Vitis – Grapevine Leaf (Vitis viniferae folium)
|Latin name of the genus:||Vitis|
|Latin name of herbal substance:||Vitis viniferae folium|
|Botanical name of plant:||Vitis vinifera l.|
|English common name of herbal substance:||Grapevine leaf|
Latin name of the genus: Vitis
Latin name of herbal substance: Vitis viniferae folium
Botanical name of plant: Vitis vinifera L.
English common name of herbal substance: Grapevine Leaf
2.2.Information on traditional/current indications and specified substances/preparations . 14
2.3.Specified strength/posology/route of administration/duration of use for relevant
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.1.1. Assessor’s overall conclusions on pharmacology
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.2.1. Assessor’s overall conclusions on pharmacokinetics
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.3.1. Assessor’s overall conclusions on toxicology
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 5.1. Overview of toxicological/safety data from clinical trials in humans
- 5.2. Patient exposure
- 5.3. Adverse events
- 5.4. Serious adverse events and deaths
- 5.5. Laboratory findings
- 5.6. Safety in special populations and situations
- 5.7. Intrinsic (including elderly and children) /extrinsic factors
- 5.8. Drug interactions
- 5.9. Use in pregnancy and lactation
- 5.10. Overdose
- 5.11. Drug abuse
- 5.12. Withdrawal and rebound
- 5.13. Effects on ability to drive or operate machinery or impairment of mental ability
- 5.14. Overall conclusions on clinical safety
- 6. Overall conclusions
The aim of this report is to assess the preclinical and clinical available data on Vitis viniferae folium for preparing a Community herbal monograph and Community List entry. This report is based on the documentation provided by the European Medicines Agency (EMA) completed by additional searches and information taken from recent international literature on Vitis viniferae folium.
Bibliographic searches have been performed in MEDLINE
Only preparations of Vitis vinifera as a single ingredient are considered for the monograph, while the studies performed with combinations are not discussed in this report.
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
The plant originates from North Africa, South Africa or South West Europe. Vitis vinifera L., Grape vine, is a perennial, defoliating limber with a wooden often twisted stem which can reach a length of 30 meters, but it is usually cut back to
Vitis vinifera belongs to the Vitaceae family. Several subspecies and varieties are distinguished among which is the subspecies sylvestris (Gmelin) Berger, recognised as the spontaneous form of V. vinifera L., the subspecies caucasica Vavilov, occurring in both wild and cultivated form. It is supposed that from these two, the cultivated form Vitis vinifera ssp. sativa DC has been grown [Bombardelli & Morazzoni 1995, Bombardelli et al. 1997].
The herbal substance consists of the dried leaves of the black to
Latin Name: Vitis viniferae folium (Vitis vinifera L., var. tinctoria, Vitaceae) “Vitis vinifera” or “Vitis folium”;
Common Names: vine leaves or vineleaves or vine leaf or vineleaf or grape leaf (English);
Feuilles de vigne (French), Rebenblätter, Weinlaub (German), Fogli della vite (Italian), Hogas de la vid (Spanish), Folhas da videira (Portuguese), Wijnstok bladeren (Dutch), liść winorośli właściwej (Polish),
Φύλλo Αμπέλου (Greek).
The crude herbal substance complies with the monograph “Vigne Rouge” French Pharmacopoeia [Pharm. Franc. X., 1996]. The powder is
of parenchyma containing twinned crystals of calcium oxalate; a few fragments of epidermis with polygonal cells and some reticulate venation.
Since the beginning of the last century in many studies the chemical constituents of the different parts of grape vine have been investigated. Fruit acids, tannins and pigments are the substances mainly responsible for taste, odour and colour [PDR for Herbal Medicines, 2004].
Comminuted herbal substance
Powdered herbal substance
Soft extract (DER
See also market overview in 1.2
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.
1.2. Information about products on the market in the Member States
1)1 hard capsule 3 times daily (5 if necessary)
350 mg of powdered drug/capsule
2)1hard capsule 2 times daily 200 mg of extract/capsule
3)1 hard capsule 1 to 3 times daily containing 169 mg of
Indications 1); 2); 3)
–Traditionally used in the symptomatic treatment of functional disorders of cutaneous capillary fragility, such as ecchymosis, petechias, etc.
–Traditionally used:, in subjective signs of venous insufficiency, such as heavy legs
–in haemorrhoidal symptoms
combination herbal preparations with Mélilot (Melilotus)
Marron d’inde (Aesculus hippocastanum) Hamamélis (Hamamelis)
Preparations: soft extract
Pharmaceutical form cream
Posology for cutaneous use in adults 10 g cream contain 282 mg soft extract
Indications Traditionally used to relieve symptoms of tired legs
Risks (adverse drug effects, literature) Allergic reactions, itching and erythema, worsening of skin irritation. Contact allergy and/or hypersensitivity reactions
1), 3) at least since 1976
all for oral use in adults
1) 1 x daily 6 ml liquid
if necessary 1 x daily 12 ml liquid
10 ml (= 11.013 g) liquid contain 0.6 g soft extract
2)1 x daily
3)1 x daily 2 containing 180 mg dry extract each
if necessary 1 x daily 4
Indications For symptomatic treatment of chronic venous insufficiency, which is characterised by swollen legs, a feeling
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.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Red grapevine leaves, from Vitis vinifera L. [Fam. Vitaceae], are rich in flavonoids including anthocyanins, oligomeric proanthocyanidins (OPCs) etc.
The knowledge of the medicinal potential of grape vine (Vitis vinifera) can be traced back far in history:
In Europe, the leaves of Vitis vinifera are documented in the literature of traditional medicine for their astringent and homeostatic properties where they are utilized in the treatment of diarrhoea, bleeding, haemorrhoids, varicose veins and other circulatory and venous diseases [Anonymous 2004; 2005; 2006; Bombardelli & Morazzoni 1995].
In Turkish folk medicine, vine leaves are known to have a diuretic effect, while the juice of leaves have been used as an eye bath [Kosar et al. 2007].
Native North American indigenous peoples used the leaf tea of related fox grape (Vitis labrusca L.) for treating diarrhoea, as well as for hepatitis, stomach aches and thrush and externally poulticed the wilted leaves for sore breasts, rheumatism, headaches and fevers. Other closely related Vitis species have been used similarly.
In Indian Medicine: Grape is used for headache, dysuria, scabies, skin disease, gonorrhoea, haemorrhoids and vomiting [PDR for herbal Medicines 2004].
Since ancient times, beneficial effects on health have been ascribed to wine and vine leaves, as confirmed by numerous “recipes” reported in Egyptian papyri, the Sumerian tablets, the writings of Hippocrates of Cos
There is evidence of the use of grapevine leaf outside France, in Italy in 1957, where the Biosedra preparation was also tested in vascular disorders in gynaecology, producing a positive effect on capillary fragility.
As early as 1960, a clinical study was published in Germany on the venous efficacy of a product, which contained a fluid extract of grapevine leaf, with a drug/extract ratio of 1:1. The content of anthocyanin was set at 600 μg/ml,which was subsequently changed to 1.2 mg bioflavonoids per ml (German Rote Liste 1974). In 1969, a company registered the preparation as a medicinal product, with the indications of varices, phlebitis, thrombophlebitis, calf cramps and leg oedema. The successor product, has been marketed since 1971. The capsules and tablets contain 180 mg and 360 mg of dried extract of grapevine leaves.
An overview of grapevine leaf components and its supposed pharmacological action as well as the polyphenol composition of Vitis vinifera can be found in the literature [Anonymous 2003; 2004; Petrini et al. 2003; Schneider, 2007i; 2007ii; Schneider et al. 2008; Schaefer & Red 2003].
Nonclinical in vitro and in vivo studies suggested protective effects of components from extracts of grapevine leaves on the venous system; e.g. procyanidines [Maffei et al. 1994; Constantini et al. 1999], and flavonoids [Nees et al. 2003]. For the extract preparation (Extractum Vitis viniferae foliae aquosum siccum,
used. Thus, the herbal substance consists of the dried leaves of the black to
Grapevine leaves and extracts thereof have been traditionally used for the treatment of symptoms associated with venous insufficiency for more than 70 years, in France. Extracts have been introduced in a number of European countries, e.g. Austria, Belgium, Czech Republic, Spain, Switzerland, Italy, and the United Kingdom. It is indicated for the prevention and treatment of Chronic venous insufficiency (CVI), associated with varicose veins including oedema of the lower leg, heavy or tired legs, sensation of tension, tingling and pain.
Based on the survey of products available in the Member states, the traditional use of red leaves preparations has been demonstrated especially in France, Germany, Spain and Austria, for at least 30 years.
Red vine leaf has been included in the French official list entitled “Avis aux fabricants concernant les demandes d’Autorisation de mise sur le marché” by virtue of which, the products containing it were subjected to a simplified registration procedure before the implementation of the Directive 2004/24/EC.
In France: “Vigne Rouge” (= red vine leaf) is regarded as one of the herbal drugs whose efficacy and safety has been proven by thorough literature studies and
Herbal medicinal products with red vine leaf have a long tradition in France. The official compendium “Médicaments à base de plantes”, issued by the French department “Ministère des Affaires sociales et de la solidarité”, released 1990, and comprised the long tradition of diverse herbals in France. There are listed many herbals that have been used in France for a long time, at least for about
Different products prepared of water extracts of “Vigne Rouge” (5:1) have been available in oral forms, in France to treat blood vessels fragility in order to reduce the feeling of heavy legs and haemorrhoids related disorders. The posology range from 169 mg to 200 mg, two to three times a day, for four weeks:
Vigne rouge, capsules: 1 capsule contains 200 mg of grapevine leaves dry aqueous extract is used, a DER of about
1 capsule contains 169 mg of grapevine leaves dry extract (3:1). The manufacturer recommends the use of up to 3 capsules per day. The product is traditionally used to reduce the feeling of heavy legs, haemorrhoids related disorder and fine blood vessels fragility.
An article from ‘Deutsches Medizinisches Journal’ published in 1960 by K. Güthenke, “Wesen und Behandlung der Bindegewebsschwäche, insbesondere der Veneninsuffizienz mit Weinblattextrakt” (Nature and Treatment of weak connective tissues, in particular venous insufficiency, ref.) describes the long traditional use of grapevine leaves for treatment of diseases of the leg veins, and demonstrates that vine leaf extracts have been already traditionally used before 1960, in Germany. Registrations for the active ingredient Extractum vitis viniferae foliae aquosum siccum exist since 1969. Since 1974 a solution for oral use has been available. 20 ml contained
In 1991 the galenical form of hard gelatine capsules was registered and marketed for the first time. One capsule contained a combination of 180 mg of Extractum vitis viniferae foliae aquosum siccum and 3 mg aesculin (a coumarine glucoside that naturally occurs in the horse chestnut Aesculus hippocastanum). This herbal medicinal product was indicated for the treatment of venous insufficiency, varices, haemorrhoids, heavy tired legs and feet, essential oedema and calf cramps. The daily posology was
A cream (ointment)
(10 g cream contain 282 mg soft extract)- has been traditionally used since 1976 to relieve symptoms of tired legs applying it several times daily.
Conclusions on traditional use
Based on information obtained from Member states and data retrieved from handbooks it can be concluded that the following extracts and uses of grapevine leaf extracts fulfil the criteria for traditional use:
Comminuted dried leaves
Powdered dried leaf
Concerning the preparation: dry extract (3:1; water), the product has been on the market since 1990 (France) and does not comply with the requirements of Directive 2004/24/EC for THMP. There is no complete information on the manufacturing process and DER of this preparation, and it is not possible to evaluate the similarity with other dry extracts under WEU.
2.2. Information on traditional/current indications and specified substances/preparations
Traditional herbal medicinal product:
a)To relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
b)For symptomatic relief of itching and burning associated with haemorrhoids.
c)For symptomatic treatment of cutaneous capillary fragility.
The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Vine leaves contain a wide range of polyphenol flavonoids including
The leaves of the red varieties are very rich in tannins from the catechin group. The composition in tannins of leaves depends on the phase of development and on their position on the plant. In autumn, catechin, gallocatechin and epicatechingallate can be found in the leaves. From catechins and/or leukoanthocyanidines so called oligomeric proanthocyanidins, colourless substances, are formed. The greatest part of anthocyans consists of malvidin glucosides but also delphinidin, cyanidin and petunidin glucosides occur [Laparra et al. 1989]. The highest content of anthocyans can be detected in the red leaf especially in autumn, in the time between the vintage and the shedding of leaves [Raynaud, 2006,
Darné & Glories 1988]. From a pharmacological point of view, the polyphenols, for example flavonoids, are the most important substance group [Bruneton 1999; 2002; Raynaud, 2005; Diaz Lanza et al. 1995].
Analytically the following chemical compounds have been determined in the leaves of Vitis vinifera:
–Flavonoids (up to 3.5% for red vine leaf, the content is higher in green leaves
–Tannins: procyanidolic oligomers (proanthocyanidins, about 4%) including constituents monomers of cathechin epicatechin
–Stilbenes: resveratrol and viniferins [Chung et al. 2003]
–Fruit acids: including tartaric acid, malic acid, succinic acid, citric acid, oxalic acid
–Phenylacrylic acid derivatives:
In a recent comparative study of 135 samples of grapevine leaves of different origin, the flavonol, anthocyanin and polyphenol contents have been determined. Total flavonol content was found to be between 0.6% and 3.5%, anthocyanin content between 0.2% and 1.45% and polyphenol content between 4.6% and 18.9%. HPLC methods used for determining anthocyanins and flavonols in grapevine leaves were validated and findings were compared to results produced by assays described in the French Pharmacopoeia. Whereas the correlation between conventional photometric and HPLC methods was satisfactory for anthocyanins, the correlation between the pharmacopoeia assay for total polyphenols and the HPLC analysis for flavonols was poor. As flavonol compounds are considered relevant for the vasoprotective effect of grapevine leaves, their content in starting material used in the production of herbal medicines needs to be quantified [Schneider et al. 2008].
Overview on main polyphenolic compounds in Grape Vine
In Europe, the leaves of Vitis vinifera are documented in the literature of traditional medicine through several comprehensive reviews for their astringent and homeostatic properties where they are utilized in the treatment of diarrhoea, bleeding, haemorrhoids, varicose veins and other circulatory and venous diseases [Bombardelli 1997; Anonymous 2003; 2004; Petrini et al. 2003; Schneider, 2007i; 2007ii; Schneider et al. 2008; Schaefer & Red 2003; Volonté & Petrini 2004; Volonté et al. 2003; Weber, 2000].
In an in vitro study, venular endothelial cells were isolated from Wistar rats and cultivated on porous filters to confluent monolayers. These preparations respond to certain release products from simultaneously activated blood platelets and polymorphonuclear granulocytes (PMN) with a rise in hydraulic conductivity that,
The grapevine leaf extract is characterized by its content in flavonol glycosides and glucuronides, in particular
constriction of microvessels. Red vine leaf RVLE extract was able to support the repair of the venular barrier after an attack by said release products. These effects could be demonstrated on cells of from animal origin as well as on cells isolated from the human heart [Nees 2003i, 2003ii].
In a publication by [Jonadet et al. 1983], the authors describe studies conducted with anthocyanosides extracted from Vitis vinifera (a), Vaccinium myrtillus (b) and Pinus maritimus (c). The results obtained in vitro indicated that these compounds inhibit elastase, a proteolytic enzyme which plays a role in the deterioration of conjunctive tissue and elastic fibers and is involved in certain pathological vascular conditions. The IC50 values are 0.13 mg/ml for (a), 0.20 mg/ml for (b) and 0.31 for (c). Lineweaver- Burk curves revealed that the inhibition was not competitive. Results obtained in vivo show that the angioprotective activities of these compounds can be classified in decreasing order as follows: (a), (b) and (c).
Nees developed a measurable and reproducible in vitro experimental model to investigate the effect of substances capable of modifying the hydraulic conductivity of the endothelial barrier of the venules. In in vitro experiments, this extract has been shown to have a “sealing” effect on the endothelium of the venules and a protective action against fluid extravasation induced by incubation with chemical mediators of inflammation [Nees S et al. 2003i].
Red vine leaf extract (RVLE) prevented the deleterious effect of the release products of P and PMN on venular endothelial cells. In addition, the extract was able to support the repair of the venular barrier after an attack by said release products [Smith, 1999].
The hepatoprotective effect of ethanolic extract and its four different fractions (CHCl3, EtOAc,
Ethanol extracts of Vitis vinifera (leaves, raw fruits, young branches; 2:1:1, v/v/v), were investigated for their antimicrobial activity against 14 pathogenic bacterial species and a yeast, Candida albicans, using the agar well diffusion method, 19 Turkish traditionally used medicinal plants. Vitis leaves showed
The effect of grape leaf extract (GLEt) on antioxidant and lipid peroxidation states in liver and kidney alcohol induced toxicity has been evaluated. In vitro studies with DPPH* and ABTS* (cation radical) showed that GLEt possesses antioxidant activity. In vivo administration of ethanol (7.9 g/kg bw/day) for 45 days resulted an activity of liver marker enzymes (AST, ALT, ALP and GGT), lipid peroxidation markers (TBARS, lipid hydroperoxides) in liver and kidney with significantly lower activity of SOD, CAT, GPx, GST and
The antioxidative activity of the ethanolic extract of Vitis vinifera L. leaves was investigated. The ethanolic extract of V. vinifera leaves at 250 mg/kg dose was found to have the highest antioxidant activity [Sendogdu et al. 2006]. Comparable results have been published by [Kosar et al. 2007], from extracts from fresh, dried and brined leaves of Vitis [Monagas M et al. 2006].
It has been investigated the effect of grape leaf hydroalcoholic extract on isolated rat tracheal contractions induced by KCl and acetylcholine. The trachea was removed from male adult Sprague- Dawley rat and placed in an organ bath containing
Vasorelaxant effect on isolated rat aorta
The relaxant effect of Vitis vinifera leaf hydroalcoholic extract (VLHE) on isolated rat thoracic aorta contractions induced by phenylephrine and KCl, and the role of aorta endothelium on this action has been investigated. Rat aorta was removed and placed in an organ bath containing
on rat aorta is
The effect of grape leaf hydroalcoholic extract (GLHE) on rat colon contractions induced by some spasmogens has been investigated. A piece of distal colon from male adult Wistar rats were dissected and mounted in an organ bath containing Tyrode solution and colon contractions recorded by an isotonic transducer under 1g resting tension. The GLHE (0.5- 4 mg/ml) reduced the contractions induced by KCl (60 mM), BaCl2 (4 mM), acetylcholine (1 mu M)
The effect of Vitis vinifera leaf hydroalcoholic extract (VLHE) on isolated rat tracheal contractions induced by KCl and acetylcholine has been also studied. The trachea was removed from male adult Sprague Dalwey rat and placed in an organ bath containing
Results: The results demonstrate that the VLHE at 0.5, 1, 2, 4 and 8 mg/ml reduces the tracheal contractions induced by KCl (60 mM) significantly and
Conclusion: These results suggest that the relaxant effect of VHLE on rat trachea is evoked via voltage dependent calcium channel blockage and
Aqueous and alcoholic extracts of Vitis vinifera leaves were tested for diuretic activity in rats. The parameters studied on individual rat were body weight before and after test period, total urine volume, urine concentration of Na+, K+ and
In vitro tests
In the context with Chronic venous insufficiency (CVI) it would be of interest to evaluate whether grapevine leaf extract exhibits any effects on platelet aggregation. The effect of flavonoids on platelet aggregation was studied in vitro using
29, 35 and 47 years. The flavonol glycoside quercetin
In vivo tests
–catechins and proanthocyanidins (flavanols)
–anorganic acids, sugars and mineral salts
The anthocyanins present in grapevine leaves are mainly glucosides of cyanidine, peonidine and malvidine [Boucheny A,
The phenolic acids present in grapevine leaves are mainly derivatives of cinnamic acid, vanillic acid and caffeic acid [Boucheny A,
The catechins found in grapevine leaves are mainly catechol and epicatechol [Boucheny A, Brum- Bousquet 1990]. Of the condensed catechins (proanthocyanidins) procyanidins B1 and B2 are the prevailing compounds, followed by procyanidins B3 and B4. Procyanidins have been reported to possess antioxidant and
Oral administration of procyanidins from grape seed produced a hypocholesterolemic effect in a high- cholesterol animal feed model (rats). Specifically it prevented an increase in total and LDL plasma cholesterol and a decrease in HDL [Tebib, 1994].
In normal and hypercholesterolemic rabbit aortas, OPCs significantly lowered the amounts of cholesterol bound to aortic elastin compared to controls [Wegrowski, 1984].
The acute and subacute antidiabetic activities of the ethanolic extract of Vitis vinifera L., leaves were investigated. The acute effect was studied on the normoglycaemic, glucose hyperglycaemic and
The acute and subacute (15 days) hypoglycaemic and antihyperglycaemic effect of the two different doses (250, 500 mg/kg) of the aqueous extract from the leaves of Vitis vinifera L. were evaluated in this study. The aqueous extract was further fractionated through successive solvent extractions and the acute effect of different doses of its subfractions, 25 mg/kg for ethylacetate fraction, 80 mg/kg for
Pharmacodynamic drug interactions of whole extracts or isolated constituents have not been reported. Various sources in the literature have suggested that the desired therapeutic effect of many flavonoids is usually obtained only after repeated oral intake of the respective preparations. This implies that the flavonoids and their metabolites accumulate in the body, and do not exert the pharmacodynamic effects seen in in vitro studies until a pharmacological threshold dose and relevant plasma levels has been reached. This hypothesis was confirmed by the results of a clinical study by [Kiesewetter et al. 2002]. A significant improvement in key CVI symptoms in the active treatment groups versus placebo could not be observed after 6 weeks, but became evident after 12 weeks of treatment. This could also explain why earlier studies reported a “small” or “undetectable” effect following single oral administration.
3.1.1. Assessor’s overall conclusions on pharmacology
The aqueous and ethanolic extracts of Vitis viniferae folium have been used as adjunctive therapy for Chronic venous insufficiency (CVI), and have shown a potential benefit [Abascal & Yarnell 2007]. Based on available preclinical data, it can be concluded that the mechanism of action of orally administered extract in CVI is not well known.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Data on the pharmacokinetics of the whole extract or relevant components are not available.
Flavonoids are the substances which are regarded as being responsible for the pharmacological properties of grapevine leaf extract. In the plant, flavonoids are generally present in genuine form as glycosides. Grapevine leaf extract as it has been referred previously contains as major flavonoid components
Various sources in the literature have suggested that the desired therapeutic effect of many flavonoids is usually obtained only after repeated oral intake of the respective preparations. This implies that the flavonoids and their metabolites accumulate in the body and do not exert the pharmacodynamic effects seen in in vitro studies until a pharmacological threshold dose and relevant plasma levels has been reached. This hypothesis was confirmed by the results of a clinical study by [Kiesewetter et al. 2000]. A significant improvement in key CVI symptoms in the active treatment groups versus placebo could not be observed after 6 weeks, but became evident after 12 weeks of treatment.
The grapevine leaf extract represents a complex mixture of different classes of compounds, having each their own pharmacokinetic characteristics. A significant portion of the components of grapevine leaf extract belongs to the group of polyphenols, such as anthocyanins, proanthocyanidins, catechins and phenolic acids [Bombardelli & Morazzoni 1995; Boucheny &
3.2.1. Assessor’s overall conclusions on pharmacokinetics
No information is available on pharmacokinetic interactions. No information is available on metabolites.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
The toxicity of vine leaf aqueous extract
The toxicity of vine leaf aqueous extract
The toxicity of vine leaf soft extract when given over a
The maximum daily dose of extract is 720 mg, which represents a dose of 10.3 mg/kg for a person weighing 70 kg. This is about
The mutagenic potential of vine leaf extract was assessed in a range of established in vitro and in vivo test models (Ames test, point mutation assay and chromosomal aberration assay). It was assessed in an Ames Salmonella/microsome plate assay using Salmonella typhimurium
Mutagenic potential of grapevine leaf extract was also assessed in two independent point mutation assays carried out on the HGPRT locus of Chinese hamster V79 cells with and without metabolic activation; S9 mix prepared from rat liver was used as the activation system in each case. The assays were designed and conducted in accordance with the guidelines and recommendations on genotoxicity testing that were current at the time. On the basis of preliminary toxicity tests, a concentration range of 3.0 – 5000 µg/ml was selected for use in the assays. Positive EMS and DMBA controls as well as a
vehicle control were included. Neither of the assays provided any evidence to suggest that the extract used had any mutagenic potential in the concentration range tested [ESCOP, 2009].
A micronucleus assay was carried out on NMRI mice (5 males and 5 females per group) to establish the potential of vine leaf soft extract for causing chromosomal aberrations. The assay, which complied with the relevant EU and OECD guidelines, was carried out using oral doses of the extract of 1.0, 3.0 and 10.0 ml/kg. Positive controls (cyclophosphamide 40 mg/kg) and vehicle controls (sodium chloride 0.9%) were included. Under the conditions employed, there was no significant increase in micronuclei frequencies in polychromatic erythrocytes.
The methanolic and aqueous extracts from Greek varieties of Vitis vinifera demonstrated in vitro antimutagenic effects against mutagenicity induced by bleomycin and hydrogen peroxide in Salmonella typhimurium strain TA102 [Stagos et al. 2006].
Oligomericproanthocyanidins from grape seed demonstrated in vitro antimutagenic activity [Liviero et al. 1993].
In addition, among the pharmacologically active flavonoids (quercetin, quercetin
No data is available. However, it was demonstrated that
There has also been no evidence in the literature so far to indicate that flavonoids as a whole have any carcinogenic properties. Indeed, a large number of in vitro studies have been carried out which suggest that flavonoids have anticarcinogenic effects. However, the results obtained in vitro have yet to be confirmed in in vivo test models. Depending on the type and quantity of food consumed, the human intake of flavonoids is between 100 and 1000 mg per day [Middleton 1996].
In toxicity and carcinogenicity studies carried out on quercetin, promoted by the FDA, four groups of 50 male and female F344 rats were given 40, 400 or 1900 mg/kg of quercetin, or a placebo, in feed over a period of two years. There was no evidence of carcinogenic activity in the female rats and only slight evidence of carcinogenic activity in male rats. The carcinogenic effects, which took the form of renal tubule hyperplasia and nephropathy, were observed only in the
The maternal and embryofoetal toxicity of an orally administered aqueous preparation of vine leaf soft extract was investigated in pregnant Himalayan rabbits in a study which was carried out in accordance with GLP standards and subjected to QAU inspection. Four groups of animals (12 per group) were used. One group received a placebo whilst the other three groups were given doses of 300, 1000 or 3000 mg/kg/day on days
In the reproduction study conducted with rabbits no evidence of any teratogenic effects was found. The recommended maximum dose is equivalent to a daily intake of 10.3 mg/kg of vine leaf extract. In the Leuschner study up to 3000 mg/kg/day of the extract, were applied without resulting in any teratogenic effect. The recommended maximum human dose of vine leaf extract is about 300 times lower than the highest dose used in the Leuschner study [Leuschner F, Mitterer KE, 1993]. Examination of the influence of Extractum vitis viniferae on the pregnant rabbit and the fetus by oral administration [LPT Report No. 7441/92. 1993; ESCOP, 2009].
Daily doses of 3000 mg/kg extract from grapevine leaves administered to female rabbits during organogenesis (6th to 18th day of pregnancy) did not exhibit teratogenic effects [Antistax® SPC, 2005].
3.3.1. Assessor’s overall conclusions on toxicology
Several recent data on oral
In vitro and in vivo studies on the mutagenic potential of vine leaf extracts have not shown any evidence of mutagenic activity. Carcinogenic effects are not expected to occur, especially as vine leaf extract has been used in medicinal products for many years without any evidence of such effects being reported.
4. Clinical Data
4.1. Clinical Pharmacology
Pathophysiology of CVI
The term Chronic venous insufficiency (CVI) describes a clinical picture in which chronic venous diseases of diverse aetiology are manifested by similar or related symptoms and complaints. CVI is mostly caused by venous and capillary hypertension, which causes a persistent, chronic, venous stasis in the skin of the lower leg, manifested most characteristically upon postural challenge [Alguire & Mathes 1997]. The impairment of venous return that is responsible for the venous capillary hypertension can be caused by degenerative, dilating venous conditions of the superficial (primary varices), the transfascial (insufficiency of the perforating veins), or the deep system (“deep” varicosis, insufficiency of the main veins) [Jünger et al. 1994]. Chronically disturbed haemodynamics of deep or superficial veins due to obstructed venous segments or valvular incompetence lead usually to trophic changes in the inner ankle area of the lower limbs and disturbances in the microcirculation of the skin have been considered to be major contributors for skin changes associated with chronic venous hypervolaemia and venous hypertension. Cutaneous microangiopathy of clinical relevance such as enlarged, tortuous capillaries surrounded by
Drug therapy is a treatment option in incipient and mild to moderate Chronic venous insufficiency (CVI) (Widmer grades I and II, CEAP Clinical classes 2, 3, or 4a).
Topical drug treatment
Antioedema drugs are mostly plant derived substances for which an antiexudative and antioedematous action and efficacy have been confirmed in experimental studies and clinical trials. Experimentally, most of them have a membrane stabilising action that leads to a decrease in capillary permeability. Some of these substances also have venotonic properties.
The complex syndrome of symptoms involved in CVI led to investigate the activity of vine leaf preparations on two distinct parameters affecting CVI. On the one hand the effects of the product on microcirculation, on the other on the typical objective and subjective symptoms of CVI such as the presence of oedema and the typical CVI complaints “tired, heavy, and swollen legs”, or tension and pain in the legs.
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No data available.
220.127.116.11. Assessor’s overall conclusions on pharmacodynamics
At present, the mechanism of action of vine leaf water extract in chronic venous insufficiency cannot be considered clarified.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
The vine leaf extract is a complex extract containing more than 200 different identified substances. The clinical effects of the grapevine leaf extract cannot be attributed to a specific individual constituent but can be ascribed with reasonable plausibility to the extract as a whole. It is therefore virtually impossible to perform classical pharmacokinetic studies with the complete product and pharmacokinetic studies of individual constituents such as flavonoids will only provide limited information with regard to clinical efficacy.
Flavonoids (quercetin glucuronide, kaempferol glucosides) are quantitatively important constituents of the whole extract. The systemic bioavailability of flavonoids is probably relatively low and variable. Orally administered flavonoids are susceptible to
18.104.22.168. Assessor’s overall conclusions on pharmacokinetics
Data on pharmacokinetics of vine leaf extract or relevant components are not available in humans. No reliable methods exist to determine simultaneously the plasma levels of all active ingredients present in the whole extract.
4.2. Clinical Efficacy
Several publications referring to human clinical studies with medicinal products containing Vitis vinifera were found in the literature.
Three of the published studies investigated the safety and efficacy of a dry extract of grapevine leaves
The safety and efficacy specific information of these studies is presented below.
The clinical information available for aqueous extracts of grape vine leaf investigates the activity on two distinct parameters affecting Chronic venous insufficiency (CVI). On the one hand the effects of the product on microcirculation, on the other on the typical objective and subjective symptoms of CVI such as the presence of oedema and the typical CVI complaints “tired, heavy, and swollen legs”, or tension and pain in the legs.
Clinical parameters measured
In all clinical studies, changes in leg volume and/or calf and ankle circumference were included in the endpoints studied. All confirmatory studies planned to show efficacy on subjective symptoms of CVI used the lower leg volume determined by water displacement plethysmography as the primary efficacy endpoint. Other endpoints included the lower leg diameter (at calf height and at the ankle), visual analogue scales (VAS:
Patients were usually questioned about their subjective
4.2.1. Dose response studies
From the results of [Kiesewetter et al. 2000], a single daily dose of 360 mg of grapevine leaf extract is as effective and well tolerated as a daily dose of 720 mg. On average, the higher dose regimen offers greater efficacy in terms both of the extent and duration of action, but is roughly equivalent with regard to subjective symptoms reduction. The lower dose, however, is considered to be sufficient in the majority of patients and has been chosen to reduce the intake of extract, thus most likely decreasing the likelihood of observing adverse events. Consequently, this is the dosage that has been approved in some marketing authorisations.
No pharmacokinetic or pharmacodynamic studies, however, were performed to support the posology and daily dose proposed.
4.2.2. Clinical studies (case studies and clinical trials)
Several publications referring to human clinical studies investigating the safety and efficacy of a dry extract of red Vitis vinifera leaves
[Kiesewetter et al. 2000]: In a
Patients were randomly assigned to a
Subjectively, there was an improvement in CVI symptoms at 6 weeks with all treatments, but a further improvement at week 12 was seen only in the active treatment groups: at 12 weeks, the changes compared to baseline were significantly greater (p < 0.001) in both active treatment groups than in the placebo group. The study demonstrated that once daily doses of 360 and 720 mg RVLE were effective in the treatment of mild CVI, reducing significantly lower leg edema and improved
The treatments were well tolerated. All 260 patients who were enrolled and randomized were included in the safety analysis. This included three patients who withdrew from the study before visit 2 (i.e. before entering the treatment phase). 257 patients received at least one dose of the randomized study medication. Most patients completed the study up to 84 days of treatment. The mean duration of treatment for the
reported in patients treated with 360 mg AS 195, whilst the other four occurred in patients treated with placebo. Gastrointestinal disorders (abdominal discomfort, diarrhea, dyspepsia, dry mouth or retching) were the most frequently cited AEs (n = 11), followed by infections (n = 6), headache (n = 4) and disorders of the musculoskeletal system (n = 4). Two AEs which occurred during treatment with placebo required hospitalization and were labelled as „serious“; there was one incident of vaginal hemorrhage during the
[Kalus et al. 2004]: The effect of AS 195 on cutaneous microvascular blood flow, transcutaneous oxygen pressure (tcpO2), and leg oedema was investigated in a randomised,
Microcirculation, measured in arbitrary units (AU) (laser Doppler flow measurement at Doppler frequencies of
The TcpO2 oxygen reading also rose significantly from baseline levels in the AS 195 group, by 1.35±0.97 mmHg, contrasting with a reduction in the placebo group of 7.27±0.97 mmHg.
Transcutaneous oxygen pressure (mean ± SEM, after 10 minutes of standing) (from [Kalus et al. 2004])
These changes in the measured parameters were associated with corresponding volume changes in the lower leg. After just three weeks of treatment, statistically significant differences were also observed in ankle and calf circumference. After six weeks, these circumferences had fallen by 0.39 and 0.54 cm respectively, in the active group, compared to increases in the placebo group of 0.29 and 0.14 cm respectively. The authors of the study concluded that the administration of AS 195 could have a positive effect on the course of CVI. The minimum number of days of exposure was 38 in the AS 195 and 24 in the placebo group, the maximum number 46 in the AS 195 and 45 in the placebo group. Thirteen (18.3%) subjects out of 71 experienced 16 adverse events (AEs) during the 16 week trial. Ten AEs (14.1%) were of mild, 4 (5.6%) of moderate and 1 (1.4%) of severe intensity. None of the AEs were assessed as related to the trial medication. One patient died from a cardiac arrest. He had been treated with placebo and never received AS 195 in this trial. All patients assessed the overall tolerability as good or satisfactory. Laboratory parameters did not change during the study [Kalus et al. 2004].
[Limoni C, 1996]: A
[Vix et al. 2007]: This
The time course of the change from baseline in limb volume was similar for both treatment groups with a more marked improvement of leg oedema over time in patients treated with these tablets. After 84 days of treatment, limb volume was reduced by
For the secondary endpoint “change from baseline in calf circumference”, the adjusted mean difference to placebo after 42 days of treatment with these tablets was
[Schaefer & Petrini 2004]: This placebo controlled, randomised, parallel group study was carried out in 2004. 247 CVI patients
[Schaefer E & Petrini LE, 2003]: A 17 week, randomised,
suffering from chronic venous insufficiency The microcirculation study has demonstrated that objective signs associated with CVI (microvascular blood flow, tcpO2, ankle circumference and calf circumference) can be improved significantly after just 3 weeks of oral treatment with a single daily dose of 360mg of the grapevine leaf extract AS 195. These results build on those from Harrison trial (1998) showed that AS 195 reduces lower leg oedema and calf circumference in patients suffering from CVI treated once daily for 12 weeks. Out of the 179 evaluable subjects 38.5% experienced a marked and 42.5% a moderate global improvement of CVI symptoms. Improvement was rated as “moderate” by 59.8% of the patients with regards to heaviness/tiredness, 69.9% with regards to tension, 79.2% to tingling, 74.0% to pain, and 74.4% to itching. Circumference of calf (mean±SD) was 33.5±2.99 cm prior to treatment and 33.0±2.94 cm at 12 weeks, of the ankle (mean±SD) 22.3±1.84 cm prior to treatment and 21.9±1.82 cm at 12 weeks after treatment (p<0.05). These differences were not statistically significantly different from baseline.
[Schaefer et al. 2003]: The
Assessment The present
[Monsieur & Van Snick 2006]: A small, open observational clinical study was conducted in 39 patients suffering from Chronic Venous Insufficiency (CVI), grade I or II according to the Widmer
classification, (grade 2 to 4 of the international CEAP classification). Patients were treated with 180 mg of RVLE (AS 195) twice daily (360 mg in total) for six weeks. The parameters investigated were objective measurements of lower leg volume and the circumference of the leg as well as subjective criteria such as heaviness and pain in the leg. A clear and significant improvement of all parameters was observed after two weeks of treatment. This effect was still present and increased slightly after four and six weeks in all objective and subjective parameters tested in this study.
Assessment This study has shown a fast onset of action and an efficacy of the AS 195 extract in chronic venous insufficiency. Adverse events/side effects: not specified. In general, the treatments were well tolerated. Three patients prematurely stopped the trial for reasons not linked to the treatment or to the disease. No change of the safety profile.
Clinical studies with grapevine leaf extract
r et al.
Grade I, II
Changes in CVI
Grade I, II
Changes in CVI
I, II. III
4.2.3. Clinical studies in special populations (e.g. elderly and children)
No information available.
4.3. Overall conclusions on clinical pharmacology and efficacy
The clinical efficacy of an extract from red vine leaves (RVLE; AS 195) was investigated in double blind,
The extract AS 195 was consistently more effective than placebo in reducing leg oedema and improving symptoms of Chronic Venous Insufficiency (CVI) across most efficacy parameters evaluated, even though not always a statistically significant superiority could be shown.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
The safety profile of vine leaf extracts can be described as acceptable from all clinical studies in Chronic Venous Insufficiency (CVI) patients and from its use from products on the market. The safety results obtained from the clinical studies conducted so far show that the oral use of vine leaf extracts are well tolerated by most patients. No
5.2. Patient exposure
The controlled studies evaluated 1073 patients in total [Kiesewetter et al. 2000; Kalus et al. 2004; Schaefer & Petrini 2004; Vix 2006, Limoni 1996]. The open studies, evaluated by [Schaefer et al. 2003] and by [Monsieur and Van Snick, 2006] comprised 104 patients.
5.3. Adverse events
No health hazards or side effects are known in conjunction with the proper administration of designated therapeutic dosages. A reversible inhibition of intestinal enzyme activity (alkaline phosphatase, sucrose and dipeptidyl peptidase) was demonstrated in animal models [Tebib, 1994; PDR for Herbal Medicines, Thomson, 2004].
Brito et al. ; Mur et al. : Vine pollen allergies have been reported with Vitis vinifera pollen and an extract thereof In
The results of this prospective study show that V. vinifera pollen has a moderate clinical relevance from an allergic point of view, particularly affecting those subjects who are exposed to it during the working hours and those who perform leisure activities close to vine fields. During a period of four months, the authors performed skin prick tests to vine pollen in patients who attended the outpatient clinic with suspected respiratory allergy, finding sensitisation to Vitis vinifera pollen in 9 of the 200 patients seen (98 patients had allergy to other pollen). In conclusion, in areas with a high density of vineyards, vine pollen can reach midrange air concentrations and could be the cause of hay fever in those individuals with the highest level of exposure [Brito et al. 2008; Mur et al. 2006].
Assessment: In summary, there is no new safety specific information provided. No change of the safety profile is suggested.
Reports on immunoglobulin E
object of a prospective study by Kalogeromitros et al.  was to present clinical features, in vivo and in vitro allergy testing, and human leukocyte antigen (HLA) serotyping in patients with recurring reactions to grapes and grape products. Eleven unrelated Greek patients, six men and five women (aged
The authors suggest that allergy to grapes may not be as uncommon as generally believed in the literature and should be considered as a possible offending cause in certain episodes of
Assessment: If hypersensitivity reactions are labelled correctly in the PIL and SPC, there is no change of the safety profile of medicinal products.
[Crowell et al. 2004]:
Assessment: These results cannot be transferred to medical products containing Vitis vinifera or extracts thereof.
In summary, there is no safety specific information that is relevant for medical products. The reported adverse events / side effects were mild to moderate. The majority of the above mentioned events are considered to be related to underlying diseases, incidental concomitant disorders or other coincidences but not causally related to Vitis vinifera. From these published adverse events, no change of the safety profile of Vitis vinifera can be concluded. According to current knowledge, gastrointestinal disorders and hypersensitivity reactions should be labelled in the PIL and SPC.
The Periodic Safety Update Report for Vitis vinifera has been compiled within the joint BAH PSUR project. It summarizes safety data from 01/Nov/2003 to 01/Sep/2008 [BAH 2008].
In the report period no new safety relevant issues were found in the literature. There were no reports, clinical or experimental studies identified that give reason for a change in the assessment of the safety and benefit/risk ratio of Vitis vinifera.
5.4. Serious adverse events and deaths
The case of a 51 years old female patient is reported. She was hospitalized due to an acute icterus, which had developed over 15 days and was associated with asthenia, nausea and anorexia. Beyond the mucocutaneous icterus, the clinical examination did not show any abnormality, especially no chronic hepatopathy. The laboratory parameters suggested a cytolysis due to an ALAT value that was twelve times higher than normal,
This case is classified as serious because of a significant medical reaction including hospitalisation.
A causal relationship with Vitis vinifera cannot be excluded (plausible temporal relationship). However, the used herbal products are insufficiently described; additionally relevant information on the dosage are lacking. Moreover, the concomitant use of acetaminophen must be considered. Acetaminophen is well known for its hepatotoxicity.
5.5. Laboratory findings
5.6. Safety in special populations and situations
The product is not suitable for patients with known hypersensitivity against the herbal substance, the plant family, the herbal preparation or to the excipients of the final product.
5.7. Intrinsic (including elderly and children) /extrinsic factors
Grapevine leaf is not intended for use in children, while no restrictions are known for its use in elderly.
5.8. Drug interactions
No drug interactions have been reported.
5.9. Use in pregnancy and lactation
Grapevine leaf should not be used during pregnancy and lactation as there are not data available.
5.11. Drug abuse
5.12. Withdrawal and rebound
5.13. Effects on ability to drive or operate machinery or impairment of mental ability
5.14. Overall conclusions on clinical safety
The safety profile of grapevine leaf extracts can be judged as good from clinical studies and from its long term use and market availability. The available literature, on pharmacological and toxicological studies, does not give rise to safety concerns. A special focus was set on the polyphenolic constituents of the extract (proanthocyanidins, flavonoids) that can be linked with the pharmacological effects. The proof of an acceptable safety is not only given by the period of time over which this extract has been used and by the quantitative aspects of their use but also by PSURs data and the safety data obtained during the clinical trials.
Overall, Vitis vinifera, leaves can be considered as safe in herbal medicinal products with a positive benefit/risk ratio.
6. Overall conclusions
The clinical efficacy and safety of the dry aqueous extract of grapevine leaves
The above referred extract showed an influence to the microcirculation and transcutaneous oxygen pressure at the predominantly affected perimalleolar area of the leg in Chronic venous insufficiency (CVI) patients who were treated for six weeks. Moreover, the assayed grapevine leaves extract has shown to lead to a reduction of the volume of oedema and to improvement of the typical subjective symptoms of CVI such as tired, heavy and swollen legs or pain and tension in the legs.
circumference in the secondary endpoints investigated. In several of the clinical trials objective and subjective symptoms of CVI appeared to be effectively reduced, while there were some others giving negative results such as the ones of Schaefer & Petrini 2004 and Vix et al. 2006. The trials were performed according to
This extract can therefore be regarded as an active substance with a
The use of herbal medicinal products prepared with this extract is not recommended during pregnancy and lactation and should not be taken in children and adolescents under 18 years of age, due to the lack of adequate data.
The proposed indication is:
Herbal medicinal product for treatment of chronic venous insufficiency, which is characterised by swollen legs, varicose veins, a feeling of heaviness, pain, tiredness, itching, tension and cramps in the calves.
Other extracts and herbal preparations from grapevine leaves have been widely used. The safe use of the extract can be stated on the basis of the
Sufficient data are available to develop a Community monograph on the well established and traditional use of Vitis vinifera L., leaves. The indications are suitable for
Traditional herbal medicinal product to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
Traditional herbal medicinal product for symptomatic relief of itching and burning associated with haemorrhoids.
Traditional herbal medicinal product for symptomatic treatment of cutaneous capillary fragility.
The use of the traditional herbal medicinal products is not recommended during pregnancy and lactation and should not be taken in children and adolescents under 18 years of age.
The minimum required data on mutagenicity (Ames test) are available for herbal preparations of grapevine leaves. The inclusion in the Community list of traditional herbal substances and preparations is recommended.