Grapevine Leaf – Vitis viniferae folium (Vitis vinifera L.)
|Latin name of the genus:||Vitis viniferae folium|
|Latin name of herbal substance:||Vitis vinifera l.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Grapevine leaf|
Latin name of the genus: Vitis viniferae folium
Botanical name of plant: Vitis vinifera L.
English common name of herbal substance: Grapevine Leaf
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
The herbal substance Vitis vinifera L., folium, (Vitaceaea) consists of the dried leaves of the black to
The crude herbal substance complies with the monograph “Vigne Rouge” French Pharmacopoeia (Pharmacopée Française, 10th ed., 1996).
Grapevine 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, 2005).
Overview of main polyphenolic secondary metabolites in grapevine leaf (Bruneton 1999; Bombardelli and Morrazzoni 1995).
Figure 1. Chemical structures of the main polyphenolic secondary metabolites in grapevine leaf (Bruneton 1999; Bombardelli and Morrazzoni 1995)
a)Comminuted herbal substance
b)Powdered herbal substance
c)Soft extract (DER
d)Dry extract (DER
The powder is
venation. Since the beginning of the last century in many studies the chemical constituents of the different parts of grapevine have been investigated. Fruit acids, tannins and pigments are the substances mainly responsible for taste, odour and colour (PDR for Herbal Medicines, 2004).
For the extract preparation (Extractum Vitis viniferae foliae aquosum siccum,
•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.
This assessment and the monograph refer exclusively to the use of Vitis vinifera folium as a single ingredient.
1.2. Search and assessment methodology
The assessment is based on the sources mentioned in the list of references. Publications in other languages than English (at least abstract in English or other language available) were also included in the assessment.
Scientific databases: Scifinder, Scopus; HealLink, Medline, PubMed, search date
Only articles found to be relevant for assessment are included in the list of references.
Search engines used: Google, Google Scholar.
Medical databases: Pubmed key words: Vitis viniferae L., red vine leaf, grapevine leaf, vine leaf.
For the research, the databases of PubMed, ScienceDirect, Cochrane Database of Systematic Reviews and TOXLINE were used.
Reviews were searched in Cochrane Database of Systematic Reviews, typing in “Vitis vinifera”.
Data from EU and
Other resources: Library of the National Kapodistrian University of Athens (Pharmacy and Pharmacognosy library.
2. Data on medicinal use
2.1. Information about products on the market
2.1.1. Information about products on the market in the EU/EEA Member States
Information on medicinal products marketed in the EU/EEA
Table 1: Overview of data obtained from marketed medicinal products
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
Information on relevant combination medicinal products marketed in the EU/EEA
Information on other products marketed in the EU/EEA (where relevant)
2.1.2. Information on products on the market outside the EU/EEA
2.2. Information on documented medicinal use and historical data from literature
The knowledge of the medicinal potential of grapevine leaf can be traced back far in history:
•In Europe, the leaves of Vitis vinifera are documented in the literature of traditional medicines for their astringent and homeostatic properties where they are utilised in the treatment of diarrhoea, bleeding, haemorrhoids, varicose veins and other circulatory and venous diseases (Anonymous 2004; 2005; 2006; Bombardelli and Morazzoni 1995).
•In Turkish folk medicine, grapevine leaves are known to have a diuretic effect, while the juice of leaves has 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. (Anonymous 2004; 2005; 2006).
•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 grapevine 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 (Schneider, 2007i).
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 2004; 2005; Petrini et al. 2003; Schneider, 2007i; 2007ii; Schneider et al. 2008; Schaefer et al. 2003).
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, United Kingdom etc. 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.
Red grapevine 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 grapevine leaf) is regarded as one of the herbal medicinal products whose efficacy and safety has been proven by thorough literature studies and
Herbal medicinal products with red grapevine 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 and comprised the long tradition of diverse herbals in France in 1990. In this Official French list, there are cited 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” (3:1; 4:1; 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 a max period of 4 weeks.
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.
Table 2: Overview of historical data
2.3. Overall conclusions on medicinal use
Information obtained from member states and data retrieved from handbooks confirm the medical use of red grapevine leaves in the European Union.
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
formulation. The recommended dosage is
In 1991 the galenic 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), containing soft extract
Based on information obtained from Member states and data retrieved from handbooks it can be concluded that the following extracts of grapevine leaf extracts have been on the European market for a period of at least 30 years fulfil the criteria for traditional use in accordance with Directive 2004/24/EC and are proposed for the monograph on traditional use (see table 3):
•Comminuted herbal substance
•Powdered herbal substance
•Soft extract (DER
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.
The following herbal preparation is on the European market for a period of at least 10 years and was proposed for the monograph on well establish use (see table 3 and section 4 ‘Clinical data’):
WEU herbal medicinal product:
Table 3: Overview of evidence on period of medicinal use
For safety reasons, as preliminary haemorrhoids symptoms could be associated with other serious medical conditions and in accordance with recent monographs sharing the same indication, the phrase “after serious conditions have been excluded by a medical doctor” has been added to the indication “Traditional herbal medicinal product for symptomatic relief of itching and burning associated with haemorrhoids”.
Duration of use TU
The recommended duration of use is 4 weeks.
If the symptoms persist for more than 2 weeks during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
Indications 2) and 3)
If the symptoms persist for more than 1 week during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
Duration of use WEU
The recommended duration of use is 12 weeks.
2 to 3 weeks of treatment may be required before beneficial effects are observed.
Long term use is possible in consultation with a doctor.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
The phenolic acids present in grapevine leaves are mainly derivatives of cinnamic acid, vanillic acid and caffeic acid (Boucheny and
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,
In another study, the scavenge by procyanidines (polyphenol oligomers from Vitis vinifera seeds CAS
magnitude greater than that of the monomeric unit catechin (IC50 = 50 µmol/L). In the second model, procyanidines were effective in preventing conjugated diene formation in both the induction (IC50 = 0.1 µmol/L) and propagation (IC50 = 0.05 µmol/L) phases. The scavenging effect of tocopherol was weaker with IC50 of 1.5 and 1.25 µmol/L (Maffei Facino et al. 1994; Wollina et al. 2006).
The grapevine leaf extract is characterised by its content in flavonol glycosides and glucuronides, in particular
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 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).
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
of these two groups were 0.454±0.08 and 1.73±0.23 mg/ml respectively. VLHE also reduced the aorta contractions induced by KCl (80 mM). The relaxatory effects of VHLE on
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 was dissected and mounted in an organ bath containing Tyrode solution and colon contractions recorded by an isotonic transducer under 1 g resting tension. The GLHE (0.5- 4 mg/ml) reduced the contractions induced by KCl (60 mM), BaCl2 (4 mM), acetylcholine (1 µM)
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
Table 4: Overview of the main
3.1.2. Secondary pharmacodynamics
Platelet aggregation inhibition
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
The catechins found in grapevine leaves are mainly catechol and epicatechol (Boucheny and 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
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, and 19 Turkish traditionally used medicinal plants. Vitis leaves showed
The effect of grapevine leaf extract (GLEt) (extraction solvent not declared) on antioxidant and lipid peroxidation states in liver and kidney alcohol induced toxicity were 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 per 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 an ethanolic extract of Vitis vinifera L. leaves was also investigated. The ethanolic extract of Vitis 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 et al. 2006).
Anthocyanins have been reported to possess antioxidant and vasoprotective properties. There are some doubts whether these effects measured in in vitro experiments or in animal studies using high doses are relevant for humans (Prior, 2004).
The effect of grape leaf hydroalcoholic extract was investigated on isolated rat tracheal contractions induced by KCl and acetylcholine. The trachea was removed from male adult
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
Oral administration of procyanidins (OPCs) from grape seed produced a hypocholesterolemic effect in a
In normal and hypercholesterolemic rabbit aortas, OPCs significantly lowered the amounts of cholesterol bound to aortic elastin compared to controls (Wegrowski et al. 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
A reversible inhibition of intestinal enzyme activity (alkaline phosphatase, sucrose and dipeptidyl peptidase) was demonstrated in animal models (Tebib et al. 1994; PDR for Herbal Medicines, Thomson, 2004).
3.1.3. Safety pharmacology
No data available.
3.1.4. Pharmacodynamic interactions
Pharmacodynamic drug interactions of the herbal substance, herbal preparations or isolated constituents have not been reported.
The data obtained with herbal preparations and pure secondary metabolites differ, but show in most cases positive spasmolytic, vasorelaxant and
The data available allow only very limited conclusions on the plausibility of the therapeutic effects of the traditional use preparations of the monograph.
Based on available preclinical data, it can be concluded that the mechanism of action of orally administered extract in CVI is not known (i.e.
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 herbal substance, herbal preparations or isolated constituents are not available.
Flavonoids are the substances which are regarded to be 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
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
The toxicity of grapevine leaf aqueous extract
3.3.2. Repeat dose toxicity
Repeated dose – chronic toxicity
The toxicity of grapevine 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
Crowell et al. 2004:
histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats (corresponding to 21 g in a 70 kg human).
The mutagenic potential of grapevine leaf water extract
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 controls as well as a vehicle control were included. Neither of the assays provided evidence to suggest that the extract used had 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 grapevine 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).
Oligomeric proanthocyanidins from grape seed have demonstrated in vitro antimutagenic activity (Liviero et al. 1993).
In addition, among the pharmacologically active flavonoids (quercetin, quercetin
No data available.
So far, there is no evidence in the literature to indicate that flavonoids have any carcinogenic properties. On the contrary, a large number of in vitro studies have been carried out which suggest that flavonoids have
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. No carcinogenic activity was observed in the female rats and only slight carcinogenic activity in male rats. The carcinogenic effects, which manifested as renal tubule hyperplasia and nephropathy, were observed only in the
3.3.5. Reproductive and developmental toxicity
The maternal and embryofoetal toxicity of an orally administered aqueous preparation of grapevine 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 per day on days
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 by a commercial water extract from grapevine leaves
3.3.6. Local tolerance
No data available.
3.3.7. Other special studies
No data available.
Data on oral
In vitro and in vivo studies on the mutagenic potential of grapevine leaf extracts did not show mutagenic activity.
3.4. Overall conclusions on
The reported pharmacological effects are not considered contradictory to the traditional uses.
Specific data on pharmacokinetics and interactions are not available.
Data on oral
In vitro and in vivo studies on the mutagenic potential of grapevine leaf extracts did not show mutagenic activity.
Tests on carcinogenicity have not been performed.
As there is not sufficient information on reproductive and developmental toxicity, the use during pregnancy and lactation cannot be recommended.
Oral and cutaneous administration of grape leaf can be regarded as safe at traditionally used doses with the exception of patients with severe renal or cardiac disease e.g. renal and heart failure.
The data on safety are considered sufficient to support a European Union list entry for the following herbal preparation: Soft extract
4. Clinical Data
4.1. Clinical pharmacology
Pathophysiology of 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 and 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.
Procyanidins, like the anthocyanins, are flavonoids that are not available as monosubstances. Procyanidins are present in relevant amounts in standardised extracts such as grapevine leaf extracts (Vitis vinifera) and are formed through condensation reactions of flavonols (Hostettmann et al. 1994).
The complex syndrome of symptoms involved in CVI led to investigate the activity of grapevine 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.
Assessor’s overall conclusions on pharmacodynamics:
At present, the mechanism of action of grapevine leaf water extract in chronic venous insufficiency is not known.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
The grapevine 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 should be ascribed to the extract as a whole. It is 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 extract. The systemic bioavailability of flavonoids is probably relatively low and variable. Orally administered flavonoids are susceptible to
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 have 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.
The grapevine leaf extract represents a complex mixture of different classes of compounds, each having their own pharmacokinetic characteristics. An important portion of the components of grapevine leaf extract belongs to the group of polyphenols, such as anthocyanins, proanthocyanidins, catechins and phenolic acids (Bombardelli and Morazzoni 1995; Boucheny and
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.
The clinical information available for aqueous extracts of grapevine leaf includes the activity on mainly 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.
In all clinical studies, changes in leg volume and/or calf and ankle circumference were included in the endpoints studied. All confirmatory studies were designed 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 questioned about their subjective
4.2.1. Dose response studies
In all published clinical trials (Limoni C, 1996; Monsieur and Van Snick 2006; Schaefer et al. 2003; 2004; Kalus et al. 2004; Vix et al. 2007) film coated red grapevine leaf tablets, extract Vitis viniferae
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 week 6 with all treatments, but a further improvement at week 12 was seen only in the active treatment groups: at week 12, 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 oedema and improved CVI- related symptoms to a clinically relevant extent.
The treatments were well tolerated. All 260 patients who were enrolled and randomised 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 randomised study medication. Most patients completed the study up to 84 days of treatment. The mean duration of treatment for the 360 mg dose of RVLE was 81.9 days (n = 86) whilst the mean duration of treatment for the 720 mg dose of RVLE was 79.7 days (n = 84). Placebo was taken by 87 patients during the randomised treatment period (mean duration of treatment: 79.3 days) and by all patients during the
Kalus et al. 2004: The effect of RVLE on cutaneous microvascular blood flow, transcutaneous oxygen pressure (tcpO2), and leg oedema was investigated in a randomised,
Figure 2. 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 RVLE (AS 195) group, by 1.35±0.97 mmHg, contrasting with a reduction in the placebo group of 7.27±0.97 mmHg (fig. 3).
Figure 3. 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 3 weeks of treatment, statistically significant differences were also observed in ankle and calf circumference. After 6 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 RVLE could have a positive effect on the course of CVI. The minimum number of days of exposure was 38 in the RVLE and 24 in the placebo group, the maximum number 46 in the RVLE and 45 in the placebo group. Thirteen (18.3%) subjects out of 71 experienced 16 adverse events (AEs) during the
Limoni, 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 and Petrini 2004: This placebo controlled, randomised, parallel group study was carried out in 2004. 247 CVI patients
Petrini and Schaefer 2003: A
grapevine leaf extract RVLE. These results build on those from Harrison trial (1998) showed that RVLE 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
Monsieur and 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 6 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 2 weeks of treatment. This effect was still present and increased slightly after four and 6 weeks in all objective and subjective parameters tested in this study.
Table 5: Clinical studies on humans, in venous insufficiency
4.3. Clinical studies in special populations (e.g. elderly and children)
No information available.
4.4. Overall conclusions on clinical pharmacology and efficacy
The clinical efficacy of an extract from the red grapevine leaves (RVLE) was investigated in double blind,
Treatment with RVLE has been shown to lead to a reduction of leg volume, measured using both water plethysmography and calf and ankle circumference, and of the subjective symptoms investigated in the studies reviewed.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
The safety profile of grapevine 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 included 1073 patients in total (Kiesewetter et al. 2000; Kalus et al. 2004; Schaefer and 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, serious adverse events and deaths
Brito et al. (2008); Mur et al. (2006): Vine pollen allergies have been reported with Vitis vinifera pollen and an extract thereof in
The results of this prospective study show that Vitis 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).
Reports on immunoglobulin E
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
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 German Medicines Manufacturers’ Association (BAH) PSUR project. It summarises safety data from 01/Nov/2003 to 01/Sep/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.
Serious adverse events and deaths
The case of a 51 years old female patient is reported. She was hospitalised 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,
was negative for infections, immunological and metabolic causes. A hepatic
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 herbal products used 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.
5.4. Laboratory findings
No data available.
5.5. 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.
5.5.1. Use in children and adolescents
In the absence of sufficient safety data, the use of grapevine leaf in children and adolescents below 18 years of age is not recommended.
Hypersensitivity to the active substance.
5.5.3. Special warnings and precautions for use
To ensure a safe use the following statement should be labelled:
In the absence of sufficient safety data, the use in children and adolescents below 18 years of age is not recommended.
If the symptoms worsen during the use of the medicinal product, a doctor or a pharmacist should be consulted.
WEU indication and TU indication 1:
If there is inflammation of the skin, thrombophlebitis or subcutaneous induration, severe pain, ulcers, sudden swelling of one or both legs, cardiac or renal insufficiency, a doctor should be consulted.
In the event of inadequate or unsatisfactory symptomatic response within 2 weeks, a doctor should be consulted as oedema may have alternative causes.
Cutaneous use: The product should not be used on broken skin, around the eyes or on mucous membranes.
TU indication 2:
If rectal bleeding occurs during the treatment of haemorrhoids a doctor or a qualified health care practitioner should be consulted.
In the event of inadequate or unsatisfactory symptomatic response within 1 week, a doctor should be consulted.
TU indication 3:
In the event of inadequate or unsatisfactory symptomatic response within 1 week, a doctor should be consulted as oedema may have alternative causes.
5.5.4. Drug interactions and other forms of interaction
Drug interactions from clinical trials or case studies have not been reported so far.
5.5.5. Fertility, pregnancy and lactation
Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use of grapevine leaf during pregnancy and lactation is not recommended.
No fertility data available.
No data available.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect on the ability to drive and use machines have been performed.
5.5.8. Safety in other special situations
5.6. 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. The proof of safety is further supported 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.
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 6 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.
In several of the clinical trials objective and subjective symptoms of CVI appeared to be effectively reduced. 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.
Herbal preparations from grapevine leaves have been widely used. The safe use of the herbal preparations can be concluded on the basis of the
Sufficient data are available to develop a European Union monograph on the 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 after serious conditions have been excluded by a medical doctor.
•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 the soft water extract (2.5- 4:1). Therefore, inclusion of this herbal preparation in the European Union list of traditional herbal substances and preparations is recommended.