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A comprehensive review on nettle effect and efficacy profiles, Part I: Herba urticae.

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-inflammatory 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 find out if these effects are surrogates for clinical relevant effects in humans.

[c] 2007 Elsevier GmbH. All rights reserved.

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

Introduction

Dried or fresh leaves or flowering aerial parts of Urtica dioica L., Urtica urens L., their hybrids or mixtures of these are recommended for symptomatic treatment of rheumatoid arthritis or osteoarthritis and for increased diuresis, e.g. in case of urinary tract infections (Anonymous, 2003). The suggested (empirically used) doses for internal use include hydroalcoholic extracts corresponding to 8-12 g nettle leaf daily or up to 5 g as an infusion up to three times daily over an unlimited period. For external use once daily application of a fresh leaf rubbed onto the painful area is recommended (Anonymous, 2003).

Main constituents identified in the plant material are summarized in Table 1. The aim of this systematic review was to collect data on the effects and efficacy of nettle herb.

Methods

Systematic literature searches were conducted on Medline (via Pubmed). The database was searched from its inception until end of July 2006. Additionally, experts were contacted to identify further studies. Hand-searches were performed by searching the authors' own files and the bibliographies of all located papers. No restrictions regarding the language of publication were imposed. Controlled and uncontrolled clinical studies and pre-clinical studies were eligible for inclusion.

Pharmacological properties: in vitro experiments (Table 2a)

Impact on inflammatory mediators

Aqueous nettle extract (1) had no inhibitory effect on prostaglandin biosynthesis, but inhibited platelet activating factor (PAF)-induced exocytosis of elastase from human neutrophils in a dose of 250 mg/ml (Tunon et al., 1995). In contrast, ethanolic extract IDS23 (2) inhibited cyclooxygenase-dependent biosynthesis of prostaglandins dose-dependently ([IC.sub.50] 92 [micro]g/ml). Its component caffeic malic acid was shown to be a leucotriene [B.sub.4]-inhibitor ([IC.sub.50] 83 [micro]g/ml, Obertreis et al., 1996a). IDS23 inhibited LPS-induced release of TNF[alpha], and interleukin-1[beta] dose-dependently (not, however, interleukin-6) ([IC.sub.50] 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 1-10 mg/ml inhibited dose-dependently interleukin-2 gene expression (Pearce et al., 1999) indicating immunomodulatory properties. It seemed likely that the IDS23 cytokine release inhibition is caused by inhibition of NF-[kappa]B since dose-dependent inhibition of TNF[alpha]-stimulated expression of NF-[kappa]B driven luciferase gene by IDS23 (2) and its watersoluble fraction was found. The degradation of inhibitory subunit I[kappa]B-[alpha] was prevented by the water-soluble IDS23 fraction in a dose of up to 320 [micro]g/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-specific interleukin-4 whereas interleukin-2 and IFN-[gamma] expression were inhibited dose-dependently (ranges: up to 400 [micro]g/ml; [IC.sub.50] values not stated, Klingelhoefer et al., 1999). For IDS30 (3) in a dose up to 25 [micro]g/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 [micro]g/ml also significantly suppressed interleukin-1[beta]-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 extract (4) demonstrated weak inhibition of thrombin 1 U/ml and ADP 10 [micro]M-induced platelet aggregation (IC50 15.5 and 12.8 mg/ml, respectively; Mekhfi 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: 0.5-3 mg/ml; El Haouari et al., 2006). Ethyl acetate extract exhibited the most aggregant effect. Flavonoid compounds were shown to be involved in this action. A methanolic extract (6) had only 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) identified 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, five orders of magnitude less potent than PAF. The effect was not inhibited by indomethacin but by a PAF receptor-specific agent indicating that a receptor is involved in the effect mechanism.

Antioxidative effect

Aqueous nettle extract (7) in a dose of 50, 100 and 250 [micro]g inhibited peroxidation in linoleic acid emulsion dose-dependently and more pronounced than [alpha]-tocopherol 60 [micro]g. Likewise was its reductive capability higher than that of [alpha]-tocopherol. Its percentage inhibition of superoxide generation was greater than that of butylated hydroxyanisole, butylated hydroxytoluene or [alpha]-tocopherol. Aqueous extract and butylated hydroxyanisole 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 hydroxyanisole, [alpha]-tocopherol or butylated hydroxyanisole (Gulcin et al., 2004). Compared to Melissae folium aquous extract, aqueous nettle extract (8) had a low ferric reducing/antioxidant power (3 vs >20mM), but a moderate phenol antioxidant coefficient (2.2 vs > 3mM/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 50-500 mg/l). Lipopolysaccharide-stimulated NO[2.sup.(-)] production was inhibited by aqueous nettle extract (9) in a dose-dependent manner without affecting cell viability (dose range tested 12.5-800 [micro]g/ml). The expression of iNOS protein was not affected (Harput et al., 2005). Polyphenol oxidase was identified as an antioxidative principle (Gullcin et al., 2005). A hydroalcoholic nettle extract (10) (solvent 80% ethanol) inhibited brain lipid 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 potassium-sodium 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-inflammatory, analgesic and local anaesthetic effects

No anti-inflammatory effect was detected when an unspecified 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-inflammatory effect in rats with experimental gonarthritis induced by bovine gammaglobulin and silicon particles (diclofenac served as control). Behaviour, food intake and body weight remained unchanged and mortality was not increased. Histo-pathological evaluation confirmed a significantly lower lymphocyte infiltration compared to control (p < 0.05), 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 significantly and in the same range as an equivalent dose of diclofenac. This dose reduced carageenan-induced pleural fluid 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 significant difference on weight over time was observed after treatment with IDS30 (see Table 3) at a final concentration of 0.5 mg/ml in drinking water. However, during the 3 cycles of dextran sulphate sodium application, 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-deficient mice suffering from chronic murine colitis and receiving IDS30 or water. The improvement was supported by significantly lower faecal IL-1[beta] and mucosal TNF[alpha] in the treated mice. Mononuclear LPS-induced cell proliferation was significantly reduced in mice treated with IDS30. Unfortunately, treatment durations had been very short (Konrad et al., 2005).

In the hot-plate test in mice, aequeous nettle extract (11) 1200mg/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 extract (7) in a dose of 50, 100 and 200mg/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 significantly the number of writhes as a response to phenylquinone (Tita et al., 1993). The analgesic effect of oral 10mg/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 extract (11) 100 mg/ml was associated with an increase of the thermal threshold in the tail flick 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 C[Cl.sub.4]-treated rats (Kanter et al., 2003). Ethanolic nettle extract (12) 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 final body weight was not increased. Kidney, lung and forestomach biotransformation enzymes were less attenuated. There was no evidence of damage (Ozen and Korkmaz, 2003). Food containing 1% dried nettle significantly 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-[kappa]B activity. The authors concluded that nettle may be an effective antioxidant and possibly an antiapoptotic promoting cell survival in 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 100mg/kg doses after suspending in a mixture of distilled water and 0.5% sodium carboxymethyl cellulose by using a gastric gavage.

Diuretic and other effects

A 50% ethanolic extract (15) 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. nettle (16)--and furosemide-treated rats at a dose of 4 and 24 mg/kg/h (nettle) and 2 mg/kg/h (furosemide), respectively. 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 of aqueous extract (11) 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 findings of Caceres et al. (1987) who calculated cumulative urine production after a 10% nettle decoction (17) in rats at a dose of 1 g/kg by a nasogastric catheter. Urine production increase was one quarter of that of hydrochlorothiazide. Oral administration of an unspecified ethanolic extract had also no effect on diuretic activity, while urine output increased significantly 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 uninfluenced (Tita et al., 1993) indicating that the ingested electrolytes of the nettle preparation may have caused this effect. 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 (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 concentrations (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 definitive conclusion can be drawn. Likewise, more data are needed to confirm the other observed in vivo effects.

Clinical studies

There are only few clinical studies available, investigating the effect of nettle juice for increased diuresis in cardiac insufficiency or chronic venous insufficiency, 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 of effectiveness in the domains investigated, which needs, however, to be proven in confirmatory studies. Thus, there is currently no evidence beyond reasonable doubt that nettle preparations in the doses employed are effective for specific complaints. Unpublished open documentations did not leave doubt, that nettle tea and juice are ineffective for the treatment of osteoarthritic 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-Goossens, 1994; Morgan and Khan, 2003; Caliskaner et al., 2004). Besides an immediate response, delayed hypersensitivity to nettle plant was observed (Edwards and Edwards, 1992). Dose-finding studies are urgently needed as well as confirmatory 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 fluid extract had a paralysing effect and caused asystolia to isolated frog hearts (Starkenstein and Wasserstrom, 1933). Keeser (1940) and Ludwig (1945) confirmed 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 [LD.sub.50] of aqueous extract in mice was found to be 3625mg/kg. Doses >750mg/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 unspecified ethanol extract up to 2 g/kg (Tita et al., 1993). Intravenous doses >500mg/kg caused transient hypotension and cardiac arrhythmias. Following intravenous injection in mice, the [LD.sub.50] was 1.9 g/kg for a nettle infusion of 100mg/ml 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 4h (Bathe, 1994).

Nettle flavonoids 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 (Ilarinova et al., 1992).

Conclusion

The presence of a relatively high concentration of flavonoids and caffeic acid derivatives enriched in the lipophilic fraction of the Urtica herb, suggest mainly anti-inflammatory, antioxidant and analgesic activities as assessed in a series of pharmacaological in vitro and animal studies, some of them also against the synthetic Diclofenac[R]. The results of the clinical studies, however, are not yet convincing and need further confirmation by placebo controlled double blind studies with standardized extracts.

Furthermore, it must be emphasized that the results of pharmacological and clinical studies were carried out with extracts produced with different solvents (ethylalcohol 50%, propanol or water) under different conditions. 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.

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Julia E. Chrubasik (a), Basil D. Roufogalis (b), Hildebert Wagner (c), Sigrun A. Chrubasik (a,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

*Corresponding author. Institut fur Rechtsmedizin, Universitat Freiburg, 79104 Freiburg, Germany. Tel.: +49 761 203 6853; fax: +49 761 203 6851.

E-mail address: sigrun.chrubasik@klinikum.uni-freiburg.de (S.A. Chrubasik).

(1) Plant material was collected around Uppsala (Sweden), rinsed in cold water and immediately dried in an oven at 40 [degrees]C 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 [degrees]C until its use.

(2) See Table 3.

(3) See Table 3.

(4) Ten grams aerial parts before flowering in 100 ml of boiled distilled water for 30min.

(5) Aqueous extract: 20 g of dried aerial part before the flowering period was infused into 300 ml boiled distilled water, the filtrate 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 June-September 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, 1131-1132).

(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 filtrate was frozen and lyophilized, 20 mg was dissolved in 20 ml water. Doses 50-250 [micro]g were used in the tests.

(8) Three grams of plant material was added to 200 ml of deionized water (initial temperature 98 [degrees]C). Infusion time was 30min.

(9) Ten grams 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 [degrees]C. Freeze-drying and solvent elimination under reduced pressure finally 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 reflux for 30min, the extract filtered, the volume concentrated under vacuum and finally freeze dried.

(11) Dried flowering aerial parts were mixed with 500 ml water and boiled for 10 min, filtered, evaporated and lyophilized.

(12) Plants were collected from Samsun (Turkey) in July-August 2001 during the early hours of the day. They were shade dried, sliced, purified with a mixture of ethanol and water (80:20) using a soxhlett apparatus and then lyophilized.

(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 [degrees]C 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 x 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 [degrees]C. 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 filtrate was evaporated and dissolved in 0.9% NaCl. Before using this fraction the lead needs to be removed with [H.sub.2]S.

(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 filtration, the filtrate was again dried at 50[degrees]C and different concentrations were prepared.

(17) Ten grams of dried plant material were boiled in 100 ml of water for 5 min, following by filtration using Whatman No. 2 paper.
Table 1. Main constituents identified 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: 1-5%)

Table 2a and b. Other in vitro (a) and in vivo (b) effects of nettle
herb preparations or constituents [section] quercetin-3-0-rutinoside,
kaempherol-3-0-rutinoside and isorhamnetin-3-0-glucoside

 Nettle preparations

(a) In vitro effects
Immunomodulatory and 10 g were boiled with water (1 h), filtrated,
 chemopreventive evaporated to 2.4 g aqueous extract
 5 g powdered plant material was stirred for 2 h
 at room temperature with 100 ml 95% ethanol.
 The mixture was centrifuged for 10 min and the
 supernatant decanted and filtered. The residue
 was washed twice with a small volume 95%
 ethanol and filtered. Filtered extract and
 washings were combined and evaporated to
 dryness
 Isolated compounds [section]
 5 g in 100 ml ethyl alcohol (5% v/v) for 1 week
 at room temperature, then homogenized,
 centrifuged at 5000 rpm for 10 min. The upper
 layer was used
Central depressive Water-soluble fraction
On smooth muscle Aqueous extract (50 mg corresponding to 0.165 g
 stripes plant material); 0.5-1 ml ethanolic extract
 (see footnote 15 in text) equivalent to 0.41 g
 crude drug
 Ethanolic extract (see footnote 15 in text)
 Ethanolic extract (see footnote 15 in text)
On Langendorff rat 1 and 2 g/l of aqueous extract (10 g per 100
 heart ml)
On intact/denuded aorta 0.1-0.5 g/l and 1 and 2 g/l of aqueous extract
 (10g per 100 ml)
Endocrine Aqueous extract (10 g per 200 ml. evaporated to
 l/5th)
 Aqueous extract (1 g per 40 ml. evaporated to 1
 ml)
 1 g per 10 ml was boiled, filtered, centrifuged
 at 10,000 g and supernatants used
 10 g infused in 100 ml for 20 min and
 evaporated
Antimicrobial Aqueous extract (5 g per 50 ml or 20 g per 400
 ml), ethanolic extract (50 g per 250 ml 80%
 ethanol) or diethyl ether extract (200 g per
 500 ml) or isolated patuletin (Urtica urens)
 Aqueous extract (0.5 g powder in 100 ml,
 further diluted: 0.1 g or 0.05 g in 100 ml)

(b) In vivo effects
Central depressive Aqueous nettle infusion according to the
 Spanish Pharmacopeia (DER 3:1) i.p. or unknown
 amount mixed with 500 ml water, boiled for 10
 min (see footnote 11 in text), application mode
 not stated
Cardiovascular 25 mg/kg of aqueous extract (see footnote 11 in
 text) i.v.
 26.6 mg/kg of hot water extract (30.209%) i.v.
 Ethanolic extract, details not stated, per os
 or i.p.
 Ethanolic extract (see footnote 15 in text) (1
 ml equivalent to 0.083) i.v.
Endocrine Details not stated
 Aqueous extract (l0 g per 200 ml. evaporated to
 1/5th. TLC separation) i.p.
 500 mg/kg aqueous extract (10 g per 100 ml).
 evaporated, yield 21% orally
 Aqueous 0.5% infusion (0.5 g per 100 ml)
 orally; 132 g boiled in 11 for 10 min, 4 ml/kg
 orally; 1 g per 400 ml water, boiled for 5 min.
 infused for 15 min before given in place of
 drinking water;
 15 g powder per 300 ml water or ethanol 80%,
 oral doses corresponded to 25 g crude plant
 material/kg
 Ethanolic extract (see footnote 15 in text)
Gastrointestinal A fraction from 50 g per 350 ml sulfuric acid,
 boiled for 10 h for s.c. injection
 10 mg/kg of aqueous extract (20 g per 400 ml),
 filtrate lyphilized
 10 mg/kg isolated patuletin (Urtica urens) per
 os
Liver-protecting 50 g per 1000 ml boiled for 10 min, filtered
 and given with drinking water. Fixed oils were
 extracted with diethyl ether, 2 ml/kg were
 given i.p.
Antilipidaemic l0 g by maceration in 1000 ml preboiled hot
 water for 20 min, filtration; 100 g per 1000 ml
 petroleum ether for 48 h, filtration,
 evaporation, residue dissolved in 400 ml
 absolute ethanol, solution sprayed on food
 100 mg/kg aqueous extract (see footnote 14 in
 text), 100 mg/kg of ethanolic extract (see
 footnote 14 in text)
Antianaemic Food supplemented with squeezed juice

 Test Results References

(a) In vitro effects
Immunomodulatory and Selective stimulation of T Harput et al.
 chemopreventive lymphocyte proliferation (2005)
 by 50-800 [micro]g/ml
 About 600 [micro]g/ml Kapadia et al.
 inhibited Epstein-Barr (2002)
 virus early antigen
 promotion by phorbol ester
 Chemoattractants for Akbay et al. (2003)
 neutrophils
 Dose-dependent inhibition Durak et al. (2004)
 of adenosine deaminase
 activity in prostate
 tissue
Central depressive Inhibition of type A light Gul et al. (2004)
 chain protease activity of
 botulinum toxin
On smooth muscle Inhibition of Broncano et al.
 stripes contractility (1987a) and Keeser
 (1940)
 Stimulation of Starkenstein and
 contractility Wasserstrom (1933)
 No effect on leech muscle Keeser (1940)
On Langendorff rat Positive inotropic, Legssyer et al.
 heart negative chronotropic (2002)
On intact/denuded aorta Vasoconstriction
Endocrine 1 ml increased insulin Farzami et al.
 secretion (2003)
 No impact on glucose Gallagher et al.
 movement through dialysis (2003)
 tube
 Inhibition of [alpha]- Onal et al. (2005)
 glucosidase
 250 mg/kg reduced glucose Bnouham et al.
 absorption in perfused (2003)
 jejunum segments
Antimicrobial Growth inhibition of Brantner and Grein
 against various Gram- (1994)
 positive and negative Keles et al. (2001)
 bacteria, Candida Gulcin et al.
 albicans, no activity vs (2004)
 Pseudomonas aeruginosa, Dostbil et al.
 Klebsiella pneumoniae (2005)
 Saeed et al. (1995)
 Against Paramecium Oswiecimska et al.
 primaurelia and Lepidium (1980)
 sativum

(b) In vivo effects
Central depressive Decrease of spontaneous Broncano et al.
 motility and body (1987b) and
 temperature at doses of Lasheras et al.
 1.74 and 3.75 g/kg or 750 (1986)
 mg/kg extract
Cardiovascular Hypotensive effect in rats Lasheras et al.
 (1986)
 Hypotensive effect in cats Broncano et al.
 (1983)
 Hypotensive effect in rats Tita et al. (1993)
 and rabbits
 Hypotensive effect in Keeser (1940) and
 rabbits Ludwig (1945)
Endocrine Arteficial decrease of Haznagy (1943)
 blood glucose
 Increase in serum insulin Farzami et al.
 in (diabetic) rats (2003)
 Decrease of blood glucose, Bnouham et al.
 no effect in alloxan- (2003)
 induced diabetic rats
 No blood glucose lowering Gunes et al.
 effect, aggravation of (1999), Ramos et
 diabetic condition al. (1992) and
 Swanston-Flatt et
 al. (1989)
 Both extracts resulted in Neef et al. (1995)
 glucose increase
 No effect on blood glucose Keeser (1940) and
 Ludwig (1945)
Gastrointestinal Increase in Dobreff (1924)
 gastrointestinal fluid
 10 mg/kg i.p. were Gulcin et al.
 gastroprotective (2004)
 Did not damage gastric Saeed et al. (1995)
 mucosa
Liver-protecting Hepatoprotective against Turkdogan et al.
 C[Cl.sub.4] (2003) and Kanter
 et al. (2003)
Antilipidaemic 150 mg/kg/day aqueous Daher et al. (2006)
 extract, to a lesser
 extent 20 mg/kg/day
 resulted in improvement of
 the blood lipid profile
 Aqueous extract no effect, Avci et al. (2006)
 ethanolic extract weak
 effect
Antianaemic Restitution of induced Cremer (1934)
 anaemia

Table 3. Studies of nettle herb preparations for different indications
in chronological order

 Medication (MED)
 prepared for the
 Study or Brand of Dose per
Study References Nettle Product day Sort Solvent

Peripheral oedema
 1 Kirchhoff MED 45 ml Juice
 (1983)

Osteoarthrins (OA) or rheumatoid arthritis (RA) or other rheumatic
diseases (O)
 2 Hansen Rheuma Hek (2) 1340 mg Dried 50% ethanol
 (1996) extract
 3 Chrubasik MED 50 g (a) Stew
 et al.
 (1997)
 4 Ramm and Rheuma Hek (2) 1340 mg Dried 50% ethanol
 Hansen extract
 (1997)
 5 Wolf Rheuma Hek (2) 1340 mg Dried 50% ethanol
 (1998) extract
 6 Randall Crude leaf 1 leaf
 (1999)
 7 Randall Crude leaf 1 leaf
 (2000)
 8 Wolf Hox alpha (3) 145 mg Dried 95% propanol
 (2001) extract
 9 Hubbe Hox alpha (3) 145 mg Dried 95% propanol
 (2002) extract

Allergic Rhinitis
10 Mittman MED 600 Powder
 (1990)

 Mean Number of
 (raw) patients Nettle Improvement
 drug to (N) Control [c] Main outcome suggested
Study extract Disease Placebo (P) measure with nettle

Peripheral oedema
 1 Oedema 32 N Urine volume Urine volume
 etc. increase

Osteoarthrins (OA) or rheumatoid arthritis (RA) or other rheumatic
diseases (O)
 2 8-10:1 OA, RA, 219 N Pain VRS 0-4 Improvement
 O etc. over time
 3 OA 20 N, 20 C Pain VRS 0-4, Improvement
 CRP, etc. over time
 4 8-10:1 OA, RA 8955 N Pain VRS 0-4 Improvement
 etc. over time
 5 8-10:1 OA 819 N Pain VRS 0-4 Improvement
 etc. over time
 6 OA 18 N Pain VRS 0-4 Improvement
 etc. over time
 7 OA 13 N, 14 P Pain VRS 0-4 N superior to
 cross over etc. placebo
 8 19-33:1 OA 20 N Pain VRS 0-4, Improvement
 cytokines, etc. over time
 9 19-33:1 OA 763 N Pain VRS 0-4, Improvement
 etc. over time

Allergic Rhinitis
10 Hay 31 N, 38 P Symptom N superior to
 fever scores (-1,0-2) 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.

Table 4. Internal and external validity items in chronologically listed
studies on nettle herb products (according to Chrubasik et al., 2003)

 Internal validity
 Appropriate
 tests of
 null &
 Attrition-number alternative
 of dropouts hypotheses
 Randomisation Blinding and and intention- in pre-
Study and/or masking of to-treat and/or specified
number from allowance for outcome sensitivity POM and/or
Table 1 confounding assessment analyses MV testing

 Null Alt

 1 n n n 0 n n n n
 2 n n n nr n n n n
 3 n n n 4 n n n n
 4 n n n nr n n n n
 5 n n n nr n n n n
 6 n n n 0 n n n n
 7 y n y 1 n n n n
 8 n n n 3 y n n n
 9 n n n 93 n n n n
10 y n y 29 n n n

 External validity
 Inclusion and
 exclusion criteria Treatment
 and/or baseline type &
Study description of availability Setting
number from patients and of additional (number of
Table 1 their complaints treatments centres)

 1 y y n 1
 2 y y y 71
 3 y y y 1
 4 y y y nr
 5 y y y nr
 6 y y nr nr
 7 y y y nr
 8 y y y 2
 9 y y y nr
10 y y n 1

 Duration
 Validated of study External validity
Study outcome w -- weeks Documentation
number from measures m -- months of adverse
Table 1 included ys -- years events

 1 n 2 w Not in detail
 2 y 3 w nr
 3 y 2 w y
 4 y 3 w y
 5 y 12 m y
 6 n Up to 2 ys y
 7 y 1 w y
 8 y 12 w y (none)
 9 y 6 m y
10 n 1 w y

nr, not reported; POM, principal outcome measure; n, no; y, yes; MV,
multivariate
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Author:Chrubasik, Julia E.; Roufogalis, Basil D.; Wagner, Hildebert; Chrubasik, Sigrun A.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:Jun 1, 2007
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