Abstract
Extracts from different parts of hawthorn plants (Crataegus spp.) are used worldwide for the treatment of cardiovascular diseases. So far, almost
all clinical studies have been conducted with standardized hydroalcoholic extracts
from leaves and flowers. These trials with more than 4000 patients have provided evidence
for clinical benefits in the therapy of mild chronic heart failure. Besides cardiotonic
effects, recent pharmacological investigations indicate that hawthorn extracts also
possess cardio- and vasoprotective properties. Thus, these extracts may also be employed
in the prophylactic and therapeutic treatment of such conditions as endothelial dysfunction,
atherosclerosis, coronary heart disease, or prevention of restenosis/reocclusion following
peripheral endovascular treatment. In this review the pharmacological and clinical
data relating to these standardized extracts are summarized.
Key words
Crataegus spp.
- Rosaceae - cardiovascular diseases - cardioprotection - vasoprotection - atherosclerosis
- nitric oxide - restenosis
References
- 1 Koch E, Busse W R, Juretzek W, Chevts V.
Hawthorn. Encyclopedia of dietary supplements, 2nd edition. New York; Informa Healthcare 2010:
411-422
- 2 European Pharmacopoeia 7.0, Vol. 1. Strasbourg; Council of Europe 2007: 1148-1151
- 3
Crataegi folium cum flore (hawthorn leaf and flower). ESCOP Monographs on the medicinal uses of plant drugs. Exeter; European Scientific
Cooperative on Phytotherapy 1999: 1-11
- 4
Folium cum flore crataegi. WHO Monographs on selected medicinal plants. Geneva; World Health Organization 2002:
66-82
- 5 Kaul R. Der Weißdorn. Stuttgart; Wissenschaftliche Verlagsgesellschaft 1998
- 6
Poepping S, Rose H, Ionescu I, Fischer Y, Kammermeier H.
Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes.
Arzneimittelforschung.
1995;
45
1157-1161
- 7
Siegel G, Casper U, Schnalke F, Hetzer R.
Molecular physiological effector mechanisms of hawthorn extract in cardiac papillary
muscle and coronary vascular smooth muscle.
Phytother Res.
1996;
10
S195-S198
- 8
Schwinger R H, Pietsch M, Frank K, Brixius K.
Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently.
J Cardiovasc Pharmacol.
2000;
35
700-707
- 9
Wang H, Haas M, Liang M, Cai T, Tian J, Li S, Xie Z.
Ouabain assembles signaling cascades through the caveolar Na+/K+-ATPase.
J Biol Chem.
2004;
279
17250-17259
- 10
Liu J, Tian J, Haas M, Shapiro J I, Askari A, Xie Z.
Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and
Ca2+ concentrations.
J Biol Chem.
2000;
275
27838-27844
- 11
Arnon A, Hamlyn J M, Blaustein M P.
Ouabain augments Ca(2+) transients in arterial smooth muscle without raising cytosolic
Na(+).
Am J Physiol Heart Circ Physiol.
2000;
279
H679-H691
- 12
Schmidt-Schweda S, von Burstin J, Möllmann H, Wollner S, Holubarsch C.
Der positiv inotrope Effekt des Crataegus Spezialextrakt WS-1442 in isolierten Myozyten aus menschlichem Vorhof- und Ventrikelmyokard
wird vorwiegend durch oligomere Procyanidine vermittelt.
Z Kardiol.
2000;
89 (Suppl. 5)
164
- 13
Müller A, Linke W, Klaus W.
Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes.
Planta Med.
1999;
65
335-339
- 14
Joseph G, Zhao Y, Klaus W.
Pharmakologisches Wirkprofil von Crataegus-Extrakt im Vergleich zu Epinephrin, Amrinon, Milrinon und Digoxin am isoliert perfundierten
Meerschweinchenherzen.
Arzneimittelforschung.
1995;
45
1261-1265
- 15
Long S R, Carey R A, Crofoot K M, Proteau P J, Filtz T M.
Effect of hawthorn (Crataegus oxycantha) crude extract and chromatographic fractions on multiple activities in a cultured
cardiomyocyte assay.
Phytomedicine.
2006;
13
643-650
- 16
Salehi S, Long S R, Proteau P J, Filtz T M.
Hawthorn (Crataegus monogyna Jacq.) extract exhibits atropine-sensitive activity in a cultured cardiomyocyte assay.
J Nat Med.
2009;
63
1-8
- 17
Al Makdessi S, Sweidan H, Mullner S, Jacob R.
Myocardial protection by pretreatment with Crataegus oxyacantha: an assessment by means of the release of lactate dehydrogenase by the ischemic and
reperfused Langendorff heart.
Arzneimittelforschung.
1996;
46
25-27
- 18
Krzeminski T, Chatterjee S S.
Ischemia and reperfusion induced arrhythmias: beneficial effects of an extract of
Crataegus oxyacantha L.
Pharm Pharmacol Lett.
1993;
3
45-48
- 19
Veveris M, Koch E, Chatterjee S S.
Crataegus special extract WS 1442 improves cardiac function and reduces infarct size in a rat
model of prolonged coronary ischemia and reperfusion.
Life Sci.
2004;
74
1945-1955
- 20
Chatterjee S S, Koch E, Jaggy H, Krzeminski T.
In-vitro- und In-vivo-Untersuchungen zur kardioprotektiven Wirkung von oligomeren Procyanidinen in einem
Crataegus-Extrakt aus Blättern mit Blüten.
Arzneimittelforschung.
1997;
47
821-825
- 21
Jayachandran K S, Khan M, Selvendiran K, Devaraj S N, Kuppusamy P.
Crataegus oxycantha extract attenuates apoptotic incidence in myocardial ischemia-reperfusion injury
by regulating Akt and HIF-1 signaling pathways.
J Cardiovasc Pharmacol.
2010;
56
526-531
- 22
Koch E, Spörl-Aich G.
Oral treatment with the Crataegus special extract WS® 1442 inhibits cardiac hypertrophy in rats with DOCA-salt or aortic
banding induced hypertension.
Planta Med.
2006;
72
1061
- 23
Hwang H S, Bleske B E, Ghannam M M, Converso K, Russell M W, Hunter J C, Boluyt M O.
Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1
month of pressure overload-induced cardiac hypertrophy in rats.
Cardiovasc Drugs Ther.
2008;
22
19-28
- 24
Hwang H S, Boluyt M O, Converso K, Russell M W, Bleske B E.
Effects of hawthorn on the progression of heart failure in a rat model of aortic constriction.
Pharmacotherapy.
2009;
29
639-648
- 25
Bleske B E, Zineh I, Hwang H S, Welder G J, Ghannam M M, Boluyt M O.
Evaluation of hawthorn extract on immunomodulatory biomarkers in a pressure overload
model of heart failure.
Med Sci Monit.
2007;
13
BR255-BR258
- 26
Mävers W H, Hensel H.
Veränderungen der lokalen Myokarddurchblutung nach oraler Gabe eines Crataegusextraktes
bei nichtnarkotisierten Hunden.
Arzneimittelforschung.
1974;
24
783-785
- 27
Koch E, Chatterjee S S.
Crataegus extract WS®-1442 enhances coronary flow in the isolated rat heart by endothelial
release of nitric oxide.
Naunyn Schmiedeberg's Arch Pharmacol.
2000;
361
R48
- 28
Brixius K, Willms S, Napp A, Tossios P, Ladage D, Bloch W, Mehlhorn U, Schwinger R H.
Crataegus special extract WS 1442 induces an endothelium-dependent, NO-mediated vasorelaxation
via eNOS-phosphorylation at serine 1177.
Cardiovasc Drugs Ther.
2006;
20
177-184
- 29
Anselm E, Socorro V F, Dal-Ros S, Schott C, Bronner C, Schini-Kerth V B.
Crataegus special extract WS 1442 causes endothelium-dependent relaxation via a redox-sensitive
Src- and Akt-dependent activation of endothelial NO synthase but not via activation
of estrogen receptors.
J Cardiovasc Pharmacol.
2009;
53
253-260
- 30
Furst R, Zirrgiebel U, Totzke F, Zahler S, Vollmar A M, Koch E.
The Crataegus extract WS® 1442 inhibits balloon catheter-induced intimal hyperplasia in the rat
carotid artery by directly influencing PDGFR-beta.
Atherosclerosis.
2010;
211
409-417
- 31
Koch E, Chatterjee S S.
Crataegus extract WS® 1442 compensates the decrease of cardiac output in endotoxemic rats.
Eur Cytokine Network.
2000;
11
527
- 32
Fürst R, Bubik M, Bihari P, Juergenliemk G, Ammer H, Krombach F, Zahler S, Vollmar A.
The hawthorn special extract WS® 1442 protects against endothelial barrier dysfunction
– elucidation of the underlying molecular mechanisms.
Planta Med.
2010;
76
1191
- 33
Rajendran S, Deepalakshmi P D, Parasakthy K, Devaraj H, Devaraj S N.
Effect of tincture of Crataegus on the LDL-receptor activity of hepatic plasma membrane of rats fed an atherogenic
diet.
Atherosclerosis.
1996;
123
235-241
- 34
Shanthi R, Parasakthy K, Deepalakshmi P D, Niranjali D S.
Protective effect of tincture of Crataegus on oxidative stress in experimental atherosclerosis in rats.
J Clin Biochem.
1996;
20
211-223
- 35
Zhang Z, Ho W K K, Huang Y, Chen Z Y.
Hypocholesterolemic activity of hawthorn fruit is mediated by regulation of cholesterol-7α-hydroxylase and acyl CoA: cholesterol acyltransferase.
Food Res Int.
2002;
35
885-891
- 36
Lin Y, Vermeer M A, Trautwein E A.
Triterpenic acids present in hawthorn lower plasma cholesterol by inhibiting intestinal
ACAT activity in hamsters.
Evid Based Complement Alternat Med.
2011;
article ID 801272
DOI: 10.1093/ecam/nep007
- 37
Koch E, Lanzendörfer-Goossens H, Weibezahn C.
Crataegus extract WS® 1442 inhibits apolipoprotein B100 (ApoB) secretion and increases low-density
lipoprotein receptor (LDL-R) transcription in human HepG2 cells.
Z Phytother.
2006;
27
S25-S26
- 38 Hecker-Niediek A. Untersuchungen zur Biogenese, Markierung und Pharmakokinetik
der Procyanidine aus Crataegus-Spezies. Marburg; Marburg University 1983
- 39
Liang M, Xu W, Zhang W, Zhang C, Liu R, Shen Y, Li H, Wang X, Pan Q, Chen C.
Quantitative LC/MS/MS method and in vivo pharmacokinetic studies of vitexin rhamnoside, a bioactive constituent on cardiovascular
system from hawthorn.
Biomed Chromatogr.
2007;
21
422-429
- 40
Ma L Y, Liu R H, Xu X D, Yu M Q, Zhang Q, Liu H L.
The pharmacokinetics of C-glycosyl flavones of hawthorn leaf flavonoids in rat after
single dose oral administration.
Phytomedicine.
2010;
17
640-645
- 41
Schlegelmilch R, Heywood R.
Toxicity of Crataegus (hawthorn) extract (WS® 1442).
J Am Coll Toxicol.
1994;
13
103-111
- 42
Yao M, Ritchie H E, Brown-Woodman P D.
A reproductive screening test of hawthorn.
J Ethnopharmacol.
2008;
118
127-132
- 43
Loew D.
Phytotherapy in heart failure.
Phytomedicine.
1997;
4
267-271
- 44
Hawthorn leaf with flower. The Complete German Commission E Monographs. Boston; Integrative Medicine Communications
1998: 142-144
- 45
Pittler M H, Guo R, Ernst E.
Hawthorn extract for treating chronic heart failure.
Cochrane Database Syst Rev.
2008;
(1)
CD005312
- 46
Zick S M, Vautaw B M, Gillespie B, Aaronson K D.
Hawthorn extract randomized blinded chronic heart failure (HERB CHF) trial.
Eur J Heart Fail.
2009;
11
990-999
- 47
Tauchert M.
Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients
with chronic stable New York Heart Association class-III heart failure.
Am Heart J.
2002;
143
910-915
- 48
Eichstädt H, Störk T, Möckel M, Danne O, Funk P, Köhler S.
Wirksamkeit und Verträglichkeit von Crataegus-Extrakt WS® 1442 bei herzinsuffizienten Patienten mit eingeschränkter linksventrikulärer
Funktion.
Perfusion.
2001;
14
212-217
- 49
Zapfe Jr G.
Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class
II.
Phytomedicine.
2001;
8
262-266
- 50
Förster A, Förster K, Bühring M, Wolfstädter H D.
Crataegus bei mäßig reduzierter linksventrikulärer Auswurffraktion.
Münch Med Wschr.
1994;
136
S21-S26
- 51
Schmidt U, Kuhn U, Ploch M, Hübner W D.
Efficacy of hawthorn (Crataegus) preparation LI132 in 78 patients with chronic congestive heart failure defined as
NYHA functional class II.
Phytomedicine.
1994;
1
17-24
- 52
Boedigheimer K, Chase D.
Wirksamkeit von Weissdorn-Extrakt in der Dosierung 3mal 100 mg täglich. Multizentrische
Doppelblindstudie mit 85 herzinsuffizienten Patienten im Stadium NYHA II.
Münch Med Wschr.
1994;
136
7-11
- 53
Weikl A, Assmus K D, Neukum-Schmidt A, Schmitz J, Zapfe G, Noh H S, Siegrist J.
Crataegus-Spezialextrakt WS-1442. Objektiver Wirksamkeitsnachweis bei Patienten mit Herzinsuffizienz
(NYHA II).
Fortschr Med.
1996;
114
291-296
- 54
Leuchtgens H.
Crataegus-Spezialextrakt WS-1442 bei Herzinsuffizienz NYHA II. Eine plazebokontrollierte randomisierte
Doppelblindstudie.
Fortschr Med.
1993;
111
352-354
- 55
Weikl A, Noh H S.
Der Einfluss von Crataegus bei globaler Herzinsuffizienz.
Herz Gefässe.
1992;
12
516-524
- 56
Eichstädt H, Bäder M, Danne O, Kaiser W, Stein U, Felix R.
Crataegus-Extrakt hilft dem Patienten mit NYHA II-Herzinsuffizienz: Untersuchung der myokardialen
und hämodynamischen Wirkung eines standardisierten Crataegus-Präparates mit Hilfe computergestützter Radionuklidventrikulographie.
Therapiewoche.
1989;
39
3288-3296
- 57
Koller M, Lorenz W, Aubke W, Jensen A, Gerlach F M, Kühl J, Pfeil T, Regitz-Zagrosek V,
Rusche H, Rychlik R.
Weissdorn-Spezialextrakt in der Therapie früher Stadien der KHK-assoziierten Herzinsuffizienz.
MMW Fortsch Med.
2005;
147
159-164
- 58
Holubarsch C J, Colucci W S, Meinertz T, Gaus W, Tendera M.
The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial.
Eur J Heart Fail.
2008;
10
1255-1263
- 59
Walker A F, Marakis G, Simpson E, Hope J L, Robinson P A, Hassanein M, Simpson H C.
Hypotensive effects of hawthorn for patients with diabetes taking prescription drugs:
a randomised controlled trial.
Br J Gen Pract.
2006;
56
437-443
- 60
Daniele C, Mazzanti G, Pittler M H, Ernst E.
Adverse-event profile of Crataegus spp.: a systematic review.
Drug Saf.
2006;
29
523-535
- 61
Asher G N.
Herbal products review. What do we really know?.
J Am Coll Cardiol.
2010;
56
903
- 62
Tankanow R, Tamer H R, Streetman D S, Smith S G, Welton J L, Annesley T, Aaronson K D,
Bleske B E.
Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha).
J Clin Pharmacol.
2003;
43
637-642
Dr. Egon Koch
Preclinical Research
Dr. Willmar Schwabe GmbH & Co. KG
Willmar-Schwabe-Strasse 4
76227 Karlsruhe
Germany
Telefon: +49 72 14 00 53 56
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