Distribution and Importance of the Plant
The genus Crataegus originates from northern temperate regions and comprises about 280 species depending upon botanical sources. It is widespread in western Asia, North America and in Europe, where 21 species have been indexed. Hybridization is frequent in this genus, causing many identification difficulties. Among the best-known species are Crataegus monogyna Jacq. and Crataegus laevigata (Poiret) DC (= C. oxyacantha auct.= C. oxyacanthoides Thuill.) belonging to the Eurasian subgenus Crataegus which are most common and are of growing pharmaceutical use. They have lobed or divided leaves, while the northern American subgenus americanae is characterized by entire or weakly lobed leaves.
These deciduous, ramified, thorny shrubs produce white-pinkish scented flowers in corymbs during midsummer and the resulting red fruits remain on the trees until eaten by birds in winter. They show some differences in habitat: C. monogyna is found mainly in open fields, thickets and used as quickset hedges, while C. laevigata prefers woods or their borders. Ornamental pink- or red-flowered cultivars of C. laevigata such as uCoccinea plena”, “Rosea”, “Rubra” () are planted in avenues, parks and gardens.
C. laevigata is characterized by ovobate leaves, with 3-5 obtuse few profound lobes, 2-3 styled flowers, red anthers and a fruit with 2-3 seeds. C. monogyna shows 3-7 more acute lobes on the leaves, more pleasantly perfumed one-styled flowers with black anthers and a one-seeded fruit. C. monogyna, considered as a Euro-Siberian species, covers a wide area in Europe from Sweden to Russia and Greece and was introduced into northern America, while C. laevigata is a sub-Atlantic species found in western and central Europe.
Unripe hawthorn fruits are astringent and unpleasant but ripe fruits are edible; generally insipid except those of C. azarolus which are acidulous and aromatic. Seeds have been found in European prehistoric lacustrine sites, while a flour made from the fruit (preferably cooked before being ground) was used in a kind of bread in central Europe until the mid-20th century.
Nevertheless, hawthorn, besides its wide horticultural use, should mainly be considered a pharmaceutical plant. Hawthorn teas and pharmaceutical preparations belong to the most commonly studied drugs of plant origin, which are widely prescribed or used in self-medication. Many Pharmacopoeias index indiscriminately both C. monogyna and C. laevigata parts, mainly flowers or leaves with flowers (flowering tops), and sometimes fruits. The third edition of the European Pharmacopoeia includes the following five genera as pharmaceutical sources: C. laevigata and C. monogyna are more commonly used, while C. pentagyna Waldst. et Kit. ex Willd., C. nigra Waldst. et Kit., and C. azarolus L. have less frequent utilizations.
Pharmacological properties mainly focus on the cardiovascular effects and sedative actions. Hawthorn is officially recognized by health authorities in different countries for its action against mild cardiac insufficiency not requiring digitalis glycosides (stages I—II of the New York Heart Association, NYHA), against mild bradyarrhythmias in the elderly, and also as a sedative in neurotony including sleep and common anxiety disorders.
Its action on the heart has received special attention in Germany. It is mainly characterized by a positive inotropic action (enhanced myocardial contractility), partly due to inhibition of c-AMP and c-GMP phosphodiesterases (Weihmayr and Ernst 1996) but also to other mechanisms. This was demonstrated on heart preparations or in animals for extracts (water, alcoholic), plant powder, flavonoid-rich fractions, and isolated flavonoids such as vitexin-2′-O-rhamnoside, luteolin-7-O-glucoside, rutin, quercetin, while hyperoside gave either negative or positive effects according to the system used. It must be noted that flavanolic fractions, such as total, polymeric and more particularly oligomeric proanthocyanidins exhibit an important influence.
Other important cardiac properties include a neutral, or more often, moderately positive chronotropic action (heart rate increase), in addition to an enhancement of atrioventricular conductibility (positive dromotropic action. A few cases of heart rhythm attenuation have been reported.
Another well-known effect of Crataegus is the increase in coronary flow observed in the perfused heart. Other parameters, such as improvement of the heart ejection fraction, the occurrence of a mild anti-arrhythmic effect and a decrease in vascular peripheral resistance, all result in better cardiovascular performance. Consequently, a better tolerance to oxygen deficiency and exercise in clinical studies is observed.
Moreover, oral administration of the standardized extract induces a significant decrease in mortality after ischemia reperfusion in animals. An aqueous fraction of this extract, rich in low-molecular oligomeric procyanidins and poor in flavonoids, is significantly more active against ischemia-reperfusion. This fraction also proved to be a more efficient free radical scavenger and elastase inhibitor than the flavonoids alone.
These protective activities have frequently been attributed to polyphenols. Antioxidant or Free radical scavenging properties have been demonstrated for many flavonoids, for flavanols and procyanidins. We reported important anti-lipoperoxidative actions in extracts of fresh hawthorn organs, especially floral buds, young leaves and unripe fruits, clearly correlated to high phenolic contents. This led us to study phenolics and their action in hawthorn tissue cultures.
Conventional Practices for the Propagation and Production of Pharmaceuticals, and Demand on the World Market
Propagation of specific cultivars such as ornamental ones can be made by grafting, for example on C. laevigata (). It should be considered that exposure to cold in winter is necessary for the very slow seed germination process, which can take up to 18 months. This delay can be reduced by scarification, diluted sulfuric acid, fermentation treatments, or by the early sowing of unripe fruits.
Crataegus belongs to the Rosaceae, which together with other genera like Chaenomeles, Sorbus, Pyrus, Malus, Cydonia, Cotoneaster, and Pyracantha are susceptible to fire blight (Erwinia amylovora). This is responsible for spectacular damage to fruit trees or its transmission. In France, a decree (24 December 1994) officially prohibits “the importation, propagation, marketing and planting” of different species known as vectors of this disease. This includes “all species and cultivars of Crataegus” besides some varieties of Cotoneaster, Pyracantha, Pyrus, and Malus.
In north-eastern France, however, the decree of 1994 authorizes, by special demand, the sowing and planting of hawthorn by professionals in regions neighboring Benelux and Germany where its propagation is not prohibited.
Production of Pharmaceuticals, Demand on the World Market
Hawthorn is not a source of isolated individual pharmaceutical molecules. Moreover, the major therapeutically used flavonoids are ubiquitous molecules, rather easy to extract, found in high yields in other plant sources (rutin, citroflavonoids, diosmin).
Flowers and flowering tops are often used in herbal teas, especially in Europe, the fruits are used less often – except in the USA. The plant powder (dried or freeze-dried) as well as spray-dried extracts are commonly used in capsules sold as OTC or under medical prescription. The dried plant powder is an extraction product used for the manufacture of galenical forms (tincture, fluid or concentrated extract) or other standardized preparations used either alone or more frequently in complex pharmaceuticals. In Europe, despite the extensive distribution of the plant, Italy, Yugoslavia, and Albania are the main producers. France, although the plant is very common, imports it from southern Europe.
In the USA, the market for medicinal botanicals, one of the fastest-growing pharmaco-economical segments, approached $4billion in 1998, including nearly 270 million prescriptions. The sales figures for hawthorn fruit closely follow those of the presently popular herbal medicines such as green tea, kava, ginseng, grape seed, echinacea, and ginkgo.
In Europe, the top sales of herbal remedies are in Germany and France, followed to a lesser extent by Italy and the United Kingdom. In Germany, 19% of the total cardiac drug prescriptions are phytotherapeutic and hawthorn is one of the major ones. In France, an increased number of phytotherapeutical neurosedative prescriptions has been noted. Hawthorn, in association with Valeriana, Passiflora, and Ballota, is considered by an increasing number of practitioners as a potential “non-harmful” alternative to synthetic tranquilizers to be tested first in moderate neurotonic disorders.
In 1996, the number of hawthorn-specific preparations (alone or associated with other plants or pharmaceuticals) was 81 in Germany, 39 in France, 20 in Switzerland, 14 in Italy and 1 in the United Kingdom.
Crataegus (Hawthorn): Summary and Conclusion
Hawthorn is one of the major modern plant sources for phytotherapeutics applied in mild heart disorders and neurotony. Its activities and those of standardized extracts are demonstrated in many modern ex vivo or in vivo experiments in animals and in a growing number of clinical studies in humans. The main actions have long been attributed to its high content in polyphenols, flavonoids and flavanols – mainly oligomeric proanthocyanidins which seem more efficient in myocardial and vascular effects. These polyphenols are also present in other pharmaceutical plants and in plant foods. The intake of polyphenol-rich foods such as onions, tea, grapes, and wine plays a role in the prevention of heart disease, atherosclerosis and some degenerative processes. Many pharmacological properties were shown with various intensities according to the kind of phenol: antioxidative properties (inhibition of lipid peroxidation, radical scavenging, protection of human low density lipoproteins against oxidation), enzyme inhibitions (elastase, collagenase, lipo- and cyclo-oxygenase) etc.
Studies on phenolics in hawthorn were made mainly on tissue cultures of the widespread Crataegus monogyna. As early as 1977, Schrall et al. aimed to obtain active phenols by means of vitrocultures and found phenolic acids together with proanthocyanidins, including unidentified dimers. The study of Kartnig et al. showed the possibility of not only obtaining flavonoids, but also proanthocyanidins, and like Schrall, they found a higher proportion of proanthocyanidin oligomers in tissue culture than in the plant. These oligomers have been demonstrated in several plants and hawthorn to be more active.
Our aim was to establish a long-term, high phenolic-producing tissue culture from hawthorn. The floral bud produced calluses which, during the first 63 weeks of their establishment, showed the formation of reddish areas. Due to prior experience in buckwheat tissue cultures, the presence of anthocyanins led us to expose the cultures to continuous light which induced higher phenolic synthesis. Calluses and suspension cultures showed similar phenolic profiles, especially for proanthocyanidins and catechins, except that cell suspensions produced very few anthocyanins and practically no flavonoids. Feeding with shikimic acid markedly enhanced the production of one of the most interesting substances, B2 dimeric proanthocyanidin (also present in fruit and vegetables). Our cell suspension produced more B2 dimer and epicatechin than the plant flower bud in these experiments. The callus extracts exerted important oxygen-scavenging activities, clearly bound to phenolics as seen by the comparison between IC50 of young (days 0-12) and older (20 days), phenolic-rich calluses. Despite the fact that the bud and other plant-part extracts are far better antioxidants, while containing much higher yields of phenols, an optimization and systematic study of the production in cell suspension of derivatives such as B2 dimer could be interesting. Proanthocyanidin B2 and other type B dimers or trimers are absent from the catalogues of fine chemicals and are needed for further pharmacological experiments, particularly on their metabolism in organisms.
Selections from the book: “Medicinal and Aromatic Plants XII” (2002).