ARTICLE IN PRESS

Phytomedicine 14 (2007) 423435

www.elsevier.de/phymed

A comprehensive review on nettle effect and efcacy proles, Part I:

Herba urticae
Julia E. Chrubasika, Basil D. Roufogalisb, Hildebert Wagnerc, Sigrun A. Chrubasika,b,
a
Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany
b
Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia
c
Department of Pharmacy Zentrum fur Pharmaforschung- Haus B, University of Munich, Butenandtstrasse 5-13, D-81377
Munchen, Germany

Received 4 October 2006; accepted 15 February 2007

Abstract
Nettle herb is recommended for complaints associated with rheumatoid arthritis, osteoarthritis and urinary tract
infections. We therefore conducted a comprehensive review of the literature to summarize the pharmacological and
clinical effects of this plant material. Although clinical and experimental studies suggest that nettle herb has some anti-
inammatory properties, clinical evidence beyond doubt is lacking. Nettle preparations exert a number of promising in
vitro and in vivo effects, however, further studies are needed to support these results and to nd out if these effects are
surrogates for clinical relevant effects in humans.
r 2007 Elsevier GmbH. All rights reserved.

Keywords: Urticae herba; stinging nettle herb; in vitro- and in vivo pharmacology; clinical studies

Introduction tion of a fresh leaf rubbed onto the painful area is

recommended (Anonymous, 2003).
Dried or fresh leaves or owering aerial parts of Main constituents identied in the plant material are
Urtica dioica L., Urtica urens L., their hybrids or summarized in Table 1. The aim of this systematic
mixtures of these are recommended for symptomatic review was to collect data on the effects and efcacy of
treatment of rheumatoid arthritis or osteoarthritis and nettle herb.
for increased diuresis, e.g. in case of urinary tract
infections (Anonymous, 2003). The suggested (empiri-
cally used) doses for internal use include hydroalcoholic
extracts corresponding to 812 g nettle leaf daily or up
Methods
to 5 g as an infusion up to three times daily over an
Systematic literature searches were conducted on
unlimited period. For external use once daily applica-
Medline (via Pubmed). The database was searched from
Corresponding author. Institut fur Rechtsmedizin, Universitat
its inception until end of July 2006. Additionally, experts
were contacted to identify further studies. Hand-
Freiburg, 79104 Freiburg, Germany. Tel.: +49 761 2036853;
fax: +49 761 203 6851. searches were performed by searching the authors
E-mail address: sigrun.chrubasik@klinikum.uni-freiburg.de own les and the bibliographies of all located papers.
(S.A. Chrubasik). No restrictions regarding the language of publication

0944-7113/$ - see front matter r 2007 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2007.03.004
 ARTICLE IN PRESS
424 J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
Table 1. Main constituents identied in nettle herb (Wichtl,
2002; Anonymus, 1998)
Flavonoids
Glucosides and rutinosides of quercetin, kaempferol and
isorhamnetin
Caffeoyl-esters
Caffeoylmalic acid (only Urtica dioica)
Chlorogenic acid
Neochlorogenic acid
Caffeic acid
Scopoletin (Cumarin)
Sitosterol (-3-O-glucoside)
Polysaccharides
Fatty acids (e.g. 13-hydroxyoctadecatrienoic acid)
Minerals (Herba: up to 20%; leaves: 15%)
were imposed. Controlled and uncontrolled clinical
studies and pre-clinical studies were eligible for
inclusion.
Pharmacological properties: in vitro
experiments (Table 2a)
Impact on inammatory mediators
Aqueous nettle extract1 had no inhibitory effect on
prostaglandin biosynthesis, but inhibited platelet acti-
vating factor (PAF)-induced exocytosis of elastase from
human neutrophils in a dose of 250 mg/ml (Tunon et al.,
1995). In contrast, ethanolic extract IDS232 inhibited
cyclooxygenase-dependent biosynthesis of prostaglan-
dins dose-dependently (IC50 92 mg/ml). Its component
caffeic malic acid was shown to be a leucotriene B4-
inhibitor (IC50 83 mg/ml, Obertreis et al., 1996a). IDS23
inhibited LPS-induced release of TNFa, and interleukin-
1b dose-dependently (not, however, interleukin-6) (IC50
values not stated). Neither caffeic malic acid, caffeic
acid, chlorogenic acid, nor rutin or quercetin were
involved in this action (Obertreis et al., 1996b). The
impact on stimulated cytokine release was also shown in
healthy volunteers consuming 1072 mg of IDS23 over 21
days with maximum ex vivo/in vitro effects after 3 weeks
(Teucher et al., 1996). In these patients dose-dependent
inhibition of LPS-induced release of IL-10 was also
demonstrated, but no inhibition of interleukin-6. In
healthy controls as well as in rheumatoid arthritis
patients, IDS23 110 mg/ml inhibited dose-dependently
interleukin-2 gene expression (Pearce et al., 1999)
1
Plant material was collected around Uppsala (Sweden), rinsed in
cold water and immediately dried in an oven at 40 1C for 24 h. Two
extractions with water, 1st 1:20, 2nd 1:10 for 48 h. A small amount of
toluene was added to prevent growth of moulds. The combined
extracts were lyophilized and stored at 20 1C until its use.
2
See Table 3.
indicating immunomodulatory properties. It seemed
likely that the IDS23 cytokine release inhibition is
caused by inhibition of NF-kB since dose-dependent
inhibition of TNFa-stimulated expression of NF-kB
driven luciferase gene by IDS232 and its watersoluble
fraction was found. The degradation of inhibitory
subunit IkB-a was prevented by the water-soluble
IDS23 fraction in a dose of up to 320 mg/ml (Riehemann
et al., 1999). It also seems likely that the active principle
acts by mediating a switch in T helper cell-derived
cytokine patterns: IDS23 stimulated the secretion of
Th2-specic interleukin-4 whereas interleukin-2 and
IFN-g expression were inhibited dose-dependently
(ranges: up to 400 mg/ml; IC50 values not stated,
Klingelhoefer et al., 1999). For IDS303 in a dose up to
25 mg/ml, a suppressive effect on the maturation of
human myeloid dendritic cells was demonstrated, that
lead to reduced induction of primary T cell responses
(Broer and Behnke, 2002). IDS30 10 mg/ml also sig-
nicantly suppressed interleukin-1b-induced expression
of matrix metalloproteinases ( 1, 3 and 9) (Schulze-
Tanzil et al., 2002) which may correspond to a cartilage-
protective effect. Isolated 13-hydroxyoctadecatrienic
acid was also effective at a similar concentration.
However, whether the observed cytokine changes
are a surrogate for clinical improvements needs to be
demonstrated.
Platelet-aggregating effect
Aqueous nettle extract4 demonstrated weak inhibition
of thrombin 1 U/ml and ADP 10 mM-induced platelet
aggregation (IC50 15.5 and 12.8 mg/ml, respectively;
Mekh et al., 2004). The more lipophilic the extraction
solvent (water, methanol, ethyl acetate, petroleum
ether)5 the more potent was the antithrombotic effect
(doses investigated: 0.53 mg/ml; El Haouari et al.,
2006). Ethyl acetate extract exhibited the most aggre-
gant effect. Flavonoid compounds were shown to be
involved in this action. A methanolic extract6 had only
3
See Table 3.
4
Ten grams aerial parts before owering in 100 ml of boiled distilled
water for 30 min.
5
Aqueous extract: 20 g of dried aerial part before the owering
period was infused into 300 ml boiled distilled water, the ltrate was
evaporated; Soxhlet extraction: 28 g of dried small leaf pieces was
extracted and evaporated to dryness in vacuo successively with the
different solvents. Extraction yields were 3.61%, 1.73%, 14.8% and
12.6% for petroleum ether, ethyl acetate, methanol and water,
respectively.
6
Two hundred grams aerial parts collected in the period of
JuneSeptember 1999 in the Krasnoda, Khabarovsk and Perm regions
of Russia were extracted in sequence with methylene chlorid (24 h) and
ethanol (24 h) in a soxhlet apparatus. The solvent was removed under
vacuum to yield the methylene chloride extract and then the methanol
extract. Further details in Miles et al. (1991, Phytochemistry 30,
11311132).
Table 2a and b. Other in vitro (a) and in vivo (b) effects of nettle herb preparations or constituents y
quercetin-3-0-rutinoside, kaempherol-3-0-rutinoside and isorhamnetin-3-0-glucoside

Nettle preparations Test Results References

(a) In vitro effects

Immunomodulatory and 10 g were boiled with water (1 h), ltrated, evaporated to 2.4 g aqueous extract Selective stimulation of T lymphocyte Harput et al. (2005)
chemopreventive proliferation by 50800 mg/ml

5 g powdered plant material was stirred for 2 h at room temperature with 100 ml 95% About 600 mg/ml inhibited Epstein-Barr virus Kapadia et al. (2002)
ethanol. The mixture was centrifuged for 10 min and the supernatant decanted and ltered. early antigen promotion by phorbol ester
The residue was washed twice with a small volume 95% ethanol and ltered. Filtered
extract and washings were combined and evaporated to dryness

Isolated compounds y Chemoattractants for neutrophils Akbay et al. (2003)

5 g in 100 ml ethyl alcohol (5% v/v) for 1 week at room temperature, then homogenized, Dose-dependent inhibition of adenosine Durak et al. (2004)
centrifuged at 5000 rpm for 10 min. The upper layer was used deaminase activity in prostate tissue

Central depressive Water-soluble fraction Inhibition of type A light chain protease activity Gul et al. (2004)
of botulinum toxin

On smooth muscle stripes Aqueous extract (50 mg corresponding to 0.165 g plant material); 0.51 ml ethanolic Inhibition of contractility Broncano et al. (1987a) and Keeser
extract (see footnote 15 in text) equivalent to 0.41 g crude drug (1940)

Ethanolic extract (see footnote 15 in text) Stimulation of contractility Starkenstein and Wasserstrom (1933)

Ethanolic extract (see footnote 15 in text) No effect on leech muscle Keeser (1940)

On Langendorff rat heart 1 and 2 g/l of aqueous extract (10 g per 100 ml) Positive inotropic, negative chronotropic Legssyer et al. (2002)
ARTICLE IN PRESS

On intact/denuded aorta 0.10.5 g/l and 1 and 2 g/l of aqueous extract (10 g per 100 ml) Vasoconstriction

Endocrine Aqueous extract (10 g per 200 ml, evaporated to 1/5th) 1 ml increased insulin secretion Farzami et al. (2003)
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435

Aqueous extract (1 g per 40 ml, evaporated to 1 ml) No impact on glucose movement through dialysis Gallagher et al. (2003)
tube

1 g per 10 ml was boiled, ltered, centrifuged at 10,000g and supernatants used Inhibition of a-glucosidase Onal et al. (2005)

10 g infused in 100 ml for 20 min and evaporated 250 mg/kg reduced glucose absorption in Bnouham et al. (2003)
perfused jejunum segments

Antimicrobial Aqueous extract (5 g per 50 ml or 20 g per 400 ml), ethanolic extract (50 g per 250 ml 80% Growth inhibition of against various Gram- Brantner and Grein (1994)
ethanol) or diethyl ether extract (200 g per 500 ml) or isolated patuletin (Urtica urens) positive and negative bacteria, Candida albicans, Keles et al. (2001)
no activity vs Pseudomonas aeruginosa, Klebsiella Gulcin et al. (2004)
pneumoniae Dostbil et al. (2005)
Saeed et al. (1995)

Aqueous extract (0.5 g powder in 100 ml, further diluted: 0.1 g or 0.05 g in 100 ml) Against Paramecium primaurelia and Lepidium Oswiecimska et al. (1980)
sativum
425
 426
Table 2a and b. (continued )

Nettle preparations Test Results References

(b) In vivo effects

Central depressive Aqueous nettle infusion according to the Spanish Pharmacopeia (DER 3:1) i.p. or Decrease of spontaneous motility and body Broncano et al. (1987b) and Lasheras et
unknown amount mixed with 500 ml water, boiled for 10 min (see footnote 11 in text), temperature at doses of 1.74 and 3.75 g/kg or al. (1986)
application mode not stated 750 mg/kg extract

Cardiovascular 25 mg/kg of aqueous extract (see footnote 11 in text) i.v. Hypotensive effect in rats Lasheras et al. (1986)

26.6 mg/kg of hot water extract (30,209%) i.v. Hypotensive effect in cats Broncano et al. (1983)

Ethanolic extract, details not stated, per os or i.p. Hypotensive effect in rats and rabbits Tita et al. (1993)

Ethanolic extract (see footnote 15 in text) (1 ml equivalent to 0.083) i.v. Hypotensive effect in rabbits Keeser (1940) and Ludwig (1945)

Endocrine Details not stated Artecial decrease of blood glucose Haznagy (1943)

Aqueous extract (10 g per 200 ml, evaporated to 1/5th, TLC separation) i.p. Increase in serum insulin in (diabetic) rats Farzami et al. (2003)

500 mg/kg aqueous extract (10 g per 100 ml), evaporated, yield 21% orally Decrease of blood glucose, no effect in alloxan- Bnouham et al. (2003)
induced diabetic rats

Aqueous 0.5% infusion (0.5 g per 100 ml) orally; 132 g boiled in 1 l for 10 min, 4 ml/kg No blood glucose lowering effect, aggravation of Gunes et al. (1999), Ramos et al. (1992)
orally; 1 g per 400 ml water, boiled for 5 min, infused for 15 min before given in place of diabetic condition and Swanston-Flatt et al. (1989)
drinking water;

15 g powder per 300 ml water or ethanol 80%, oral doses corresponded to 25 g crude plant Both extracts resulted in glucose increase Neef et al. (1995)
material/kg

Ethanolic extract (see footnote 15 in text) No effect on blood glucose Keeser (1940) and Ludwig (1945)
ARTICLE IN PRESS

Gastrointestinal A fraction from 50 g per 350 ml sulfuric acid, boiled for 10 h for s.c. injection Increase in gastrointestinal uid Dobreff (1924)

10 mg/kg of aqueous extract (20 g per 400 ml), ltrate lyphilized 10 mg/kg i.p. were gastroprotective Gulcin et al. (2004)

10 mg/kg isolated patuletin (Urtica urens) per os Did not damage gastric mucosa Saeed et al. (1995)
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435

Liver-protecting 50 g per 1000 ml boiled for 10 min, ltered and given with drinking water. Fixed oils were Hepatoprotective against CCl4 Turkdogan et al. (2003) and Kanter et
extracted with diethyl ether, 2 ml/kg were given i.p. al. (2003)

Antilipidaemic 10 g by maceration in 1000 ml preboiled hot water for 20 min, ltration; 100 g per 1000 ml 150 mg/kg/day aqueous extract, to a lesser extent Daher et al. (2006)
petroleum ether for 48 h, ltration, evaporation, residue dissolved in 400 ml absolute 20 mg/kg/day resulted in improvement of the
ethanol, solution sprayed on food blood lipid prole

100 mg/kg aqueous extract (see footnote 14 in text), 100 mg/kg of ethanolic extract (see Aqueous extract no effect, ethanolic extract weak Avci et al. (2006)
footnote 14 in text) effect

Antianaemic Food supplemented with squeezed juice Restitution of induced anaemia Cremer (1934)
 ARTICLE IN PRESS
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
weak antithrombotic activity (Goun et al., 2002).
Adrenaline-induced aggregation of human platelets by
nettle extract was also described by Sajid et al. (1991);
details are not available. Antonopoulo et al. (1996)
identied in nettle herb collected in spring 1989 from
Marousi (Attica Greece) a phopholipid fraction that was
able to induce platelet aggregation in a dose-dependent
manner, ve orders of magnitude less potent than PAF.
The effect was not inhibited by indomethacin but by a
PAF receptor-specic agent indicating that a receptor is
involved in the effect mechanism.
Antioxidative effect
Aqueous nettle extract7 in a dose of 50, 100 and
250 mg inhibited peroxidation in linoleic acid emulsion
dose-dependently and more pronounced than a-toco-
pherol 60 mg. Likewise was its reductive capability
higher than that of a-tocopherol. Its percentage inhibi-
tion of superoxide generation was greater than that of
butylated hydroxyanisole, butylated hydroxytoluene or
a-tocopherol. Aqueous extract and butylated hydro-
xyanisole had equal 1,1-diphenyl-2-picrylhydrazyl
(DPPH)-scavenging activity but the effect was lower
than that of quercetin. The metal chelating capacity of
the extract was higher than that of butylated hydro-
xyanisole, a-tocopherol or butylated hydroxyanisole
(Gulcin et al., 2004). Compared to Melissae folium
aquous extract, aqueous nettle extract8 had a low ferric
reducing/antioxidant power (3 vs 420 mM), but a
moderate phenol antioxidant coefcient (2.2 vs
43 mM/l; Katalinic et al., 2006). Likewise, Mavi
et al. (2004) found some antioxidative activity for
aqueous (5% decoction) and methanolic (solvent 5%
methanol) nettle extracts (concentrations tested
50500 mg/l). Lipopolysaccharide-stimulated NO2( )
production was inhibited by aqueous nettle extract9 in
a dose-dependent manner without affecting cell viability
(dose range tested 12.5800 mg/ml). The expression of
iNOS protein was not affected (Harput et al., 2005).
Polyphenol oxidase was identied as an antioxidative
principle (Gullcin et al., 2005). A hydroalcoholic nettle
extract10 (solvent 80% ethanol) inhibited brain lipid
7
Twenty grams dried aerial parts of nettle collected in May in Damlu
in Erzurum, Turkey, powdered and mixed with 400 ml boiling water
during 15 min. The ltrate was frozen and lyophilized, 20 mg was
dissolved in 20 ml water. Doses 50250 mg were used in the tests.
8
Three grams of plant material was added to 200 ml of deionized
water (initial temperature 98 1C). Infusion time was 30 min.
9
Ten grams air-dried aerial parts were boiled with water for 1 h. The
aqueous solution was claried by ltration and evaporated under
reduced pressure at 40 1C. Freeze-drying and solvent elimination under
reduced pressure nally yielded 2.4 g of powdery, crude aqueous
extract (24% w/w).
10
Ten grams of dried powdered plant material was extracted in
100 ml ethanol (4:1) under reux for 30 min, the extract ltered, the
volume concentrated under vacuum and nally freeze dried.
427
peroxidation by more than 50% (30 mg extract in 4.8 ml
of ethanol and 7.2 ml of phosphate buffer), caused about
30% inhibition in the xanthine oxydase assay (15 mg
extract in 1.2 ml of ethanol and 1.8 ml of phosphate
buffer), but had no effect in the diphenylpicrylhydrazil
assay (Pieroni et al., 2002).
Diuretic and other in vitro effects
The high potassiumsodium ratio of nettle herb
decoctions may explain the nettle herb diuretic effect
(Szentmihalyi et al., 1998). Other in vitro effects are
summarized in Table 2a.
Pharmacological properties: in vivo experiments
(Table 2b)
Anti-inammatory, analgesic and local anaesthetic
effects
No anti-inammatory effect was detected when an
unspecied ethanol nettle extract was administered in
the caragenan-induced paw oedema test in rats (dose not
stated) (Tita et al., 1993). However, extract IDS23
(solvent 50% ethanol, 25, 100 and 300 mg/kg) produced
a dose-dependent anti-inammatory effect in rats with
experimental gonarthritis induced by bovine gammaglo-
bulin and silicon particles (diclofenac served as control).
Behaviour, food intake and body weight remained
unchanged and mortality was not increased. Histo-
pathological evaluation conrmed a signicantly lower
lymphocyte inltration compared to control (po0.05),
the effect was similar to diclofenac (Schoening, 1996).
Compound patuletin from Urtica urens administered
orally in a dose of 10 mg/kg dissolved in 20% propylene
glycol in distilled water reduced the carageenan-induced
oedema volume signicantly and in the same range as an
equivalent dose of diclofenac. This dose reduced
carageenan-induced pleural uid volume even more
pronounced than diclofenac (Saeed et al., 1995).
In a chronic colitis model in mice in which dextran
sulphate sodium was used to induce colitis, no
signicant difference on weight over time was observed
after treatment with IDS30 (see Table 3) at a nal
concentration of 0.5 mg/ml in drinking water. However,
during the 3 cycles of dextran sulphate sodium applica-
tion, the weight loss was earlier and more severe in the
control group associated with more frequent signs of
colitis (redness and ulcerations of the anus, bloody
diarrhea), reduced colon length and more severe
histological scores. Similar differences were observed
in interleukin 10 gene-decient mice suffering from
chronic murine colitis and receiving IDS30 or water.
The improvement was supported by signicantly lower
faecal IL-1 and mucosal TNFa in the treated mice.
 428
Table 3. Studies of nettle herb preparations for different indications in chronological order

Medication (MED) Number of

prepared for the patients Nettle Improvement
Study or Brand of Mean (raw) (N) Control r Main outcome suggested with
Study References Nettle Product Dose per day Sort Solvent drug to extract Disease Placebo (P) measure nettle

Peripheral oedema

1 Kirchhoff MED 45 ml Juice Oedema 32 N Urine volume Urine volume

(1983) increase

Osteoarthritis (OA) or rheumatoid arthritis (RA) or other rheumatic diseases (O)

2 Hansen (1996) Rheuma Hek2 1340 mg Dried extract 50% ethanol 810:1 OA, RA, O 219 N Pain VRS 04 Improvement
etc. over time

3 Chrubasik et MED 50 ga Stew OA 20 N, 20 C Pain VRS 04, Improvement

al. (1997) CRP, etc. over time

4 Ramm and Rheuma Hek2 1340 mg Dried extract 50% ethanol 810:1 OA, RA 8955 N Pain VRS 04 Improvement
Hansen (1997) etc. over time

5 Wolf (1998) Rheuma Hek2 1340 mg Dried extract 50% ethanol 810:1 OA 819 N Pain VRS 04 Improvement
etc. over time

6 Randall (1999) Crude leaf 1 leaf OA 18 N Pain VRS 04 Improvement

etc. over time

7 Randall (2000) Crude leaf 1 leaf OA 13 N, 14 P Pain VRS 04 N superior to

cross over etc. placebo

8 Wolf (2001) Hox alpha3 145 mg Dried extract 95% propanol 1933:1 OA 20 N Pain VRS 04, Improvement
ARTICLE IN PRESS

cytokines, etc. over time

9 Hubbe (2002) Hox alpha3 145 mg Dried extract 95% propanol 1933:1 OA 763 N Pain VRS 04, Improvement
etc. over time
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435

Allergic Rhinitis

10 Mittman MED 600 Powder Hay fever 31 N, 38 P Symptom N superior to

(1990) scores ( 1,02) placebo

Raw drug to extract ratio dry weight of raw material per unit weight of extracted solids.
a
Minimum content of caffeoylmalic acid 14 mg.
 ARTICLE IN PRESS
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
Mononuclear LPS-induced cell proliferation was sig-
nicantly reduced in mice treated with IDS30. Unfortu-
nately, treatment durations had been very short
(Konrad et al., 2005).
In the hot-plate test in mice, aequeous nettle extract11
1200 mg/kg administered i.p. showed much greater
resistance to thermal stimulation in mice than control
animals (Lasheras et al., 1986). In the acetic acid-
induced writhing test in mice, aqueous nettle extract7 in
a dose of 50, 100 and 200 mg/kg i.p. produced a dose-
dependent inhibition in writhing which was more
pronounced than that of metamizol (Gulcin et al.,
2004). In contrast, i.p. or oral ethanolic nettle extract
(DER and ethanol percentage not stated) was ineffective
in the hot plate test in rodents (Tita et al., 1993).
However, the same extract reduced signicantly the
number of writhes as a response to phenylquinone (Tita
et al., 1993). The analgesic effect of oral 10 mg/kg
isolated palutein was more pronounced than that of
diclofenac in terms of higher voltages tolerated by the
rat when electric current was used as noxious stimulus
on rat tails and minimum voltage determined that
caused the rat to emit a cry (Saeed et al 1995). Local
application to the tail of a lyophilized aqueous nettle
leaf extract11 100 mg/ml was associated with an increase
of the thermal threshold in the tail ick test. The effect
was comparable to that of lidocaine (Lasheras et al.,
1986).
Antioxidative effect
Nettle seed oil 2 ml/kg was shown to increase the
antioxidant defense system activity in CCl4-treated rats
(Kanter et al., 2003). Ethanolic nettle extract12 50 mg/kg
had a marked effect on some hepatic biotransformation
enzyme systems and antioxidant enzymes which are vital
for enzymatic and nonenzymatic activation pathways.
The ratio of liver weight and nal body weight was not
increased. Kidney, lung and forestomach biotransfor-
mation enzymes were less attenuated. There was no
evidence of damage (Ozen and Korkmaz, 2003). Food
containing 1% dried nettle signicantly reduced free
electron accumulation in the cerebellum and frontal lobe
of rats, whereas regular exercise (forced swimming) did
not affect electron spin resonance signals. Nettle
supplementation also increased the DNA-binding of
activator protein-1. The combination of nettle and
exercise increased NF-kB activity. The authors con-
cluded that nettle may be an effective antioxidant and
possibly an antiapoptotic promoting cell survival in
11
Dried owering aerial parts were mixed with 500 ml water and
boiled for 10 min, ltered, evaporated and lyophilized.
12
Plants were collected from Samsun (Turkey) in JulyAugust 2001
during the early hours of the day. They were shade dried, sliced,
puried with a mixture of ethanol and water (80:20) using a soxhlett
apparatus and then lyophilized.
429
brain. Cetinus et al. (2005) found lower malonyldialde-
hyde in rat muscels after tourniquet ischemia and
reperfusion as a possible sign of a potential antioxidant
effect of aqueous nettle extract.13 Rats had received
500 mg/100 g body weight in 2.5 ml KCL aqueous
solution via intraoesophageal canule for 5 days before
the experiment. But Avci et al. (2006) did not observe
any effect on total antioxidative activity in rats receiving
aqueous or ethanolic nettle extracts.14 Extracts were
given orally in 100 mg/kg doses after suspending in a
mixture of distilled water and 0.5% sodium carbox-
ymethyl cellulose by using a gastric gavage.
Diuretic and other effects
A 50% ethanolic extract15 was used to prepare an
ether or a lead acetate fraction and to investigate their
effect on the enzyme urikase. In contrast to ascorbinic
acid 250 mg%, the fractions were ineffective. After geese
and ducks had been deprived of food for 24 h, uric acid
levels in the animals remained rather constant. The ether
fraction resulted in a reduction, the lead acetate fraction
(minus the substances transferred to the petroleum ether
phase) in a considerable increase in uric acid blood
levels: 30 and 60 min after administration of 10 ml in
geese and 4 ml in ducks. Neither effect was attributable
to uric acid metabolism and possibly related to a diuretic
action which needs to be evaluated (Keeser, 1940).
Increased diuresis and natriuresis was observed in i.v.
nettle16 and furosemide-treated rats at a dose of 4 and
24 mg/kg/h (nettle) and 2 mg/kg/h (furosemide), respec-
tively. This was dose-dependently associated with a
decrease in blood pressure. However, whereas the effects
of low dose nettle extract and furosamide infusions were
reversible, that of high dose nettle infusion was not
(Tahri et al., 2000) indicating a possible direct nettle
effect on renal function and the cardiovascular system
(higher nettle doses may act toxic). Oral administration
13
Leaves from the Cukurova region of Turkey on October 2002 were
washed twice with distilled water. About 2 g of each leaf sample was
homogenized in 10 ml of 1.15% KCl. Homogenates were centrifugated
at 3000g for 20 min. The supernatant was recovered and stored at 4 1C
until its use.
14
Plant materials from Turkey were dried under shade and
powdered. Ten grams were used to prepare the extracts, solvents
90% ethanol or distilled water. The two extractions, 2  200 ml and the
combined ethanolic layers were evaporated to dryness in vacuo: w/w
22.54; 48.82%.
15
Fifty grams dried leaf was given to 700 ml 50% ethanol for 48 h at
37 1C. Following evaporation, one third was dissolved in 20 ml 0.9%
NaCl, one third extract with petrol ether, evaporated and thereafter
dissolved in 20 ml 0.9% NaCl. Lead acetate was added to the latter.
The ltrate was evaporated and dissolved in 0.9% NaCl. Before using
this fraction the lead needs to be removed with H2S.
16
Aerial parts were collected in northeastern Morocco. Ten grams of
small pieces were infused into 100 ml boiled distilled water during
20 min. After decantation and ltration, the ltrate was again dried at
50 1C and different concentrations were prepared.
 ARTICLE IN PRESS
430 J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
of aqueous extract11 in a dose of 1 g/kg had no effect on
diuresis or ion excretion in rats (Lasheras et al., 1986).
This result contrasts to the ndings of Caceres et al.
(1987) who calculated cumulative urine production after
a 10% nettle decoction17 in rats at a dose of 1 g/kg by a
nasogastric catheter. Urine production increase was one
quarter of that of hydrochlorothiazide. Oral adminis-
tration of an unspecied ethanolic extract had also no
effect on diuretic activity, while urine output increased
signicantly after i.p. administration of the extract. This
was associated with increased potassium total excretion
and increased potassium concentration in urine whereas
sodium excretion remained uninuenced (Tita et al.,
1993) indicating that the ingested electrolytes of the
nettle preparation may have caused this effect. Admin-
istration of freshly squeezed nettle juice diluted in water
1:10 via a gastric tube to rats increased urine output.
Sodium, potassium and chloride concentrations in-
creased, whereas urea content remained unaffected
(Frank, 1981). In an earlier study, Balansard (1952)
had observed increased chloride and urea excretion in
rabbits after parenteral administration of 0.1 g/kg
glycolic or glyceric acid (which is also contained in
nettle). In another experiment in rats, a 10% suspension
containing 185 mg nettle herb or 35 mg of a nettle herb
mazerate 7:1, urine volume increased associated with an
increase of sodium, potassium and chloride concentra-
tions (Frank, 1981). Both nettle preparations had only a
weak effect in dogs. Due to the lack of statistical
analysis and great variation of data, further studies are
necessary to clarify the diuretic effect of nettle herb
(Frank, 1981).
Other in vivo effects are summarized in Table 2b. The
detailed effect mechanism of aqueous and ethanolic
nettle leaf extract on the cardiovascular system is still
unclear, an adrenolytic effect as well as a potassium
effect were discussed. The effects on blood glucose are
not uniform. The reason for this may be different doses,
different modes of application, different timings and
study designs. Further studies are required before a
denitive conclusion can be drawn. Likewise, more data
are needed to conrm the other observed in vivo effects.
Clinical studies
There are only few clinical studies available, investi-
gating the effect of nettle juice for increased diuresis in
cardiac insufciency or chronic venous insufciency, of
a stew and proprietary extracts or topical leaf for
osteoarthritis and a freeze-dried powder for allergic
rhinitis (Table 3). The quality of all studies (7 open
uncontrolled, one open controlled and 2 double-blind
studies) has been poor (Table 4). They all show a trend
17
Ten grams of dried plant material were boiled in 100 ml of water
for 5 min, following by ltration using Whatman No. 2 paper.
of effectiveness in the domains investigated, which
needs, however, to be proven in conrmatory studies.
Thus, there is currently no evidence beyond reasonable
doubt that nettle preparations in the doses employed are
effective for specic complaints. Unpublished open
documentations did not leave doubt, that nettle tea
and juice are ineffective for the treatment of osteoar-
thritic pain. The active principle for the treatment of
osteoarthritic pain is thus contained if at all in the
lipophilic fraction of nettle herb (Chrubasik and
Eisenberg, 1999). More than 10,000 patients were
treated in clinical studies with nettle preparations. In
the doses employed, the risk for adverse events was very
low with rare cases of systemic allergic skin reactions or
mild gastrointestinal adverse events. Local contact
sensitivity may also occur (Bossuyt and Dooms-Goos-
sens, 1994; Morgan and Khan, 2003; Caliskaner et al.,
2004). Besides an immediate response, delayed hyper-
sensitivity to nettle plant was observed (Edwards and
Edwards, 1992). Dose-nding studies are urgently
needed as well as conrmatory and safety studies
if nettle herb wants to compete with conventional
treatments.
Toxicology
In acute toxicity studies in rabbits oral ethanol extract
(solvent ethanol 50%) was associated with occasional
diarrhea. A single subcutaneous injection was well
tolerated, a very high dose resulted in death of the
animals. Chronic subcutaneous administration of the
same extract was also associated with diarrhea. Body
weight decreased by 40% and several days later the
animals died. Autopsy revealed purrulent blisters
around the injection site. Prior to death, the respiration
increased and a central excitatory behaviour was
observed in the rabbits. Boiling of the extract decreased
its toxicity (Starkenstein and Wasserstrom, 1933). High
doses of ethanol uid extract had a paralysing effect and
caused asystolia to isolated frog hearts (Starkenstein
and Wasserstrom, 1933). Keeser (1940) and Ludwig
(1945) conrmed these results. According to Hughes et
al. (1980) the observed organic changes in guinea pigs,
rats and mice were attributable either to direct toxicity
of nettle extract or to a lack of amino acids. The
intraperitoneal LD50 of aqueous extract in mice was
found to be 3625 mg/kg. Doses 4750 mg/kg were
associated with a decrease in spontaneous activity, loss
of muscle tone and hypothermia (Lasheras et al., 1986).
A low toxicity was also observed after oral and
intraperitoneal administration of an unspecied ethanol
extract up to 2 g/kg (Tita et al., 1993). Intravenous doses
4500 mg/kg caused transient hypotension and cardiac
arrhythmias. Following intravenous injection in mice,
the LD50 was 1.9 g/kg for a nettle infusion of 100 mg/ml
Table 4. Internal and external validity items in chronologically listed studies on nettle herb products (according to Chrubasik et al., 2003)

Study Internal validity External validity

number from
Table 1 Randomis- Blinding and Attrition- Appropriate tests of null & Inclusion Treatment type & Setting Validated Duration of study Documentation
ation and/or masking of number alternative hypotheses in pre- and availability of (number outcome w weeks of adverse
allowance outcome of drop- specied POM and/or MV exclusion additional of measures m months events
for assessment outs and testing criteria treatments centres) included ys years
confounding intention- and/or
to-treat baseline
and/or description
sensitivity of patients
analyses and their
complaints
Null Alt

1 n n n 0 n n n n y y n 1 n 2w Not in detail

2 n n n nr n n n n y y y 71 y 3w nr

3 n n n 4 n n n n y y y 1 y 2w y

4 n n n nr n n n n y y y nr y 3w y
ARTICLE IN PRESS

5 n n n nr n n n n y y y nr y 12 m y

6 n n n 0 n n n n y y nr nr n Up to 2 ys y
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435

7 y n y 1 n n n n y y y nr y 1w y

8 n n n 3 y n n n y y y 2 y 12 w y (none)

9 n n n 93 n n n n y y y nr y 6m y

10 y n y 29 n n n y y n 1 n 1w y

nr, not reported; POM, principal outcome measure; n, no; y, yes; MV, multivariate
431
 ARTICLE IN PRESS
432 J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
and 1.7 g/kg for an aqueous nettle extract (3:1) 109 mg/
ml. For chronic oral application in rats, the DL50 was
1310 mg/kg (Baraibar et al., 1983). The hydrosoluble
compound(s) that contribute to the toxic effect may
have a pyran-coumarine structure (Broncano et al.,
1987b).
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).
Nettle avonoids as well as their aglycones were
shown to be nonmutagenic but not completely safe
(Basaran et al., 1996). Natural antioxidants in nettle
may contribute to the antimutagenic effect (Kalaycioglu
and Oner, 1997). The direct cytotoxic effect of the
essential oil from Urtica dioica was shown to be
concentration and time of incubation-dependent (Ilar-
inova et al., 1992).
Conclusion
The presence of a relatively high concentration of
avonoids and caffeic acid derivatives enriched in the
lipophilic fraction of the Urtica herb, suggest mainly
anti-inammatory, antioxidant and analgesic activities
as assessed in a series of pharmacaological in vitro and
animal studies, some of them also against the synthetic
Diclofenacs. The results of the clinical studies, however,
are not yet convincing and need further conrmation by
placebo controlled double blind studies with standar-
dized extracts.
Furthermore, it must be emphasized that the results
of pharmacological and clinical studies were carried out
with extracts produced with different solvents (ethylal-
cohol 50%, propanol or water) under different condi-
tions. Therefore, the results so obtained are not
comparable.
As the toxicology of Urtica herbal extract is
concerned, it has to be carfully proven, whether in the
allergic skin side-effects observed in some patients after
administration of the Urtica extract, the caffeoylesters
are involved.
References
Anonymous, 2003. Urticae folium/herba. In: European
Scientic Cooperative on Phytotherapy, (Eds.), ESCOP
Monographs. Thieme, Stuttgart, New York, pp. 521527.
Anonymus, 1998. In: Blaschek, W., Hansel, R., Kelber, K.,
Reichling, J., Rimpler, H., Schneider, G. (Eds.), Hagers
Handbuch Sequential, vol. 3. Springer-Publ. Comp., Berlin,
Heidelberg, pp. 710723.
Antonopoulou, S., Demopoulos, G.C., Andrikopoulos, N.K.,
1996. Lipid separation from Urtica dioica: existence of
platelet-activating factor. J. Agric Food Chem. 44,
30523056.
Akbay, P., Basaran, A.A., Undeger, U., Basaran, N., 2003. In
vitro immunomodulatory activity of avonoid glycosides
from Urtica dioica L. Phytother. Res. 17, 3437.
Avci, G., Kupeli, E., Eryavuz, A., Yesilada, E., Kucukkurt, I.,
2006. Antihypercholesterolaemic and antioxidant activity
assessment of some plants used as remedy in Turkish folk
medicine. J. Ethnopharmacol. 107, 418423.
Balansard, J., 1952. Les principes actifs des diuretiques hepato-
renaux: acides glycolique et glyerique. Prod. Pharmaceut. 7,
456458.
Baraibar, P.C., Broncano, F.J., Lazaro-Carrasco, M.J.,
Villanua, M.R.L., 1983. Estudio de la toxicidad aguda y
cronica de la ortiga (Urtica dioica L.). Anal. Bromatol. 35,
99103.
Basaran, A.A., Yu, T.W., Plewa, M.J., Anderson, D., 1996.
An investigation of some Turkish herbal medicines in
Salmonella typhimurium and in the COMET assay in
human lymphocytes. Teratog. Carcinog. Mutagen. 16,
125138.
Bathe, A.P., 1994. An unusual manifestation of nettle rash in
three horses. Vet. Rec. 134, 1112.
Bnouham, M., Merhfour, F.Z., Ziyyat, A., Mekh, H., Aziz,
M., Legssyer, A., 2003. Antihyperglycemic activity of the
aqueous extract of Urtica dioica. Fitoterapia 74, 677681.
Bossuyt, L., Dooms-Goossens, A., 1994. Contact sensitivity to
nettles and camomile in alternative remedies. Contact
Dermatitis 31, 131132.
Brantner, A., Grein, A., 1994. Antibacterial activity of plant
extracts used externally in traditional medicine. J. Ethno-
pharmacol. 44, 3540.
Broer, J., Behnke, B., 2002. Immunosuppressant effect of IDS
30, a stinging nettle leaf extract, on myeloid dendritic cells
in vitro. J. Rheumatol. 29, 656658.
Broncano, F.J., Rebuelta, M., Vivas, J.M., Serranillos, M.G.,
1983. Etude de leffet sur le centre cardiovasculaire de
quelques preparations de lUrtica dioica L. Plantes Med.
Phytother. 17, 222229.
Broncano, J., Rebuelta, M., Vivas, J.M., Diaz, M.P., 1987a.
Estudio de diferentes preparados de Urtica dioica L. sobre
SNC. An Real Acad. Farm. 53, 284291.
Broncano, F.J., Rebuelta, M., Lazaro-Carrasco, M.J.Y.,
Vivas, J.M., 1987b. Estudio del efecto sobre musculatura
lisa uterina de distintos preparados de las hojas de Urtica
dioica L. An Real Acad. Farm. 53, 6976.
Caliskaner, Z., Karaayvaz, M., Ozturk, S., 2004. Misuse of a
herb: stinging nettle (Urtica urens) induced severe tongue
oedema. Comp. Ther. Med. 12, 5758.
Carceres, A., Giron, L.M., Mart nez, A.M., 1987. Diuretic
activity of plants used for the treatment of urinary ailments
in Guatemala. J. Ethnopharmacol. 19, 233245.
Cetinus, E., Kili, M., Inanc, F., Kurutas, E.B., Buzkan, N.,
2005. The role of Urtica dioica (Urticaceae) in the
prevention of oxidative stress caused by tourniquet
application in rats. Tohoku J. Exp. Med. 205, 215221.
Chrubasik, S., Eisenberg, E., 1999. Treatment of rheumatic
pain with kampo medicine in Europe. Part II. Urtica dioica.
Pain Clin. 11, 179185.
 ARTICLE IN PRESS
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
Chrubasik, S., Enderlein, W., Bauer, R., Grabner, W., 1997.
Evidence for antirheumatic effectiveness of herba urticae
dioicae in acute arthritis: a pilot study. Phytomedicine 4,
105108.
Chrubasik, S., Conradt, C., Black, A., 2003. The quality of
clinical trials with Harpagophytum procumbens. Phytome-
dicine 10, 613623.
Cremer, H., 1934. Wissenschaftlicher Teil: Biologische Ver-
suche mit Panzensaften. Dtsch. Apoth. Zeit. 80,
12771279.
Daher, C.F., Baroody, K.G., Baroody, G.M., 2006. Effect of
Urtica dioica extract intake upon blood lipid prole in the
rats. Fitoterapia 77, 183188.
Dobreff, M., 1924. Ueber ein neues Sekretin in der Brennessel
(Urtica dioica L.). Munch. Med. Woch. 77, 773774.
Dostbil, N., Agaoglu, S., Alemdar, 2005. The antibacterial
activity of common nettle. Indian Vet. J. 82, 492494.
Durak, I., Biri, H., Devrim, E., Sozen, S., Avci, A., 2004.
Aqueous extract of Urtica dioica makes signicant inhibi-
tion on adenosine deaminase activity in prostate tissue from
patients with prostate cancer. Cancer Biol. Ther. 3,
855857.
Edwards Jr., E.K., Edwards Sr., E.K., 1992. Immediate and
delayed hypersensitivity to the nettle plant. Contact
Dermatitis 27, 264265.
El Haouari, M., Bnouham, M., Bendahou, M., Aziz, M.,
Ziyyat, A., Legssyer, A., Mekh, H., 2006. Inhibition of rat
platelet aggregation by Urtica dioica leaves extracts.
Phytother. Res. 20, 568572.
Farzami, B., Ahmadvand, D., Vardasbi, S., Majin, F.J.,
Khaghani, S.h., 2003. Induction of insulin secretion by a
component of Urtica dioica leave extract in perifused Islets
of Langerhans and its in vivo effects in normal and
streptozotocin diabetic rats. J. Ethnopharmacol. 89, 4753.
Frank, B., 1981. Kneipp-Werke data on le. See: Anonymous,
1998. Urtica. In: Blaschek, W., Hansel, R., Keller, K.,
Reichling, J., Rimpler, H., Schneider, G. (Eds.), Hagers
Handbuch der Pharmazeutischen Praxis, fth ed. Publisher
Heidelberg, Bew York, etc., pp. 710736.
Gallagher, A.M., Flatt, P.R., Duffy, G., Abdel-Wahab,
Y.H.A., 2003. The effects of traditional antidiabetic plants
on in vitro glucose diffusion. Nutr. Res. 23, 413424.
Goun, E.A., Petrichenko, V.M., Solodnikov, S.U., Suhinna,
T.V., Kline, M.A., Cunningham, G., Nguyen, C., Miles,
H., 2002. Anticancer and antithrombin activity of Russian
plants. J. Ethnopharmacol. 81, 337342.
Gul, N., Ahmed, S.A., Smith, L.A., 2004. Inhibition of the
protease activity of the light chain of type A botulinum
neurotoxin by aqueous extract from stinging nettle (Urtica
dioica) leaf. Basic Clin. Pharmacol. Toxicol. 95, 215219.
Gulcin, I., Lifrevioglu, O.I., Oktay, M., Buyukokuroglu, M.E.,
2004. Antioxidant, antimicrobial, antiulcer and analgesic
activities of nettle (Urtica dioica L.). J. Ethnopharmacol.
90, 205215.
Gullcin, I., Kufrevioglu, O.I., Oktay, M., 2005. Purication
and characterization of polyphenol oxidase from nettle
(Urtica dioica L.) and inhibitory effects of some chemicals
on enzyme activity. J. Enzyme Inhib. Med. Chem. 20,
297302.
433
Gunes, H.V., Degirmenci, I., Aydin, M., Bozan, B., Aral, E.,
Tunalier, Z., Ustuner, C., Ercakir, M., Baser, K.H.C.,
Basaran, A., 1999. The effects of Rumex patientia L. and
Urtica dioica L. on some blood and urine parameters, and
liver and kidney histology in diabetic rats. Tr. J. Med. Sci.
29, 227232.
Hansen, C., 1996. Brennesselblatter-Extrakt wirksam bei
Arthroseschmerzen. Der Allgemeinarzt 6, 654657.
Harput, U.S., Saracoglu, I., Ogihara, Y., 2005. Stimulation of
lymphocyte proliferation and inhibition of nitric oxide
production by aqueous Urtica dioica extract. Phytother.
Res. 19, 346348.
Haznagy, A., 1943. Beitrage zur Blutzuckerspiegel beeinus-
senden Wirkung der Urtica dioica und Urtica urens. Chem.
Zentrbl. 114 (II), 247255.
Hubbe, M., 2002. Rheumatische Erkrankungen eine
beherrschbare Herausforderung. Der Kassenarzt 16/17,
3238.
Hughes, R.E., Ellery, P., Harry, T., Jenkins, V., Jones, E.,
1980. The dietary potential of the common nettle. J. Sci.
Food Agric. 31, 12791286.
Ilarinova, M., Todorov, D., Burov, P., Dimitrova, N.,
Parvanova, V., 1992. Cytotoxic effect on leukemic cells of
the essential oils from rosemary, wild geranium and nettle
and concrete of royal Bulgarian rose. Anticancer. Res. 12,
1915.
Kalaycioglu, A., Oner, C., 1997. Observation of the anti-
mutagenic potencies of plant extracts against pesticides in
the Salmonella typhimurium strains TA98 and TA1000. J.
Bot. 21, 127130.
Kanter, M., Meral, I., Dede, S., Gunduz, H., Cemek, M.,
Ozbek, H., Uygan, I., 2003. Effects of Nigella sativa L. and
Urtica dioica L. on lipid peroxidation, antioxidant enzyme
systems and some liver enzymes in CCl4-treated rats. J. Vet.
Med. A Physiol. Pathol. Clin. Med. 50, 264268. See
Kanter, M., Coskun, O., Budancamanak, M., 2005.
Hepatoprotective effects of Nigella sativa L. and Urtica
dioica L. on lipid peroxidation, antioxidant enzyme systems
and liver enzymes in carbon tetrachloride-treated rats.
World J. Gastroenterol. 14, 66846688.
Kapadia, G.J., Azuine, M.A., Tokuda, H., Hang, E.,
Mukainaka, T., Nishino, H., Sridhar, R., 2002. Inhibitory
effect of herbal remedies on 12-O-tetradecanoylphorbol-13-
acetate-promoted Epstein-Barr virus early antigen activa-
tion. Pharmacol. Res. 45 (3), 213220.
Katalinic, V., Milos, M., Kulisic, T., Jukic, M., 2006.
Screening of 70 medicinal plant extracts for antioxidant
capacity and total phenols. Food Chem. 94, 550557.
Keeser, E., 1940. Zur Wirkungsweise der Brennessel (Urtica
dioica) insbesondere auf den Harnsaurestoffwechsel. DMW
66, 849851.
Keles, O., Bakirel, T., AK, S., Alpmar, A., 2001. The
antibacterial activity of some plants used for medicinal
purposes against pathogens of veterinary importance. Folia
Veterinaria 45, 2225.
Kirchhoff, H.W., 1983. Brennesselsaft als Diuretikum. Z.
Phytother. 4, 621626.
Klingelhoefer, S., Obertreis, B., Quast, S., Behnke, B., 1999.
Antirheumatic effect of IDS 23, a stinging nettle leaf
 ARTICLE IN PRESS
434 J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
extract, on in vitro expression of T helper cytokines. J.
Rheumatol. 26, 25172522.
Konrad, A., Mahler, M., Ari, S., Flogerzi, B., Klingelhofer, S.,
Seibold, F., 2005. Ameliorative effect of IDS 30, a stinging
nettle leaf extract, on chronic colitis. Int. J. Colorectal Dis.
20, 917.
Lasheras, B., Turillas, P., Cenarruzabeitia, E., 1986. Etude
pharmcologique preliminaire de Prunus spinosa L., Ame-
lanchier ovalis Medikus, Juniperus communis L. et Urtica
dioica L. Plantes Med. Phytother. 20, 219226.
Legssyer, A., Ziyyat, A., Mekh, H., Bnouham, M., Tahri, A.,
Serhrouchni, M., Hoerter, J., Fischmeister, R., 2002.
Cardiovascular effects of Urtica dioica L. in isolated rat
heart and aorta. Phytother. Res. 16, 503507.
Ludwig, G., 1945. Zur Pharmakologie der Brennessel [Eroff-
nungsdissertation]. Berlin (Dtsch): Friedrich Wilhelm Uni-
versitat. [pages unknown]. Available from: Friedrich
Wilhelm Universitat Berlin.
Mavi, A., Terzi, Z., Ozgen, U., Yildiri, A., Coskun, M., 2004.
Antioxidant properties of some medicinal plants: Prangos
ferulacea (Apiaceae), Sedum sempervivoides (Crassulaceae),
Malva neglecta (Malvaceae), Cruciata taurica (Rubiaceae),
Rosa pimpinellifolia (Rosaceae), Galium verum subsp. verum
(Rubiaceae), Urtica dioica (Urticaceae). Biol. Pharm. Bull.
27, 702705.
Mekh, H., Haouari, M.E., Legssyer, A., Bnouham, M., Aziz,
M., Atmani, F., Remmal, A., Ziyyat, A., 2004. Platelet
anti-aggregant property of some Moroccan medicinal
plants. J. Ethnopharmacol. 94, 317322.
Mittman, P., 1990. Randomized double-blind study of freeze-
dried Urtica dioica in the treatment of allergic rhinitis.
Planta Med. 56, 4447.
Morgan, M., Khan, D.A., 2003. Stinging nettle anaphylaxis. J.
Allergy Clin. Immunol. 3 (Suppl.), 98.
Neef, H., Declercq, P., Laekeman, G., 1995. Hypoglycaemic
activity of selected European plants. Phytother. Res. 9,
4548.
Obertreis, B., Giller, K., Teucher, T., Behnke, B., Schmitz, H.,
1996a. Antiphologistische Effekte von Extractum Urticae
dioicae foliorum im Vergleich zu Kaffeoylapfelsaure.
Arzneimittelforschung 46, 5256.
Obertreis, B., Ruttkowski, T., Teucher, T., Behnke, B.,
Schmitz, H., 1996b. Ex-vivoin-vitro-Hemmung der Lipo-
polysaccharid-stimulierten Tumor-Nekrose-Faktor-a- und
Interleukin-1b-Sekretion in humanem Vollblut durch Ex-
tractum Urticae dioicae foliorum. Arzneimittelforschung
46, 389394.
Onal, S., Timur, S., Okutucu, B., Zihnioglu, F., 2005.
Inhibition of alpha-glucosidase by aqueous extracts of
some potent antidiabetic medicinal herbs. Prep. Biochem.
Biotechnol. 35, 2936.
Oswiecimska, M., Komala, Z., Liszka, B., 1980. Sensitivity of
Paramecium primaurelia and Lepidium sativum to extracts
from Folia Urticae. Folia Biol. 28, 245251.
Ozen, T., Korkmaz, H., 2003. Modulatory effect of Urtica
dioica L. (Urticaceae) leaf extract on biotransformation
enzyme systems, antioxidant enzymes, lactate dehydrogen-
ase and lipid peroxidation in mice. Phytomedicine 10,
405415.
Pearce, G.J., Chikanza, I.C., McCloskey, D.J., 1999. The in
vitro effects of a water soluble extract of the stinging nettle
(Urtica dioica folium) leaf preparation Rheumaheks on
TNF-alpha, IL-1b, IL-6 and IL-10 production by blood
monocytes. Arthritis Rheum. 42, 80.
Pieroni, A., Janiak, V., Durr, C.M., Ludeke, S., Traschsel, E.,
Heinrich, M., 2002. In vitro antioxidant activity of non-
cultivated vegetables of ethnic Albanians in southern Italy.
Phytother. Res. 16, 467473.
Ramm, S., Hansen, C., 1997. Brennesselblatterextrakt: Wirk-
samkeit und Vertraglichkeit bei Arthrose und rheumatoider
Arthritis. In: Chrubasik, S., Wink, M. (Eds.), Rheumather-
apie mit Phytopharmaka. Hippokrates, Stuttgart, pp.
97106.
Ramos, R.R., Alarcon-Aguilar, F., Lara-Lemus, A., Flores-
Saenz, J.L., 1992. Hypoglycemic effect of plants used in
Mexico as antidiabetics. Arch. Med. Res. 23, 5964.
Randall, C., Meethan, K., Randall, H., Dobbs, F., 1999.
Nettle sting of Urtica dioica for joint pain an exploratory
study of this complementary therapy. Comp. Ther. Med. 7,
126131.
Randall, C., Randall, H., Dobbs, F., Hutton, C., Sanders, H.,
2000. Randomized controlled trial of nettle sting for
treatment of base-of-thumb pain. J. R. Soc. Med. 93,
305309.
Riehemann, K., Behnke, B., Schulze-Osthoff, K., 1999. Plant
extracts from stinging nettle (Urtica dioica) an antirheu-
matic remedy, inhibit the proinammatory transcription
factor NF-kappaB. FEBS 442, 8994.
Saeed, A., El-Eraqy, W., Ahmed, Y., 1995. Flavonoids of
Urtica urens L. and biological evaluation. Egypt J. Pharm.
36, 16.
Sajid, T.M., Rashid, S., Saeed, S.A., 1991. Inhibition of
adrenaline-induced aggregation of human platelets by
Pakistani medicinal plants. Pak. J. Pharm. Sci. 4, 145152.
Schoning, U., 1996. Strathmann data on le.
Schulze-Tanzil, G., de Souza, P., Behnke, B., Klingelhoefer, S.,
Scheid, A., Shakibaei, M., 2002. Effects of the antirheu-
matic remedy Hox alpha-a new stinging nettle leaf extract-
on matrix metalloproteinases in human chondrocytes in
vitro. Histol. Histopathol. 17, 477485.
Starkenstein, E., Wasserstrom, Th., 1933. Pharmakologische
und chemische Untersuchungen uber die wirksamen
Bestandteile der Urtica dioica und Urtica urens. Naunyn-
Schmiedebergs Arch. 172, 137148.
Swanston-Flatt, S.K., Day, C., Flatt, P., Gould, B., Bailey,
C.J., 1989. Glycaemic effects of traditional European plant
treatments for diabetes. Studies in normal and streptozo-
tocin diabetic mice. Diabetes Res. 10, 6973.
Szentmihalyi, K., Kery, A`., Then, M., Lakatos, B., Sandor, Z.,
Vinkler, P., 1998. Potassiumsodium ratio for the char-
acterization of medicinal plant extracts with diuretic
activity. Phytother. Res. 12, 163166.
Tahri, A., Yamani, S., Legssayer, A., Aziz, M., Mekh, H.,
Bnouham, M., Ziyyat, A., 2000. Acute diuretic, natriuretic
and hypotensive effects of a continuous perfusion of
aqueous extract of Urtica dioica in rats. J. Ethnopharmacol.
73, 95100.
Teucher, T., Obertreis, B., Ruttkowski, T., Schmitz, H., 1996.
Zytokin-Sekretion im Vollblut gesunder probanden nach
 ARTICLE IN PRESS
J.E. Chrubasik et al. / Phytomedicine 14 (2007) 423435
oraler Einnahme eines Urtica dioica L.-Blattextraktes.
Arzneimittelforschung 46, 906910.
Tita, B., Faccendini, P., Bello, U., Martinoli, L., Bolle, P.,
1993. Urtica dioica L.: pharmacological effect of ethanol
extract. Pharmacol. Res. 27 (Suppl. 1), 2122.
Tunon, H., Olavsdotter, C., Bohlin, L., 1995. Evaluation of
anti-inammatory activity of some Swedish medicinal
plants. Inhibition of prostaglandin biosynthesis and PAF-
induced exocytosis. J. Ethnopharmacol. 48, 6176.
Turkdogan, M.K., Ozbek, H., Yener, Z., Tuncer, I., Uygan, I.,
Ceylan, E., 2003. The role of Urtica dioica and Nigella
435
sativa in the prevention of carbon tetrachloride-
induced hepatotoxicity in rats. Phytother. Res. 17,
942946.
Wichtl, M., (Ed.), Tee-Drogen und Phytopharmaka 4, Au,
2002. Wiss. Verlagsgesellschaft mbH, Stuttgart, p. 617.
Wolf, F., 1998. Gonarthrose: Brennesselblatter-Extrakt IDS
23 in der Langzeitanwendung. Kassenarzt 44, 5254.
Wolf, F., Gulbin, K., Mlelke, F., 2001. Aktivierte Arthrose:
Brennesselblatter-Extrakt mit Leitsubstanz HOTrE
(STRAT 59) hemmt Tumor-Nekrose-Faktor-a. Kassenarzt
16, 4247.