Ononis – Restharrow root (Ononidis radix)

Latin name of the genus: Ononis
Latin name of herbal substance: Ononidis radix
Botanical name of plant: Ononis spinosa l.
English common name of herbal substance: Restharrow root

Latin name of the genus: Ononis
Latin name of herbal substance: Ononidis radix
Botanical name of plant: Ononis spinosa L.
English common name of herbal substance: Restharrow root

Ononis - Restharrow root - Ononis spinosa L.

Table of Contents

1. Introduction

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

Herbal substance(s)

In the Ph. Eur. monograph 7.0 ref. 01/2008:1879, Restharrow root (Ononidis radix) is defined as the whole or cut, dried root of Ononis spinosa (L.).

Restharrow root is more or less flattened, twisted and bent with a greyish brown to dark brown outer surface and deep longitudinal grooves. Characteristic of the transversely cut surface is the conspicuously radiate structure of the xylem due to the unequal width of the medullary rays. The fracture of the root is short and fibrous. It has bitter taste resembling that of liquorice and is regarded as an aperitif, diuretic, anti-inflammatory and astringent [Thurzová et al. 1973; Wichtl 2004; European Pharmacopoeia monograph 7.0; Gruenwald et al. 2004].

In some older literature two species – Ononis spinosa L. and Ononis arvensis L. have been mentioned as source plants for Ononidis radix. According to information from Member States only products containing Ononis spinosa L., radix are available on the European market. In many other well-known European handbooks and Pharmacopoeias only Ononis spinosa L. is mentioned as source for Ononidis radix. Ononis arvensis L. can be mainly found in the literature from the former USSR, for instance in the Pharmacopoeia [USSR Pharmacopoeia 1990]. Taking into account the above mentioned considerations and also the definition of European Pharmacopoeia, this assessment report and the following monograph reflects information regarding Ononis spinosa L, radix only.

Ononidis radix is known under the following common name: Restharrow root.

Other names: Spiny restharrow root; German: Hauhechelwurzel, Haudornwurzel, Ochsenbrechwurzel; Dutch: Kattedoorn, Stalkruid; Czech: Kořen jehlice trnité; French: Racine de bugrane; Arrête-boeuf; Italian: Ononide radice, Latvian: blaktenes saknes; Polish: Korzeń wilżyny; Raiz de gatuña, busktörnerot, Krageklo, Jooksjarohi, Dirvenių šaknys, Gatunha, Koreň ihlice, Гръмотрън, корен.

Description and origin of the plant:

Leguminosae is the second largest family of flowering plants containing 600 genus and about 12 000 species. It is divided into three subfamilies – the Papilionidceae (377 genera), the Mimosoideae

(40 genera) and Caesalpinoideae (133 genus). The Ononis genus belongs to the Papilionaceae subfamily including 75 species [Evans 2002; Kloda et al. 2008]. Ononis spinosa (L.) is native throughout in Europe, western Asia and northern Africa, and widely distributed mainly in semi-arid grasslands, alternately dry meadows and pastures [Wichtl 2004; Wyk and Wink 2005; Kloda et al. 2008]. In the literature can be found several subspecies and one nothosubspecies of Ononis spinosa L. [Hocking 1997; Wichtl 2004; The database of the International Plant Names Index; Flora Europaea]. The word Ononis essentially derives from the Greek word ‘onos’ which means donkey that in their diet consumed by this plant [Brem 2010]. The material of commerce is reported to originate usually from wild collection in Southeast Europe [Wichtl 2004].

Ononis spinosa L. (Spiny restharrow) is a perennial, spiny subshrub up to 80 cm tall. The branches of the plant are spreading, villous, and densely covered short shoots, which terminate in straight thorns. The lower leaves are ternate while the upper ones are single and papilionaceous, pinkish white flowers generally flowered from June-July, followed by the small seed pods. Spiny restharrow has an unpleasant smell [Wichtl 2004].

Constituents:

The following chemical constituents were identified in Restharrow root:

Isoflavones: formononetin (aglycone), ononin (formononetin 7-O-glucoside), pseudobaptigenin glucoside, genistein (1.7 – 3.8 mg/100g herbal substance), biochanin A 7-O-glucoside, biochanin A 7- O-glucoside 6”-malonate (biochanin A 0.08 – 0.70 mg/100g), formononetin 7-O-glucoside 6”-malonate (3.2 – 5.9 mg/100g), 2.3-dihydro-ononin and also tectoridin, trifolirhizin, rothinidin [Háznagy et al.1978; Pietta and Calatroni 1983; Köster et al. 1983; Blaschek et al. 1998; Klejdus et al. 2007; Benedec et al. 2012].

Glucosides: Spinonin, a glucoside with unusual structure has been detected, as well as medicarpin, a pterocarpan derivative [Kirmizigül et al. 1997; Wichtl 2004].

Triterpenes include particularly α-onocerin (4.1 mg/1g herbal substance), also known as onocol [Barton and Overton 1955; Fujise et al. 1965; Rowan et al. 1971; Blaschek et al. 1998; Pauli 2000].

Sterols: mainly β-sitosterol, stigmasterol, campesterol, cholesterol, α-spinasterol [Blaschek et al. 1998].

Saponins: triterpenoid saponin (e.g. 3-O-[α-L-rhamnopyranosyl-(12)-β -D-xylopyranosyl-(12)- β – D-glucuronopyranosyl]-3β ,22α-dihydroxyolean-13-en-11). [Shaker et al. 2004].

Phenolic acids: p-hydroxybenzoic, vanillic acid, caffeic acid, syringic acid, p-coumaric acid, cinnamic acid, sinapin acid, salicylic acid, gentisin acid etc. can be detected in the Ononis spinosa L., radix [Luczak et al. 1990; Blaschek et al. 1998; Klejdus et al. 2008].

Lectins: Index Nomenclature LECp.Ono.Spi.ro.Hga1 [Horejsi and Kocourek 1978; Uhlenbruck et al. 1978].

Small amounts of essential oil (0.02- 0.2%) are found, containing trans-anethole as the major constituent, with carvone, menthol, menthone, isomenthone, linalool, estragole, borneol and cis– anethole [Jaretzky 1940; Hilp et al. 1974; Wren et al. 1988; Gruenwald et al. 2004, 2007; ESCOP Monographs 2003].

Other constituents are: tannins, sucrose, lipids, citric acid.

Herbal preparation(s)

According to information from the Member States and literature Restharrow root is used as a comminuted herbal substance for single herbal tea preparation and also as a component of combination herbal tea products. The tea infusion is prepared by pouring boiling water over 2-3 g of the coarsely powdered dried root, steeped for 20-30 min and strained.

The ESCOP Monograph (2003), Herbal drugs and phytopharmaceuticals by Wichtl (2004), and The complete German Commission E monograph (Blumenthal et al. 1998) report that extracts (not specified) of Restharrow root are components of phytomedicines in tablet and coated tablets form.

Following extracts are included in combination products authorised or registered in EU Member States:

dry extract from Ononidis radix (DER 6-9:1), extraction solvent: ethanol 20% (m/m);

dry extract from Ononidis radix (DER 5-8:1), extraction solvent: water;

liquid extract from Ononidis radix (DER 1:1, extraction solvent: ethanol about 23%).

Extracts are included in combination products only and no data are available from the market or literature regarding the use of extracts in mono-products. This assessment report and the community

herbal monograph cover monocomponent products only, which is in this cases the comminuted herbal substance for tea preparation only.

Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.

Restharrow root is often used in combinations with many other diuretic herbal substances/herbal preparations (Betulae folium, Ilex paraguariensis folium/mate, Orthosiphonis folium, Solidaginis herba, Urticae herba, Uvae ursi folium etc.) as bladder and kidney teas [Muszyński 1954; Weiss 1988, 1999; Schulz et al. 2004].

1.2. Information about products on the market in the Member States

In European Member States, the herbal substance (Ononis spinosa L., radix) is available in Poland as single herbal substance products (2 products as herbal teas) and in Germany as authorised single herbal substance products (German Standard Marketing Authorisations; single active ingredient in 66 herbal teas).

Restharrow root (Ononis spinosa L.) is also included in combinations products with many other herbal substances/herbal preparations (for instance: Betulae folium, Phaseoli fructus, Fumaria officinalis L., flos, Herniarieae herba, Ilex paraguariensis folium/mate, Menthae piperitae herba, Millefolii herba, Orthosiphonis folium, Petroselini radix, Polygonii avicularis herba, Sambuci nigrae flos, Solidaginis herba, Urticae herba, Uvae ursi folium etc) and available on the Austrian, Belgian, Czech, German and Italian market.

Single preparations:

Children: 25 g 1-2 times daily corresponding to 0.0066 g of Ononis extract

Indication: As an adjuvant in spasmodic and painful complaints of the biliary and urinary ways Legal status: Authorised herbal medicinal product

Since when is on the market: since 1951 (1) and 1961 (2) Other information on relevant combination products:

The presence of Ononis spinosa liquid extract in the combination is justified by the following pharmacological action: relevant diuretic activity with increase of urinary elimination of chloride and urea nitrogen.

Regulatory status overview

MA: Marketing Authorisation TRAD: Traditional Use Registration

Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’

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

1.3. Search and assessment methodology

Databases assessed (date, search terms) and other sources used to research available pharmaceutical, non-clinical and clinical data on Ononis arvensis L., Ononis spinosa L., Ononidis radix

or its relevant constituents:

Search terms: Ononis arvensis L., Ononis spinosa L., Ononidis radix, combination

Articles and references retrieved from data bases: Pubmed, Medline, Scopus, SciFinder, Science direct, Web of Science etc.

Handbooks, textbooks and Pharmacopoeias

Libraries: EMA library, University of Latvia, Rigas Stradinu University, The State Agency of Medicines of Latvia, Central library in Riga.

2.Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

Ononis spinosa L., radix (Restharrow root) has been widely used since ancient times and it is mentioned in many old documents such as Dioskurides (increases diuresis and breaks stones), Plinius (the root expels bladder-stones), Matthiolus (stimulates diuresis, powerfully breaks the stones), Lonicerus (expels the stone and urine) or Schroder (stimulates diuresis and against kidney- and bladder-stones) [Benedum et al. 2006]. It has been traditionally used for the treatment of the lower urinary tract disorders in the irrigation therapy as a diuretic medicine for inflammatory conditions of the lower urinary tract and for preventing and treating kidney and bladder disorders, gravel and small stones [Pharmacopoea Germanica 1884; Deutsches Arzneibuch 1947; Deutsches Arzneibuch. Kommentar 1928; Jaretzky 1940; Československý lékopis (Pharmacopoeia Bohemoslovenica) 1954, 1970, 1987; Österreichisches Arzneibuch 1960; Farmakopea Polska 1970; Wren et al. 1988; European Pharmacopoeia 7.0 2010; ESCOP Monographs 2003; Blumenthal et al. 1998) etc]. Restharrow root appears in several well-known handbooks such as Hoppe 1942; Bergen 1960; Thurzová et al.1973; Borkowski 1974; Schilcher 1997; Hocking 1997; Blaschek et al. 1998; Bartram 1998; Weiss 1988, 1999; Evans 2002; A Guide to Traditional Herbal Medicines 2003; Wichtl 1997, 2004; Gruenwald et al. 2004, 2007; Wyk and Wink 2005; Gehrmann et al. 2005; Benedum et al. 2006; Fintelmann and Weiss 2006; Quer 2008; Braun 2011 etc.

In folk medicine, Restharrow root is also used for gout and rheumatic complaints and skin disorders [Wichtl 2004]. Ononis species have been used for centuries as folk remedies in Turkey as diuretic, antiseptic and antimicrobial aids. In Turkey Ononis spinosa L. is known as kayişkiran and found in Central Anatolia. Ononis spinosa L. has been reported to have diuretic, antibacterial, analgesic, anti- inflammatory, antiviral, cytotoxic, and antifungal effects.

In the USA, Restharrow root is a dietary supplement and in Canada it is an approved active ingredient in a few OTC Traditional Herbal Medicines and homeopathic medicines [Wichtl 2004].

Restharrow root has been traditionally used in Poland with evidence in the liturature going back at least to the middle of the last century [Muszyński 1954; Roeske 1955; Deryng 1961; Farmakopea Polska 1970; Borkowski 1974; Ożarowski 1976; Ożarowski 1978]. Currently two medicinal products as single ingredient herbal teas are available for more than 20 years on the Polish market.

Restharrow root is offered as a single herb tea (German Standard License) and as a component of ‘bladder and kidneys’ tea formulas, extracts of Restharrow root are components of phytomedicines in tablet and dragée form [Wichtl 2004].

In the Czech Republic, Restharrow root is available on the market in multicomponent herbal teas since 1969. Extracts of Restharrow roots in combination products are present on the market more than

30 years (e.g. since 1951 in Italy).

Overall conclusion on the traditional medicinal use

Preparations from Restharrow root have been traditionally used as an infusion for diuresis stimulation. Literature data supporting the medicinal use of Restharrow root in Europe goes back at least as far as to the beginning of the 20th century. Therefore, for the above mentioned, it can be stated that the Restharrow root evidence a period of at least 30 years in medical use as requested by Directive 2004/24/EC for qualification as a traditional herbal medicinal product is fulfilled.

2.2. Information on traditional/current indications and specified substances/preparations

The following indications have been reported in the literature for Restharrow root (Ononis spinosa L.)

Lehrbuch der Pharmakognosie fur Hochschulen (Karsten 1949)

Uses and properties: diuretic

Zarys Fitoterapii. Farmakologia i receptura ziół leczniczych. Radix Ononidis – Korzeń wilźyny [Roeske 1955]

Uses and properties: diuretic

Österreichisches Arzneibuch [1960] Uses and properties: diuretic

Handbuch Der Drogenkunde [Bergen 1960]

Usage: diuretic

Farmakopea Polska IV [1970]

Uses and properties: diuretic

The Complete German Commission E Monographs [Blumenthal et al. 1998]

Indications: Irrigation therapy for inflammatory diseases of the lower urinary tract and for the prevention and treatment of kidney gravel.

Hagers Handbuch [Drogen L-Z, Blaschek et al. 1998]

Indications: Irrigation therapy for inflammatory diseases of the lower urinary tract and for the prevention and treatment of kidney gravel.

ESCOP Monographs [2003]

Indications: Irrigation of the urinary tract, especially in cases of inflammation and renal gravel, and as an adjuvant in treatment of bacterial infections of the urinary tract.

Herbal Drugs and Phytopharmaceuticals [Wichtl, 2004]

Indications: as a mild diuretic

PDR For Herbal Medicines [Gruenwald et al. 2004; 2007]

Infections of the urinary tract

Kidney and bladder stones

Preparations of the drug are used for irrigation therapy for inflammatory diseases of the lower urinary tract and also for prevention and treatment of kidney gravel.

Medicinal Plants of the World [Wyk and Wink 2005]

Indications: Irrigation therapy as a diuretic medicine for inflammatory conditions of the lower urinary tract and for preventing and treating kidney gravel.

Medicinal Herbs: A Compendium [Gehrmann et al.2005]

Usage: Irrigation therapy for inflammatory diseases of the lower urinary tract; prophylaxis and treatment of renal gravel.

Standardzulassungen für Fertigarzneimittel [Braun 2011]

Indications: Herbal medicinal product used to increase the amount of urine to achieve flushing of the urinary tract; prophylaxis and treatment of renal gravel.

Plantas Medicinales [Quer 2008]

Uses and properties: diuretic

Literature data support the traditional use of Restharrow root as a traditional herbal medicinal product for traditional use and the specified indication exclusively based upon long-standing use.

The current indications are:

Poland

Traditionally used as a diuretic medicine (2 products as single ingredient herbal tea) for treatment of symptoms of mild lower urinary tract inflammatory conditions and as an aid in preventing of kidney gravel.

Germany

Traditionally used to support the elimination function of the kidney.

Based on the available literature data the following text on the indication in the Monograph is recommended:

Traditional herbal medicinal product used to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary tract complaints. The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon long-standing use.

For more detailed information see section: Information about products on the market in the Member States.

2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications

The following posologies have been reported in the literature for Restharrow root (Ononis spinosa L.):

Österreichisches Arzneibuch [1960]

Dosage: The recommended dose is 1.5 g for one tea cup. Route of administration: oral administration

Farmakopea Polska [1970]

Dosage: The recommended dose is 1-2.5 g for one tea cup.

Route of administration: oral administration

The Complete German Commission E Monographs [Blumenthal et al. 1998]

Dosage: The daily dose is 6-12 g of the comminuted herb or equivalent preparations.

Route of administration: oral administration, comminuted herb for teas or other galenic preparations for internal use

Duration of use: no information

Contraindication: no irrigation therapy in case of oedema due to impaired heart and kidney function Interaction with other drugs: none known.

Hager’s Handbuch [Drogen L-Z, Blaschek et al. 1998]

Dosage: The recommended dose is 3-4 g two to three times per day between meals.

Route of administration: oral administration, comminuted herb for teas. Boiling water (150 ml) is poured over the material and the mixture strained after 30 min.

ESCOP Monographs [2003]

Dosage: For adults the recommended dose is an infusion of 2-3 g of dried material two to three times per day; or the equivalent for preparations

Route of administration: oral administration

For infusion, boiling water is poured over the material and the mixture strained after 20-30 min. Duration of use: no restriction

Contraindication: none known

Interaction with other drugs: None reported.

PDR For Herbal Medicines [Gruenwald et al. 2004; 2007]

Dosage: 2-2.5 g finely cut or coarsely powdered drug, strain 20-30 min, daily dosage: 6-12 g of the drug

Route of administration: Teas and other galenic preparations for internal use. Ample liquid intake (at least 2 litres per day) should accompany the use of the drug.

Contraindication: Should not be used in the presence of oedema resulting from reduced cardiac or renal activity.

Duration of use: No information

Precautions and adverse events: No health hazards or side effects are known in conjunction with the proper administration of designated therapeutic dosages.

Herbal Drugs and Phytopharmaceuticals [Wichtl, 2004]

Dosage: Pour boiling water over 2-2.5 g of finely cut or coarsely powdered dried root. Steep for 20-30 min and then strain. 1 teaspoon = about 3 g

Route of administration: Oral administration.

Medicinal Plants of the World [Wyk and Wink 2005]

Dosage: to prepare a tea, boiling water poured over 2-2.5 g of the coarsely powdered root and taken

several times a day. The recommended daily dose is 6-12 g of the herb. Route of administration: Oral administration.

Medicinal Herbs: A Compendium [Gehrmann et al.2005]

Dosage: 2-2.5 g (1 scant teaspoon) in 150 ml boiling water, steeped for 20-30 min, 1 cup 3-4 times/day, daily dose: 6-12 g.

Route of administration: Oral administration. Ensure sufficient liquid intake, minimum 2 l/day. Duration of use: acute complaints > 1 week or recurring illness: consult medical practitioner. Contraindication: Not to be used in dehydration or oedema due to reduced heart and renal activity. Interaction with other drugs: Unknown.

Adverse events: Unknown.

Standardzulassungen für Fertigarzneimittel [Braun 2011]

Dosage: For adults and adolescents the recommended dose is 2 g (1 scant teaspoon) of dried material 3 to 6 times per day.

Route of administration: Oral administration. For infusion, boiling 150 ml water is poured over the material and strained after 20-30 min.

Duration of use: 1 week. Contraindication: none known. Interaction with other drugs: Unknown. Adverse events: Unknown.

Posology in children and adolescents up to 14 years of age:

A posology for children and adolescents is provided in Kinderdosierungen von Phytopharmaka [Dorsch et al. 1998] for Restharrow root and is based on calculations.

Posology in adolescents from age of 12 years:

The usage of Restharrow root for adolescents is mentioned in Braun [2011].

1 teaspoon = approximately 2 g, 3-6 times daily.

The dosage recommendation for adolescents from the age of 12 years found in a handbook:

2 g (1 scant teaspoon) of dried material 3 to 6 times per day [Braun 2011] are similar to those for adults recommended in the monographs: 2-3 g of dried material two to three times per day [ESCOP Monographs 2003] and 6-12 g daily [Blumenthal et al. 1998]. According to the literature the maximum daily dosage for adolescents over 12 years of age, adults and elderly is 12 g.

The following posology for ‘traditional herbal medicines’ is recommended in the Community herbal monograph: 2-3 g of comminuted herbal substance in 150 ml of boiling water as a herbal infusion up to 3-4 times daily corresponding to the maximum daily dose of 12 g.

For children under 12 years the use of diuretic drugs in self medication is not appropriate. Therefore the use for children is not recommended. Oral administration of Ononidis radix can be regarded as safe at traditionally described and used doses in elderly, adults and adolescents.

Duration of use

Adolescents, adults and elderly

In generally Restharrow root infusions should be given on a short-term basis as the diuretic effect will decrease with continued use [Weiss 1988]. In Braun [2011] the following is mentioned: if urinary tract complaints worsen and symptoms such as fever or blood in the urine occur during the 7 days use of medicinal product, a doctor or a qualified health care practitioner should be consulted. In an other source the duration of application is suggested as follows: acute complaints > 1 week or with recurring illness [Gehrmann et al. 2005].

Based on the duration of use recommended in other monographs on herbal substances with similar effect and data for Ononis spinosa L., radix available in the literature [Gehrmann et al.2005; Braun 2011], the following duration of use is recommended in the Community Monograph:] if the symptoms persist longer than 1 week during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

Primary Pharmacodynamics

Aqueos extracts

Saponin is supposed to be the active ingredient responsible for the diuretic effect. In normal subjects the diuretic action of Restharrow root containing saponin is considerably increasing urinary output by more than 20% [Weiss 1988].

In vivo experimental studies on the diuretic effect of Ononidis radix were performed and described in a dissertation thesis of Wilhelm Bulow already in 1891 [Bulow 1891].

In the late 1930’s and early 1940’s the studies by Jaretzky and Vollmer had established the pharmacology of Ononis spinosa L., radix showing the diuretic effects in animal experiments [Vollmer und Hübner 1937; Jaretzky and Neuwald 1937; Jaretzky 1940; Vollmer 1939 ,Vollmer 1940]. Vollmer described that an aqueous extract of Restharrow root administered per os to rats (0.250 g, 0.5 g and 1 g/animal) induced the most pronounced diuretic effect at the dose of 1 g [Vollmer and Hübner 1937]. An infusion of Restharrow root that was administrated orally to rabbits showed an increase in urinary output by 26% [Vollmer 1937].

An aqueous extract prepared from roots of Ononis spinosa L. was administered intragastrically to male Wistar rats (250±50 g, n=4 per group) at the dose of 0.3 g/per animal in 20 ml of water. The controls were the same rats, that several days later have received distillate (5 ml) water or theophylline

(5 mg/kg in 5 ml). Every hour over a 5-hour period the samples of urine were collected from the rats following administration of aqueous infusion 21.4 ml, compared to 15.1 ml for distillate water and 17.9 ml for theophylline. The obtained results are summarised in Table 1.

Table 1: Effects of intragastrical administration of aqueous extract (0.3 g/animal), ash (0.3 g/animal) of the Restharrow root on excretion of urine volume expressed as ml and percentage in male Wistar rats. Distillate water and theophylline used for controls [Rebuelta et al. 1981].

The amounts of sodium in the urine collected over 5 hours were 23.55 mg for an aqueous extract compared to 6 and 16 mg of sodium with water and theophylline controls respectively. The amount of potassium was 62.20 mg compared to 43.87 and 60.95 mg of potassium with water and theophylline controls respectively. The amounts of sodium and potassium were determined by the atomic absorption spectrophotometry. The experiment was repeated several times (according to the paper 50 times) confirming the diuretic activity of the Restharrow root. The results demonstrated moderate diuretic and saluretic activity of the extract which was higher than that produced by theophylline (5 mg/kg). The conclusion was made that the diuretic activity of Restharrow root was caused by its content of potassium salts and flavonoid glycosides [Rebuelta et al. 1981]

Other extracts

Bolle et al. (1993) showed that an ethanolic extract (not further defined) at a dose corresponding to 2 g/kg per animal, administered p.o. significantly increased urinary volume by 103% (p<0.05) in mice

and rats during 2 h observation time compared to saline control whereas no influence was observed on sodium or potassium elimination. This diuretic activity was not confirmed by intraperitoneal injection of the drug at doses up to 500 mg/kg/animal [Bolle et al. 1993].

A moderate diuretic activity was shown following intragastrical administration of a dried methanolic extract equivalent to 0.3 g of root per animal, ash, a mixture of the methanolic extract and ash (see Table 2). The amount of urine was evaluated every hour over a 5-hour period in male Wistar rats [Rebuelta et al 1981].

Table 2: Effects of intragastrical administration of dried methanolic extract (0.3 g/animal), ash

(0.3 g/animal) and a mixture of methanolic extract and ash (0.3 g/animal) of the Restharrow root on excretion of urine volume expressed as ml and percentage in male Wistar rats [Rebuelta et al. 1981]

In the study the controls were the same male Wistar rats, that several days later were administered with water or theophylline (5 mg/kg). The controls data with water or theophylline see above at aqueous extract description [Rebuelta et al. 1981]. The amounts of sodium in urine were 20.31 mg for dried methanolic extract, 32.69 mg for ash and 20.97 mg for mixture of methanolic extract and ash determined by atomic absorption spectrophotometry and compared to 6 and 16 mg of sodium with water and theophylline controls respectively. The potassium levels were 95.50 mg for dried methanolic extract, 78.89 for ash and 65.87 mg for mixture of methanolic extract and ash, compared to 44 and 61 mg with water and theophylline [Rebuelta et al. 1981].

Essential oil

Hilp (1974, dissertation Marburg University) reported that the aqueous residue of an aqueous preparation after steam distillation expressed an antidiuretic effect (7-16%) that was depending on the duration of distillation, whereas 0.5-1.0 ml of the essential oil obtained by steam distillation (2-4 hours) produced a diuretic effect. The conclusion of this study was that the essential oil of Restharrow root exhibits diuretic activity [Hilp 1974, cited in Blaschek et al. 1998].

Vollmer and Jaretzky discussed the role of the essential oil for the diuretic action of Restharrow root [Vollmer 1939; Vollmer 1940; Jaretzky 1940].

Isolated compounds

A study performed by Melzig and Schmidt (2001) indicates that genistein, a component of Restharrow root has a diuretic action comparable to furosemide [Melzig MS, Schmidt UJ. Dtsch. Apoth. Ztg. 2001, 141, cited in Wichtl 2004].

Secondary Pharmacodynamics

Aqueous extracts

Joksić et al. (2003) assessed the cytogenetic effects of the aqueous extract from Ononidis radix on the micronuclei formation in vitro studies by using irradiated human blood lymphocytes obtained from healthy, non-smoking, young male donor. In the study the acquired micronucleus formation in unirradiated and irradiated samples of cultured blood lymphocytes was examined using the cytochalasin block micronucleus test (CBMN). Centromere-positive micronuclei (MNC+) were recognised by fluorescence in situ hybridisation using DNA probe labelled with α-satellite digogsigenin. Ononidis radix (0.2 mg/ml) potentiated the yield of radiation-induced micronuclei up to 1.7-fold [Joksić et al. 2003]

Extracts of Restharrow root have been shown to exert antifungal activity [Wolters 1966].

Other extracts

In vitro studies have shown that a methanolic Restharrow root extract (6:1) selectively inhibited 5- lipoxygenase with an IC50 of 7.8 g/ml and the isolated pterocarpan medicarpin inhibited leukotriene B4 formation with an IC50 of 6.7 M [Dannhardt et al. 1992].

The application of acetylcholinesterase inhibitors is currently the only approved therapy for Alzheimer’s disease. Petroleum ether, dichloromethane and methanol extracts of Restharrow root (from Ononis

spinosa L.) at the concentration of 100 g extract/ml using Ellman’s reagent in a microplate assay showed no significant inhibitory activity on acetylcholinesterase not even with the isolated α-onocerin [Rollinger at al. 2005].

No analgesic effects were obtained after oral or intraperitoneal (i.p.) administration of an ethanol Restharrow root extract (not further defined) in mice using the hot plate test. Restharrow root extract reduced the reaction to pain by up to 80% at doses of 100 and 500 mg/kg after i.p. injection, while no effect was observed after oral administration of the extract in mice followed by the phenylquinone writhing test. The same extract induced a significant (p<0.05) reduction of an oedema (46%) in the carrageenan-induced rat paw oedema test after 3 hours following i.p. injection of Restharrow root at the dose of 500 mg/kg in mice while no significant effects were obtained at the dose of 100 mg/kg [Bolle et al. 1993].

Dried and powdered roots of Ononis spinosa subsp. leiosperma was extracted with methanol and then evaporated in vacuo. The crude extract washed with hexane and acetone was applied on a Si gel column for isolation of spinonin. The applied paper-disk diffusion method was chosen to test activity of compounds against the Gram-positive bacteria B. subtilis ATTC 6633, S. aureus ATCC 6538P, S. epidermidis ATTC 12228, E. faecalis ATCC 29212, beta-hemolytic Streptococcus 48 and the Gram- negative bacteria P. mirabilis ATTC 9027 and K. pneumonia ATCC 4352, and the yeast C. albicans ATCC 10231. Isolated spinonin and pterocarpan produced weak (MIC 200 g/ml) activity against Pseudomonas aeruginosa. Ononin was more active (MIC = 25 g/ml) against β-hemolytic Streptococcus. Spinonin was tested against human cancer cell lines (BC1, Lu1, KB-V(+VLB)) and HIV-1 reverse transcriptase in which it was inactive [Kirmizigül et al. 1997].

Isolated compounds

Restharrow root contains the isoflavone genistein that is reported in the literature to produce a mild estrogenic effect [Gruenwald et al. 2004, 2007]. No studies on a particular extract of Restharrow root are available. Farmakalidis et al. (1985) have described the oestrogenic response to 1.5 mg genistin, equivalent to that of 1 mg genistein, giving a 1:1 molar relationship in oestrogenic activity between genistin and genistein in the mouse B6D2F1 strain [Farmakalidis et al. 1985].

Safety Pharmacology

No data available.

Pharmacodynamic interactions

No data available.

3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

There is no Restharrow root specific data on pharmacokinetics and interactions available.

3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof

Acute toxicity

No data available.

Repeated dose toxicity

An ethanolic extract at a daily dose of 2 g/kg per animal injected orally or intraperitoneally for 14 days in rats and mice did not produce any visible toxic effect [Bolle et al. 1993].

Genotoxicity

Aqueous extracts

In vitro cytogenetic effects of aqueous extracts of Ononidis radix were examined with cytochalasin block micronucleus test, an centromere-positive micronuclei were identified by fluorescence in situ hybridisation using a DNA probe labelled with α-satellite digogsigenin. The aqueous extracts (concentration ranging from 0.025 to 0.1 mg/ml) of Ononidis radix showed clastogenic properties inducing 5- to 6-fold increase in the incidence of micronuclei compared to the control. Concentration of 0.2 mg/ml decreased slightly the incidence of micronuclei and was followed by lesser proliferation of the cells (CBPI=1.81). The percentage of MNC+ micronuclei ranged from 18.8 to 23.8%. The name of species from the genus Ononis was not specified by the authors of this paper [Joksić et al. 2003]. Thus it is difficult to use these findings in the assessment of safety of Ononi spinosa.

Carcinogenicity, reproductive and developmental toxicity

No studies concerning carcinogenicity and reproductive toxicity have been reported for Restharrow root or Restharrow root preparations.

3.4. Overall conclusions on non-clinical data

Limited pharmacodynamic data on Restharrow root aqueous extracts and other extracts indicate diuretic, anti-inflammatory and antimicrobial effects. Restharrow root specific data on pharmacokinetics and interactions are not available.

The data on toxicology of Restharrow root and Restharrow root preparations are limited. The repeated dose toxicity study was performed with ethanol extracts but studies with aqueous preparations of the roots are lacking. No adverse toxic reactions have been reported in scientific literature.

Neither the chemical composition nor the long-term widespread use in the European Community suggests that there is a high risk associated with the use of Restharrow root preparations.

Tests on reproductive and developmental toxicity and carcinogenicity have not been reported in the scientific literature. Due to a lack of adequate genotoxicity testing a list entry cannot be recommended.

The published non-clinical data with respect to preparation diuretic activity is mostly limited to old scientific papers and mainly from the beginning of the 20th century. Diuretic effects of Ononis spinosa L., radix aqueous extracts are discussed in more detail for a more recent study from 1981. Available information on diuretic activity indicates the use of Restharrow root in the short-term treatment as a mild diuretic for the lower urinary tract disorders.

4. Clinical Data

4.1. Clinical Pharmacology

No relevant data are available.

4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

No relevant data are available on human pharmacodynamics.

4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

No relevant data are available on human pharmacokinetics.

4.2. Clinical Efficacy

No studies for clinical efficacy were found.

4.2.1. Dose response studies

No dose-response studies were performed to support the posology and daily dose proposed in the literature.

4.2.2. Clinical studies (case studies and clinical trials)

No relevant data are available.

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

No clinical studies in special populations are reported.

4.3. Overall conclusions on clinical pharmacology and efficacy

No relevant data are available on clinical research assessing the effects of Restharrow root. Therefore the well-established use cannot be supported.

Overall, the medicinal use of Restharrow root has to be regarded as traditional.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

There are no specific data available.

5.2. Patient exposure

There are no specific data on patient exposure to Restharrow root available.

5.3. Adverse events and serious adverse events and deaths

No side effects are known in conjunction with the proper administration and therapeutic dosages.

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

The safety of Restharrow root in humans is based on the traditional use. Without any further specification it is mentioned that Restharrow root should not be used in the presence of accumulation of water (oedema) due to impaired cardiac or renal function and dehydration [Blumenthal et al. 1998; Wichtl 2004; Gruenwald et al. 2004; Gehrmann B et al. 2005].

Sufficient liquid intake should be ensured, minimum 2 l/day [Medicinal Herbs. A Compendium 2005].

Intrinsic (including elderly and children)/extrinsic factors

No clinical studies in children or adolescents are available.

In the marketed preparations and in Braun (2011), the dosages are recommended for adolescents and adults only. The dosage for adolescents is the same as for adults and elderly.

No data for a posology in children from clinical trials are available. As the use of diuretic treatment in self-medication for the children under age of 12 years is not appropriate, the use of Restharrow root in children under age of 12 is not recommended.

Drug interactions

In phytotherapeutic books such as ESCOP Monographs (2003), Blumenthal et al. (1998), interactions with other drugs are not mentioned.

Use in pregnancy and lactation

Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use of the Restharrow root during pregnancy and lactation is not recommended.

Overdose

From literature, monographs and databases of the Member States, no case reports on overdose of Ononis spinosa preparations are available. Therefore it is stated in the monograph that no case of overdose has been reported.

Drug abuse

There are no reports on drug abuse of Ononis spinosa preparations.

Withdrawal and rebound

There are no reports on withdrawal of Ononis spinosa preparations.

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

No studies on the ability to drive and use machines have been performed. There are no reports on impairment of mental ability. No concerns arise regarding the ability to drive or operate machinery caused by the known ingredients of Ononis.

5.6. Overall conclusions on clinical safety

No data for a posology in children from clinical trials are available. As the use of diuretic treatment in self-medication for the children under age of 12 years is not appropriate, the use of Restharrow root in children under the age of 12 is not recommended.

If the symptoms persist longer than 1 week during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.

There are no data on reproductive and developmental toxicity, therefore the use during pregnancy cannot be recommended.

Available information from the Member States of the European Union shows no reports of side effects. The traditional use over a long period has shown that Restharrow root is not harmful used in the specified indications.

6. Overall conclusions

The medicinal application of the Restharrow root has been consistently described to be used for a long period of time in many European pharmacopeias, relevant handbooks and scientific papers. Restharrow

root (comminuted herbal substance as herbal tea) as included in the monograph fulfills the requirement of Directive 2004/24/EC for use in traditional herbal medicinal products (medicinal use for at least 30 years including at least 15 years within the European Union). The use in the treatment of minor urinary complaints is considered plausible on the bases of bibliography and pharmacological data available.

In the absence of clinical studies using relevant herbal preparations, the well-established use cannot be supported for the herbal substance or extracts.

No studies on carcinogenicity and reproductive and developmental toxicity have been reported in the scientific literature. Due to inadequate genotoxicity data a community list entry for Ononis spinosa L., radix cannot be recommended. Oral administration of Ononidis radix can be regarded as safe at traditionally described and used doses in adults and adolescents. No data for a posology in children from clinical trials are available. As the use of diuretic treatment in self-medication for the children under age of 12 years is not appropriate, the use of Restharrow root in children under age of 12 is not recommended.

Due to lack of data Restharrow root cannot be recommended in pregnancy and lactation. The use is contraindicated in conditions where a reduced fluid intake is recommended (e.g. cardiac or renal diseases) and in patients with hypersensitivity to the active substance. [Blumenthal et al. 1998; Wichtl 2004; Gruenwald et al. 2004, 2007; Medicinal Herbs. Gehrmann et al. 2005].

In the documentation of medicinal use no adverse effects have been mentioned. Toxicological data on Ononidis radix are very limited and available data do not indicate a noteworthy risk associated with the Ononidis radix treatment.

Based on literature data and information received from the Member States, Ononis spinosa L., radix can be recommended for use in adolescents over 12 years of age, adults and elderly as 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.

Available data are sufficient to establish a Community herbal monograph on the traditional use of Restharrow root.

Annex