IVY EXTRACTS
Transcription
IVY EXTRACTS
Effectiveness and use of an old medicinal plant Hartmut Landgrebe and Rudolf Matusch, Marburg, Frank Runkel and Martina Hecker, Frankfurt am Main Translation from: ”Wirkung und Anwendung einer alten Heilpflanze” Pharm. Zeitung Nr. 35, September 1999,, S. 11-15 Ivy leaves have been used for centuries to treat numerous diseases. Today, they are used successfully in the treatment of respiratory tract disease in particular. Dry extracts of the drug, which is hardly found officially any more, are administered as finished medicines in the form of syrups, drops, suppositories and, more recently, effervescent tablets. The expectorant and anti-obstructive effects and the excellent therapeutical results achieved in obstructive respiratory tract disease, which are supported with recent clinical studies, places the drug ivy in the centre of attention as far as phytopharmaceuticals are concerned. Further fields of application for ivy leaves ought to result from the elucidation of causal connections with regard to their effects. Respiratory tract disease is a wide-spread disease of great socio-economic significance. Apart from coronary heart disease, chronic bronchitis counts among the most frequent diseases of modern civilisation. Approximately 15 per cent of all medical certificates are handed out as a result of respiratory tract disease and over 10 per cent of all deaths in Germany are attributed to bronchopulmonary disease. The overall costs caused by lung disease amount to close on 38 billion DM (17) annually. In the case of respiratory tract disease, the bronchial mucosa is more or less inflamed to a great extent. Consequently, the normal composition of glandular secretion, which is necessary for effective mucociliary clearance, is altered, as a result of which trouble-free removal of germs and contaminants is no longer guaranteed. The inflamed and swollen bronchial mucosa and mucus, which continues to be become more viscous, lead to the symptoms cough, shortness of breath and expectoration. Whereas small children get acute bronchitis, for the most part due to a virus, approximately four to eight times a year, adults suffer from such an infection approximately two to three times a year. In the case of infants and small children, the infections often lead to congestion of secretion and mucosal swelling with subsequent obstruction of the respiratory tract due to viscous mucus. Because of the small lumen of the respiratory tract in children, minor accumulation of secretion is sufficient to constrict the airways dramatically. Measures which encourage expectoration in the case of bronchitis are therefore of central importance as far as infants and small children are concerned and are considered essential by paediatricians 2 . Figure 1: non-flowering branch with lobed leaves edged Photos: Hartmut Landgrebe, Marburg Figure 2: flower-bearing branch with smooth leaves Chronic bronchitis predominates within the group of lung disease, the definition of which, according to the WHO, is when coughing and/or expectoration occurs on at least two successive years for the majority of at least three months. The main symptom of chronic bronchitis is an increased production of mucus. In the course of time, respiratory tract obstruction develops in approximately 15 to 20 per cent of all chronic bronchitis cases; progressive shortness of breath reduces resilience. Without intervention, these patients die on average ten years earlier than a person with healthy lungs (17). A reduction in the exacerbation rate through expectorants can improve the course of the disease and is associated with benefits for the patient, particularly as far the risk of developing right ventricular heart failure as chronic bronchitis advances is concerned. In the case of both acute and chronic bronchitis, an increase in the production of mucus, which is usually of a viscous nature, leads as a result to coughing which should serve to remove excess secretion. The object of treating chronic bronchitis is to relieve symptoms by improving expectoration with the help of medicaments which have secretolytic and mucolytic properties and to prevent eventual bronchial spasms. Extracts made from ivy leaves can liquefy secretion through their secretolytic and mucolytic properties and thus facilitate expectoration. Spasmolytic effects counteract bronchial obstruction which frequently occurs in the case of respiratory tract infections (22, 24, 31). Spread world-wide Ivy (Hedera helix L.) is a winding plant with clinging roots which it uses to climb up trees or walls. Its evergreen leaves on the non-flowering branches are triangularly to pentagonally lobed and have white veins (illustration 1). The leaves on the flowering branches have, on the other hand, entire margins and are rhomboid to lanciform (figure 2). As a result of these different leaf forms, it can occur that both the lobed leaves of non-flowering branches as well as the smooth edged leaves of flowering branches are found in the drug which is collected in spring through to early summer. Ivy and its various subspecies are spread almost throughout the world. The plant has been used for centuries in different forms of administration to treat diverse diseases. Decoctions made from the leaves of the ivy plant were already used in folk medicine during the 19th century to treat among other things catarrh of the respiratory tract. Today, respiratory tract disease is still being 3 treated successfully with extracts made from ivy. Moreover, ivy leaves and its components have been described as having antiviral (29), antimycotic (15, 36, 39), anthelmintic (16), molluscicidal (13), cytotoxic (28) and anti exudative (37) effects. Figure 3: structural comparison of hederacoside C and α-hederin Components of ivy extracts The most important therapeutic substances found in ivy leaf extracts are those belonging to the class of triterpenoid saponins, particularly saponin glycosides of a hederacoside nature which bring about the expectorant effect of the drug. The main saponin is hederacoside C and αhederin which results from ester hydrolysis (figure 3) and which is principally responsible for the spasmolytic effect. The presence of triterpenoid saponins in a normal dried ivy leaf extract can be rapidly detected and their content determined by employing HPLC and ultraviolet detection (38) (figure 4). The amount of components present in a given extract depends on the method used for its preparation, so that extracts made from ivy leaves using different procedures may indeed vary with respect to their effectiveness. Although a number of effects related to dried ivy leaf extracts and their components have been described, the majority of the uses handed down from folk medicine (8) has not as yet been causally clarified. For this reason, the therapeutic effectiveness of ivy should not be limited only to the presently recognised indication ”bronchial diseases” and the components causally responsible for the treatment of this indication. This supposition is supported by the fact that numerous and to a certain extent unknown components have been identified. The outline chromatogram (figure 5) from an ELS detector shows a large number of various substances found in a normal dried ivy leaf extract, where the content of saponins amounts to only approximately 10 per cent of the total content of the components. Further constituents are rutin 4 flavonoids as well as numerous vegetable acids such as chlorogenic acid and caffeic acid and their derivatives (figure 6). Figure 4: HPLC chromatogram of a dried ivy leaf extract; 1: hederacoside C, 2: α-hederin Pump: Waters-MSDS 600E; detector: photodiode array detector Waters 991; column: Macherey and Nagel Nucleosil 100-5 C-18; 4.6x250; mobile phase: 1.3 ml/min.; acetonitrile:water = 25:75, to 35 in five minutes; to 43 in 11, to 60 in 16 and to 100% acetonitrile in 25. Chromatogram evaluation: Waters 991 software. 5 Figure 5: HPLC outline chromatogram of a dried ivy leaf extract; 1: hederacoside C; 2: α-hederin; 3: rutin; 4: chlorogenic acid Pump: Waters-MSDS 600E; detector: ELSD detector SEDEX 55 (2.1 bar; 50 °C), modified (publication in preparation); column: Macherey and Nagel Nucleosil 100-5 C-18; 4.6 x 250; mobile phase: 1.3 ml/min., acetonitrile (0.1% TFA) : water (0.1% TFA) = 8 : 92; to 25 in 25 minutes, to 40 in 60 and to 805 acetonitrile in 80 (0.1% TFA). Chromatogram evaluation: Waters 991 software. Chlorogenic acid Figure 6: further components of ivy leaves Rutin Caffeic acid 6 Therapeutically relevant effects The expectorant action of ivy is based on secretolytic and mucolytic effects which the hederaglycosides have as a result of their saponin character. Secretolysis is initiated via parasympathetic afferent fibres by reflexed stimulation of the beaker cells in the bronchi and bronchial glands (27). The increased production of liquid which consequently follows reduces mucous viscosity and thus facilitates its removal. At the same time, the surface tension of the mucus is reduced as a result of the surface-active effect of the saponins; this explains mucolysis. Mucous becomes thinner, facilitating previously obstructed ciliary movement and accelerating the ciliary current; mucus is able to be removed more easily. The anti-obstructive effect is based on a spasmolytic action of the components on bronchial muscles. This spasmolytic effect has been studied both in vitro on the isolated ileum of the guinea-pig (35) as well as in vivo on the counter-action of an induced increase in defaecation in mice. In addition, bronchial spasm provoked in guinea-pigs was able to be relieved (3). The range of the spasmolytic effectiveness was measured using papaverine, which acts directly on muscle fibre, as a reference preparation. Results from clinical trials The trials published up to now on the clinical effectiveness of ivy were carried out using a dry extract of ivy leaves (Prospan®), which is manufactured according to a special procedure, in various forms of administration. As far back as in the fifties, studies were published, where this extract proved to be an effective and very well tolerated therapeutic in both children and approximately 240 adults all of whom were suffering from pertussis or bronchial disease. In comparison with the control group, the length of time the subjects were ill reduced by up to ten days (5, 20, 34). In further studies of approximately 500 children, amongst whom about fifty were infants, who were suffering from chronic obstructive respiratory tract disease and, to a certain extent, spastic bronchitis, whooping cough, tracheitis and tracheobronchitis, treatment led in almost all cases to a significant improvement in symptoms or to disappearance of complaints (4, 6, 14, 32, 33). Similarly good results were achieved after treating a total of approximately 230 adults with acute and chronic bronchitis (1, 2, 19, 30) and 260 children with whooping cough and spastic or uncomplicated bronchitis (33). These positive results were also clearly confirmed in more recent studies. The practical secretolytic and anti-obstructive effectiveness was proved in a multicentric study of 113 children with obstructive respiratory tract disease carried out in pneumological centres (18). In addition, it was able to be shown, in the course of a double-blind clinical trial where an extract made from ivy leaves was compared with the synthetic mucolytic Ambroxol, that the ivy extract was just as effective as Ambroxol and had a tendency to being even better with regard to objective (spirometry and auscultation) and subjective parameters (patient diary) as far the treatment of 99 patients with chronic, and to a certain extent obstructive, bronchitis was concerned (25). The rectal administration of suppositories also proved to be effective upon consideration of the change in bioavailability: in order to achieve the same effect, the extract must be applied in doses approximately 4.5 times higher than the oral doses of an ethanolic preparation (21). You may find links to the title topic in the Internet on the PZ’s service page under http://www.pharmazeutische-zeitung.de/service.htm 7 A comparative study of the various oral forms of administration demonstrated that the addition of ethanol obviously improves the effectiveness of the ivy extract, so that an aqueous preparation needs to be administered in doses which are approximately 2.5 times higher than those of an ethanolic preparation (7). This result was confirmed by a current study on the effectiveness of an ethanolic extract in comparison with a normal ethanol-free preparation (9). The dosage recommendations for ethanol-free preparations made from ivy leaf extracts must more surely be thought over again. In a current, double-blind, cross-over clinical trial, the special extract was clinically clearly superior to and statistically significantly more convincing than placebo treatment, when given to children with obstructive respiratory tract disease (22). It was also demonstrated at the same time that the bronchodilating effect of the preparation three hours after ingestion is almost comparable to that of an inhalational ß2 sympathomimetic, e.g fenoterol. This confirms the statements made by Dietrich Hofmann (University Hospital Frankfurt/M., Centre for Paediatrics) in two expert reports (11, 12). The good effectiveness and tolerance of the preparation was also confirmed in a current study of 248 patients with inflammatory respiratory tract disease carried out under practice conditions (10). The dry extract of ivy leaves is thus, as has been proved, an effective and well tolerated therapeutic when used to treat obstructive respiratory tract disease, which aids the removal of excessively produced mucus resulting from dyscrinism and which has an anti-obstructive effect. At the same time, its spasmolytic effect is almost comparable to that of a ß2 -sympathomimetic such as fenoterol. 8 References (1) Arch, F., Erfahrungsbericht über die Aerosol-Behandlung der Bronchitis mit Prospan. Notabene Medici 6 (1974) 1 - 8. (2) Böhlau, V., Therapeutische Erfahrungen mit Prospan bei chronisch-obstruktiven Atemwegserkrankungen. Notabene Medici 11 (1977) 26 - 29. (3) Bucher, K., Pharmakologische Studie über Hedera-Extrakte. Biozentrum der Universität Basel (1974). In: Mayer et al., Pharm. Ztg. 42 (1987). (4) Düchtel-Brühl, Ä., Ergebnisse der Behandlung spastischer Bronchitiden im Kindesalter mit Prospan. Med. Welt 10 (1976) 481. (5) Friede, K.H., Aerosol-Behandlung der Bronchitis mit Prospan. Med. Klinik 52 (1957) 62 - 63. (6) Gulyas, A., lämmlein, M.M., Zur Behandlung von Kindern mit chronisch-obstruktiver Bronchitis. Sozialpädiatrie 14 (1992) 632. (7) Gulyas, A., Repges, R., Dethlefsen, U., Konsequente Therapie chronisch-obstruktiver Atemwegserkrankungen bei Kindern. Atemw. Lungenkrkh. 23, Nr. 5 (1997) 291 - 294. (8) Hager, Handbuch der pharmazeutischen Praxis. Springer-Verlag Berlin-Heidelberg, 5. Aufl. 1993, S. 398 - 407. (9) Hecker, M., Hustentropfen mit Ethanol - deutlich bessere Wirksamkeit. T&E Pädiatrie 11 (1997) 648 - 650. (10) Hecker, M., Wirksamkeit und Verträglichkeit von Efeuextrakt bei Patienten mit Atemwegserkrankungen. Natura Med. 14, Nr. 2 (1999) 28 - 33. (11) Hofmann, D., Gutachterliche Stellungnahme zur Wirksamkeit und Verträglichkeit von Prospan Kinderzäpfchen. 1995 (not published). (12) Hofmann, D., Gutachten zu Prospan Hustenlöser-Saft, 1996 (not published). (13) Hostettmann, K., Saponins with Molluscicidal Activity from Hedera helix L. Helv. Chim. Acta 63 (1980) 606 - 609. (14) Huber, E.G., Gutachten, 1975 (not published). (15) Ieven, M., et al., Screening of Higher Plants for Biological Activities 1. Antimicrobial Activity. Planta Med. 36 (1979) 311 - 321. (16) Julien, J., et al., Extracts of the Ivy Plant, Hdera helix, and their Anthelmintic Activity on Liver Flukes. Planta Med. 51 (1985) 205 - 208. (17) Konietzko, N., Fabel, H., Weißbuch Lunge. 1996, S. 2 - 9, 12 - 14. (18) Lässig, W., et al., Wirksamkeit und Verträglichkeit efeuhaltiger Hustenmittel. Prospan Kindersaft bei rezidivierenden obstruktiven Atemwegserkrankungen. TW Pädiatrie 9 (1996) 489 - 491. (19) Leskow, P., Behandlung bronchialer Erkrankungen mit dem Phytotherapeutikum Prospan. Z. f. Phytotherapie 2 (1985) 61 - 64. (20) Loos, M., Erfahrungen mit Prospan in der Klinik bei krankheitsbildern des Respirationstraktes. Med. Klinik 39 (1958) 1693 1695. (21) Mansfeld, H.-J., et al., Sekretolyse und Bronchospasmolyse. Klinische Studie: Behandlung von Kindern mit chronisch obstruktiven Atemwegserkrankungen mit Prospan. TW Pädiatrie 8 (1997) 155 - 157. (22) Mansfeld, H.-J., et al., Therapie des Asthma bronchiale mit Efeublätter-Trockenextrakt. Münch. Med. Wschr. 140, Nr. 3 (1998) 32 - 36. (23) Mayer, H., et al., Der Efeu - eine alte Kult- und Heilpflanze. Pharm. Ztg. 131 (1987) 2673 - 2676. (24) Meier, E., Husten und Hustenmittel. Apoth. J. 1 (1991) 48 - 52. (25) Meyer-Wegener, J., Liebscher, K., Hettich, M., Efeu versus Ambroxol bei chronischer Bronchitis. Z. f. Allg.med. 69 (1993) 61 66. (26) Monographie der Aufbereitungskommission des BGA: Hederae helicis folium, Efeublätter. 1988. (27) Mutschler, E., Arzneimittelwirkungen. 7. Aufl. 1996, S. 518 - 519. (28) Quetin-Leclerq, J., et al., Cytotoxic Activity of Some Triterpenoid Saponins. Planta Med. 58 (1992) 279 - 281. (29) Rao, S.G., Sinsheimer, J.E., Cochran, K.W., Antiviral Activity of Triterpenoid Saponins containing acylated beta-amyrin Aglycones. J. Pharm. Sci. 63 (1974) 471 - 473. (30) Rath, F., Klinische Prüfung der Wirksamkeit des Hustenmittels Prospan. Fortschr. Med. 22 (1968) 1015 - 1016. (31) Reuter, H.D., Behandlung von Erkältungskrankheiten mit Phytopharmaka. Sozialpädiatrie 14, Nr. 3 (1992) 194 - 203. (32) Rudowski, Z., Latos, T., Hedera helix: Wirksam bei Bronchitis im Kindesalter. Ärztl. Praxis 80 (1980) 2561 - 2562. (33) Schmid, F., Indikationen für Prospan-Behandlung bei Kindern. 1973 (not published). (34) Stöcklin, P., Klinische Erfahrungen mit dem Hustenmittel Prospan. Praxis 41 (1959) 934 - 938. (35) Trute, A., et al., In Vitro Antispasmodic Compounds of the Dry Extract Obtained from Hedera helix. Planta med 63 (1997) 125 129. (36) Tschesche, R., Wulff, G., Über die antimikrobielle Wirksamkeit von Saponinen. Z. Naturforsch. 20B (1965) 543 - 546. (37) Vogel, G., Marek, M.L., Pharmacology of some Saponins. Arzneim. Forsch. 12 (1962) 815 - 825. (38) Wagner, H., Reger, H., Folium Hederae-Extrakte. Dtsch. Apoth. Ztg. 126 (1986) 2613 - 2617. (39) Wolters, B., Die Verbreitung antibiotischer Eigenschaften bei Saponindrogen. Dtsch. Apoth. Ztg. 106 (1966) 1729 - 1733. 9 Addresses of the authors: Hartmut Landgrebe Professor Dr. Rudolf Matusch Philipps University Marburg Pharmacy Faculty Marbacher Weg 6 D-35037 Marburg Dr. Frank Runkel Dr. Martina Hecker (corresponding author) Engelhard GmbH Sandweg 94 D-60316 Frankfurt/M. The authors Hartmut Landgrebe studied pharmacy in Marburg and completed his practical year at the ”Stadtapotheke” in Treysa and at Bayer AG Leverkusen in the department of pharmaceutical-technological development. Since July 1996, he has been a scientific assistant within the working group of Professor Dr. Matusch. Rudolf Matusch completed his pharmacy studies by obtaining his doctorate in 1971 and qualified as a university lecturer in 1977 in the field of xanthines. From 1979 onwards, he held a professorship in Pharmaceutical Chemistry at the FU of Berlin and moved to Marburg in 1981. His fields of work include, amongst other things, synthetic and spectroscopic processes, photochemistry and changes involving singlet oxygen, the synthesis of HPLC chiral stationary phases, the generation of artificial natural substance libraries as well as the isolation, structure determination and synthesis of active ingredients. Frank Runkel studied pharmacy in Marburg. After obtaining his licence to practise as a pharmacist in 1983, he became a scientific assistant of Professor Dr. Haake. Subsequent to gaining his doctorate in 1988, he worked at SmithKline Beecham in the Quality Assurance department. Upon joining Engelhard Arzneimittel, he took up various responsibilities within the pharmaceutical sector such as Quality Assurance and Control, Production as well as Research and Development. Since 1995, Dr. Runkel has been in charge of the pharmaceutical sector of the company. Martina Hecker studied biology and completed her dissertation which was focused mainly on microbiology in Mainz. She has worked for pharmaceutical companies since 1989, in clinical research at Klinge Pharma or as Head of the Medical and Scientific department at Abbot GmbH. Since 1997, Dr. Hecker has been the Area Head of Research and Development at Engelhard Arzneimittel.