Urtica (Urticae herba)

COMMUNITY HERBAL MONOGRAPH ON

URTICA DIOICA L. AND URTICA URENS L., HERBA

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 marketing authorisation

application of Article 10(a) of Directive

2001/83/EC as amended

With regard to the registration application of

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

amended

Urtica dioica L., Urtica urens L., their hybrids or

mixtures, herba (nettle herb)

Herbal substance

Dried cut or fragmented aerial parts of the

plant collected or harvested during the

flowering period

ii) Herbal preparations

A) Comminuted herbal substance

B) Powdered herbal substance

C) Expressed juice (1:0.5-1.1) from fresh

herb 2

D) Expressed juice (1.36-1.96:1) from fresh

herb

E) Liquid extract (1:1), extraction solvent:

ethanol 25% (V/V)

F) Liquid extract (1:1.8-2.2), extraction

solvent: ethanol 30% (V/V)

G) Tincture (1:5), extraction solvent: ethanol

45% (V/V)

H) Dry extract (5-10:1), extraction solvent:

water

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

relevant herbal quality guidance.

2 According to the method in Urticae herba monograph of Hagers Handbuch 1998

2/7

3. PHARMACEUTICAL FORM

Well-established use

Traditional use

Herbal substance or herbal preparation in solid or

liquid dosage forms or as herbal tea for oral use.

The pharmaceutical form should be described by

the European Pharmacopoeia full standard term.

4. C LINICAL PARTICULARS

4.1. Therapeutic indications

Well-established use

Traditional use

a) Traditional herbal medicinal product to

increase the amount of urine to achieve

flushing of the urinary tract as an adjuvant in

minor urinary complaints.

b) Traditional herbal medicinal product for

relief of minor articular pain

c) Traditional herbal medicinal product used in

seborrhoeic skin conditions

The product is a traditional herbal medicinal

product for use in specified indications

exclusively based upon long-standing use.

4.2. Posology and method of administration

Well-established use

Traditional use

Posology

Indication a) and b)

Adolescents over 12 years of age, adults, elderly

A) Dried cut or fragmented or comminuted

herbal substance: 2-4 g as single dose up to

3 times daily as infusion.

B) Powdered herbal substance: 380-570 mg as

single dose up to 3-4 times daily.

C) Expressed juice (1:0.5-1.1) from fresh herb:

10-15 ml as a single dose up to 3 times

daily.

3/7

E) Expressed juice from fresh herb (1.36-

1.96:1): 3.5 ml as a single dose up to 3-4

times daily

D) Liquid extract (1:1), extraction solvent:

ethanol 25% (V/V) 3-4 ml as single dose

up to 3 times daily.

E) Liquid extract (1:1.8-2.2), extraction

solvent: ethanol 30% (V/V): 100 drops as

single dose up to 4 times daily.

F) Tincture (1:5), extraction solvent: ethanol

45% (V/V): 2-6 ml as single dose up to

3 times daily.

G) Dry extract (5-10:1), extraction solvent:

water corresponding to 2-4 g of herbal

substance as a single dose up to 3 times

daily.

Indication c)

Adolescents over 12 years of age, adults, elderly

275 mg powdered herbal substance as single dose

up to 3-4 times daily

The use in children under 12 years of age is not

recommended (see section 4.4 ‘Special warnings

and precautions for use’).

Duration of use

Indication a) and c)

The herbal substance is traditionally used over a

period of two up to four weeks.

If symptoms persist within one week during the

use of the medicinal product, a doctor or a

qualified health care practitioner should be

consulted.

Indication b)

Not to be taken for more than 4 weeks.

If symptoms persist within one month during the

use of the medicinal product a doctor or a

qualified health care practitioner should be

consulted.

Method of administration

Oral use.

Indication a)

For extracts, ensure appropriate fluid intake.

4/7

4.3. Contraindications

Well-established use

Traditional use

Hypersensitivity to the active substance.

Condition where a reduced fluid intake is

recommended (e.g. severe cardiac or renal

disease).

4.4. Special warnings and precautions for use

Well-established use

Traditional use

The product is not intended to be used in case of

acute arthritis as this condition requires medical

advice.

The use is not recommended in children under

12 years of age because of the lack of available

experience.

If urinary tract complaints worsen and symptoms

such as fever, dysuria, spasm, or blood in the

urine occur during the use of medicinal product, a

doctor or a qualified health care practitioner

should be consulted.

For tinctures and liquid extracts 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.

5/7

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 gastrointestinal complaints (e.g. nausea,

vomiting, and diarrhoea) and allergic reactions

(e.g. itching, exanthema, hives) 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.

4.9. Overdose

Well-established use

Traditional use

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Well-established use

Traditional use

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

Directive 2001/83/EC as amended.

5.2. Pharmacokinetic properties

Well-established use

Traditional use

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

Directive 2001/83/EC as amended.

6/7

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.

Tests on reproductive toxicity and carcinogenicity

have not been performed.

Adequate tests on genotoxicity have not been

performed.

6. PHARMACEUTICAL PARTICULARS

Well-established use

Traditional use

Not applicable.

7. DATE OF COMPILATION / LAST REVISION

4 September 2008

7/7

Assessment Report

ASSESSMENT REPORT

FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS

THEREOF WITH TRADITIONAL USE

Urtica dioica L., Urtica urens L., herba

BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS

AMENDED

Urtica dioica L., Urtica urens L., their hybrids or

their mixtures, herba

Herbal substance(s) (binomial scientific name of

the plant, including plant part)

Dried cut or fragmented aerial parts of the plant

collected or harvested during the flowering period

Herbal preparation(s)

Comminuted herbal substance

Powdered herbal substance

Expressed juice (1:0.5-1.1) from the fresh herb

Expressed juice (1.36-1.96:1) from fresh herb

Liquid extract (1:1), extraction solvent:

ethanol 25% (V/V)

Liquid extract (1:1.8-2.2), extraction solvent:

ethanol 30% (V/V)

Tincture (1:5), extraction solvent:

ethanol 45% (V/V)

Dry extract (5-10:1), extraction solvent: water

Pharmaceutical forms

Herbal substance or herbal preparation in solid or

liquid dosage forms or as herbal tea for oral use.

Rapporteur

Dr. Zsuzsanna Biró-Sándor

2/26

TABLE OF CONTENTS

REGULATORY STATUS OVERVIEW ........................................................................................ 5

T ABLE 2: P RODUCTS ON THE G ERMAN MARKET ....................................................................................... 7

I.1 I NTRODUCTION ................................................................................................................................. 8

This assessment report reviews the available scientific data for nettle herb. Evaulation of the

literature on nettle was very difficult because in most of the cases data on nettle herb and nettle leaf

were confused. ....................................................................................................................................... 8

I.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof ........ 8

I.1.2 Information on period of medicinal use in the Community regarding the specified indication

I.2 N ON -C LINICAL D ATA ..................................................................................................................... 13

I.2.1 Pharmacology ........................................................................................................................ 14

I.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof ............................................................................................................ 14

I.2.1.2 Assessor’s overall conclusions on pharmacology ......................................................... 19

Indication a: Traditional herbal medicinal product to increase the amount of urine to achieve

flushing of the urinary tract as an adjuvant in minor urinary complaints. ....................................... 19

The anti-inflammatory effect of nettle herb (the flavonoid fractions of it) can support this

indication. ........................................................................................................................................ 19

I.2.2 Pharmacokinetics .................................................................................................................. 19

I.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and

relevant constituents thereof ............................................................................................................ 20

I.2.2.2 Assessor’s overall conclusions on pharmacokinetics ................................................... 20

I.2.3 Toxicology ............................................................................................................................. 20

I.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and

constituents thereof .......................................................................................................................... 20

I.2.3.2. Assessor’s overall conclusions on toxicology .............................................................. 21

I.3 C LINICAL D ATA .............................................................................................................................. 21

I.3.1 Clinical Pharmacology .......................................................................................................... 21

I.3.1.1 Pharmacodynamics ....................................................................................................... 21

I.3.1.2 Pharmacokinetics .......................................................................................................... 21

I.3.2 Clinical Efficacy .................................................................................................................... 21

I.3.2.1 Dose response studies ................................................................................................... 22

I.3.2.2 Clinical studies (case studies and clinical trials) ........................................................... 22

I.3.2.3 Clinical studies in special populations (e.g. elderly and children) ................................ 23

There have been no studies in special populations. ......................................................................... 23

I.3.2.4 Assessor’s overall conclusions on clinical efficacy ...................................................... 23

I.3.3 Clinical Safety/Pharmacovigilance ....................................................................................... 23

I.3.3.1 Patient exposure ............................................................................................................ 23

I.3.3.2 Adverse events .............................................................................................................. 23

ESCOP 1997, 2003: “None reported.” ............................................................................................ 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 ................................................................. 24

I.3.3.5.1 Intrinsic (including elderly and children) / extrinsic factors ......................................... 24

I.3.3.5.2 Contra indications (hypersensitivity and allergic potential to be both covered) ........... 24

I.3.3.5.3 Warnings ans precautions for use ................................................................................. 24

I.3.3.5.4 Drug interactions........................................................................................................... 24

I.3.3.5.5 Use in pregnancy and lactation ..................................................................................... 25

I.3.3.5.6 Overdose ....................................................................................................................... 25

I.3.3.5.7 Drug abuse .................................................................................................................... 25

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I.3.3.5.8 Withdrawal and rebound............................................................................................... 25

I.3.3.5.9 Effects on ability to drive or operate machinery or impairment of mental ability........ 25

I.3.3.6 Assessor’s overall conclusions on clinical safety ......................................................... 25

I.4 A SSESSOR ’ S O VERALL C ONCLUSIONS ........................................................................................... 26

ANNEXES .................................................................................................................................................. 26

C OMMUNITY HERBAL MONOGRAPH ON U RTICA DIOICA L. AND U RTICA URENS L., HERBA .................... 26

L ITERATURE R EFERENCES ....................................................................................................................... 26

4/26

I. REGULATORY STATUS OVERVIEW 1

MA: Marketing Authorization;

TRAD: Traditional Use Registration;

Other TRAD: Other national Traditional systems of registration;

Other: If known, it should be specified or otherwise add ’Not Known’

Member State

Regulatory Status

Comments 2

Austria

TRAD

Other TRAD

Other Specify:

Belgium

TRAD

Other TRAD

Other Specify: No medicinal products

Bulgaria

TRAD

Other TRAD

Other Specify:

Cyprus

TRAD

Other TRAD

Other Specify:

Czech Republic

TRAD

Other TRAD

Other Specify:

Denmark

TRAD

Other TRAD

Other Specify:

Estonia

TRAD

Other TRAD

Other Specify: No medicinal products

Finland

TRAD

Other TRAD

Other Specify: In combination

France

TRAD

Other TRAD

Other Specify:

Germany

TRAD

Other TRAD

Other Specify: + In combinations

Greece

TRAD

Other TRAD

Other Specify:

Hungary

TRAD

Other TRAD

Other Specify: + In combinations

Iceland

TRAD

Other TRAD

Other Specify:

Ireland

TRAD

Other TRAD

Other Specify: No medicinal products

Italy

TRAD

Other TRAD

Other Specify: No medicinal products,

only food supplements

Latvia

TRAD

Other TRAD

Other Specify: No medicinal products

Liechtenstein

TRAD

Other TRAD

Other Specify:

Lithuania

TRAD

Other TRAD

Other Specify:

Luxemburg

TRAD

Other TRAD

Other Specify:

Malta

TRAD

Other TRAD

Other Specify:

The Netherlands

TRAD

Other TRAD

Other Specify:

Norway

TRAD

Other TRAD

Other Specify: No medicinal products,

only food supplements

Poland

TRAD

Other TRAD

Other Specify:

Portugal

TRAD

Other TRAD

Other Specify: No medicinal products

Romania

TRAD

Other TRAD

Other Specify:

Slovak Republic

TRAD

Other TRAD

Other Specify:

Slovenia

TRAD

Other TRAD

Other Specify:

Spain

TRAD

Other TRAD

Other Specify:

Sweden

TRAD

Other TRAD

Other Specify:

United Kingdom

TRAD

Other TRAD

Other Specify:

1 This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in

the MSs concerned.

2 Not mandatory field

5/26

Table 1: Products on the market in some Member States

Name of the

Product

(country)

Active substance Indication

Posology

Legal status

Kopřivový čaj

Fragmented

Urticae herba in

tea bags

Mild diuretic, adjuvant in

the treatment of rheumatic

complaints and urinary

tract inflammation.

Adjuvant for enhance of

diuresis, for the prevention

of nephrolithiasis, and

urinary sand, and for the

treatment of irritable

bladder in women.

1 tea spoon or 1 tea bag

(1.5 g) infused with 0.25 l

of boiling water (extracted

for 15 minutes) three times

daily

1999

(Czech)

Kopřivová nať

Fragmented

Urticae herba

consissa

1997

(Czech)

Nettle tincture

(Hungary)

Urticae herb.

extr. alc. (60%

V/V) (1:5)

For relive the complaints

of rheumatic and joint

diseases, urinary sand, and

cystitis

3 times 30-35 drops

“Healing

product”

registered in 1999

Body Spring

Ortica (Italy)

Dry extract of

Urticae herba

It may have a bland

draining action on

excessive body fluids

2 capsules daily (2 times

250 mg)

as food-

supplement

2004

(Poland)

Urticae herba as

tea

Adjuvant in treating mild

arthritic complaints.

2.5g (spoon) boil in 200ml

(a glass) of water for 5

min. Drink 3-4 times daily

a glass of decoction.

More than

30 years

(two products)

(Poland)

Urticae herba as

tea, infusion

bags, 2 g

Diuretic in inflammatory

of lower urinary tract and

adjuvant in treating mild

arthritic complaints

Like above decoction made

of 1 sachet containing 2g

of herbal substance.

More than 1

5 years

(Poland)

Urticae herbae

succus (1:1) from

fresh material as

a „stabilized

juice” oral liquid

Adjuvant in treating mild

arthritic complaints and

diuretic in urolithiasis

2.5- 5ml of product, 3

times daily.

More than

15 years

(1989)

(France )

275 mg of

powdered dried

aerial parts/hard

capsule

Traditionally used in

seborrhoeic skin

conditions

1 hard capsule 3 times

daily

1992

6/26

Table 2: Products on the German market

Active substance

Indication

Posology

Legal status

powder of Urticae herba Traditional herbal medicinal

product to support the elimination

function of the kidney.

3-4 times daily 2-3

capsules containing

190 mg powder each

4 x daily 3 coated

tablets containing 190

mg powder each

THM

at least since

1976

expressed juice from fresh

Urticae herba (1.36-

1.96:1)

Traditional herbal medicinal

product to support the elimination

function of the kidney.

4 times daily 3.5 ml

oral liquid containing

100% expressed juice

THM

at least since

1979 (DDR-

AM)

expressed juice from fresh

Urticae herba (1:0.5-1.1)

As a purging in inflammatory

diseases of the urinary tract

collection system. As a purging to

prevent renal gravel. For

symptomatic treatment of

osteoarthritis.

3 times daily 10 ml

oral liquid containing

100% expressed juice

3 times daily 10-15 ml

oral liquid containing

100% expressed juice

WEU

at least since

1976

liquid extract from

Urticae herba (1:1.8-2.2)

extraction solvent:

ethanol 30 V/V

As a purging in inflammatory

diseases of the urinary tract

collection system. As a purging to

prevent and support treatment of

renal gravel.

4 times daily 100

drops containing

100% liquid extract

WEU

At least since

1976

dry extract from Urticae

herba (5-10:1),

extraction solvent: water

As a purging in inflammatory

diseases of the urinary tract

collection system. As a purging to

prevent and support treatment of

renal gravel. For symptomatic

treatment of osteoarthritis.

4 times daily 1 coated

tablet containing 300

mg dry extract

3 times daily 3 coated

tablets containing 150

mg dry extract each

WEU

At least since

1976

7/26

I.1

I NTRODUCTION

This assessment report reviews the available scientific data for nettle herb. Evaulation of the literature on

nettle was very difficult because in most of the cases data on nettle herb and nettle leaf were confused.

I.1.1

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

I.1.1.1.

Herbal substance(s) 3 :

• Definition of the herbal substance:

ESCOP :

First Edition from 1997: “Nettle leaf consist of the dried leaves , and nettle herb consists of the dried

aerial parts collected during the flowering season, of Urtica dioica L., Urtica urens L., their hybrids or

mixtures of these.”

Second Edition from 2003: “Nettle leaf consist of the dried leaves, and nettle herb consists of the

dried flowering aerial parts of Urtica dioica L., Urtica urens L., their hybrids or mixtures of these.”

In both of the two Editions:

The material complies with the Deutsches Arzneibuch (nettle leaf) or the Pharmacopoeia Helvetica

(nettle herb).

Fresh material may be used provided that when dried it complies with one of the above

pharmacopoeias.”

British Herbal Pharmacopoeia 1983 :

“Urtica consists of the dried aerial parts of Urtica dioica L. (Fam. Urticaceae) gathered during the

flowering period.”

British Herbal Compendium ( Bradley 1992 ) :

“Nettle Herb consists of the dried leaves or aerial parts of Urtica dioica L. (Urticaceae) collected

during the flowering period. Urtica urens L. (Small or Annual Nettle) is also used medically and

included with U. dioica in the Ph. Helv. VII. and the DAC 1986.“

Phytotherapie in der Urologie (Schilcher 1992):

Referring to nettle herb monograph (Urticae herba) in DAC [ Deutsches Arzneimittel Codex ] “The used

plant part: dried and/or fresh (for preparation of fresh plant juice) herb, the aerial parts of the both

Urtica genus (U. dioica L., or U. urens L.) or of their hybrids collected during the flowering season.”

Definition of the herbal substance in the Monograph : Dried cut or fragmented aerial parts of the

plant collected or harvested during the flowering period.

• Description of the herbal substance:

Pharmacopoeia Helvetica VII

British Herbal Pharmacopoeia 1983,

Hagers Handbuch (Blaschek et al. 1998)

3 According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal

products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community

monographs for herbal medicinal products with well-established medicinal use ( EMEA/HMPC/182352/2005

Rev.2)

8/26

Principal components of the herbal substance:

• Minerals:

In 100 g fresh herb: 85 g water, 3.55 g mineral substance: 1050 mg calcium, 613 mg potassium, 340

mg silicon, 50-265 mg phosphorus, 2-200 mg iron, 180 mg chloride, 175 mg magnesium, 58 mg

sodium, 8 mg manganese, 4 mg boron, 2.7 mg titanium, 1.3 mg cuprum, 0.03 mg nickel ( Blaschek et

al. 1998) .

• In the dried herb: Content of the mineral substances can be 20%. The trace element content: 0.4% mg

Cu, ~ 6 mg % Mn, ~ 1 6mg % Al and not determined quantity of cobalt and zinc. The ash consist of :

24-33% CaO, 14-20% K2O, 3-10% MgO, 3-6% Fe2O3, 1-2% Na2O, 4-9% P2O5, 6-10% SiO2 and 4-

6% chloride (Schilcher 1988).

• Flavonoids: Principally kaempferol, isorhamnetin, quercetin and their 3-rutinosides and 3-glucosides in

the herb and similar flavonol glycosides in the flowers (ESCOP 2003).

• Amines: Small amounts of histamine, choline, acethylcholine and serotonin (5-hydroxytryptamine),

particularly in the stinging hairs (Bradley 1992)

• Acids: Carbonic acid, formic acid, silicic acid, citric acid, fumaric acid, glyceric acid, malic acid,

oxalic acid, phosphoric acid, quinic acid, succinic acid, threnoic acid and threono-1,4-lactone (Barnes

et al. 2002).

Caffeic acid esters, principally caffeoylmalic acid in Urtica dioica (up to 1.6%) but none in Urtica

urens; chlorogenic acid (up to 0.5%) small amounts of neochlorogenic acid and free caffeic acid in

both species. Free amino acids (30 mg/kg) (ESCOP 2003).

• Chlorophylls a and b, chlorophyll degradation products and carotenoids (including β-carotene and

xanthophylls) (Bisset 1994).

• Vitamins (among them C, B group, K1) (Bisset 1994).

• Vitamin K content is 0.16-0.64 mg/100 g (Bertok 1956).

• Triterpenes and sterols including β-sitosterol (Bisset 1994).

• Cumarins: Scopoletin ca. 1-10 mg/kg herbal substance (Blaschek et al. 1998)

• Leukotrienes in hair (Czarnetzki et al. 1990).

I.1.1.2. Herbal preparation(s) 3

• Comminuted herbal substance as infusion ( Tea): ESCOP 1997, ESCOP 2003, British Herbal

Pharmacopoeia 1983, Blumenthal 1998, Wren 1988, Bradley 1992, Bisset 1994, Barnes et al. 2002,

Blaschek et al. 1998, Schilcher 1992)

• Powdered herbal substance ( Products on the market in Germany and in France )

• Expressed juice from fresh herb :

( Bradley 1992, ESCOP 1997, ESCOP 2003, Schilcher 1992, Kirchhoff 1983.)

The ratio of the fresh herb and expressed juice is: 1: 0.5-1.1.

Method of the preparation of this juice according to the Urticae herba monograph of Hagers Handbuch

( Blaschek et al. 1998) . Fresh nettle herb is pressed cold or for example with hot steam after

plasmolysis and it than is autoclaved for the purpose of preservation.

The ratio of fresh herb and the expressed juice is: (1.36-1.96:1) (Product on the German market)

9/26

• Extracts:

Liquid extracts with ethanol:

Liquid extract (1:1) , extraction solvent: ethanol 25% (V/V): ( BHP 1983, Wren 1988; Bradley 1992,

Barnes et al. 2002)

Liquid extract (1:1.8-2.2), extraction solvent: ethanol 30% (V/V) ( Product on the German market)

Tincture (1:5), extraction solvent: ethanol 45% (V/V) (BHP 1983, Barnes et al. 2002 )

Dry extracts:

DER: (5-10:1), extraction solvent: water ( Product on the German market)

I.1.1.3. Combinations of herbal substance(s) and/or herbal preparation(s) 4

In lots of countries nettle herb can be found in combination preparation with other herbal substances

with diuretic effects.

Vitamin(s) 5

Mineral(s) 5

I.1.2

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

indication

• Evidence regarding the indication/traditional use

Nettle was already known in the ancient times. The ancient Greeks were familiar with its effects.

Dioscorides wrote about it in his work. He regarded it as tonic, diuretic, digestive, blood-purifier,

antitussive, styptic, aid in wound- and carbuncle-healing. Scrobinius Largo claimed that nettle herb cures

poisoning and epilepsy. Plinius, Lusitanius and Sartorius described nettle herb as a very good styptic. In

the 16 th century Dioscorides’s book was the main source of information on the healing characteristics of

nettle herb. Lehnhardt used Urtica dioica and Urtica urens for dropsy. Quarin, Deider (1746) and Rosner

used nettle for cough, cutaneous eruption and as a styptic. In the Czech folk medicine nettle was used as a

substance against lung diseases (tuberculosis), sleeplessness, and as compress for swelling. In France

nettle herb was considered as a promising metabolic enhancer especially in renal- and liver diseases.

(Lutomsky et al. 1983)

In Hagers Handbuch (Blaschek et al. 1998): In folk medicine: Internally: in renal and liver disease, as an

blood-forming agent, blood-purifier, (Reile 1928) a metabolic enhancer (Kneipp 1891), in cardiac

disorders, arthritis, goutiness, podagra, rheumatism of the joints and muscles, weak or insufficient

lactation, congestive conditions, fluid accumulation, as styptic (bloody cough, haematuria, profuse period)

(Eckstein & Flamms 1932).

4 According to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal

preparations’ (EMEA/HMPC/166326/2005)

5 Only applicable to traditional use

10/26

Indication 1:

“Irrigation in inflammatory conditions of the lower urinary tract.” ( ESCOP 1997)

“As a diuretic, for example to enhance renal elimination of water in inflammatory complaints of the lower

urinary tract. “ ( ESCOP 2003 )

“For irrigation in inflammation of the urinary tract and in the prevention and treatment of kidney gravel.”

(Blumental et al. 1998, Bisset 1994)

“Mild diuretic.” ( Wren 1988, Bradley 1992)

Indication 2:

“Adjuvant treatment of rheumatic conditions.” ( ESCOP 1997 )

“Adjuvant in the symptomatic treatment of arthritis, arthroses and /or rheumatic condition. (ESCOP 2003)

“When taken internally and used externally: only supportive treatment for rheumatic complaints”

(Blumenthal et al. 1998, Bisset 1994)

“Helpful in rheumatic and arthritic condition.” (Bradley 1992 )

Indication 3:

“Anti-haemorrhagic” [ Hagers Handbuch (Blaschek et al. 1998 )]

“Uterine haemorrhage, Epistaxis. Melaena” ( BHP 1983, Barnes et al. 2002)

Indication 4:

“ Mild hypoglycaemic activity.” ( Wren 1988, Bradley 1992. Barnes et al. 2002)

Indication 5:

“ Skin complaints, including eczema and skin eruptions, usually as an infusion.” ( Wren 1988 )

“Cutaneous eruption, infantile and psychogenic eczema, and specifically for nervous eczema.” ( British

Herbal Pharmacopoeia 1983, Barnes et al. 2002 ).

In the officinal French publication “Médicaments à base de plantes” (République Française Ministère de

l’Emploi et de la Solidarité, 1997) nettle herb is accepted for traditional use in the treatment of seborrhoeic

conditions of skin.

Indication 6:

Allergic rhinitis (Bradley 1992) .

11/26

Accepted indications in the Monograph:

a) Traditional herbal medicinal product to increase the amount of urine to achieve flushing of the urinary

tract as an adjuvant in minor urinary complaints.

b) Traditional herbal medicinal product for relief of minor articular pain.

c) Traditional herbal medicinal product used in seborrhoeic skin conditions.

• Evidence regarding the specified posology

1. In indication a) and b)

Dried herb:

Thrice daily 2-4 g or by infusion. ( BHP 1983, Barnes et al. 2002)

Three times daily 3-6g or in infusion. (Bradley 1992)

Daily 8-12 g herbal substance as infusion (Blumenthal et al. 1998, Blaschek et al. 1998)

“Making the tea: 1.5g of the finely cut herbal substance is put into cold water and boiled for a short time,

or boiling water is poured directly on to it, and after 10 min. strained. As a diuretic, a cupful is drunk

several times day. 1 teaspoon=ca. 0.8g, 1 tablespoon=ca. 2.2 g.

Herbal preparations: The herbal substance is also available in tea bags (1.0-1.8g).” (Bisset 1994)

Powdered herb:

380-570 mg powdered herbal substance as single dose up to 3-4 times daily

Expressed juice from fresh herb :

(1:0.5-1.1) 10-15 ml as a single dose up to 3 times daily.

(1.36-1.96:1) 3.5 ml as a single dose up to 3-4 times daily

Liquid extracts with ethanol:

Liquid (1:1) , extraction solvent: ethanol 25% (V/V)

Three times daily 3-4 ml ( BHP 1983, Barnes et al. 2002)

Three times daily 2-4 ml ( Bradley 1992)

Liquid extract (1:1.8-2.2), extraction solvent: ethanol 30% V/V:

Up to four times daily 100 drops

Tincture (1:5), extraction solvent: ethanol 45% (V/V) :

Three times daily 2-6 ml (BHP 1983, Barnes et al. 2002 ).

Dry extracts:

Dry extract from Urticae herba (5-10:1), extraction solvent: water; corresponding to 2-4 g of herbal

substance as a single dose up to 3 times daily.

2. In indication c)

275 mg powdered dried aerial parts of nettle as single dose up to 3-4 times daily

12/26

• Evidence regarding the route of administration

Internally:

British Herbal Pharmacopoeia 1983

Commission E Monograph ( Blumenthal et al. 1998 )

Wren1988

British Herbal Compendium ( Bradley 1992 ),

Barnes et al. 2002

Hagers Handbuch ( Blaschek et al. 1998 )

Cutaneous use:

British Herbal Pharmacopoeia 1983

Wren1988

Bisset 1994

Commission E Monograph ( Blumenthal et al. 1998 )

ESCOP 2003

Method of administration in the Monograph:

Oral use.

Cutaneous use is not mentioned, because there is no product on the market for more than 30 years.

• Evidence regarding the duration of use

Four or six weeks, as a cure ( Blaschek et al. 1998 ).

Duration of use in the Monograph is harmonised with that in other monographs on herbal substances

with similar effects.

Indication a) and c)

The herbal substance is traditionally used over a period of 2 up to 4 weeks.

If symptoms persist or do not improve within one week, a doctor or a qualified health care practitioner

should be consulted.

Indication b)

Not to be taken for more than 4 weeks.

If symptoms persist or do not improve within one month, a doctor or a qualified health care practitioner

should be consulted.

I.2

N ON -C LINICAL D ATA

For all studies cited, it should be stated by means of a detailed description which herbal

substance(s)/herbal preparation(s) have been used and information should be provided for

each preparation separately.

13/26

I.2.1

Pharmacology

I.2.1.1

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

relevant constituents thereof

(e.g. primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology,

pharmacodynamic interactions)

In vitro experiments:

• Anti-inflammatory activity

An extract of nettle herb, prepared as 0.25 mg/ml of a lyophilized aqueous extract in water, produced 93%

inhibition of platelet activating factor (PAF)-induced exocytosis of elastase from human neutrophils. The

same extract (0.2 mg/ml) showed no activity in a test for inhibition of the biosynthesis of prostaglandins

from 14 C-arachidonic acid (Tunón et al. 1995).

• Immuno-modulatory activity

The major compounds isolated from the methanolic extract of the aerial parts of Urtica dioica L. were

determined as quercetin-3-O-rutinoside (1), kaempherol-3-O-rutinoside (2) and isorhamnetin-3-O-

glucoside (3) by chromatographic, chemical (acidic hydrolysis) and spectral (UV, IR, H-NMR, C-NMR)

methods. Their immuno-modulatory activities were studied in vitro by chemotaxis (Boyden Migration

Chamber) and intracellular killing activity (nitroblue tetrazolium (NBT) reduction test). Compounds 1, 2,

3 and the total flavonoid fraction were determined to have significant chemotatic effects in 4, 8, 16 g

doses. According to the results of the NBT reduction test, all flavonoid glycosides showed high

intracellular killing activity. The results of both assays confirmed the immuno-stimulatory activity of the

flavonoid fraction and the isolated flavonoid glycosides on neutrophilis suggesting that they could

possibly be useful for treating patients suffering from neutrophil function deficiency and chronic

granulomatous diseases (Akbay et al. 2003).

Czarnetzki et al. 1990: In order to clarify the mechanisms of urtication after contact with stinging plants,

nettle ( Urtica urens ) hair and whole-plant extracts were examined for the presence of leukotriene (LT) B4

and LTC4 by reverse phase high-pressure liquid chromatography (RP-HPLC) and radioimmunoassay

(RIA) and for in vitro neutrophil chemotactic activity and histamine contents. Both hair and plant extracts

contained high levels of LTB4 and LTC4 by RIA as well as histamine. The presence of LTB4 was

supported by RP-HPLC elution profiles and by in vitro chemotaxis. Nettle hairs therefore resemble insect

venoms and cutaneous mast cells with regard to their spectrum of mediators.

•

Cardiovascular effects

Urtica dioica L. is widely used in oriental Morocco to treat hypertension. Aqueous extract of nettle herb

(AEN) also exerts a hypotensive action in the rat in vivo . The aim of this work was to characterize the

specific cardiac and vascular effects of AEN (10 g plant was infused in 100 ml of boiled distilled water

and incubated for 20 min. The aqueous extract was filtered and dried at 50°C.) In the isolated Langedorff

perfused rat heart, AEN (1 and 2 g/l) markedly decreased heart rate and increased left ventricular pressure.

Higher concentration (5 g/l) even led to cardiac arrest. Although carbachol mimicked the bradycardiac

effect of AEN, atropine (1 μM) did not modify the response. Beside its action on myocardium, AEN also

affected vascular contractility. Indeed, AEN (0.1-5 g/l) produced a dose dependent increase in basal tone

of isolated rat aorta. This effect was endothelium independent and was abolished by 1 μM prazosin (an α 1 -

adrenergic antagonist). AEN had little additional effects when the aorta was preconcentrated by

noradrenaline (1 μM) or KCL (40 mM). Data indicate that AEN produces a vasoconstriction of the aorta

which is due to activation of α 1 -adrenergic receptors. However, AEN also induces a strong bradycardia

14/26

through non-cholinergic pathways which might compensate for its vascular effect and account for the

hypotensive action of Urtica dioica L. described in vivo (Legssyer et al. 2002).

•

Effect on platelet aggregation

Aqueous nettle extract (ten grams of aerial parts before flowering in 100 ml of boiled distilled water for 30

min.) demonstrated weak inhibition of thrombin 1 U/ml and ADP 10 µM-induced platelet aggregation

(IC 50 15.5 and 12.8 mg/ml, respectively (Mekhfi et al. 2004 ) .

A methanolic extract had only weak antithrombotic activity (200 g aerial parts of the plant collected in

period June-September 1999 were extracted in sequence with methylene chloride [24 h] and ethanol [24h].

The solvent was removed under vacuum to yield the methylene chloride extract and then the methanol

extract) (Goun et al. 2002).

Antonopoulou et al. (1996) identified in the nettle herb collected in spring 1989 from Marousi (Attica

Greece) a phospholipid fraction that was able to induce platelet aggregation in dose-dependent manner,

five orders of magnitude less potent than the platelet-aggregating factor (PAF). The effect was not

inhibited by indometacin but by a PAF receptor-specific agent indicating that a receptor is involved in the

effect mechanism.

• Antioxidative effect

An aqueous nettle extract was prepared the following way: 20 g dried aerial parts of nettle collected in

May in Turkey, powdered and mixed with 400 ml boiling water during 15 min. The filtrate was frozen and

lyophilized; 20 mg was dissolved in 20 ml water. 50, 100 and 250 μg amounts of this water extract

showed 39, 66 and 98% inhibition on peroxidation of linoleic acid emulsion, respectively, while 60 μg/ml

of α-tocopherol, exhibited only 30% inhibition. Moreover the aqueous nettle extract had effective

reducing power, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide

scavenging, and metal chelating activities at the same concentration (Gülcin et al. 2004).

Likewise, Mavi et al. (2004) found some antioxidative activity for aqueous (5% decoction) and for

methanolic (solvent 5% methanol) nettle extracts (concentrations tested 50-500 mg/l).

Lipopolysaccharide-stimulated NO 2 -production was inhibited by the aqueous nettle extract in a dose-

dependent manner without affecting cell viability (dose range tested 12.5-800 μg/ml). The expression of

induced nitric oxide synthetase (iNOS) was not affected (Harput et al. 2005). Aqueous nettle extract: 10 g

air-dried aerial parts were boiled with water for 1 h. The aqueous solution was clarified by filtration and

evaporated under reduced pressure at 40°C. Freeze-drying and solvent elimination under reduced pressure

finally yielded 2.4 g of powdery, crude aqueous extract.

• Uterine muscle activity

An aqueous extract of nettle herb caused slight contraction followed by relaxation in isolated uterine

smooth muscle from the non-pregnant mouse. Application of the extracts to uterine muscle from the

pregnant mouse produced a diametrically opposed effect, increase of muscular tone and contractions of

considerable amplitude. The authors concluded that extracts had adrenolytic activity, similar to the action

of dihydroergotamine (40 mg extract = 0.132 mg dried plant = 0.8 mg dihydroergotamine) and inhibited

the effect of adrenaline (2 μg). The active principle responsible of the action was isolated (Broncano et al.

1987a).

•

Inhibition of α-Glucosidase

Investigation of water extracts of some medicinal herbs: Urtica dioica , Taraxacum officinale , Viscum

album and Myrtus communis with α-glucosidase inhibitor activity was conducted to identify a

15/26

prophylactic effect for diabetes in vitro . The inhibitory effect of these plants and some common

antidiabetic herbal substances against the enzyme source (baker’s yeast, rabbit leaver and small intestine)

were searched (Önal et al. 2005).

Table 3: α-Glucosidase inhibitory activity of some plant crude extracts and drugs

IC 50 (mg/ml) *

Α-glucosidase

Baker’s yeast

Rabbit liver

Rabbit intestine

Viscum album

Urtica dioica

Myrtus communis

Taraxacum officinale

Amaryl (glymerid)

Betanorm (gliclazide)

Glycobay (acarbose)

11.7

10.1

19.2

3.7

2.3

0.038

0.5

0.31

2.3

3.5

1.83

0.4

0.88

0.5

0.8

1.4

0.8

0.5

0.75

0.25

*Plants extracts; mg plant/ml, herbal substance samples; mg active material/ml

The concentration of the α-glucosidase inhibitor required to inhibit 50% of the α-glucosidase activity

under the assay condition is defined as the IC 50 value.

In vivo experiment:

• Diuretic effects

Early studies demonstrated the diuretic effect of nettle herb in animals, accompanied by increased

excretion of chlorides and urea. Flavonoids and the high potassium content may contribute to the

diuretic action, which is not, however, fully clarified (Bradley 1992).

A study was performed on anaesthetized male Wistar rats that received a continuous i.v . perfusion for

1.25 h of an aqueous extract of aerial parts of Urtica dioica at a low dose of 4 mg/kg/h or at a high dose of

24 mg/kg/h, or furosemide (control diuretic) at a dose of 2 mg/kg/h. As compared with a control period in

each rat, the arterial blood pressure was reduced proportionally to the dose of the perfusion of the plant

extract (15 and 38%, p<0.001, respectively). These effects were accompanied by a correlative increase of

diuresis (11 and 84% p<0.001, respectively) and natriuresis (28 and 143%, p< 0.001, respectively). In the

rats perfused by furosemide, the arterial blood pressure was reduced by 28% (p<0.001). The diuresis and

natriuresis were also increased proportionally (85 and 155%, p<0.001, respectively). Nevertheless, the

hypotensive action of U. dioica was reversible during the recovery periods in about 1 h in the case of the

lower dose of the plant extract and furosemide, while the effect of the higher dose was persistent,

indicating a possible toxic effect. The results demonstrate an acute hypotensive action of U. dioica , which

indicates a direct effect on the cardiovascular system. Moreover, diuretic and natriuretic effects were also

observed, suggesting an action on the renal function. The plant extract seems to have a toxic effect at the

higher dose (Tahri et al. 2000).

No effect on diuresis or ion excretion could be demonstrated in rats after oral administration of an

aqueous extract of nettle herb at a dose of 1 g/kg body weight (Lasheras et al. 1986).

No significant diuretic effect was observed during the 2 hours following the oral administration to rats of

an unspecified ethanolic extract of nettle at 1 g/kg body weight, whereas urinary excretion increased

significantly after intraperitoneal administration of 500 mg/kg. Na + excretion was unaffected, while both

K + concentration in urine and K + total extraction were significantly enhanced (Tita et al. 1993).

16/26

Administration of freshly squeezed nettle juice diluted in water 1:10 via a gastric tube to rats increased

urine output. Sodium, potassium and chloride concentrations increased, whereas urea content remained

unaffected. In other experiments in rats, a 10% suspension containing 185 mg nettle herb or 35 mg of a

nettle macerate 7:1, urine volume increased associated with an increase of sodium, potassium and chloride

concentrations. Both nettle preparations had only a weak effect in dogs. Due to lack of statistical analysis

and great variation of data, further studies are necessary to clarify the diuretic effect of nettle herb

(Lutomski 1981 ).

•

CNS –depressant activity

A nettle herb infusion (i.p. in doses of 1.66 g/kg, and 3.33 g/kg) and an aqueous extract (drug extract ratio

3:1, i.p. in doses of 303 mg/kg and 606 mg/kg) produced inhibition of drug-induced convulsion (by i.v.

Caffeine 0.25 mg/kg, Cardiazol 60 mg/kg and Strychnine 18.6 mg/kg) and a lowering of body temperature

in rats (Broncano et al. 1987b).

•

Spontaneous motility

The above mentioned nettle herb infusion and the aqueous extract produced dose-dependent reduction in

spontaneous motility in rats and mice when administered intraperitoneally at a dose of 1.739 and

3.748 g/kg bodyweight for the infusion and 303 and 606 mg/kg for the extract (Broncano et al. 1987b).

An aqueous extract of nettle herb at a dose 750 mg/kg led to a significant reduction in spontaneous

activity in mice during the first 16 hours after administration (Lasheras et al. : 1986).

•

Hypotensive effects

In the i.v . perfusion experiments on rats described above under diuretic effects (Tahri et al. 2000), the

diuretic and natriuretic effects were accompanied by a dose-dependent hypotensive effect. Compared to

control periods (perfusion of isotonic 0.9% saline only) perfusion of dry aqueous extract from nettle herb

(in isotonic saline) reduced arterial blood pressure by 15% at 4 mg/kg/hour and 38% at 24 mg/kg/hour

(both p<0.001), while furosemide at 2 mg/kg/h reduced arterial blood pressure by 28% (p<0.001). The

hypotensive effect was reversible within about 1 h of recovery after the lower dose of nettle herb extract

or furosemide, but was persistent after the higher dose of nettle herb extract, indicating a possible toxic

effect at that dose level (Tahri et al. 2000).

Nettle herb produced a rapid but only transient decrease of 31.7% in the blood pressure of anaesthetized

rats after i.v . administration of an aqueous extract at a dose 25 mg/kg/body weight (Lasheras et al. 1986).

In cats, an aqueous extract (3.3:1) administered by cannula at a dose of 26.6 mg/kg body weight

(88 mg/kg crude herbal substance) produced a marked hypotensive effect and bradycardia, which was not

compensated by subsequent administration of adrenalin (0.066 mg/kg). In rats the hypotensive effect of

the same extract in doses of 166 or 333 mg/kg could not be inhibited by atropin (0.05 mg/kg). The effect

was similar to the effect of dihydroergotamine so a mode of action via α–adrenoceptors was suggested by

the authors. I.v. doses of 33.3 mg/kg and 333 mg/kg of this extract caused significant bradycardia in rats

(Broncano et al. 1983).

•

Blood lipids lowering effects

Aqueous (150 mg/kg/day) and to a lesser extent ether (20 mg/kg/day) extract of Urtica dioica given for 30

days to rats fed with normal or high-fat diet, improved the blood lipid profile. Significant decreases in

total cholesterol, LDL (low-density lipoproteins), cholesterol, LDL/HDL (high-density lipoproteins)

cholesterol ratio and plasma total apo B (apolipoprotein B) were observed. Assessment of liver enzymes

17/26

(GOT, GPT and LDH) activities showed that no liver damage occurred during the study period (Daher et

al. 2006).

Table 4: Effect of U. dioica aqueous and petroleum ether extracts on serum triacylglycerol, total

cholesterol, HDL cholesterol, LDL cholesterol and LDL/HDL ratio

Lipids

(mg/dl)

Regular diet

High fat diet

Control Petroleum Water

Ether extract a extract b

Control Petroleum Water

Ether extract a extract b

Triacyl-

glycerol

Total

cholesterol

HDL

cholesterol

LDL

cholesterol

62 ± 4.5 58 ± 4.2 56 ± 2.9

86 ± 4.1 74* ± 4.2 71* ± 2.6

40 ± 2.1 38 ± 2.1 42 ± 2.2

32 ± 2.7 25* ± 4.2 20* ,, ** ± 2.1

84 ± 4.6 78 ± 4.6 63* , ** ± 2.9

97 ± 4.1 86 ± 2.5 78* ± 3.1

39 ± 1.9 37 ± 2.1 40 ± 2.1

40 ± 2.7 33* ± 2.3 27* , ** ± 2.4

LDL/HDL

0.8 ± 0.06 0.66* ± 0,05 0.48* , ** ± 0.04

1 ± 0.06 0.89 ± 0.06 0.68* , ** ± 0.07

N=10

a 20 mg/kg/day extract [100 g plant material was macerated with petroleum ether (1 l), evaporated in

vacuo ] for 30 days.

b 150 mg/kg/day extract [10 g plant material was macerated with hot water (1 l), evaporated in vacuo ] for

30 days.

* p<0.05 Significant difference with respect to control group

** p<0.05 Significant difference between water and petroleum ether groups

•

Hyperglycaemic and hypoglycaemic activity

Nettle is stated to contain both hypoglycaemic and hyperglycaemic principles. The hypoglycaemic

component has been termed ‘urticin’ and nettle has been reported to lower the blood-sugar concentration

in hyperglycaemic rabbits (Barnes et al. 2002).

Bever & Zahnd (1979) in their article listed the herbal substances having hypoglycaemic action into three

categories. Urtica dioica L. plant was listed into the Group II.: Plants with more or less confirmed

hypoglycaemic action but with as yet unknown active constituents. According to the author, the known

chemical components are: “Hypoglycaemic principle=’urticin. Contains chlorophyll; flavonoids are found

in allied spp .

In oral glucose tolerance test (OGTT) animals (male Wistar rats) were fasted for 16 hours, before glucose

(1g/kg) was administered by gavage 30 min after oral administration of 250 mg/kg a water extract. [This

extract was prepared the following way: Dried aerial material (10 g) was infused in 100 ml of distilled

water for 20 min. The extract evaporated in vacuo gave a crude residue (yield: 21%), (drug extract ratio:

~5:1) ]. The decrease of glycaemia has reached to 33 ± 3.4% of the control value (glibenclamide at dose

2 mg/kg) 1 hour after glucose loading. This effect was persistent during 3 hours. In contrast, nettle

(500mg/kg) did not show hypoglycaemic effect in alloxan-induced diabetic rats (intra-peritoneally with

120 mg/kg/day of alloxan for 3 consecutive days). The amount of glucose absorbed in segment jejunum in

situ was 8.05 ± 0.68 mg in presence of nettle extract (250mg/kg) vs. 11.11 ± 0.75 mg in control rats

(perfusing solution) during 2 hours (p<0.05). The results indicate that nettle herb at high dose has a

significant anti-hyperglycaemic effect in OGTT model. This effect may be caused in part by the reduction

of intestinal glucose absorption (Bnouham et al. 2003).

18/26

Both an 80%-ethanolic extract and an aqueous decoction of nettle herb, evaporated to dryness,

resolubilized and administered to mice at the equivalent of 25 g herbal substance/kg body weight 2 h prior

to glucose load, produced hyperglycaemic effects in an OGTT (Neef et al. 1995).

•

Analgesic activity

After administration of nettle herb aqueous extract at a dose of 1200 mg/kg mice showed much greater

resistance to thermal stimulation in the hot plate test at 55°C, taking 190% longer time to react than the

control animals (Lasheras et al. 1986).

On the other hand, no analgesic activity was noted in hot plate test after oral or intraperitoneal

administration to rats of an unspecified ethanolic extract of nettle, although this extract reduced the

writhing response to phenylquinone in rats after oral (1 g/g) and intraperitoneal (500 mg/kg) treatment

(Tita et al. 1993).

In the acetic acid-induced writhing test in mice, aqueous nettle extract (20 g dried aerial parts of nettle

collected in May in Turkey, powdered and mixed with 400 ml boiling water during 15 min. The filtrate

was frozen and lyophilized; 20 mg was dissolved in 20 ml water. Doses 50-250 μg were used in the tests.)

in a dose of 50, 100 and 200 mg/kg i.p. produced a dose-dependant inhibition in writhing which was more

pronounced than that of metamizole (Gülcin et al. 2004).

•

Local anaesthetic activity

Local application to the rat tail of 0.05 ml of nettle herb aqueous extract (100 mg lyophilised extract per

ml), in the same region as subsequent application of exposure to heat in the tail flick test, produced a local

anaesthetic effect comparable to that of lignocaine (Lasheras et al. 1986).

I.2.1.2

Assessor’s overall conclusions on pharmacology

Indication a: Traditional herbal medicinal product to increase the amount of urine to achieve flushing of

the urinary tract as an adjuvant in minor urinary complaints.

If we consider the possible traditional use of nettle herb, the diuretic effect is not unambiguous. It was

clearly demonstrated only by intra-venous administration. For oral use there are some studies with

negative results. One study has positive effect only, but due to the lack of statistical analysis and great

variation of data, further studies are necessary to clarify the diuretic effect of nettle herb. Nevertheless

nettle herb has high mineral content which may explain its diuretic effect.

Indication b: Traditional herbal medicinal product for relief of minor articular pain.

The analgesic and anti-inflammatory characteristics can be supported only very weakly.

Nettle herb did not inhibit the biosynthesis of prostaglandins, but had activity in PAF-test. Its flavonoid

fractions showed in vitro immuno-modulatory activity in chemotaxis and intracellular killing activity tests.

Its analgesic doses are high.

Indication c : Traditional herbal medicinal product used in seborrhoeic skin conditions.

The anti-inflammatory effect of nettle herb (the flavonoid fractions of it) can support this indication.

I.2.2

Pharmacokinetics

19/26

I.2.2.1

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

relevant constituents thereof

(e.g. absorption, distribution, metabolism, elimination, pharmacokinetic interactions with

other medicinal products)

No relevant data available.

I.2.2.2

Assessor’s overall conclusions on pharmacokinetics

No relevant data available.

I.2.3

Toxicology

I.2.3.1

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

constituents thereof

(e.g. single/repeat dose toxicity, genotoxicity, carcinogenicity and reproductive and

developmental toxicity, local tolerance, other special studies)

Single/repeat dose toxicity:

The intraperitoneal (48 h) LD 50 of an aqueous extract of nettle herb in mice has been determined as 3.625

g/kg body weight (Lasheras et al. 1986).

LD 50 (i.v. 72 h) of an infusion (100 mg/ml) of nettle herb in rats has been found 1928 mg herbal

substance/kg body weight. Subacute LD 50 of this infusion in rats (p.o.) has been found 1310 mg/kg body

weight. LD 50 (i.v. 72 h) of an aqueous extract of nettle herb in rats has been found 1721 mg. The hydro

soluble product responsible for toxicological effects, which can be eliminated by boiling, is suspected to

have a pyran-coumarin structure (Baraibar et al. 1983).

An ethanolic extract of Urtica dioica herb showed low toxicity in both rats and mice after oral and

intraperitoneal administration at the equivalent of up to 2 g of dried herbal substance/kg body weight (Tita

et al. 1993).

Three horses with an apparent neurological disorder resulting from nettle rush showed signs of ataxia,

distress and muscle weakness, and two of them had urticaria. The condition resolved within 4 h (Bathe

1994).

Reproductive toxicity:

A nettle extract (whole plant without root, prepared with 90% ethanol) was reported to have no

antifertility activity following oral administration at 250 mg/kg dose to albino rats in days 1-7 of

pregnancy (Sharma et al 1983).

Genotoxicity:

An herbal tea from Urtica dioica proved to be weakly genotoxic in the wing Somatic Mutation and

Recombination Test (SMART). Furthermore, it was shown that quercetin and rutin, two flavonols present

in beverages of plant origin, also exhibited weak genotoxic activity in somatic cells of Drosophila . (The

standard herbal teas (infusions) were prepared by adding 20 g dry tea to 100 ml boiling tap water and

allowing it to draw for 10 min) (Graf et al. 1994).

In their study Basaran et al. (1996) investigated various Turkish medicinal herbs for their genotoxic

potential in the Salmonella typhimurium microsomal activation assay and the alkaline single cell gel

electrophoresis (COMET) assay. Among others the aerial parts of Urtica dioica were examined. The plant

extract was prepared by weight 1 g of plant sample in either 100 ml saline or 100 ml deionised water and

extracted twice at 50ºC lyophilised and stored as desiccated sample. Furthermore, flavonoid and apolar

20/26

compound-rich fractions of water extracted herbs of Urtica dioica were isolated from the extracts by

chromatographic methods generally used in phytochemistry.

The plant extracts and fractions investigated, none produced a positive response in strains TA98 and

TA100 with or without metabolic activation, but all produced an increase above negative control values in

the COMET assay. Urtica extract was investigated further and produced dose-related increases. Not only

the Urtica extract produced such responses, but so did its fractions. The flavonoid fraction over the same

dose range was less positive than the chloroform fraction possibly due to less DNA damaging agents in

the fraction or because the glycoside flavonoid may exert an antigenotoxic effect. It is known that

flavonoids in the glycoside form can act under certain conditions in antigenotoxic capacity. The breaks

that were detected in the COMET assay could be alkali-labile adenosine phosphate-sites and intermediates

in base- or nucleotide-excision repair and are difficult to interpret in terms of hazard for man. Further

studies with additional genotoxicity assays would be required to make such a prediction.

I.2.3.2.

Assessor’s overall conclusions on toxicology

Two Ames strains are not enough for evaluating of the genotoxicity. The COMET assay has not been

validated and consequently it is not known how specifically and reliably it could differentiate between

genotoxicants and non-genotoxicants. It is also sensitive to artefacts and false positives. Thus a

Community list entry for nettle herb cannot be prepared.

The accepted wording in the Monograph: Tests on reproductive toxicity and carcinogenicity have not

been performed. Adequate tests on genotoxicity have not been performed.

I.3

C LINICAL D ATA

For all studies cited, it should be stated by means of a detailed description which herbal

substance(s)/herbal preparation(s) have been used and information should be provided for

each preparation separately.

I.3.1

Clinical Pharmacology

I.3.1.1

Pharmacodynamics

I.3.1.1.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)

including data on constituents with known therapeutic activity.

No relevant data available.

I.3.1.1.2 Assessor’s overall conclusions on pharmacodynamics

No relevant data available.

I.3.1.2

Pharmacokinetics

I.3.1.2.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)

including data on constituents with known therapeutic activity.

No relevant data available.

I.3.1.2.2 Assessor’s overall conclusions on pharmacokinetics

No relevant data available.

I.3.2

Clinical Efficacy

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I.3.2.1

Dose response studies

I.3.2.2

Clinical studies (case studies and clinical trials)

Diuretic effect

In an open 2-week study, 32 patients suffering from either myocardial or chronic venous insufficiency

were treated three times daily with 15 ml of nettle herb juice (afterwards the dosage changed for once a

day in the morning). A significant increase in the daily volume of urine was observed throughout the

treatment, the volume in day 2 was 9.2% higher (p<0.0005) than the baseline in patients with myocardial

insufficiency and 23.9% higher (p<0.05) in the case of patients with chronic venous insufficiency. Minor

decreases in body weights (about 1%) and systolic blood pressure were observed. Serum parameters were

unaffected and the treatment was well tolerated apart from the tendency towards diarrhoea (Kirchhoff

1983).

Results in myocardial insufficiency:

Table 5: Urine volume and bodyweight under the therapy with expressed juice from nettle herb

(n=19)

Treatment days

Urine volume

(ml/24 h)

1674

1828***

1825***

1795**

1781***

Bodyweight (kg)

76.55

76.38ºº

76.23ººº

76.03ºº

75.53ººº

** p < 0.005 *** p < 0.0005 comparing with the baseline

ºº p < 0.005 ººº p < 0.0005 comparing with the previous value

Results in venous insufficiency:

Table 6: Urine volume and bodyweight under the therapy with expressed juice from nettle herb

(n=13)

Treatment days

Urine volume

(ml/24 h)

1483

1837*

1809**

1828*

1770*

Bodyweight (kg)

70.2

70.15

69.91ºº

69.85

69.32ººº

* p <0.05 ** p <0.005 comparing with the baseline

ºº p <0.005 ººº p <0.0005 comparing with the previous value

Anti-inflammatory effect

Previous research had established that 1340 mg of powdered extract of nettle leaves ( Urtica dioica ) allows

a 50% reduction in the dose of non-steroidal anti-inflammatory analgesics (NSAID) used to treat arthritis.

In a German study, 40 subjects suffering from an acute attack of chronic joint disease participated in an

open randomized study comparing the effectiveness of a combination of stewed stinging nettle and

50 mg of diclofenac to the standard 200 mg dosage of diclofenac. Diclofenac is an NSAID commonly

prescribed in dosages of 150 to 200 mg per day for the treatment of rheumatoid and osteoarthritis. The

subjects were randomly assigned to the nettle and 50 mg of diclofenac group (group D50+U) or the

200 mg diclofenac group (group D200). Extensive pre-screening eliminated patients with diseases,

conditions, medications, or allergies that could influence the outcome of the study.

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Group D200 received a semi-synthetic gastric protective prostaglandin analogue misoprostol in addition to

the diclofenac. Gastric bleeding is a common side effect of NSAID use. Both groups received the same

nutrition over the study period of 14 days. The primary measure of effectiveness was the improvement

(decrease) in serum concentrations of C-reactive protein (CRP). Other criteria were total joint scores for

physical impairment, subjective pain, pain on pressure, and stiffness. CRP and total joint scores improved

dramatically (70% median score change) in both treatment groups. The treatment was well tolerated over

the two-week period, with only six participants (3 from D200 and 3 from D50+U) reporting side effects.

The D200 group reported minor side effects of diarrhoea and abdominal pain during the treatment period.

The D50+U group reported the side effect of meteorism [abnormal distention due to the presence of gas or

air in the intestine or the peritoneal cavity], intestinal gas with bloating.

This study indicates that 50 mg of stewed stinging nettle plus 50 mg of diclofenac is as effective as

200 mg of diclofenac at reducing the clinical symptoms of acute arthritis. This could be great news for

those who cannot tolerate NSAIDs because of ulcers or other gastric problems. Further study is needed to

determine if stinging nettle could be effective without the use of NSAIDs (Chrubasik et al. 1997).

Anti-allergic effect

Ninety-eight individuals took part in a double-blind randomized study comparing the effects of a freeze-

dried preparation of Urtica dioica herba (2 times 300 mg) with placebo on allergic rhinitis. Sixty-nine

individuals completed the study. Assessment was based on daily symptom diaries, and global response

recorded at the follow-up visit after one week of therapy. Urtica dioica was rated higher than placebo in

the global assessments. Comparing the diary data, Urtica dioica was rated only slightly higher (Mittman

1990).

I.3.2.3 Clinical studies in special populations (e.g. elderly and children)

There have been no studies in special populations.

I.3.2.4

Assessor’s overall conclusions on clinical efficacy

The indications (myocardial or chronic venous insufficiently, acute attack of chronic joint disease, allergic

rhinitis) in these four clinical studies are not proper for traditional use. These indications are relevant only

for well-established use, but the results of these trials cannot be used because they are hardly acceptable.

The studies are not double blind (except Mittman’s study), the data are not detailed enough, and the results

are not persuasive. They may only contribute to the plausibility of the diuretic and anti-inflammatory

effect, in such way they may support the traditional indications.

I.3.3

Clinical Safety/Pharmacovigilance

I.3.3.1

Patient exposure

I.3.3.2

Adverse events

ESCOP 1997, 2003: “None reported.”

Blumenthal et al. 1998, Blaschek et al 1998: “Not known.”

Bisset 1994: ”Occasionally (rare) after taking nettle tea, allergies (cutaneous affections, oedema, oliguria,

gastric irritation) have been observed.”

Bradley 1992: “Occasional (rare) allergic reactions have been observed. ”

Barnes et al. 2002: “Consumption of nettle tea has caused gastric irritation, a burning sensation of the

skin, oedema, and oliguria.”

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The accepted wording in the Monograph : Mild gastrointestinal complaints, e.g. nausea, diarrhoea,

vomiting and allergic reactions (e.g. itching, exanthema, hives) may occur. The frequency is not known.

I.3.3.3

Serious adverse events and deaths

I.3.3.4

Laboratory findings

I.3.3.5

Safety in special populations and situations

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

No data available.

I.3.3.5.2

Contra indications (hypersensitivity and allergic potential to be both covered)

Not known. (ESCOP 1997, 2003; Blumenthal et al. 1998, Bradley 1992)

Water retention (oedema) as a result of impaired cardiac and renal function. (Blaschek et al . 1998, Bisset

1994)

The accepted wording in the Monograph:

Hypersensitivity to the active substance.

Condition where a reduced fluid intake is recommended (e.g. severe cardiac or renal disease).

I.3.3.5.3. Warnings and precautions for use

“In irrigation therapy, care must be taken to ensure an abundant fluid intake.”

(Blumenthal et al. 1998 , Blaschek et al . 1998, Bisset 1994).

“Excessive use may interact with concurrent therapy for diabetes, high or low blood pressure, and may

potentiate drugs with CNS depressant actions.” (Barnes et al. 2002)

Assessor’s comment: The above mentioned sentence was not taken into consideration for reasoning see

I.3.3.5.4 Drug interactions)

The accepted wording in the Monograph:

The product is not intended to be used in case of acute arthritis as this condition requires medical advice.

The use is not recommended in children under 12 years of age because of lack of available experience.

If urinary tract complaints worsen and symptoms such as fever, dysuria, spasm, or blood in the urine occur

during the use of medicinal product, a doctor or a qualified health care professional should be consulted.

I.3.3.5.4 Drug interactions

“Not known. “(Blumenthal et al. 1998 , Blaschek et al . 1998, Bisset 1994)

“None reported.” (ESCOP 1997, 2003)

“Excessive use of nettle preparation may interact with concurrent therapy for diabetes or high blood

pressure, and may potentiate drugs with CNS depressant action.” (Barnes et al. 2002)

Assessor’s comment: It is not necessary to mention these actions under the “Interaction” section of the

Monograph.

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See studies I.2.1 Pharmacology for reasoning:

• Inhibition of α-glucosidase, hyperglycaemic and hypoglycaemic activity: the applied doses are very

high; they are far from the therapeutic doses.

• Hypotensive effects: There was an in vitro study (Cardiovascular effects, Legssyer et al. 2002) at high

concentration 1 g - 2 g/l or two in vivo studies, where the preparation was applied intravenously

(Tahri et al. 2000, Lasheras et al. 1986).

In one study an aqueous extract was given to cats and rats by canula, but the applied doses are again

too high (88 mg/kg, 16 6mg or 333 mg/kg) (Broncano et al. 1983).

• the CNS depressant should not be mentioned as well because it was experienced only by intra-

peritoneal application (Broncano et al. 1987b).

Other question may be the vitamin K content of the nettle herb: It is very low, 0.16-0.64 mg/100g (Bertok

1956). The maximum daily dose of a nettle herb preparation, equivalent to about 15 g of dried herb,

contains 24-96 microgramm of vitamin K. These values are less than 1% of the therapeutic dosage range

of vitamin K (10-20 mg/day).

The accepted wording in the Monograph:

None reported.

I.3.3.5.5 Use in pregnancy and lactation

Nettle is reputed to be an abortifacient and to affect the menstrual cycle. Uteroactivity has been

documented in animal studies. In view of this, the use of nettle during pregnancy should be avoided. It is

best to avoid excessive use during lactation ( Barnes et al. 2002 ).

Assessor’s comment: Utero-activity was described only in an in vitro study [Broncano et al1987(1a)] see

I.2.1. Pharmacology]. A nettle extract was reported to be devoid of antifertility activity following oral

administration to mice (250 mg/kg). [Sharma et al 1983, See I.2.3.Toxicology)

It is the reason why it is not necessary to mention it in the Monograph.

ESCOP 1997, 2003: “No data available. In accordance with general medical practiced, the product should

not be used during pregnancy and lactation without medical advice.”

The wording in the Monograph is the general one:

Safety during pregnancy and lactation has not been established.

In the absence of sufficient data, the use during pregnancy and lactation is not recommended.

I.3.3.5.6 Overdose

No case of overdose has been reported.

I.3.3.5.7 Drug abuse

I.3.3.5.8 Withdrawal and rebound

I.3.3.5.9 Effects on ability to drive or operate machinery or impairment of mental ability

No studies on the effect on the ability to drive and use machines have been performed.

I.3.3.6

Assessor’s overall conclusions on clinical safety

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According to the available data nettle herb is well-tolerated in the usual dosage and in the traditional usage

form.

However, nettle herb cannot be recommended during pregnancy or breast-feeding and in children under

12 years of age due to lack of adequate data.

The use of nettle herb is contraindicated in patients with hypersensitivity to nettle herb and in condition

where a reduced fluid intake is recommended (e.g. severe cardiac or renal disease).

Nettle herb is not intended to be used in case of acute arthritis as this condition requires medical advice.

The establishment of a Community list entry for nettle herb is not possible because tests on reproductive

toxicity and carcinogenicity have not been performed and adequate tests on genotoxicity have not been

performed.

I.4

A SSESSOR ’ S O VERALL C ONCLUSIONS

For nettle herb has been in medicinal use for a period of at least 30 years as requested by Directive

2004/24/EC, this requirement for the qualification as a traditional herbal medicinal product is fulfilled

(long-standing use dating back to ancient time).

From the viewpoint of traditional indication the diuretic effect (flavonoids and the high mineral content

may contribute to the diuretic action; supported somehow by the clinical study), and the anti-inflammatory

and analgesic effect (polyphenol content; supported somehow by the pharmacodynamic experiments) can

be considered plausible.

Thus the three endorsed indications are the following:

Traditional herbal medicinal product to increase the amount of urine to achieve flushing of the

urinary tract as an adjuvant in minor urinary complaints.

Traditional herbal medicinal product for relief of minor articular pain.

Traditional herbal medicinal product used in seborrhoeic skin conditions

The use of nettle herb is considered safe in the recommended dosage. However, nettle herb cannot be

recommended during pregnancy or lactation and in children under 12 years of age due to lack of adequate

data.

The establishment of a Community list entry for nettle herb is not possible because tests on reproductive

toxicity and carcinogenicity have not been performed and adequate tests on genotoxicity have not been

performed.

ANNEXES

Community herbal monograph on Urtica dioica L. and Urtica urens L., herba

Literature references

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Source: European Medicines Agency

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