Proprietary Herbal Medicines in Circulatory Disorders Hawthorn Ginkgo Padma

Jorg Melzer and Reinhard Sailer

Abstract A look at the available clinical evidence of herbal preparations from hawthorn (leaves, flowers, fruits), Padma 28 (Swiss-Tibetan herbal preparation with 20 herbal drugs) and ginkgo (leaves) in terms of circulatory disorders shows the following: in chronic heart failure New York Heart Association (NYHA) II a metaanalysis showed that hydroethanolic extracts from hawthorn leaves and flowers, given at a daily dosage of 300 to 900 mg, can increase the maximum workload to up to 7 W when given concomitantly with standard therapy. The same was seen in one RCT with an extract from hawthorn fruits and flowers. The herbal preparations seem to be well tolerated and no interaction is known so far. The data on a possible decrease on blood pressure are inconclusive.

A meta-analysis on Padma 28 showed that two tablets given twice or three times a day over 16 weeks can increase the maximum walking distance by more than 100 m in patients with claudicatio intermittens. The preparation is well tolerated and safe. Research evidence from a meta-analysis on an extract from ginkgo shows that its use in the treatment of intermittent claudication can result in a significant but clinically modest improvement in pain-free walking for distances up to 34 m given at a dosage of 160 mg per day. Despite the general evidence that ginkgo preparations are relatively safe, physicians and therapists should be cautious when anticoagulants (i.e. warfarin) are given as well.

Keywords Circulatory disorder • Chronic heart failure • Peripheral arterial occlusive disease • Claudicatio intermittens • Hawthorn • Ginkgo • Padma 28

8.1 Introduction

To aid understanding of this chapter, some introductory remarks might be beneficial to help the reader appreciate the authors' point of view on herbal medicine.

Institute of Complementary Medicine, Department of Internal Medicine, University Hospital Zurich, Raemistr. 100, 8091 Zurich, e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4.8, © Springer-Verlag Berlin Heidelberg 2009

In our understanding, ethno-medicine is linked to cultures, traditions and empirical evidence. Modern medicine is guided by scientific results from experimental and clinical studies as well as - especially in recent years - by the method of evidence-based medicine (EBM) and regulatory policies. All these aspects might give an idea of the complex diversity that influences herbal medicine today and the medical system as such [1]. Our selection of the medicinal plants described in this chapter on circulatory disorders is somehow a subjective choice and might only highlight some of the above-mentioned aspects to a limited degree. Nevertheless, our choice of plants/drugs is clearly guided by the clinical point of view from the context of a policlinic setting at a university hospital in Switzerland and research evidence.

With respect to terminology we stick to current definitions: Herbal drug: "whole, fragmented or cut plants, parts of plants1, algae, fungi, lichen in an unprocessed state, usually in dried form but sometimes fresh" [2-4]. Herbal drug preparation: "preparations obtained by subjecting [herbal drugs] to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation" [2-4].

The herbal preparations given in this chapter come from different countries and cultures: in the Eastern tradition, as in Tibetan medicine, herbal drugs are often only cut and ground (powdered) and pressed into tablets (e.g. Padma 28). In the Western tradition, such as in European herbal medicine, herbal drugs are often used to prepare hydroalcoholic extracts, which themselves are processed into tablets or drops, for instance hydroethanolic hawthorn extracts (e.g. Faros, Crataegisan). Each of the herbal preparations mentioned in this chapter can be called an herbal medicinal product (HMP) according to the European Agency for the Evaluation of Medicinal Products (EMEA) [4]. As HMPs are approved by their respective health authorities, their efficacy and quality records cannot be compared to that of supplements (synonym: nutraceuticals, food supplements), for which different standards of approval are necessary, but have a tradition in other regions of the world (e.g. North America, Asia), too.

8.2 Hawthorn 8.2.1 Plant

Hawthorn (Crataegus) is a member of the family Rosaceae (subfamily Maloideae). The plant is a thorny shrub or small tree and grows in temperate zones especially of the Northern but also Southern Hemisphere [5].

Of over 100 species regarded as genuine, two are regularly used for officinal herbal preparations in Europe: Crataegus monogyna - hawthorn with one style or C. laevigata - with two styles (synonym: C. oxyacantha L.). Other species are C.

1 I.e.: flower (flos - in botanical terms), leaf (folium), herb (herba), fruit (fructus) root (radix, rhizome).

pentagyna - with five styles - or those well known in China or Japan, C. cuneata and C. pinnatifida [5-7]. Besides these botanical terms there exist various names in the different countries which are often used synonymously: China: Shem zha; Germany: Weissdorn; England: White thorn; France: Aubepin; Italy: Biancospino; Norway: Hagtorn; Poland: Glog [5], [8-11].

Note that some of the different Crataegus species may be preferred traditionally in one of the various medical systems in the world and that the parts of the plant used as an herbal drug may differ as well. For example, in modern European herbal medicine most often the leaves and flowers of the two species mentioned above are used today, but traditionally their fruits are used as well [5, 12].

8.2.2 Tradition

Knowledge of the use of hawthorn in ancient times is limited. According to some authors, the plant was first mentioned in Chinese medicine in the pharmacopoeia Tang Ben Cao in 659 A.D [13]. Although ancient Greek writers such as Dioscorides mention Oxyakantha in the first century A.D., it remains questionable whether he was really referring to hawthorn [14, 15]. In medieval times the fruits were said to be eaten to treat digestive disorders and the roots to treat small injuries [16]. Then, in 1753 Linnaeus named hawthorn Crataegus oxyacantha L. and Jacquin divided the species C. oxyacantha and C. monogyna [5]. But it was only in the late 1800s that European doctors set up the first experiments on the clinical use of hawthorn for heart disease [13, 16]. Beringer is said to have suggested the use of the extract of berries as a tonic for the heart [8, 17]. In traditional medicine Crataegus is still used as a kind of heart tonic as well as heart and vascular remedy or to regulate blood pressure. Finally, it has some standing as a 'calmative agent for heart and soul' (reduction of nervous heart complaints). One can still find a variety of combinations of hawthorn with other herbal plants which derive from this tradition (e.g. calming effects with hop, passion flower or valerian). For these combination preparations an additive effect of hawthorn has also been discussed in the literature [18-20].

In Traditional Chinese Medicine (TCM) berries from Chinese hawthorn are used to treat disturbed digestion, diarrhoea, feeling of fullness, inappetence of children, arteriosclerosis or hypercholesterolaemia for example [5, 13], [21-23].

For many of these traditional uses no clinical trials are available.

8.2.3 Chemistry and Pharmacology 8.2.3.1 Compounds

The main constituents of officinal hawthorn preparations are thought to be flavonoids (flavons: e.g. hyperosid, vitexinrhamnosid; flavonols: e.g. rutin) and flavanols (e.g.

catechin, epicatechin or procyanidins which, depending on degree of polymerisation, are divided into oligomeric: n = 2 to 8 and polymeric: n > 8). Flavonoids have been found in all parts of the plant of those species examined so far. But as the pattern of flavonoids can be very different, the species can be distinguished by their main flavonoid pattern (thin-layer chromatography) [5, 9, 24]. The spectrum of fla-vanols, i.e. oligomeric procyanidins (OPC), is similar between the different species, yet considerable quantitative differences can be seen between species as well as parts of the plants [5].

Further constituents of hawthorn species are triterpens (e.g. ursolic acid, oleano-lic acid, crataegolic acid) and phenolic acids (e.g. chlorogenic acid, caffeic acid) or amines (e.g. cholin, acetylcholin, phenylethylamin) [5, 25].

The herbal drug from flowers and leaves can contain 1 to 3% OPCs and 1 to 2 % flavonoids [5, 26]. The various herbal drugs from hawthorn can be processed into various herbal preparations, and their chemical compositions can differ greatly depending on factors such as vegetation period of the plant, extraction process and extractant (e.g. with water the OPCs can be extracted easily, whereas with alcohol the polymeric procyanidins and triterpens are more easily extracted).

The hydro-ethanolic hawthorn extracts, that is to say the herbal preparations made from them, can be standardized to a certain amount of constituents. Those preparations most widely studied in clinical trials are standardized to contain 18.75% OPCs or 2.2% flavonoids [25].

8.2.3.2 Pharmacology

To date, the mode of action of hawthorn preparations has not been fully explained, although quite a number of experimental studies [9,13,22,25], [27-29] and reviews do exist [5, 13, 25, 30]. Different in vitro and in vivo models showed the following pharmacological properties of hawthorn (extracts from leaves, flowers, fruits or fractions of flavonoids or procyanidins): positive inotropic and negative bath-motropic action, increased coronary blood flow and myocardial circulation, decrease of peripheral vascular resistance and hypotensive action as well as triglyceride- and cholesterol-lowering or antioxidative activities [22, 25], [27-29], [31]. According to these studies, procyanidins and flavonoids seem to be involved in the effects of extracts from crataegus [25, 27, 32].

The mechanisms of action discussed on a molecular level are the inhibition of phosohodiesterase activity with increase of intracellular cyclic adenosine monophosphate (cAMP), inhibition of membranic Na+/K+-ATPase activity of the heart muscle and the angiotensin-converting enzyme, and extension of the effective refractory time [22, 25, 27, 28, 30, 33, 34].

Whether and to what extent central nervous system effects contribute to the efficacy of herbal preparations of hawthorn has not been examined. Some clinical observations indicate that the effects of herbal preparations from hawthorn might depend on the neuro-vegetative state of the patient, i.e. they might vary according to the parasymathico- or sympathicotonus [22, 28, 34].

Concerning the daily dosage, a monograph of the European Scientific Cooperative on Phytotherapy (ESCOP) mentions, among other things, 1 to 1.5 g of the herbal drug as tea infusion 3 to 4 times or 160 to 900 mg of hydro-alcoholic extracts with a drug-to-extract ratio (DER) of 4 to 7:1 with a defined content of OPCs and flavonoids [25].

8.2.3.3 Pharmacokinetic Properties

Human studies on resorption, distribution, metabolism and elimination of herbal preparations of hawthorn or their constituents like OPCs or flavonoids are not available [13, 25, 32, 35].

Experimental studies on animals indicate that some constituents of hawthorn widely distribute into the organism including the brain [36].

Information on the influence of age and diseases (e.g. kidney or liver disorders) do not exist. Yet therapeutic evidence does not show a limitation for the use of hawthorn preparations for the elderly or multimorbid patient [16, 18, 37].

One pharmacokinetic trial examined the possible interactions between hawthorn and a synthetic drug. In that study, the concomitant administration 0.25 mg digoxin and 900 mg hawthorn extract in healthy volunteers did not show a significant difference in any measured pharmacokinetic parameter when compared to the administration of digoxin alone [38].

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