Curcuma (Curcumae longae rhizoma)

COMMUNITY HERBAL MONOGRAPH ON CURCUMA LONGA L., RHIZOMA

1. N AME OF THE MEDICINAL PRODUCT

To be specified for the individual finished product.

2. Q UALITATIVE AND QUANTITATIVE COMPOSITION 1

Well-established use

Traditional use

With regard to the registration application of Article

16d(1) of Directive 2001/83/EC as amended

Curcuma longa L., rhizoma (turmeric root)

i) Herbal substance

Not applicable

ii) Herbal preparations

A) Powdered herbal substance

B) Comminuted herbal substance

C) Tincture (Ratio of herbal substance to extraction

solvent 1:10), extraction solvent ethanol 70% (v/v)

D) Dry extract (DER 13-25:1), extraction solvent

ethanol 96% (v/v)

E) Dry extract (DER 5.5-6.5:1), extraction solvent

ethanol 50% (v/v)

F) Tincture (Ratio of herbal substance to extraction

solvent 1:5), extraction solvent ethanol 70% (v/v)

3. P HARMACEUTICAL F ORM

Well-established use

Traditional use

Comminuted herbal substance as herbal tea for oral use.

Herbal preparations in liquid or solid dosage forms for

oral use.

The pharmaceutical form should be described by the

European Pharmacopoeia full standard term.

1 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant

herbal quality guidance

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4. C LINICAL P ARTICULARS

4.1. Therapeuticindications

Well-established use

Traditional herbal medicinal product used to

increase bile flow for the relief of symptoms of

indigestion (such as sensation of fullness,

flatulence, and slow digestion).

The product is a traditional herbal medicinal

product for use in the specified indication

exclusively based upon long-standing use.

4.2. Posology and method of administration

Well-established use

Traditional use

Posology

Adults and elderly

A) Powdered herbal substance: 1.5-3.0 g daily;

B) Comminuted herbal substance for tea

preparation: 0.5-1 g, up to 3 times daily as an

infusion;

C) Tincture (1:10): 0.5-1 ml 3 times daily;

D) Dry extract (13-25:1): 80-160 mg, divided in

2-5 partial doses daily;

E) Dry extract (5.5-6.5:1): 100-200 mg, 2 times

daily;

F) Tincture (1:5): 10 ml once daily or 5 ml in

60 ml water 3 times daily;

The use in children and adolescents under

18 years of age is not recommended (see section

4.4 ‘Special warnings and precautions for use’)

Duration of use

If the symptoms persist longer than 2 weeks, a

doctor or a qualified health care practitioner

should be consulted.

Method of administration

Oral use.

4.3. Contraindications

Well-established use

Traditional use

Hypersensitivity to the active substance(s).

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Obstruction of bile duct, cholangitis, liver disease,

gallstones and any other biliary diseases.

4.4. Special warnings and precautions for use

Well-established use

Traditional use

The use in children and adolescents is not

recommended due to lack of adequate data.

If symptoms worsen during the use of the

medicinal product a doctor or a qualified health

care practitioner should be consulted.

For tinctures containing ethanol, the appropriate

labelling for ethanol, taken from the ‘Guideline on

excipients in the label and package leaflet of

medicinal products for human use’, must be

included.

4.5. Interactions with other medicinal products and other forms of interaction

Well-established use

Traditional use

None reported.

4.6. Pregnancy and lactation

Well-established use

Traditional use

Safety during pregnancy and lactation has not

been established.

In the absence of sufficient data, the use during

pregnancy and lactation is not recommended.

4.7. Effects on ability to drive and use machines

Well-established use

Traditional use

No studies on the effect on the ability to drive and

use machines have been performed.

4.8. Undesirable effects

Well-established use

Traditional use

Mild symptoms of dry mouth, flatulence and

gastric irritation may occur. The frequency is not

known.

If other adverse reactions not mentioned above

occur, a doctor or a qualified health care

practitioner should be consulted.

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4.9. Overdose

Well-established use

Traditional use

No case of overdose has been reported.

5. P PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamicproperties

Well-established use

Traditional use

Not required as per Article 16c(1)(a)(iii) of

Directive 2001/83/EC as amended.

5.2. Pharmacokineticproperties

Well-established use

Traditional use

Not required as per Article 16c(1)(a)(iii) of

Directive 2001/83/EC as amended.

5.3. Preclinical safety data

Well-established use

Traditional use

Not required as per Article 16c(1)(a)(iii) of

Directive 2001/83/EC as amended, unless

necessary for the safe use of the product.

Adequate tests on reproductive toxicity,

genotoxicity and carcinogenicity have not been

performed.

6. PHARMACEUTICAL PARTICULARS

Well-established use

Traditional use

Not applicable.

7. DATE OF COMPILATION / LAST REVISION

9 November 2009

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Assessment Report

REGULATORY OVERVIEW

I.1

..........................................................................................................3

INTRODUCTION

.................................................................................................................... 6

I.1.1

Description of the herbal substance(s), herbal preparation(s) or combinations thereof

....... 6

I.1.2

Information on period of medicinal use in the Community regarding the specified

indication

............................................................................................................................... 8

I.2

NON-CLINICAL DATA

.......................................................................................................... 9

I.2.1

Pharmacology

I.2.1.1

Overview of available data regarding the herbal substance(s), herbal preparation(s)

........................................................................................................................ 9

and relevant constituents thereof

................................................................................... 9

I.2.1.2

Overall conclusions on pharmacology

........................................................................ 15

I.2.2

Pharmacokinetics

................................................................................................................ 15

I.2.2.1

Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof

........................................................................................... 15

I.2.2.2

Overall conclusions on pharmacokinetics

................................................................... 15

I.2.3

Toxicology

I.2.3.1

.......................................................................................................................... 15

Overview of available data regarding the herbal substance(s), herbal preparation(s)

and relevant constituents thereof

................................................................................. 15

I.2.3.2

Overall conclusions on toxicology

.............................................................................. 16

I.3

CLINICAL DATA

.................................................................................................................. 16

I.3.1

Clinical pharmacology

I.3.1.1

........................................................................................................ 16

Pharmacodynamics

..................................................................................................... 16

I.3.1.2

Pharmacokinetics

........................................................................................................ 16

I.3.2

Clinical Efficacy / Longstanding use and experience

I.3.2.1

......................................................... 16

Posology and duration of use

...................................................................................... 16

I.3.2.2

Clinical studies (case studies and clinical trials)

......................................................... 17

I.3.2.3

Clinical studies in special populations (e.g. elderly and children)

.............................. 23

I.3.2.4

Overall conclusions on (clinical) efficacy / traditional medicinal use

........................ 23

I.3.3

Clinical Safety / Pharmacovigilance

I.3.3.1

................................................................................... 23

Patient exposure

.......................................................................................................... 23

I.3.3.2

Adverse effects

............................................................................................................ 23

I.3.3.3

Serious adverse events and deaths

.............................................................................. 24

I.3.3.4

Laboratory findings

..................................................................................................... 24

I.3.3.5

Safety in special populations and situations

I.3.3.5.1

............................................................... 24

Intrinsic

.................................................................................................................. 24

I.3.3.5.2

Drug interactions

................................................................................................... 24

I.3.3.5.3

Use in pregnancy and lactation

.............................................................................. 25

I.3.3.5.4

Overdose

................................................................................................................ 25

I.3.3.5.5

Drug abuse

............................................................................................................. 25

I.3.3.5.6

Withdrawal and rebound

........................................................................................ 25

I.3.3.5.7

Effects on ability to drive or operate machinery or impairment of mental ability

I.3.3.5.8

Contra-indications

................................................................................................. 25

I.3.3.6

Overall conclusions on clinical safety

........................................................................ 25

I.4

OVERALL CONCLUSIONS

................................................................................................. 26

ANNEXES

I.5

...................................................................................................................................... 26

Community Herbal Monograph on Curcuma longa L., rhizoma

............................................ 26

I.6

Literature References

.............................................................................................................. 26

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REGULATORY OVERVIEW

Member State

Herbal Medicinal Product

Well-Established Use

Herbal Medicinal Product

Traditional Use

Other Classification

Austria

Belgium

Bulgaria

Cyprus

Czech Republic - Combination medicinal product

containing Curcumae longae

rhizomatis pigmenta 1969

*Preparation:

Frangulae modinum 9 mg, Curcumae

longae rhizomatis pigmenta 22.5 mg,

Magnesii salicylas 100 mg, Eucalypti

etheroleum 1 926 mg, Menthae

piperitae etheroleum 3 600 mg,

Levomentholum 9 mg/10 ml;

*Since 1969 is the preparation on the

market;

*Pharmaceutical form: por gtt sol

*Posology: for oral use,

5-10 drops three times daily;

*Indications: cholelithiasis, chronic

cholecystitis, dyspeptic disorders in

chronic hepatitis and after surgery in

biliary duct;

*Contraindications: pregnancy (first

trimester), lactation, in serious renal

failure, acute inflammations in

hepatobiliary tract, children under 12

years of age, children and adolescents

under 17 years of age suffering with

fever;

*Special warnings: risk of Rey

syndrome due to Magnesii salicylas

content.

Pending registration:

*Preparation:

Fluid extract from

Curcuma longa L.,

rhizoma extracted with

mixture ethanol : water 1:1

(as dry residue) 100

mg/tbl, corresponding to

12.5 mg curcuminoides,

calculated as curcumin;

*Pharmaceutical form: por

tbl nob;

*Posology: for oral use, 1

to 2 tablets before meal,

maximum daily dosage 8

tablets;

*Indications (draft, not

agreed yet): choleretic and

cholagogue; treatment and

prevention of functional

digestive disorders of

hepatic origin,

hepatoprotective;

*Contraindications (draft,

not agreed yet): severe

hepatic disorders, biliary

obstruction, cholelithiasis,

hypersensitivity to the

components of the product.

Denmark

Kissinger tablets and pills, combination

products (with 10 active substances) on

market as laxative between 1956 and

1993.

Danish medicines Agency

has no information

regarding products

marketed as food

supplements.

Estonia

All products containing

Curcuma longa are

classified as non-medicinal

products, probably

classified as food

supplements which

requires registration at the

Veterinary and Food

Board.

Finland

France

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Member State Herbal Medicinal Product

Well-Established Use

Herbal Medicinal Product

Traditional Use

Other Classification

Germany

*Dry extract (13-25:1), ethanol 96%

V/V;

*for internal use, adults and adolescents

over 12 years;

*coated tablet: 3 x 1 containing 30 mg

dry extract (max. 5 daily);

hard capsule: 2 x 1 containing 81 mg

dry extract;

*Dyspeptic complaints, particularly

based on functional affections of the

biliary tract;

*AR: GI complaints like feeling of

fullness, heartburn, vomiting,

diarrhoea; longer use may cause gastric

pain; hypersensitivity reactions of the

skin (frequency unknown);

*I: no report of clinical interactions

SPC: Animal tests and human in vitro

tests indicate that there may be an

influence of different phases of the

CYP 450 system and the

p-glycoprotein. Benefit/risk assessment

has to be made carefully, if medicinal

products which are metabolised by

these systems, are taken concomitantly;

*Authorised products on market, no

pharamovigilance actions.

*Dry extract (13-25:1), ethanol 96%

V/V;

*for internal use, adults and

adolescents over 12 years;

*soft capsule: 3 x 1 containing 13.5 mg

dry extract;

*Traditional used to promote the

digestion;

*AR: GI complaints like feeling of

fullness, heartburn, vomiting,

diarrhoea; longer use may cause gastric

pain; hypersensitivity reactions of the

skin (frequency unknown);

*Authorised products on market, no

pharamovigilance actions.

Greece

Hungary

Iceland

Ireland

Italy

Latvia

Liechtenstein

Lithuania

Luxemburg

Malta

The Netherlands -

Norway

One product a product

containing curcuma and an

amino acid, classified as

food supplement, is widely

used. 3 reports on

pharmacovigilance

associated with this

product.

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Member State Herbal Medicinal Product

Well-Established Use

Herbal Medicinal Product

Traditional Use

Other Classification

Poland

Curcumae longae rhizoma extractum

DER 1:5, extraction solvent: ethanol

70% v/v;

*Indication: treatment of mild digestive

disturbances and minor biliary

dysfunction;

*Posology: Adults: in digestive

disturbances 10 ml once daily; as an

adjuvant in biliary dysfunction 5 ml of

the drug diluted with 60 ml water 3

times daily. Children from 12 years: in

digestive disturbances 5 ml of the drug

diluted with 60 ml water once daily;

*AR: none known with exception

hepersensitivity reactions

*Authorised product on market

Portugal

Romania

Slovakia

The herbal substance is only available

in one authorised combination product.

*Composition: Curcumae radicis

pigmenta 0.0225 g, magnesii salicylas

0.18 g, menthae piperitae aetheroleum

3.6 g, eucalypti aetheroleum 1.926 g,

frangulaemodinum 0.009 g;

*indicated for cholelithiasis, chronic

cholecystithis and dyspeptic disorders.

Slovenia

Spain

Dry hydroethanolic extract of dried

rhizomes of Curcuma longa L. (5.5-

6.5:1 ethanol 50% V/V) corresponding

to 10-15 mg curcuminoids;

*Posology: adults 1-2 tablets,

2 times a day, before meals.

Adolescents over 12 years of age: 1

tablet, 2 times a day, before meals

(tablets of 100 mg of dry extract as

declared)

*Indication: symptomatic treatment of

mild digestive disturbances due to

biliary disfunction

* product is on the market, status:

Publicitarias

Sweden

Only one combination

product is approved as

natural remedy.

Composition:

Curcuma longa, Cynara

scolymus, Gentiana lutea

United Kingdom -

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I.1

INTRODUCTION

I.1.1

Description of the herbal substance(s), herbal preparation(s) or combinations thereof

Herbal substance

Curcumae longae rhizoma or turmeric, consists of the scalded and dried rhizomes of Curcuma

longa L . (C. domestica Valeton) [102].

Other documented synonyms of C. longa : C. aromatica Salisbury and Amomum curcuma Jacq.)

[18, 92]. Common names for C. longa : turmeric, curcuma.

Besides C. longa also C. rotunda is mentioned in some older references. Nowadays C. rotunda is

considered to be a former trade name for the product containing the primary rhizomes (bulb or

round turmeric) in distinction to the product consisting of the thinner and longer secondary

rhizomes (longa-form), both originating from C. domestica L. [4, 46].

Other names : Curcuma, Indian saffron, Haridra (Sanskrit, Ayurvedic), Jianghuang (= yellow ginger

in Chinese), Kyoo or Ukon (Japanese) [113].

The European Pharmacopoeia describes in the monograph for Curcumae xanthorrhizae rhizoma a

TLC-test for C. domestica and its modifications for identifying C. xanthorrhizae [100] .

The monographs of ESCOP and Commission E mention that the herbal substance contains not less

than 2.5 resp. 3 percent dicinnamoylmethane derivates, calculated as curcumin, and not less than

2.5 resp. 3 percent volatile oil, both calculated on a dry–weight basis of the drug [108, 93].

Constituents

(see also Fig. 1)

Carbohydrates: 69.4% of total mass [2].

Curcuminoids: this is a mixture of curcumin (diferuloylmethane), monodexmethoxycurcumin and

bisdesmethoxycurcumin [3-7]. Curcumin makes up approximately 90% of the curcuminoid content

in turmeric [8].

The phenolic groups in the structure of curcumin explain the ability of curcumin to eliminate

oxygen-derived free radicals. [9] The free radicals which can be eliminated by curcumin are

hydroxyl radical [10], singlet oxygen [11], superoxide radical [12], nitrogen dioxide [13] and NO

[14].

The curcumin content of the Curcuma longa rhizome varies from 0.6 to 5% of the dry mass [15].

The dry turmeric rhizomes contain 3-5% curcumin, the curcumin content of turmeric oleoresin is

40% [16].

Essential oil: 5.8% of total mass, constituents are: a-phellandrene 1%, sabinene 0.6%, cineol 1%,

borneol 0.5%, zingiberene 25%, and sesquiterpenes 53% [2]. The mono- and sesquiterpenes include

zingiberene, curcumene, α- and β-turmerone [3-7].

Mineral matter: 3.5% of total mass [2].

Moisture: 13.1% of total mass [2].

Polypeptides: [6, 7].

Protein: 6.3% of total mass [2].

Fatty oil: [17]

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Fig. 1: Structures of main components of Rhizoma Curcumae longae [18].

Treatment of the herbal substance immediately after harvesting

According to some handbooks the plant material is processed before drying [92, 93,108]. Hager’s

Handbuch describes that after harvest, the rhizomes are cooked for a short time or heated with hot

water [44-46]. The Indian and Japanese Pharmacopoeias also describe the ‘curing’, consisting of

boiling and (sun) drying of the rhizomes as well as identification by different color reaction tests.

The Chinese Pharmacopoeia mentions: collection of rhizomes, washing, boiling or steaming,

cutting in thick slices, sun drying and separation from roots [117].

Max Wichtl’s Herbal Drugs mentions that the yellowish brown color of the herbal substance is due

to the steaming or scalding treatment after harvesting [4].

As pharmacological and (pre)clinical studies do not contain any data on the pretreatment of the

plant material, and research data on the scalding effect are missing, the impact of the scalding

treatment on the active compounds c.q. efficacy of C. longa preparations remains unclear. The

scalding treatment is considered to be a traditional procedure mainly for food purposes.

Herbal preparations, specified for the individual final product

Powdered Curcuma longa rhizome [18, 93, 99, 108].

Ethanolic (80%) extract [19], [20-28]

Aqueous extract: [29, 30]

Ointment: 0.5% [31]

Tincture: (1:10) [18]

Paste: 15 g turmeric powder in 85 g petroleum jelly [32], or a mix of 1 part of turmeric powder with

4 parts of neem leaves ( Azadirachta indica ) [33].

Oil: 3-5.5% [34]

Oleoresin powder: 40% [35]

Essential oil: 70% (w/w) [35]

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I.1.2

Information on period of medicinal use in the Community regarding the specified indication

Curcuma longa has been documented in the following handbooks:

Reference

Indication

“Lehrbuch der

Phytotherapie” by R.F.

Weiss (1974) [39]

Hauptbestandteil von Curry, das reizend auf die Schleimhäute des

Magen wirkt und anregend auf der Gallenfunktion.

“Lexikon der

Arzneipflanzen und

Drogen” by K. Hiller (year

unknown) [40]

Dyspeptische Beschwerden. In den Herkunftsgebieten bei

entzündlichen und septischen Haut- sowie Augenerkrankungen.

“Pflanzliche Drogen” by

W. Schneider (1974) [41]

Früher als Magenmittel und bei Gelbsucht, jetzt nur noch als

Färbemittel.

“Drogenkunde” by H.

Hoppe (1943) [42]

Mittel bei Leber- und Gallenleiden. Gegen Wechselfieber und

Wassersucht. Magenmittel und Gewürz.

“Lehrbuch der biologischen

Heilmittel” by G. Madaus

(1938, reprint 1979) [43]

Gallen- und Gallentreibemittel, das auch bei Cholelithiasis.

Cholangitis, Cholecystitis, dyspeptische Leberleidender und

Ikterus angewandt wird.

“Hagers handbuch der

pharmazeutischen praxis”

by B. Reichert (1944, 1949)

[44, 45]

Gegen Leberleiden, wirkt abführend [44].

Früher als Magenmittel und bei Gelbsucht, jetzt nur noch als

Färbemittel [45].

“Hagers handbuch der

pharmazeutischen praxis”

by P.H. List (1973) [46]

Cholagogum und cholereticum, früher als Magenmittel und bei

Gelbsucht.

Information on period of medicinal use outside the Community

Experience with C. longa in traditional medicinal systems outside the EU

In many Asian countries the use of turmeric as a food spice, colorant and medicine has a long

tradition.

China, Japan, Korea, Vietnam, Nepal

Turmeric is used extensively in traditional Chinese medicine. It is official in the Pharmacopoeia of

the People’s Republic of China as well as in the Japanese Herbal Medicines Codex (JSHM, 1993)

and is used in these countries and Korea for a range of indications including abdominal fullness,

kidney pain, and amenorrhea. In China an aqueous decoction dosage form is ingested orally and

applied topically [117].

India

Turmeric is used extensively in the Indian systems of medicine (Ayurvedha, Unani, and Siddha)

and is official (Haridra) in the Ayurvedic Pharmacopoeia of India (API, 1989). In Ayurvedic

medicine turmeric has a long history of use as an anti-inflammatory drug for arthritis. In both the

Ayurvedha and Siddha systems of medicine, a turmeric paste is used topically to treat ulcers and

scabies [117].

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The Swami Prakashananda Ayurveda Research Centre lists as indications for turmeric: urticaria and

skin allergy, viral hepatitis, inflammatory conditions of joints, sore throat and wounds [117].

I.2

NON-CLINICAL DATA

I.2.1

Pharmacology

I.2.1.1

Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof

Documentation regarding the route of administration

Oral administration is the main route of administration for Curcuma longa preparations.

Curcuma longa can also be used topically and via inhalation (Ayurvedic tradition).

Topical use of C. longa

Turmeric is applied topically for the treatment of acne, wounds, boils, bruises, blistering, ulcers,

eczema, insect bites, parasitic infections, heamorrhages and skin diseases like herpes zoster and

pemphigus [18, 37,113].

It is used in the form of a paste or ointment (mixture with oil or other substances), as a tincture or

extract. However, no information could be found in literature on the composition of the products,

the posology and the duration use.

Phytochemical research data on major components in Curcuma longa

Pozharitskaya et al. describe a HPTLC method to determine the total of curcuminoids and to

determine curcumin, demethoxycurcumin and bisdemethoxycurcumin in Curcuma longa .

A combination of HPTLC, with a diode array detector (DAD) and post chromatographic DPPH

radical derivatisation was developed to separate and quantify the free-radical scavenging activity of

individual compounds of Curcuma longa [47].

Sacchetti et al. characterized Curcuma longa essential oil using GC and GC-MS. Radical-

scavenging and antioxidant properties were tested using 1,1-diphenyl-2-picrylhydrazyl (DPPH)

assay and luminol-photochemiluminescence (PLC) assay [48].

Pharmacodynamics

Anti-inflammation

Curcuminoids inhibit LOX, COX, phospholipases, leukotrienes, prostaglandins, thromboxane, nitric

oxide [49, 50], elastase, hyaluronidase, collagenase, monocyte chemoattractant protein-1, interferon

inducible protein, TNF and interleukin-12 [50].

Curcuminoids decrease prostaglandin formation and inhibit leukotriene biosynthesis via the

lipoxygenase pathway [51].

Anti-depression

The effect of curcumin was investigated in a rat chronic mild stress (CMS) model. In comparison

with normal rats, rats suffering the CMS procedure have a significant lower intake of sucrose,

increased IL-6, TNF-α levels, CRF- and cortisol levels. Treatment with ethanolic extract increased

the sucrose intake to normal control levels, reduced the CMS-induced increase in serum IL-6 and

TNF-α levels and reduced the CRF levels in serum and medulla oblongata to lower than normal. It

also lowered the cortisol levels in serum to normal levels [20].

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A turmeric ethanolic extract was found to prevent chronic mild stress induced increase of serum IL-

6, TNF-α, CRF- and cortisol levels [20].

Curcuma longa has antidepressant effects mediated through inhibition of monoamine oxidize A

[61].

Curcuma longa ethanolic extract reversed the decrease in serotonin, noradrenalin and dopamine

concentrations as well as the increase in serotonin turnover, cortisol levels and the in serum

corticotrophin-releasing factor [21].

Curcumin increased brain-derived neurotropic factor in the frontal cortex and hippocampus [20].

Atherosclerosis

Curcumin mobilizes α-tocopherol from adipose tissue, this results in protection against oxidative

damage produced during atherosclerosis development. Curcumin increases VLDL cholesterol

transport in plasma, which results in increasing levels of α-tocopherol [52].

Cancer

Curcumin inhibits cell growth by inhibiting expression of basic fibroblast growth factor (FGF) and

the angiogenesis factors vascular endothelial growth factor (VEGF) and basic fibroblast growth

factor (b-FGF) [53].

Curcumin induces apoptosis of cancer cells [54] and it inhibits angiogenesis [55].

Curcumin blocks cyclosporine A-resistant phorbol myristate acetate + anti-CD28 pathway of

T-cell proliferation [56].

Curcumin reduces the testicular damage caused by exposure to di-n-butylphthalate (DBP), by

increase in Glutathion (GSH), testosterone levels and glucose-6-phosphate dehydrogenase (G6PD)

activity and decrease in malondialdehyde (MDA) levels. These effects may be due to intrinsic

antioxidative abilities of curcumin [57-59].

Dietary curcumin inhibits DMBA- and TPA-induced expression of ras-p21 and fos-p62 oncogenes

[60].

Diabetes

A hexane extract (containing ar-turmerone), ethanolic extract (containing containing ar-turmerone,

curcumin, demethoxycurcumin and bisdemethoxycurcumin) and ethanolic extract from the residue

of the hexane extraction (containing curcumin, demethoxycurcumin and bisdemethoxycurcumin)

were found to dose-dependently stimulate adipocyte differentiation. The results indicate that

turmeric ethanolic extract containing both curcuminoids and sesquiterpenoids is more strongly

hypoglycemic than either curcuminoids or sesquiterpenoids [22].

Hepatoprotective activity

Curcumin protects cells against lipid peroxidation induced by paracetamol. This may be due to the

antioxidative effects of the phenolic groups of curcumin [74].

Curcumin was found to decrease serum aspartate transaminase and alkaline phosphatase activity,

and free fatty acid, cholesterol and phospholipid levels [62] .

The exact mechanism of action is still unclear.

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Pharmacological activities of extracts of Curcuma longa

Antifungal, antibacterial, phytotoxic, cytotoxic and insecticidal activity

Khattak et al. studied the antifungal, antibacterial, phytotoxic, cytotoxic and insecticidal activity of

an ethanolic extract of Curcuma longa (extract preparation not specified). The extract showed

antifungal activity towards Trichophyton longifusus and Microsporum canis and weak antibacterial

activity against Staphylococcus aureus . Toxic activity was observed against Lemna minor .

The LD50 in a brine shrimp lethality bioassay Curcuma longa was 33 μg/ml. Curcuma showed no

insecticidal activity [25].

Atherosclerosis

A high-cholesterol diet given to New Zealand White rabbits leads to development of atherosclerosis

in the rabbits. Rabbits given a dietary supplement of a Curcuma longa extract in combination with a

high-cholesterol diet showed a positive effect on the animals’ antioxidant status compared to

controls. Curcumin has shown to mobilize α-tocopherol from adipose tissue, thus protecting their

body against oxidative damage produced during the development of atherosclerosis. Also more

LDL cholesterol could be transported in plasma, increasing levels of α-tocopherol. Overall the fatty

acids in the animals were less susceptible to oxidation in the vessel wall [52].

Diabetes

The effect of an ethanolic extract of turmeric on blood glucose levels in type 2 diabetic KK-A y mice

and stimulated human adipocyte differentiation was investigated by Kuroda et al. The extract was

prepared by a two time extraction of powdered turmeric, with five volumes of ethanol. The extract

was concentrated under reduced pressure to give 12.2 g of ethanolic extract. In the experiment on

the human adipocytes a stimulation of adipocyte differentiation was observed. The activity of

5.0 μg/ml and 10.0 μg/ml ethanolic extract was more potent than that of 0.22 μg/ml and 0.44 μg/ml

of troglitazone, which was therapeutically used as anti-diabetic and anti-inflammatory drug in

humans, until it was withdrawn in 2000 for causing drug-induced hepatitis [23].

Nishiyama et al . studied the influence of three turmeric extracts on blood glucose levels in type

2 diabetic KK-A y mice. The extracts used were an ethanolic extract, a hexanic extract and an

ethanolic extract from the residue of the hexane extraction. The ethanolic extract and hexanic

extract were obtained from powdered Curcuma longa by extracting twice with five volumes of

ethanol or hexane and filtration and evaporation of the solvent. The ethanolic extract from the

residue of the hexane extraction was obtained using the same method. To determine the mechanism

of action the extracts were tested for adipocyte differentiation. No difference in bodyweight were

observed between treated and control animals. The ethanolic extract stimulated adipocyte

differentiation dose-dependently. The hexanic extract and the ethanolic extract from the residue of

the hexane extraction showed similar effects but at higher concentration as the ethanolic extract

[22].

Hepatotoxicity

Soni et al. investigated the preventive effect of an aqueous extract of turmeric on liver damage in

ducklings induced by aflatoxin. The extract was prepared by boiling 1 g of turmeric powder in

100 ml water. After concentration it was made up to 10 ml. The aqueous turmeric extract

(10 mg/ml) inhibited toxin production by 99%. An alcoholic extract of turmeric showed inhibition

as well, except on a much lower level. Turmeric and curcumin treatment showed almost complete

reversal of fatty changes and necrosis induced by aflatoxin [29].

Mutagenicity

Azuine et al. investigated the protective effect of an aqueous turmeric extract on chemically

induced mutagenicity in Salmonella typhimurium strains and clastogenicity in mammalian bone

marrow in female Swiss mice. The anticarcinogenic effects were assessed in the benzo(a)pyrene-

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induced forestomach neoplasia model. The extract was prepared adding 5 ml boiling distilled water

to 50 mg turmeric powder. This was mixed at room temperature for

20 minutes by vortexing at 150 rpm (Orbit Shaker, Lab Line). The supernatant was collected and

lyophilized. Aqueous turmeric extract exhibited antimutagenic activity against direct acting

mutagens. The turmeric extract also inhibited the mutagenicity of benzo(a)pyrene in Salmonella

typhimurium strains. Treatment with the aqueous tumeric extract inhibited the development of

forestomach tumors induced by benzo(a)pyrene significantly. These findings were all dose-

dependent [30].

Myocardial apoptosis

The effect of Curcuma longa on myocardial apoptosis in experimentally induced myocardial

ischemic-reperfusion injury was investigated by Mohanty et al. Winstar rats were fed 100 mg/kg

Curcuma longa once a day, for one month. Curcuma longa treated rats demonstrated significant

anti-apoptotic property, which might contributed to the observed preservation in cardioprotective

effects and cardiac function [63].

Pregnancy/neonates

Singh et al. followed dams and their suckling neonates to determine the modulatory influence of

turmeric and curcumin on hepatic biotransformation system enzymes. Turmeric and curcumin

induced a significant increase in hepatic levels of glutathione S-transferase (GST) and sulfhydryl

(SH) levels. Cytochrome b5 and cytochrome P450 levels were significantly elevated as well. This

indicates that turmeric and/or curcumin metabolites can be transferred through lactation [64].

Ulcers

Kim et al. investigated the protective effect of Curcuma longa ethanolic extract against gastric

ulcers by blocking H 2 histamine receptors (H 2 R) of male Sprague-Dawley (pylorus-ligated) rats.

The extract was prepared by fluxing 100 g Curcuma longa with 80% ethanol. This was shaken at

room temperature for 24 hours, this was performed twice. After extraction, the fluid was

concentrated with rotary vacuum evaporator (EYELA, Japan). The ethanolic extract was dissolved

in 100 ml H 2 O and fractionated with organic solvents, n butanol and ethyl acetate. For in vitro tests

the dried material was resuspended in DMSO, for in vivo tests the dried material was resuspended

in saline. The effect of Curcuma longa extract was compared to the effects of ranitidine. Curcuma

was found to protect the gastric mucosal layer as effective as ranitidine. Orally administerd

ethanolic extract (unknown amount) inhibited gastric acid, gastric juice secretion and ulcer

formation comparable to the effects of ranitidine. Curcuma also suppressed histamine-induced

cAMP production, caused by direct inhibition of H 2 R, curcumin however had no effect on cAMP

formation [24].

Rafatullah et al. investigated the antiulcer activity of an ethanolic extract of turmeric in inbred

Winstar albino rats. The extract tested was a dried 96% ethanol extract. Administration of turmeric

extract led to a significant decrease in ulcer index and acidity of stomach contents. Pretreatment

with the turmeric extract reduced the intensity of ulceration induced by indomethacin or reserpine

administration. Hypothermic-restraint stress reduction of gastric wall mucus, was inhibited by

turmeric extract treatment. Treatment with turmeric extract reduced the severity of lesions induced

by various necrotizing agents. Turmeric extract reduced the decrease in gastric mucosal non-protein

sulfhydryl groups induced by administration of 80% ethanol [19].

Wound healing

The woundhealing effects of Curcuma longa paste were studied in rabbits. The Curcuma longa

treated group showed a significant higher mean value for contraction of the wound compared to

controls. Furthermore the wounds showed less inflammation and an increasing trend in the

formation of collagen [32].

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Pharmacological activities of combination preparations

No data available.

Pharmacological activities of curcumin

Antiplatelet property

The antiplatelet property of ar-turmerone was investigated. Ar-turmerone showed strong inhibitory

activity against platelet aggregation mediated by collagen and arachidonic acid.

At higher concentrations curcumin showed the same effect. However, only a weak or no inhibitory

effect was observed against PAF or thrombin activated platelets. The other components in the

ethanolic extract showed no inhibitory effects [27].

Comparison between ar-turmerone and aspirin showed that ar-turmeron inhibited platelet

aggregation induced by collagen more effective and aspirin inhibited platelet aggregation induced

by arachidonic acid 1.2 times more effective [27].

Cancer

Curcumin was found to inhibit in vitro tumor cell growth by inhibiting expression of basic

fibroblast growth factor (FGF) in breast cancer-cell cultures and the angiogenesis factors vascular

endothelial growth factor (VEGF) and basic fibroblast growth factors (b-FGF) [53].

Curcumin was effective in squamous-cell carcinoma model. The study of Li et al. showed a reduced

occurrence of chemically induced tumors by 50 percent [65].

Curcumin blocks cyclosporine A-resistant phorbol myristate acetate + anti-CD28 pathway of

T-cell proliferation and thus may be a potential adjuvant immunosuppressive agent for the treatment

of cancer [56].

Farombi et al. carried out a study to determine the ameliorative effects of curcumin and kolaviron

(a biflavonoid from the seeds of Garcinia kola ) on the di-n-butylphthalate (DBP)-induced testicular

damage in rats [66]. The level of glutathione (GSH), the glucose-6-phosphate dehydrogenase

(G6PD) activity and the decreased testosterone levels were significantly increased [66].

The increased levels of malondialdehyde (MDA) were decreased, which is in agreement with

Ishihara et al. [66, 67]. This may be due to the intrinsic antioxidative abilities to combat oxidative

damage induced by DBP [66].

Mice exposed to human prostate cancer cells were treated with curcumin. The curcumin-treated

animals showed a decrease in microvessel density and cell proliferation and an increase in apoptosis

compared to controls [55, 68].

Incubation of endothelial cells from bovine aorta with curcumin (in a concentration range of

5-15 μM) showed induction of heme oxygenase expression. Heme oxygenase is an enzyme that

reacts to oxidative stress, by producing the antioxidant biliverdin, and it enhances resistance tot

oxidative damage to cells [73].

The efficacy of curcumin or turmeric extract in reducing chemically-induced tumours in male Swiss

albino mice was studied by Soudamini and Kuttan. The extract was prepared by extraction of 5 g of

powdered turmeric with 100 ml acetone/methanol (45:55). The extract was filtered using filter

paper. 40 mg of curcumin was dissolved in 5 ml acetone/methanol (45:55). DMBA was used to

induce tumors. Single application of curcumin or turmeric extract failed to inhibit papilloma

formation. A small, non significant, reduction in papilloma formation was seen in the turmeric

extract treated group, compared to the control group. Application of both curcumin and turmeric

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extract during carcinogenesis and promotion resulted in less papilloma production, compared to

controls. This indicates that both curcumin and turmeric extract produce their best effects during

tumour promotion [70].

The effect of dietary curcumin (0.2% and 1.0%) on 7,12-dimethylbenz(a)anthracene (DMBA) and

12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice

was investigated by Limtrakul et al. They found a significant lower number of papillomas in the

curcumin treated group compared to the control group. The enhanced expression of ras-p21 and fos-

p62 oncogenes were decreased dose dependently in the curcumin treated group [57].

Antioxidant properties

Curcumin is not an efficient hydroxyl radical scavenger or quencher of superoxide [71].

Mutagens

Nagabhushan et al. tested curcumin against tobacco products and several environmental mutagens

in a Salmonella/microsome test with or without Aroclor 1254-induced rat liver homogenate (S-9

mix), in order to determine the difference between mutagens which require metabolic activation and

those who do not. Curcumin inhibited the mutagenicity of bidi smoke condensate, cigarette smoke

condensate and masheri (a tobacco product) and tobacco extracts in a dose-dependant manner.

Curcumin is only antimutagenic against mutagens which require metabolic activation [72].

Diabetes

Arbiser and Okamoto et al. reported that curcumin reduces the destructive angiogenesis associated

with diabetic retinopathy [58, 59].

Hepatoprotective activity

Tacrine is known for its T-cell destructive activity and hepatotoxicity. In a study with cultures of

human hepatocytes, which had been destroyed by tacrine, curcumin showed to be nearly ten times

more effective than the regular treatment, ascorbic acid [60]. However, a study on carbon

tetrachloridetoxicity in mice, performed in 1996, showed no protective effects due to curcumin

administration at dosages of 200 mg per kg [69].

Donatus et al. investigated the effect of curcumin on the cytotoxic effect of paracetamol in rat

hepatocytes. Curcumin showed no protective effect against paracetamol induced GSH-depletion in

hepatocytes of 3-methyl-cholanthrene pretreated rats. Curcumin in a concentration of 5 x 10 -5 , 5 x

10 -4 and 5 x 10 -3 M protected the cells against lipid peroxidation induced by paracetamol. This

effect may be due to the two phenolic groups of curcumin, which give it strong anti-oxidant effects

[74].

The effect of curcumin on alcohol induced hepatotoxicity in alcoholic rats were studied by

Rajakrishnan et al. Compared to the control group curcumin administration resulted in a decrease of

serum aspartate transaminase and alkaline phosphatase activity. The levels of serum free fatty acids,

cholesterol and phospholipids decreased as well [62].

Stress

Xu et al. investigated the effect of orally administered curcumin on behavior in a chronic stress

model of depression in rats. The molecular targets of curcumin were studied as well. The

antidepressant imipramine was used as a positive control. Chronic curcumin administration

(at 10 mg/kg) showed similar effects as imipramine. These findings suggest that the effects of

chronic administration of curcumin on the behavior of chronic stressed rats may be related to the

modulating effects of the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, through

selective increase in brain-derived neurotropic factor in the frontal cortex and the hippocampus of

the rats [20].

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Blood lipids

In a small study with 10 healthy volunteers it was observed that oral intake of 500 mg/d curcumin

for 7 days resulted in a significant decrease in the level of serum lipid peroxides (33%) and increase

in HDL cholesterol (29%) and a decrease in level of total serum cholesterol (12%) [116].

Toxicity

A study in which monkeys were fed 0.8 mg/kg of curcumin a day for 90 days and rats 1.8 mg/kg a

day for 90 days showed no adverse effects [75].

I.2.1.2

Overall conclusions on pharmacology

Results from in vitro and in vivo studies with whole extracts of Curcuma longa , and isolated

compounds, support the traditional use of Curcuma longa .

I.2.2

Pharmacokinetics

I.2.2.1

Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof

Little is known about the pharmacokinetic pathway of curcumin [76]. Doses up to 5 μg/ml of

curcumin added to microsome- and hepatocyte suspensions disappeared within 30 minutes [77].

In rats, 40-75% of orally administered curcumin is excreted in the feces. Blood levels of less than

5 μg/ml indicate poor absorption from the gut [77, 78].

I.2.2.2

Overall conclusions on pharmacokinetics

Available data suggests that curcumin is poorly absorbed from the gut, rapidly metabolized and

excreted in feces.

I.2.3

Toxicology

I.2.3.1

Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof

Donatus et al. found curcumin to be moderate cytotoxic. At a concentration of 5 x 10 -3 curcumin

slightly increased LDH-leakage from rat hepatocytes. This increase was accompanied by an

increase in GSH-depletion, which can result in increased susceptibility to cytotoxicity [74].

Liver toxicity has been reported, but most of these incidents involved large dietary doses (turmeric

0.2%, 1.0%, 5.0%) or turmeric ethanolic extract 0.05%, 0.25%) given to mice or rats [26].

No mutagenic effects were found in the Ames tests for curcumin and turmeric extracts (information

on preparation could not be found) [79].

A single feeding of 30% turmeric diet to rats produced no toxic effects [75].

No effects on chromosomal damage, pregnancy rate, number of dead embryos, total implants and

mutagenic effects were observed in mice fed with turmeric (0.5%) or curcumin (0.015%) [80].

In mice fed for 14 days with a diet containing 1% and 5% turmeric hepatotoxicity was observed

[26, 81]. Rats fed with turmeric 1% for the same period showed no adverse affect. The rats fed

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turmeric at a dose of 5% of their diet for a period of 90 days showed a reduction in body weight

gain and hepatotoxicity [26].

I.2.3.2

Overall conclusions on toxicology

Neither Curcuma longa nor curcumin appear to be mutagenic, or toxic for embryos or implants.

However, with a high (dietary) intake hepatotoxicity was observed.

I.3

CLINICAL DATA

I.3.1

Clinical pharmacology

I.3.1.1

Pharmacodynamics

No published data available.

I.3.1.2

Pharmacokinetics

In humans the estimated bioavailability of curcumin after oral administration is 65%. Cytochrome P

450 isoenzyme 1A1 is inhibited by curcumin and is metabolized by glucuronidation [28].

In a phase I clinical study subjects had average peak serum concentrations of 0.5, 0.6 and 2 μM

after taking 4-, 6- or 8-g doses of curcumin. Urinary excretion of curcumin was not detectable [89].

I.3.2

Clinical Efficacy / Longstanding use and experience

Medicinal uses of Curcuma longa have been reported in several European handbooks:

- septic skin disease [40, 43]

- liver disease [40, 42, 44]

- anti-tumor [40]

- anti-mutagenic [40]

- dyspepsia [43, 45]

- parasitic infections [43]

- jaundice [45]

- muscle relaxant [46]

I.3.2.1

Posology and duration of use

Turmeric is taken orally or applied on the skin. It is used as a powder (e.g. in capsules or to dissolve

in fluid), as an ethanolic or aqueous extract, as paste, ointment and as oil [15, 19, 30-33, 36, 64, 79,

80, 90-94].

There are no dose-response studies available. The following posology is described in literature:

1.5-3 g of powdered turmeric root is usually recommended for use against dyspeptic/digestive

disorders [18, 92, 93,108].

Turmeric is taken in doses of 5-30 g daily for acute problems or 3-10 g daily for chronic problems

in inflammatory conditions [95].

According to the Professional’s Handbook of CAM, a three times daily dosage of 400-600 mg of

curcumin or 8-60 g of fresh turmeric root is recommended in arthritis [97].

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For chemopreventive use, the recommended daily dose of curcumin is approximately 500 mg per

day [96]. This corresponds to a daily intake of 170 g of powdered turmeric of raw rhizome, when

assuming that the rhizome contains an average quantity of curcumin of 3% [15].

Other dosage recommendations are:

- powdered plant material: 1.5-3.0 g daily [18, 93, 99, 100, 108]

- oral infusion: 0.5-1 g three times a day [4, 18]

- tincture (1:10): 0.5-1 ml three times per day [18]

In Germany, there are two preparations with C. longa dry extract (DER 13-25:1; ethanol 96%) on

the market: As a ‘WEU’ product: coated tablet/hard capsule with posology 3 x 30 mg/2 x 81 mg

daily for dyspeptic complaints; as a ‘Traditional Use’ product: soft capsule with posology

3 x 13.5 mg daily to promote the digestion.

In Poland, an oral liquid with turmeric extractum (DER 1:5, ethanol 70%) is authorized as

medicinal product for traditional use for the symptomatic treatment of mild digestive disturbances

and minor biliary dysfunction (posology 10 ml once daily or 5 ml in 60 ml water

3 times daily, respectively).

In Spain there is one preparation containing C. longa dry extract (DER 5.5-6.5:1 , ethanol 50%)

authorized as a ‘WEU’ medicinal product (posology 2 x 1-2 tablets of 100 mg) for traditional use

for the symptomatic treatment of mild digestive disturbances due to biliary dysfunction. See also

Regulatory Overview.

For topical application no clear indications for posology could be found in literature.

Duration of use

Information on the recommended duration of use could not be found. As clinical safety studies are

lacking, it is proposed to limit the duration of use to two weeks.

I.3.2.2

Clinical studies (case studies and clinical trials)

Dyspepsia

In a randomized, double-blind, placebo-controlled multicentre study of Thamlikitkul et al . (1989),

106 patients with dyspeptic complaints (such as abdominal pain, epigastric discomfort, flatulence or

belching) were treated daily for 7 days with 2 g of turmeric (n=38), a herbal combination including

cascara and nux vomica and ginger (n=30) or placebo (n=38). At the end of the study 87% patients

in the turmeric group, 83% in the herbal extract mixture group and 53% in the placebo group

reported a notable improvement. The difference between turmeric and placebo was significant and

clinically relevant (p=0.003) [115].

Irritable bowel syndrome

A partially blinded trail was performed with 207 volunteers with self-reported irritable bowel

syndrome. Patients were divided in 2 groups: one was treated with 72 mg (1 tablet) and the other

with 144 mg (2 tablets) of a standardized extract of tumeric extract (Cynara Lichtwer from Pharma

UK), No data were provided on the extraction solvent and the compound(s) used for

standardization. Intake of tumeric resulted in a significant reductions (compared to baseline) of IBS

prevalence, 53% and 60% in the one- and two-tablet groups respectively (p<0.001)) as well as in a

significant decrease in pain and discomfort (22% and 25% in the one- and two-tablet group

respectively). Also a significant improvement of quality of life, improvement of IBS and increased

normal bowel pattern was observed [49]. However, no significant difference was observed between

the two groups. There was no placebo group in the trial, According to the authors there is “ little

doubt that the placebo effect contributed to the improvement seen .” [49].

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Mutagens

In a clinical trial performed in 1992 the effects of turmeric administration on urinary excretion of

mutagens (in 16 chronic smokers and 6 non-smokers) were investigated. Turmeric was

administered at a dose of 1.5 g/day for 30 days. The non-smokers had low excretion of mutagens at

baseline, compared to smokers. Intake of turmeric by the smokers resulted in a significant decrease

in urinary mutagen excretion, compared with baseline [82].

Peptic ulcers

The effect of turmeric on peptic ulcers was studied in 2001 in an uncontrolled trial performed in

Thailand. A group of 25 subjects received five doses of 600 mg of turmeric a day, for 12 weeks.

After 12 weeks 19 subjects had no ulcers [83].

Cancerous lesions

In the study of Kuttan et al . (1987) an ethanol extract of turmeric ("Curcuma longa") as well as an

ointment of curcumin were found to relieve the symptoms associated with external cancerous

lesions. Reduction in smell was noted in 90% of the cases and reduction in itching in almost all

cases. Dry lesions were observed in 70% of the cases, and a small number of patients (10%) had a

reduction in lesion size and pain. In many patients the effect continued for several months. An

adverse reaction was noticed in only one of the 62 patients evaluated [31].

For an overview of clinical studies with C. longa preparations, combination preparations and

curcumine, see the tables below.

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Overview of clinical studies with C. longa preparations.

Author, date Study type

and duration

Patients

Treatment,

daily dosage

Parameters Results

Conclusion/Discussion

Bundy et al .,

2004

[49]

Pilot study,

partially blinded,

R 1 two-doses,

8 weeks

207 volunteers

selected with

Rome II criteria

1 or 2 tablets of

72 mg

standardised

turmeric extract

(no details)

IBS prevalence,

symptom

related Q of

Life and self-

reported

effectiveness

IBS prevalence reduced in both

groups, abdominal pain/discomfort

score reduced sign. by 22% and

25% in 1 tablet and 2 tablet groups

resp. , improvement in symptoms,

no significant differences between

groups.

No data on the extraction solvent and

the compound(s) used for

standardization.

No placebo group in the trial.

According to the authors there is

“little doubt that the placebo effect

contributed to the improvement

seen..”

Häringer, 2004

[113]

MC 1

Anwendungsbeo

bachtung (AWB)

12 weeks

221 patients

with functional

dyspepsy

(Rome II

criteria)

2.8 g

(2 tablets of

81 mg dry extract

(13-25:1))

Nepean

Dyspepsy Index

(15 symptoms);

fat metabolism

154 patients finished trial; after 6

weeks 33%, after 12 weeks 54%

less symptoms.

No Placebo, subjective assessments;

Methodological short comings

Kammerer &

Fintelmann,

2001

[114]

31 days

440 patients

with dyspepsy,

functional

disorders of

bileducts

2.8 g

(2 tablets of

81 mg dry extract

(13-25:1)) for 28

days

9 symptoms

64% reduction of symptoms; 36%

of patients symptom free; 56%

continued treatment; 7% ended

prematurely, for no relief.

No Placebo, subjective assessments;

Methodological short comings

Kuttan et al .,

1987

[31]

62 patients

Ethanolic extract

of C. longa as

well as ointment

of curcumin

Smell, itching,

lesion size

Reduction in smell (90% of cases),

Reduction of itching (all cases), dry

lesions (70% of cases), reduction in

lesion size and pain (10% of cases)

No details on study type, formulation

and application

Polasa et al .,

1992

[82]

Uncontrolled,

30 days

22 normal men

(16 chronic

smokers, 6 non-

smokers),

India

1.5 g

(2 tablets of

750 mg turmeric)

Urine testing

after 0,15, 30

days,

biochemical

parameters,

mutagenicity

assay

Reduction of urinary excretion of

mutagens in smokers

Turmeric administration may reduce

the genotoxicity of tobacco

mutagens. Clinical relevance is not

clear.

1 R = randomised

P = placebo-controlled

DB = double blind

MC = multi centre

CO = cross-ove r

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Prucksunand et

al .,

2001

[83]

Phase II,

uncontrolled

4 weeks

45 patients with

symptoms

indicating

peptic ulcer, 16-

60 years

3 g

(2 capsules

300 mg turmeric

five times daily)

Symptoms pain

and discomfort,

blood chemistry

and hematology

Abdominal pain and discomfort

subsided in 1 st and 2 nd week, no

significant changes in blood

chemistry and hematology, liver

and renal functions

Methodological shortcomings (e.g.

baseline, not all patients endoscoped)

Thamlikitkul et

al .,

1989

[115]

MC R P DB 1

3-arm,

7 days

116 patients

with dyspepsia

(acid / flatulent

/atonic)

domestica: 39

P: 41

‘Flatulence’: 36

2 g

powder of dried

turmeric rhizome

(2 x 250 mg

capsules

4 times)

or ‘Flatulence’

(traditional

treatment)

Symptoms,

adverse events,

compliance &

acceptance

Response: P: 53%, F: 83%,

C: 87%

In all groups mild adverse events

This s the only placebo controlled

trial performed with Curcuma longa .

However the article contains very

little information on the medical

protocol used.

No information on the blinding of

the clinical assessors. No difference

was observed with regard in the

patient’s satisfaction. Comparator is

not a standard treatment

Overview of clinical studies with C. longa containing combination preparations.

Author, date Study type

and duration

Patients

Treatment,

daily dosage

Parameters Results

Conclusion/Discussion

Charles and

Charles,

1992

[33]

Pilot study

814 patients

with scabies

Ayurvedic

formulation of

turmeric and

Azadirachta

indica (Neem)

as paste (topical

use)

Number, size

and type of

lesions

In 97% of cases cure within

3-15 days, no adverse effects

Efficacy was not assessed

because efficacy of a combination

can not be extrapolated to mono-

preparations

Kulkarni et

al .,

1991

[38]

R DB P CO 1 ,

2 x 3 months

42 patients

with

osteoarthritis

3 x 2 capsules

of 650 mg of

C. longa

containing

Ayurvedic

herbomineral

formulation

(corresponding

to 50 mg

turmeric each)

Pain and

disability

score

Significant drop in severity of

pain and disability score, mild

side-effects (nausea, dermatitis,

pain in abdomen)

Efficacy was not assessed

because efficacy of a combination

can not be extrapolated to mono-

preparations

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Overview of clinical studies with curcumin.

Author, date Study type

and duration

Patients

Treatment,

daily dosage

Parameters Results

Conclusion/Discussion

Rasyid, Lelo

1999

[91]

R DB P CO 1

12 healthy

volunteers

20 mg curcumin

single dose

Contraction

effect on

human gall-

bladder

Significant reduction of gall

bladder volume after 0.5 h-2.0 h

(12-29%, resp.), no side-effects

Further dose-responding studies

needed to find optimal dose of

curcumin to induce 50%

contraction

Soni, Kuttan

1992

[29]

Uncontrolled,

7 days

10 healthy

volunteers

500 mg

curcumin

Serum level of

cholesterol

and lipid

peroxides

Decrease serum lipid peroxides

(33%), increase in HDL

cholesterol (29%), decrease in

total serum cholesterol (12%)

Follow-up study needed of

curcumin as preventive substance

against arterial diseases

1 R = randomised

P = placebo-controlled

DB = double blind

MC = multi centre

CO = cross-ove r

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Pharmacological activities of combination preparations

Osteoarthritis

Kulkarin et al. investigated the effect of a herbomineral formulation (a combination of turmeric

with Ashwagandha ( Withania somnifera ), Sallai Guggul ( Boswellia serrata ) and Jasad Bhasma

(zinc) based on Ayurvedic medicine) on osteoarthritis. Short term effects of the herbomineral

formulation were significant alterations in the severity of pain and disability. Other changes like

less morning stiffness, better grip strength and joint score, however, were not significant [38].

Scabies

In a pilot study with 814 patients, a combination of turmeric and neem in the form of a topical paste

was found to effective in treating scabies. 97% of the patients were cured within 3-15 days of

treatment [33].

Pharmacological activities of curcumin

Arthritis

The efficacy of a combination of curcumin and frankincense was studied in a placebo controlled

trail in 90 patients with osteoarthritis. Patients were treated for 32 weeks. After 16 weeks and 32

weeks of treatment a significant reduction in pain (P<0.05) was observed. The treatment resulted in

a significant improvement in WOMAC (Western Ontario McMaster University OA Index, Likert

scale, version 3.0) scores (P<0.01) [84].

Deodhar et al. performed a double-blind clinical trial in which curcumin 1200 mg/day was

compared with phenylbutazone 300 mg/day in 18 patients with rheumatoid arthritis. Both curcumin

and phenylbutazone improved walking time, morning stiffness, and swelling, but only

phenylbutazone improved ‘fatigue time’. Both drugs were assessed as producing an overall

improvement over baseline. However, the patients only rated phenylbutazone as better for

controlling symptoms, compared with baseline [85].

Biliary effects

In animal models an increase of the bile flow and the bile excretion were observed after intravenous

administration of up to 500 mg/kg of an aqueous alcohol turmeric extract [109-112].

Gall-bladder function

In a randomised double-blind crossover study in 12 healthy volunteers ultrasonic examination

revealed that the contraction of the human gall-bladder is stimulated by a single oral dose of 20 mg

of curcumin [91].

Cancer

In an open clinical trial a curcumin 0.5% ointment was tested in 62 patients with skin and mucous

membrane cancers. The ointment was applied three times daily for a minimum of four weeks. A

total of 68% of the patients responded (reduction in exudates 70%, lesion smell 90%, and pain 50%)

[31].

Chronic anterior uveitis

In an open clinical trial, curcumin was administered in an oral dose of 375 mg three times daily for

12 weeks to 53 patients with chronic anterior uveitis. Symptoms improved after 12 weeks of

therapy in about 90% of the patients who completed the trial. 47% had repeated episodes of anterior

uveitis in a three-year follow-up [36].

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Inflammation

Human trials have demonstrated that a dose of 400 mg of curcumin, three times per day, can reduce

postoperative inflammation as effectively as the NSAID phenylbutazone [87].

Pancreatitis

Durgaprasad et al. investigated the effect of oral administration of curcumin with piperine in

20 patients with tropical pancreatitis on pain and markers of oxidative stress. The patients received

500 mg of curcumin in combination with 5 mg of piperine or placebo for a period of

6 weeks. A significant reduction in erythrocyte MDA levels was observed, as well as a significant

increase in GSH levels compared to placebo. No effect was observed on the pain. These effects

indicate that curcumin in combination with piperine reverses lipid peroxidation in patients with

tropical pancreatitis [88].

I.3.2.3

Clinical studies in special populations (e.g. elderly and children)

No published data available.

I.3.2.4

Overall conclusions on (clinical) efficacy / traditional medicinal use

The use of Curcuma longa against dyspepsia, skin and liver diseases is well documented in a

number of handbooks.

The traditional use is supported by a substantial amount of data on the pharmacological effects of

curcuma root, curcuma extract and curcumin. However clinical data is very limited. Only

5 trials have been published for curcuma (extract), of which one is placebo controlled and relevant

as to the mentioned indications.

The study of Thamlikitkul et al . performed in 1989, is the only placebo controlled trial performed

with Curcuma longa . However the article contains very little information on the medical protocol

used. For example according to the title of the article the trial was double-blinded but the article

does not contain information on the blinding of the clinical assessors. The comparison to placebo

treatment with curcuma resulted in a statistically significant improvement of dyspeptic symptoms,

yet no difference was observed with regard to the patient’s satisfaction.

Several trials were performed with curcumin. Not withstanding the fact that it is questionable if the

activity of an isolated constituent can be used to justify the efficacy of a herbal medicinal product,

the studies performed with curcumin have limited value for the monograph because they were

performed with either a very high dose or with combination products. Furthermore the trials were

conducted on diseases for which curcuma has no well established use in the EU. In conclusion the

available data is not sufficient to support a “well established use” indication for curcuma.

I.3.3

Clinical Safety / Pharmacovigilance

I.3.3.1

Patient exposure

No data available.

I.3.3.2

Adverse effects

The Food and Drug Administration classifies turmeric as a substance Generally Recognized as Safe

[50].

No major side effects have been reported in the clinical studies [3, 49, 91].

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No side-effects were reported in patients with rheumatoid arthritis treated with 1200 mg/day of

curcumin for two weeks [85].

In a phase I trial with 25 subjects, who had various high-risk cancerous conditions, no toxic

reactions were observed. The subjects received up to 8 g of curcumin a day for

3 months [89].

In a clinical study in patients with irritable bowel syndrome dry mouth and flatulence was reported

by approximately 25% of the patients [49]. In another study two of 19 patients treated with 2500 mg

of curcumin per day, complained of gastric irritation. No other adverse effects were reported [101].

In the study of Thamlikitkul mild side-effects as nausea, diarrhoea, headache, tiredness and

sleepiness have been reported in the turmeric group (2 g/day) as well as in the other groups (placebo

and comparitive herbal combination) [115].

Rare cases of allergic contact dermatitis have been reported [102, 103]. In an 18-month study on the

topical use of curcumin to treat skin and mucous membrane cancers, scalp itching was observed in

1 patient of 62 patients, [31]. Patch testing led to allergic reactions (not further classified) in persons

who were regularly exposed to the substance or who already had dermatitis of the finger tips. Few

allergic reactions (skin rash) occurred to people not previously exposed to curcumin [104].

Pharmacovigilance problems have been reported for a product containing curcuma and a amino

acid. Further study revealed that the observed liver toxicity was not due to curcuma.

Assessors comment :

The inhibitory effects of curcuminoids on COXs correlates with the ulcerogenic activity in observed

rats: ulcus index 8-10 times higher than control. These findings suggest that curcuma extracts

should not be used by patients with duodenal/gastric ulcers. However in a phase II study, a gastro

protective action was observed in patients with peptic ulcer disease after oral intake of 600 mg

curcumin 5 times daily [Prucksunand et al. , 2001]. Therefore no contraindication for

duodenal/gastric ulcers was included in the monograph.

I.3.3.3

Serious adverse events and deaths

No data available.

I.3.3.4

Laboratory findings

No data available.

I.3.3.5

Safety in special populations and situations

No data available.

I.3.3.5.1 Intrinsic (including elderly and children) / extrinsic factors

No data available.

I.3.3.5.2 Drug interactions

Turmeric may interact with NSAIDs, antiplatelet agents or antihyperlipidemics [94], although there

have been no reports in humans [97].

The antiplatelet activity has only been observed in animal studies. Clinical data is lacking [97].

Therefore this interaction is not included in the monograph.

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Fetrow suggested that curcumin could decrease the effect of immunosuppressants, although no

supporting data was provided [97].

Reports on interaction between warfarin and turmeric are mainly based on in vitro data, animal

studies or individual case reports. More studies are needed to confirm and assess the clinical

significance of this potential interaction [105].

Several studies reported interactions between curcumin and other phytochemicals. When healthy

human subjects took a 2 g dose of curcumin in combination with 20 mg of piperine, extracted from

black pepper, the bioavailability of curcumin increased twenty-fold compared to subjects who took

only 2 g of curcumin [106].

Green tea enhances the effect of curcumin. In Swiss mice and Syrian golden hamsters tumor models

the combination of catechin and turmeric was more effective than the individual components [107].

Recently it has been suggested that curcumin and green tea extract have synergistic effect in

reducing oral squamous-cell carcinomas in hamsters [65].

I.3.3.5.3 Use in pregnancy and lactation

There are no reports on the use of curcumin during pregnancy and lactaction [15, 92].

Singh et al. observed pharmacological effects in dams as well as their suckling neonates when

turmeric and/or curcumin was administrated to the dams. The results indicate that turmeric and/or

curcumin metabolites (not specifically mentioned) can be transferred through lactation [64]. Hence

the use of curcumin during breast-feeding is not recommended [92].

I.3.3.5.4 Overdose

No toxic effects were observed after three months oral intake of 8,000 mg or 2.2 g of turmeric

(equivalent to 180 mg of curcumin) a day for four months [89, 96].

I.3.3.5.5

Drug abuse

No data available.

I.3.3.5.6

Withdrawal and rebound

No data available.

I.3.3.5.7

Effects on ability to drive or operate machinery or impairment of mental ability

No data available.

I.3.3.5.8

Contra-indications

Because curcumin was found to stimulate the gall bladder, the use of curcumin or turmeric is

contraindicated in patients with obstruction of the biliary tract [18, 91, 92, 108]. This

contraindication is also mentioned in the WHO monograph and in the Kommisson E monograph

[18, 92].

I.3.3.6

Overall conclusions on clinical safety

No serious side effects have been reported up to now. Furthermore the chemical composition of

Curcuma longa does not give any reason for concerns regarding safety.

Potential interactions between Curcuma longa and NSAIDs, antiplatelet agents, antihyper-

lipidemics and immunosuppressants have been reported, but this has not clinically been proven The

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use of Curcuma longa in pregnant women and during lactation is not recommended while there are

indications that metabolites of Curcuma longa can be transferred through lactation.

I.4

OVERALL CONCLUSIONS

Curcuma longa has been used in Europe for a long time, mainly against dyspepsia, skin and liver

diseases and infections. However, the available data is not sufficient to support a “well established

use” indication for curcuma. As the medicinal use of curcuma has been documented continuously in

European handbooks, C urcuma longa fulfils the requirements of Directive 2004/24 EC for

classification of traditional herbal medicinal products. The use of Curcuma longa is considered

plausible in the treatment of dyspeptic complaints on the basis of bibliography and pharmacological

data.

Although the use for skin diseases is also described in authoritative texts, it is not included in the

monograph because no data could be found on the preparations and the posology.

The pharmacological activity is attributed to the whole extract; however the majority of activities

were also observed with curcumin.

Curcuma longa is used in the following pharmaceutical forms and posology:

- powdered plant material: 1.5-3.0 g daily

- oral infusion: 0.5-1 g up to three times daily

- tincture (1:10): 0.5-1 ml three times daily

- dry extract (13-25:1): 80-160 mg daily, divided in 2-5 partial doses

- dry extract (5.5-6.5:1): 100-200 mg 2 times daily

- tincture (1:5) : 10 ml once daily or 5 ml in 60 ml water 3 times daily

Only mild side effects have been reported for Curcuma longa : dry mouth, flatulence, and gastric

irritation. No serious side effects have been reported.

Due to lack of data, the use of Curcuma longa in children under the age of 18 years cannot be

recommended.

As relevant data on the use during pregnancy and lactation is lacking, Curcuma longa can not be

recommended in these cases.

ANNEXES

I.5

C OMMUNITY H ERBAL M ONOGRAPH ON C URCUMA LONGA L., RHIZOMA

I.6

L ITERATURE R EFERENCES

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Source: European Medicines Agency

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