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
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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
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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.
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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
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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).
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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.
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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.
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(32) Rudowski, Z., Latos, T., Hedera helix: Wirksam bei Bronchitis im Kindesalter. Ärztl. Praxis 80 (1980) 2561 - 2562.
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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.