 days in combination with a TCM (Xueshuantong) and 160 subjects treated with
Citicoline (0.5g IV)for 15 days in combination with Xueshuantong and BNJ. The latter group
treated with BNJ showed improvements in scores on a neuro-functional defects scale, plasma
viscosity level and cholesterol level.

A second comparative study compared 30 subjects treated with aspirin (150mg), Citicoline
(0.75g IV)and salvia miltiorrhizae injection (60mL), with 30 subjects treated with aspirin (150mg),
Citicoline (0.75g IV), salvia miltiorrhizae injection (60mL) and BNJ for 1 month. The BNJ-treated
group showed significantly better results in neurological and functional outcomes.

Citicoline (CDP-choline) is a key intermediary in the biosynthesis of phosphatidylcholine, an

important component of the neural cell membrane that stabilizes cells membranes and inhibits
the formation of cytotoxic free fatty acids. It has been shown to produce beneficial effects in
both animal models and clinical stroke trials. A significant difference between the groups,
favoring citicoline treatment, was seen in terms of functional outcome as measured by the
Barthel Index and Rankin scale, neurologic evaluation as measured by the National Institutes
of Health (NIH) stroke scale, and cognitive function as measured by the Mini Mental Status

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WO 2007/106049 PCT/SG2007/000072
Examination. 'As efficacy trials on Citicoline have been demonstrated to be superior to the
placebo, it can be inferred from the above two comparative studies that treatment with BNJ
would likewise be superior to a placebo.

EXAMPLE 4
Safety Study: Phase IV open-label study on effect of NeuroAid* on hemostasis
Blood samples of 30 healthy individuals were collected before-they received NeuroAid* and 2
and 8 hours after NeuroAid* initiation (4 capsules). Five coagulation tests were performed on the
blood samples.

Table 1.
Quick Prothrombine Time
Blood Sampling First (%) Second (%) Third (%)
Average 12.75 12.71 12.92
Std Deviation 0.68 0.72 0.67
Activated Partial Prothrombine Time
Blood Sampling First (%) Second (%) Third (%)
Average 37.64 37.15 38.66
Std Deviation 4.28 4.44 4.26
Fibrinogen
Blood Sampling First (%) Second (%) Third (%)
Average 2.98 3.05 3.06
Std Deviation 0.61 0.59 0.57
Platelet Aggregation
Blood Sampling First (%) Second (%) Third (%)
Average 63.01 62.19 61.52
Std Deviation 15.50 12.08 13.37
D-Dimer
Blood Sampling First (%) Second (%) Third (%)
Control Device 2.7 2.4 1.9

The results confirmed that NeuroAid* has no effect on hemostasis blood factors and thus does
not increase bleeding risks.

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WO 2007/106049 PCT/SG2007/000072
EXAMPLE 5
Safety Study: Phase IV open-label study on potential interaction between NeuroAid* and
acetylsalicylic acid (aspirin) in healthy volunteers and its effect on hemostasis and blood
pressure
An open randomized one-day study was conducted on 11 healthy volunteers receiving
NeuroAid* treatment (12 capsules per day) and aspirin (ASA 300mg per day) from day 1 to day
5, and 11 healthy volunteers receiving aspirin alone (300mg per day) from day 1 to day 5. Blood
samples of the subjects were collected before they received treatment and 2 and 8 hours after
treatment initiation. The blood samples were analyzed with the 5 coagulation tests, namely quick
prothrombine time, activated partial prothrombine time, fibrinogen dosage, platelet aggregation
and D-dimer, to identify the coagulation mechanisms triggered by potential interaction between
NeuroAid* and aspirin. Blood pressure of the 22 subjects was also measured before treatment,
and 2, 4, 6 and 8 hours after treatment initiation.

Results of this trial show that NeuroAid* can be safely associated with aspirin and does not have
any interaction with aspirin regarding blood coagulation (Table 2) and blood pressure (Figure 3).

Table 2.
Quick Prothrombine Time (Seconds)
Aspirin alone Mean
T=0 12.9
T + 2 hours 12.6
T + 8 hours 12.4
Aspirin + NeuroAid* Mean
T=0 12.7
T + 2 hours 12.6
T + 8 hours 12.4
Activated Partial Prothrombine Time (Seconds)
Aspirin alone Mean
T=0 38.8
T + 2 hours 39.0
T + 8 hours 38.2
Aspirin + NeuroAid" Mean
T=0 37.1
T + 2 hours 38.2
T + 8 hours 37.2
Fibrinogen (G/L)
Aspirin alone Mean
T=0 3.2

17
WO 2007/106049 PCT/SG2007/000072

T + 2 hours 3.2
T + 8 hours 3.0
Aspirin + NeuroAid" Mean
T=0 3.2
T + 2 hours 3.0
T + 8 hours 2.9
Platelet Aggregation (Percentage)
Aspirin alone Mean
T=0 62.82
T + 2 hours 62.87
T + 8 hours 48.01
Aspirin + NeuroAid" Mean
T=0 61.82
T + 2 hours 58.28
T + 8 hours 46.98
D-Dimer (pG/L)
Aspirin alone Mean
T=0 0.16
T + 2 hours 0.16
T + 8 hours 0.16
Aspirin + NeuroAid" Mean
T=0 0.13
T + 2 hours 0.09
T + 8 hours 0.15

EXAMPLE 6
Safety Study: Pilot open-label study on potential interaction between NeuroAid* and
Western drugs in ischemic stroke patients and its effect on hemostasis and blood
pressure
A pilot open-label study was conducted on 10 ischemic stroke patients within the first week of the
onset of stroke (early phase). The test patients were selected based on the following criteria:
a) aged above 18 years old;
b) have had a cerebral infarction with compatible imaging on Computed Tomography (CT) scan
or Magnetic Resonance Imaging (MRI); and
c) the time window between stroke onset and the open-label study was less than one week,

Conversely, patients that were excluded from the study include:

a) female patients who were pregnant, lactating or nursing;

18
WO 2007/106049 PCT/SG2007/000072
b) patients showing signs of intra-cerebral hemorrhage on brain Computed Tomography (CT)
scan or Magnetic Resonance Imaging (MRI);
c) patients having a history of easy bruising or blood coagulation disorders;
d)patients receiving other Traditional Chinese Medicine than NeuroAid*;
e) patients who received thrombolysis;
f) patients who have used NeuroAid* within a 3-month period prior to screening and enrolment in
the open-label study.

Each patient received 4 capsules of NeuroAid* 3 times a day for one month in addition to the
other Western medicine the patient was receiving. The Western medicine includes platelet
aggregation inhibitors, nitrates, oral anti-hypertensive drugs, lipid regulating drugs, oral anti
diabetic, or anti-convulsant drugs.

Safety assessment tests were performed on blood samples collected from the test patients at
three intervals: a) before NeuroAid* intake (to form the baseline); b) 1 week after NeuroAid*
initiation; and c) 4 weeks after NeuroAid* initiation. The blood samples were analyzed using the
following hematology and biochemical laboratory analytical tests:
a) Prothrombine Time (PT);
b)Activated Partial Prothrombine Time (APPT);
c)fibrinogene dosage;
d)platelet aggregation;
e) D-dimer test;
f blood cell count;
g)creatinine;
h)SGOT SGPT;
i) glycemia; and
j) CRP-C-reactive protein.

The results of the open-label study (Table 3) demonstrated that NeuroAid* does not have any
effect on renal and hepatic functions, glycemia, and C-Reactive-protein when used in
combination with Western medicine for managing risk factors of secondary stroke. For example,
in the five coagulation tests (Prothrombine Time (PT), Activated Partial Prothrombine Time
(APPT), fibrinogene dosage, platelet aggregation, D-dimer test) performed on Patients 4 and 5
(both receiving NeuroAid* and four different types of Western medicine) (Table 3, columns 5
and 6), the test readings taken I week and 4 weeks after NeuroAid* initiation do not differ
significantly from the baseline readings taken before the start of NeuroAid* intake.

19
WO 2007/106049 PCT/SG2007/000072

The statistical analysis of the readings for the open-label study (Table 4) also show that the
readings from all 10 patients do not differ significantly from the mean values. For example, in
the Prothrombine Time (PT) test, the Standard Deviation (SD) values after 1 week and 4
weeks of NeuroAid* initiation are 1.09 and 0.77, respectively, which do not deviate
significantly from the baseline value of 0.88. Similarly, in the fibrinogen dosage test, the
Standard Deviation (SD) values after 1 week and 4 weeks of NeuroAid* initiation are 1.22 and
1.11, respectively, which do not deviate significantly from the baseline value of 1.13.

Hence, the results of the open-label study further demonstrated that NeuroAid* can be safely
used in combination with Western medicine such as platelet aggregation inhibitors, nitrates, oral
anti-hypertensive drugs, lipid regulating drugs, oral anti-diabetic, or anti-convulsant drugs.

20
WO 2007/106049 PCT/SG2007/000072

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LO6- I': -oU) ')0 co L)N co co0 (CD C

(400 0 1- w - 0 'Zt1 qC 0(0( t-: q 0(0(0

* 0)

U, a 0 0 0 0 0o

0 0
M o"
3. -r -
WO 2007/106049 PCT/SG2007/000072

666c o C)C

000 N 0-C q C )00

000) 0 00 D (0c o CDr-'

N '- - 000Cl r
Oc0C O
r-DL C
o66 CD 66
0C ) C0c ( )' 7q

Nt 7 C C1 ce 0) cl0 00

Cl) It IT C'

000 6660 CO lU . 0I

0 0 L

0 l 00 400 ' 1 t L
WO 2007/106049 PCT/SG2007/000072
Table 4.
SUMMARY MEAN SD - SD + SD
Gender F=5 M=4
Age 65.11 53.24 76.98 11.87
Days) from stroke 3.33 0.94 5.73 2.40
onset
On Aspirin? Y=5 N=4
OtherTreatment'
administered

NIHSS
Baseline 7.11 0.86 13.36 6.25
1 Week 4.89 -0.17 9.95 5.06
Month 4.11 -0.37 8.60 4.48
Rankin score
BaselIne 3.11 1.57 4.65 1.54
1 Week 2.22 0.83 3.62 1.39
1 Month 1.78 0.21 3.34 1.56
PT secss)
Baseline 13.04 12.17 13.92 0.88
1 Week 12.50 11.41 13.59 1.09
1 Month 12.41 11.64 13.18 0.77
APTT (secs)
Baseline 30.96 28.70 33.21 2.26
1Week 32.10 29.17 35.03 2.93
1 Month 30.68 28.87 32.48 1.80
Fibrinogen dosage
~(gIL)
Baseline 4.10 2.97 5.23 1.13
i Week 4.03 2.81 5.25 1.22
1~Month 4.06 2.95 5.18 1.11
Platelet segregation
Baseline, 63.61 54.67 72.55 8.94
1 Week - 52.31 40.68 63.94 11.63
1 Month 48.44 36.31 60.58 12.14
D-Dimer (ng/mL)
Baseline 0.25 0.08 0.42 0.17
1 Week 0.45 -0.12 1.02 0.57
1 Month 0.49 -0.23 1.22 0.73
SGPT - ALT (IU/L)
Baseline 13.87 9.75 17.98 4.11
1Week 20.80 11.13 30.47 9.67
1 Month 17.77 10.48 25.06 7.29
566~T - AST (Iu/L)
Baseline 19.14 9.03 29.26 10.11
IWeek 18.09 12.00 24.18 6.09
I Month 16.12 12.26 19.99 3.87

Baseline 5.88 3.60 8.16 2.28

I~9eek 5.21 3.44 6.98 1.77
1 Month 4.91 3.81 6.02 1.10
creatinine (pmol/I) __

25
WO 2007/106049 PCT/SG2007/000072
Baseline 70.56 48.97 92.14 21.58
I Week 75.56 55.81 95.30 19.75
I Month 67.89 48.94 86.84 18.95
Red-blood cells
"Baseline 4.42 3.87 4.96 0.55
1 Week 4.51 4.00 5.02 0.51
1 Month 4.56 4.01 5.11 0.55
Mean RBC volume
Baseline 90.71 85.73 95.70 4.99
1 Week 90.93 86.00 95.86 4.93
1 Month 90.09 84.36 95.82 5.73
white-blood cells
Baseline 6.63 4.33 8.94 2.30
I Week 5.88 4.10 7.65 1.77
I Month 6.68 3.79 9.57 2.89
granulocytes
Baseline 4.67 2.83 6.51 1.84
I Week 4.10 2.43 5.77 1.67
1 Month 4.43 2.43 6.44 2.01
lymphocytes
Baseline 1.41 0.65 2.17 0.76
1 Week 1.68 0.77 2.59 0.91
1 Month 1.74 1.01 2.48 0.74
monocytes
Baseline 0.31 0.15 0.47 0.16
1 Week 0.29 0.15 0.43 0.14
1Month 0.34 0.19 0.50 0.15
eosinophiles
Baseline 0.11 0.05 0.17 0.06
I Week 0.13 0.08 0.18 0.05
I Month 0.13 0.06 0.20 0.07
basophiles
Baseline 0.03 -0.02 0.08 0.05
1 Week 0.02 -0.02 0.07 0.04
1 Month 0.04 -0.01 0.10 0.05
hemoglobin (Hb) in glL
Baseline 139.56 123.41 155.70 16.15
I Week 142.89 128.42 157.36 14.47
I Month, 143.67 126.96 160.38 16.71
hematocrit (Hct) in %
Baseline 39.96 35.65 44.26 4.31
1 Week 41.71 37.19 46.23 4.52
I Month 40.99 36.58 45.40 4.41
CRP (mgldL)
Baseline 2.04 -0.49 4.57 2.53
1 Week 1.90 -1.73 5.54 3.63
1 Month 1.06 -0.61 2.73 1.67

It will be understood that the invention has been described by way of example only and
modifications may be made whilst remaining within the scope and spirit of the invention.

26
WO 2007/106049 PCT/SG2007/000072
CLAIMS

1. A method of treating a patient having a condition selected from the group of cerebral
stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma and
conditions related to neuroplasticity, the method comprising administering to the patient, (i) a
composition which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following
ingredients: Radix Astragali root (Membranous Milkvetch root or Huang Qi), Radix et Rhizoma
Salviae Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae Rubra root (Red
Peony root or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong), Radix et
Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of Odoriferous
Rosewood (Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae root (Yuan
Zhi), Grassleaf sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground
Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or
Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou
Teng); and (ii) an agent used in Western medicine for the treatment of cerebral stroke, heart
stroke, neurodegenerative diseases, brain trauma, nervous system trauma or conditions
related to neuroplasticity.

2. Use of: (i) a composition which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14
of the following ingredients: Radix Astragali root (Membranous Milkvetch root or Huang Qi),
Radix et Rhizoma Salviae Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae
Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong),
Radix et Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of
Odoriferous Rosewood (Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae
root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi),
Ground Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or
Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou
Teng); and (ii) an agent used in Western medicine for the treatment of stroke, in the
manufacture of a medicament for use in treating patients with cerebral stroke, heart stroke,
neurodegenerative diseases, brain trauma, nervous system trauma or conditions related to
neuroplasticity.

3. Use of: a composition which comprises at least 4, 5, 6, 7, 8, 9, 10, 11, 12,13 or 14 of

the following ingredients: Radix Astragali root (Membranous Milkvetch root or Huang Qi),
Radix et Rhizoma Salviae Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae
Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong),
Radix et Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of
Odoriferous Rosewood (Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae
root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi),
Ground Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or

27
WO 2007/106049 PCT/SG2007/000072
Rengong Niuhuang), Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou
Teng), in the manufacture of a medicament for treating a patient having a condition selected
from the group consisting of cerebral stroke, heart stroke, neurodegenerative diseases, brain
trauma, nervous system trauma and conditions related to neuroplasticity, where the patient
also receives an agent used in Western medicine for the treatment of patients with cerebral
stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma or
conditions related to neuroplasticity.

4. Use of an agent used inWestern medicine for the treatment of cerebral stroke, heart
stroke, neurodegenerative diseases, brain trauma, nervous system trauma or conditions
related to neuroplasticity in the manufacture of a medicament for treating a a patient having a
condition selected from the group consisting of cerebral stroke, heart stroke,
neurodegenerative diseases, brain trauma, nervous system trauma and conditions related to
neuroplasticity where the patient also receives a composition which comprises at least 4, 5, 6,
7, 8, 9, 10, 11, 12, 13 or 14 of the following ingredients: Radix Astragali root (Membranous
Milkvetch root or Huang Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red Sage root or
Dan Shen), Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome of Ligusticum
Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex moutan (Peony
or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried body of Scorpion (Quan
Xie), Radix Polygalae root (Yuan Zhi), Grassleaf sweefflag rhizome (Shi Changpu), Leeches
(Hirudo or Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial Cow-bezoar
(calculus Bovis artifactus or Rengong Niuhuang), Gambirplant stem with hooks (Ramulus
uncariae cum uncis or Gou Teng).

5. A product comprising as a combined preparation: (i) a composition which comprises

at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the following ingredients: Radix Astragali root
(Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae Miltiorrhizae root (Red
Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root or Chi Shao), rhizome
of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma Notoginseng (Sanqi), Cortex
moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood (Jiang Xiang), dried body of
Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf sweetflag rhizome (Shi
Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie Chong), Natural or Artificial
Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang), Gambirplant stem with hooks
(Ramulus uncariae cum uncis or Gou Teng); and (ii) an agent used in Western medicine for
the treatment of stroke, for simultaneous, separate or sequential use in the treatment of
patient with a cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma,
nervous system trauma or conditions related to neuroplasticity, and optionally instructions for
use.

28
WO 2007/106049 PCT/SG2007/000072
6. A method of treating a patient having a condition selected from the group of cerebral
stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma and
conditions related to neuroplasticity, the method comprising administering to the patient, (i)
NeuroAid*; and (ii) an agent used in Western medicine for the treatment of cerebral stroke,
heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma or conditions
related to neuroplasticity.

7. A product comprising as a combined preparation (i) NeuroAid*; and (ii) an agent used
in Western medicine for the treatment of stroke, for simultaneous, separate or sequential use
as a medicament for the treatment of a patient having a condition selected from the group of
cerebral stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system
trauma and conditions related to neuroplasticity, and optionally instructions for use.

8. A product according to any one of claims 5 or 7 wherein (i) and (ii) are present as
separate formulations.

9. Use of any one of claims 2, 3 or 4 wherein the medicament comprises (i) and (ii) as
separate formulations suitable for simultaneous, separate or sequential administration.

10. A method of identifying at least one compound for treating at least one of cerebral
stroke, heart stroke, neurodegenerative diseases, brain trauma, nervous system trauma or
conditions related to neuroplasticity, the method comprising the step of selecting one or more
isolated compounds from one or more herbs selected from the group consisting of Radix
Astragali root (Membranous Milkvetch root or Huang Qi), Radix et Rhizoma Salviae
Miltiorrhizae root (Red Sage root or Dan Shen), Radix Paeoniae Rubra root (Red Peony root
or Chi Shao), rhizome of Ligusticum Chuanxiong (Chuan Xiong), Radix et Rhizoma
Notoginseng (Sanqi), Cortex moutan (Peony or Mudanpi), Wood of Odoriferous Rosewood
(Jiang Xiang), dried body of Scorpion (Quan Xie), Radix Polygalae root (Yuan Zhi), Grassleaf
sweetfiag rhizome (Shi Changpu), Leeches (Hirudo or Shuizhi), Ground Beetle (or Tu Bie
Chong), Natural or Artificial Cow-bezoar (calculus Bovis artifactus or Rengong Niuhuang),
Gambirplant stem with hooks (Ramulus uncariae cum uncis or Gou Teng).

11. A compound, or selected combination of compounds, identifiable by the method of

claim 10.

12. A compound, or selected combination of compounds, identifiable by the method of

claim 10, said compound, or selected combination of compounds, selected from the group
consisting of gamma-muurolene; cyperene; alpha-elemene; gamma-cadinene; delta
cadinene; alpha-gurjunene; alpha-guaiene; alpha-copaene; beta-cuabebene; caryophyllene;

29
WO 2007/106049 PCT/SG2007/000072

delta-guaiene; alpha-cedrene; 1,9,9-trimethyl-4,7-dimethano-2,3,5,6,7,8-hexahydroazulene;

1,1,5,5-tetramethyl-4-methano-2,3,4,6,7,10-hexahydronaphthalene; cuparene; beta-elemene;
gamma-elemene; alpha-muurolene; beta-guaiene; 2,6-ditert-butyl-4-methyl phenol; 2,8
dimethyl-5-acetyl-bicylo[5,3,0] decadiene-1,8; methyl palmitate; ethyl palmitate; methyl
heptadecadienoate; methyl octadecadienoate; ethyl octadecadienoate; a-ditertbuty phthalate;
dicapryl phthalate; diisocapryl phthalate; acetic acid; heptanoic acid; octanoic acid; nonanoic
acid; palmitic acid; isoallyl-benzene; phenylethanone; octadecadienoic acid; 3-ene-nonanone
2; cyclododecanone; trans-nonenal-2; tridecene; 1-methyl-4-dioximethylthino
bicycle[2,2,2]octane; tetradecane; pentadecane; hexadecane; heptadecane; octadecane;
nonadecane; eicosane; heneicosane; docosane; alpha, alpha-dimethyl-benzenemethanol; 1
methoxthyl-benzene; 2,2,2-tri-ethoxyl-ethanol; 1-methyl-4-isoallyl-cyclohexane[1,2];
ginsenoside Rb1; ginsenoside Rd; ginsenoside Re; ginsenoside Rg; ginsenoside Rg2;
ginsenoside Rh1; gypenoside XV 11; notoginsenoside RI; notoginsenoside R2;
notoginsenoside R3; notoginsenoside R4; notoginsenoside R6; dencichine; beta-N-oxalo-L
alpha, beta-diaminopropionic acid; quercetin; beta-sitosterol; stigmasterol; daucostgerol;
sanchinan A; dextrose aldehyde acide; picrates; choline; betaine; folic acid (2', 4'
Dihydroxy-5, 6-dimethoxyis of lavane); kumatakenin; tanshinone I; cryptotanshinone;
hydroxytanshinone; methyltanshinonate; methylene tanshiquinone; przewatanshinquinone A,
przewatanshinquinone B; miltirone; dihydrotanshinone I;tanshinol A; tanshinol B; tanshinol C;
3-a-hydroxy tanshinone 11; nortanshinone; 1,2,15,16-tetrahydrotanshiquinone; tanshinone iIA;
tanshinone I B; cryptotanshinone; isotanshinone I; isotanshinone 11; isocryptotanshinone;
miltirone; isotanshinone; isocryptotanshinone; tanshiquinone A; tanshiquinone B;
tanshiquinone C; saloilenone; danshenspiroketallactone; tanshilactone; salviol;
tanshialdehyde; danshensuan A; danshensuan B; danshensuan C; protocatechuic acid;
protocatechuic aldehyde; baicalin; P-sitosterol; ursolic acid; daucosterol; isoferulic acid;
dihydroisotanshinone I; paeoniflorin; paeonol; -paeonin; albiflorin; triterpenoids; sistosterol;
oxypaeoniflorin; benzoylpaeoniflorin; benzoic acid; p-sitosterol; gallotannin; pedunculagin; 1
O-galloylpedunculagin; eugeniin; tannin acid; resin; naphtha; cnidiumlactone; chuanxingol; 4
hyroxy-3-butylidene-phthalide; 4,5-dihydro-3-butylidene-phthalide; 3-butyl-phthalide; 7
hydroxy-3-butylidenephthalide; 3-butyl-4,5-dihydrophthalide; (Z)-4,5-dihydro-6,7-trans
dihydroxy-3-butylidene-phthalide; (Z)-4,5-dihydro-6,7-cis-dihydroxy-3-butylidene-phthalide;
senkyunolide K; senkyunolide L; senkyunolide M; (Z)-6,7-epoxy-ligustilide; 3,6,7-trihydroxy
4,5,6,7-tetrahydro-3-butyl-phthalide; neocnidilide; 3-n-butyl-3-hydroxyl-4,5,6,7-tetrahydro-6,7
dihydroxyphthalide; (Z,Z')-diligustilide; (Z)-6,8',7,3'-diligustilide; wallichilide; (Z')-3,8-dihydro
6,6',7,3' a-diligustilide; chuanxingzine; tetramethyl-pyrazine; L-isoleucine-L-valine anhydride;
adenine; L-valine-L-valine anhydride; trimethylamine; perlolyrine; ferulic acid; sedanonic acid;
vanillic acid; caffeic acid; protocatechuic acid; linolenic acid; chrysophanol; methyl
phenylacetate; sedanoic acid lactone; methyl pentadecanoate; ethyl p entadecanoate; ethyl
heptadecanoate; ethyl isohepta-decanoate; ethyl octadecanoate; ethyl isoctadecanoate;
methyl linolenate; lactone; asafetida acid; vanillin; bis-5,5'-formylfurperye ether; 5

30
WO 2007/106049 PCT/SG2007/000072
hydroxymethyl-6-endo-3'-methoxy-4'-hydroxyphenyl-8-oxa-abicyclo(3,2,1)-oct-3-en-2-one;
spathulenol; p-sitosterol; vitamin A; arasaponin A; paeonol; paeonoside; apiopaeonoside;
paeconol; paeonolide (paeconol, arabian sugar and paeoniflorin); paeoniflorin;
ozypaeoniflorin; benzoylpaeoniflorin; benzoyl-oxypaeoniflorin; gallic acid; 1,2,3,4,6
pentagalloylglucose; hirudin, heparin; rhynchophylline; isorhynchophylline; corynoxeine;
isocorynoxeine; corynantheine; dihydrocorynantheine; hirsutine; hirsuteine; heter-Gouteng
alkali; katsutoxin; secaline; lycine; cow sulfonic acid; cetylic acid; octadecanoic acid;
cholesterin; lecithin; P-Asarone (cis-form); asaryl-aether; Caryophyllene; a-Humulene;
Sekishone; 1-allyl-2,4,5-trimethyl-oxy-benzene; P-Asarone; asarone; cis-methylisoengenol;
trans-methylisoeugenol; shyobunone; isoshyobuncne; epishyobunone; linalool; calamenene;
p-gurjunene; 6-cadinene; calamendiol; isocalamendiol; preisocalamendiol; acoronene;
acorone; acoragermacrone; acolamone; isoacolamone; caryophyllene; cis-metylisoeugenol;
onjisaponin A, onjisaponin B, onjisaponin C, onjisaponin D, onjisaponin E, onjisaponin F,
onjisaponin G; tenuifolin; 2-beta-2,7-dihydroxy-2,3-carboxyoleanolic acid 3-beta-O-glucoside;
tenuigenin A; tenuigenin B; Saponin; onjixanthone; 1,6-dihydroxy-3,7-dimethoxy xanthone; 1
hydroxy-3, 6,7-trimethoxy xanthone; 5-anhydro-D-sorbitol; N-acetyl-D-glucosamine; 3,4,5
trimethoxy-cinnamic acid; polygalitol; tenuidine; bilirubin; biliverdin; cholic acid;
chenodeoxycholic acid; lithocholic acid; stero-cholic acid; conjugated bile acid; cholestrol;
mucigen; carotin; SMC-S; SMC-F; cow cholalic powder; cholalin; pig deoxygenated cholalin;
cow sulfonic acid; cholesterin; Dalbergin; Nordalbergin; Isodalbergin; o-Methyldalbergin;
Dalbergenone and Dalbergichromene, analogues of said selected compounds and any
pharmaceutically acceptable salts thereof.

31