1: Pharmazie. 2003 Aug;58(8):577-81.

2: Food. 2003 Jun;47(3):191-8.

Crataegus (Hawthorn) has long been used as a folk medicine and is widely utilized in pharmaceutical preparations mainly because of its neuro- and cardiosedative actions and its low toxicity. The pharmacological effects of Crataegus have mainly been attributed to the polyphenolic contents. In this study, the production of polyphenols by ten-year-old Crataegus monogyna calli was studied in relation to growth variation and antioxidant capacity within a subculture period. Assays based on the Trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and stability in oil-in-water emulsion were used to characterize the antioxidant actions of the callus cultures. High TEAC (3.66 micromol/g dry weight) and FRAP (208.19 micromol Fe2+/g dry weight) values were observed when maximal growth was reached(days 30-35), and this seemed to be influenced by optimum total phenol (47.40 mg/g dry weight), proanthocyanidin (20.81 mg/g dry weight), flavonoid (7.01 mg/g dry weight), anthocyanin (6.18 mg/g dry weight), (-)-epicatechin (1.77 mgl/g dry weight), procyanidin B2 (3.97 mg/g dry weight), and chlorogenic acid (1.11 mg/g dry weight) production during that period. The TEAC values were strongly associated with total flavonoids and to a lesser extent with total phenols, anthocyanins and total proanthocyanidins. The FRAP antioxidant values correlated to total phenols, proanthocyanidins and flavonoids, respectively. The polyphenolic rich calli were as effective as butylated hydroxytoluene (BHT) in preventing hydroperoxide and conjugated diene formation in a 30% oil-in-water emulsion prepared with stripped sunflower oil, during 7days storage at 30 degrees C. Crataegus monogyna cell culture represents an important alternative source for natural antioxidants.

3: Phytomedicine. 2003;10(5):363-9.

A placebo controlled, randomised, parallel group, multicentre trial conducted in accordance with the guidelines of Good Clinical Practice (GCP) shows the efficacy and safety of a standardised extract of fresh berries of Crataegus oxyacantha L. and monogyna Jacq. (Crataegisan) in patients with cardiac failure NYHA class II. A total of 143 patients (72 men, 71 women, mean age of 64.8 (8.0 years) were recruited and treated with 3 times 30 drops of the extract (n = 69) or placebo (n = 74) for 8 weeks. The primary variable for the evaluation of efficacy was the change in exercise tolerance determined with bicycle exercise testing, secondary variables included the blood pressure-heart rate product (BHP). Subjective cardiac symptoms at rest and at higher levels of exertion were assessed by the patient on a categorical rating scale. An overall assessment of efficacy at the final visit was provided by the patient and the investigator. In the ITT population there was a significant increase in exercise tolerance in both groups between visit 1 and visit 3. The difference between the treatment groups was 8.3 watts in favour of the standardised extract of fresh Crataegus berries (p = 0.045). The result is confirmed in the PP population (p = 0.047). Changes in BHP at 50 watts and at comparable maximum load were in favour of Crataegus extract but the results are not statistically significant. The subjective assessment of cardiac symptoms at rest and at higher levels of exertion did not change significantly and the patient and investigator overall assessment of efficacy were similar for the two groups. The medication was well tolerated and had a high level of patient acceptability. The significant improvement, due to the fact that dyspnoea and fatigue do not occur until a significantly higher wattage has been reached in the bicycle exercise testing allows the conclusion that the recruited NYHA II patients may expect an improvement in their heart failure condition under long term therapy with the standardised extract of fresh Crataegus berries.

Publication Types:

•  Clinical Trial . Multicenter Study Randomized Controlled Trial

4: J Agric Food Chem. 2003 Jul 2;51(14):3973-6.

Crataegus laevigata and Crataegus monogyna (hawthorn) were subjected to drought and cold stress treatments, and polyphenolic extracts from control and stress-treated plants were assayed for antioxidant capacities using a modified version of the Total Antioxidant Status Assay (Randox, San Francisco, CA). In addition, these plants were analyzed for levels of flavanol-type substance [(-)-epicatechin] and flavonoid (vitexin 2' '-O-rhamnoside, acetylvitexin 2' '-O-rhamnoside, and hyperoside) constituents that are important metabolites in hawthorn herbal preparations used to treat patients with heart disease. Drought and cold stress treatments caused increases in levels of (-)-epicatechin and hyperoside in both Crataegus species. Such treatments also enhanced the antioxidant capacity of the extracts. The results from this study thus indicate that these kinds of stress treatments can enhance the levels of important secondary metabolites and their total antioxidant capacities in leaves of Crataegus.

5: J Clin Pharmacol. 2003 Jun;43(6):637-42.

Interaction study between digoxin and a preparation Crataegus oxyacantha.

Tankanow R, Tamer HR, Streetman DS. University of Michigan College of Pharmacy, University of Michigan Health Systems, Ann Arbor, Michigan, USA.

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorn's beneficial effects in the treatment of heart failure. However, these components may also affect P-glycoprotein function and cause interactions with drugs that are P-glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0-infinity, Cmax-Cmin, Cmin, and renal clearance for the D group were 79 +/- 26 mcg.h/L, 1.4 +/- 0.7 mcg/L, 0.84 +/- 0.2 mcg/L, and 74 +/- 10 mL/min versus 73 +/- 20 mcg.h/L, 1.1 +/- 0.1 mcg/L, 0.65 +/- 0.2 mcg/L, and 81 +/- 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, may be coadministered safely.

Publication Types: Clinical Trial. Randomized Controlled Trial

6: Am J Med. 2003 Jun 1;114(8):665-74.

The aim of this meta-analysis was to assess the evidence from rigorous clinical trials of the use of hawthorn extract to treat patients with chronic heart failure. We searched the literature using MEDLINE, EMBASE, the Cochrane Library, CINAHL, CISCOM, and AMED. Experts on and manufacturers of commercial preparations containing hawthorn extract were asked to contribute published and unpublished studies. There were no restrictions about the language of publication. Two reviewers independently performed the screening of studies, selection, validation, data extraction, and the assessment of methodological quality. To be included, studies were required to state that they were randomized, double-blind, and placebo controlled, and used hawthorn extract monopreparations. Thirteen trials met all inclusion criteria. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Eight trials including 632 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (weighted mean difference, 7 Watt; 95% confidence interval [CI]: 3 to 11 Watt; P < 0.01; n = 310 patients). The pressure-heart rate product also showed a beneficial decrease (weighted mean difference, -20; 95% CI: -32 to -8; n = 264 patients) with hawthorn treatment. Symptoms such as dyspnea and fatigue improved significantly with hawthorn treatment as compared with placebo. Reported adverse events were infrequent, mild, and transient; they included nausea, dizziness, and cardiac and gastrointestinal complaints. In conclusion, these results suggest that there is a significant benefit from hawthorn extract as an adjunctive treatment for chronic heart failure.

7: Ther Umsch. 2002 Jun;59(6):301-6.

Phytotherapy in cardiovascular medicine.

Zbinden S, Seiler Ch. Schweizer Herz- und Gefasszentrum Bern, Universitatsspital, Bern.

There is widespread use of herbal medicine in patients suffering from cardiovascular diseases. The discussion about the benefit of these drugs is still controversial because of lack of scientific evidence. Ginkgo biloba, Crataegus and Garlic are often recommended substances for patients with cardiovascular diseases. For these substances there is a lot of data available from experimental and clinical studies, unfortunately not always adhering to the criteria of evidence based medicine. Extracts from ginkgo biloba contain several active constituents, mainly flavonoids and terpens, which have antioxidative properties and an inhibitory effect on platelet aggregation by inhibiting platelet activation factor PAF. Ginkgo is mainly used in vascular dementia and peripheral vascular disease. Garlic shows a modest lipid-lowering effect in the same range as a low-cholesterol diet. Effect on blood pressure seems to be at best minor. Crataegus is often used in patients with heart failure because of its positive inotropic effect. Additionally, crataegus acts as an antiarrhythmic substance by prolonging refractory period of the action potential.

8: Am Heart J. 2002 May;143(5):910-5.

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.

Tauchert M. Klinikum Leverkusen, Leverkusen, Germany.

OBJECTIVE: The purpose of this study was to investigate whether long-term therapy with crataegus extract WS 1442 is efficacious as add-on therapy to preexisting diuretic treatment in patients with heart failure with a more advanced stage of the disease (New York Heart Association [NYHA] class III), whether effects are dose dependent, and whether the treatment is safe and well tolerated. METHODS: Exercise capacity was assessed by use of seated bicycle ergometry with incremental workloads. Scores for subjective symptoms and complaints made by the patients were analyzed. Efficacy and tolerability of the treatments were judged by both the patients and investigators. Safety was assessed by the documentation of adverse events and the safety laboratory. RESULTS: A total of 209 patients were randomized to treatment with 1800 mg of WS 1442, 900 mg of WS 1442, or with placebo. After 16 weeks of therapy with 1800 mg of WS 1442 per day, maximal tolerated workload during bicycle exercise showed a statistically significant increase in comparison with both placebo and 900 mg of WS 1442. Typical heart failure symptoms as rated by the patients were reduced to a greater extent by WS 1442 than by placebo. This difference was significant for both doses of WS 1442. Both efficacy and tolerability were rated best for the 1800 mg of WS 1442 group by patients and investigators alike. The incidence of adverse events was lowest in the 1800 mg of WS 1442 group, particularly with respect to dizziness and vertigo. CONCLUSIONS: The data from this study confirm that there is a dose-dependent effect of WS 1442 on the exercise capacity of patients with heart failure and on typical heart failure-related clinical signs and symptoms. The drug was shown to be well tolerated and safe.

Publication Types: Clinical Trial. Multicenter Study. Randomized Controlled Trial

9: J Clin Pharmacol. 2002 Jun;42(6):605-12.

A review with 54 references covers all aspects of hawthorn, the genus Crataegus, including its traditional uses, chemical constituents, pharmacological activities, and clinical effects. Although the effectiveness of hawthorn on the treatment of cardiovascular diseases has received extensive attention worldwide, further scientific research on various areas such as pharmacokinetics, mechanism of actions will be necessary to ensure its safe and effective usage.

10: Am J Health Syst Pharm. 2002 Mar 1;59(5):417-22.

Hawthorn: pharmacology and therapeutic uses.

Rigelsky JM, Sweet BV. H. H. McGuire Veterans Affairs Medical Center, Richmond, VA, USA.

The uses, pharmacology, clinical efficacy, dosage and administration, adverse effects, and drug interactions of hawthorn are discussed. Hawthorn (Crataegus oxyacantha) is a fruit-bearing shrub with a long history as a medicinal substance. Uses have included the treatment of digestive ailments, dyspnea, kidney stones, and cardiovascular disorders. Today, hawthorn is used primarily for various cardiovascular conditions. The cardiovascular effects are believed to be the result of positive inotropic activity, ability to increase the integrity of the blood vessel wall and improve coronary blood flow, and positive effects on oxygen utilization. Flavonoids are postulated to account for these effects. Hawthorn has shown promise in the treatment of New York Heart Association (NYHA) functional class II congestive heart failure (CHF) in both uncontrolled and controlled clinical trials. There are also suggestions of a beneficial effect on blood lipids. Trials to establish an antiarrhythmic effect in humans have not been conducted. The recommended daily dose of hawthorn is 160-900 mg of a native water-ethanol extract of the leaves or flowers (equivalent to 30-169 mg of epicatechin or 3.5-19.8 mg of flavonoids) administered in two or three doses. At therapeutic dosages, hawthorn may cause a mild rash, headache, sweating, dizziness, palpitations, sleepiness, agitation, and gastrointestinal symptoms. Hawthorn may interact with vasodilating medications and may potentiate or inhibit the actions of drugs used for heart failure, hypertension, angina, and arrhythmias. The limited data about hawthorn suggest that it may be useful in the treatment of NYHA functional class II CHF.

Publication Types:

•  Review

•  Review, Tutorial

11: Prev Cardiol. 2000 Winter;3(1):24-32.

Herbs and dietary supplements can have significant physiological effects. Garlic (Allium sativum) has shown beneficial lipid effects in a majority of trials; dried garlic preparations are superior to oil preparations. There is preliminary evidence that indicates that hawthorn (Crataegus species) may provide benefits in congestive heart failure. Coenzyme Q also may be of benefit in congestive heart failure. Although observational studies indicate a protective effect of dietary or supplemental vitamin E, controlled trails have not shown a beneficial effect on angina and have been mixed on whether supplementation decreases major cardiac events. Although several observational studies have noted that fish intake protects against cardiovascular disease, prospective studies are less impressive. Fish oil supplementation may have a mild beneficial effect on hypertension, but there is no effect on total cholesterol levels. Trials are inconsistent on whether fish oil reduces restenosis rates following coronary angioplasty. Carnitine appears to have beneficial effects on congestive heart failure and angina; there is also preliminary evidence that arginine may benefit patients with congestive heart failure or angina. Herbs and supplements have been associated with adverse effects and interactions; for example, garlic inhibits platelet aggregation and can cause significant anticoagulation, and the Chinese herb danshen (Salvia miltiorrhiza) appears to potentiate warfarin. Several herbs and supplements hold promise as adjuncts in the prevention and treatment of cardiovascular disease. There is a need for definitive research on the potential risks and benefits of these compounds, including appropriate dosages and formulations, and delineation of adverse events and interactions.

12: Phytother Res. 2002 Feb;16(1):48-54.

Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension.

Walker AF, Marakis G, Morris AP. Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, The University of Reading, Whiteknights, Reading, UK.

This pilot study was aimed at investigating the hypotensive potential of hawthorn extract and magnesium dietary supplements individually and in combination, compared with a placebo. Thirty-six mildly hypertensive subjects completed the study. At baseline, anthropometric and dietary assessment, as well as blood pressure measurements were taken at rest, after exercise and after a computer 'stress' test. Volunteers were then randomly assigned to a daily supplement for 10 weeks of either: (a) 600 mg Mg, (b) 500 mg hawthorn extract, (c) a combination of (a) and (b), (d) placebo. Measurements were repeated at 5 and 10 weeks of intervention. There was a decline in both systolic and diastolic blood pressure in all treatment groups, including placebo, but ANOVA provided no evidence of difference between treatments. However, factorial contrast analysis in ANOVA showed a promising reduction (p = 0.081) in the resting diastolic blood pressure at week 10 in the 19 subjects who were assigned to the hawthorn extract, compared with the other groups. Furthermore, a trend towards a reduction in anxiety (p = 0.094) was also observed in those taking hawthorn compared with the other groups. These findings warrant further study, particularly in view of the low dose of hawthorn extract used. Copyright 2002 John Wiley & Sons, Ltd.

Publication Types: Clinical Trial, Randomized Controlled Trial

13: Arzneimittelforschung. 2001 Oct;51(10):793-8.

[Actions of standardized extracts of Crataegus berries on exercise tolerance and quality of life in patients with congestive heart failure]

14: Phytomedicine. 2001 Jul;8(4):262-6.

Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II.

Zapfe jun G.

In a randomised, placebo-controlled, double-blind clinical study the clinical efficacy and safety of Crataegus extract WS 1442, standardised to 18.75% oligomeric procyanidines, were investigated in 40 female and male outpatients suffering from congestive heart failure NYHA class II. Following a wash-out period of up to seven days, the patients were randomised to be treated for 12 weeks with either WS 1442 (3 x 1 capsule) or placebo. The primary outcome variable was exercise tolerance determined with bicycle exercise testing; as a secondary outcome variable the difference of the double product was calculated. On average, the exercise tolerance increased by 66.3 W x min (10.8%) in the WS 1442 group while in the placebo group a reduction of 105.3 W x min (16.9%) was measured. This difference between the groups was borderline statistically significant (p = 0.06). During the three month therapy the difference of the double product (heart rate x systolic blood pressure x 10(-2)) decreased by 14.4 mmHg s(-1) (26.8%) in the WS 1442 group and by 1.3 mmHg s(-1) (2.7%) in the placebo group, respectively. Recording of laboratory parameters and adverse events showed that WS 1442 was safe and well tolerated. The data show that Crataegus extract WS 1442 is clinically effective in patients with congestive heart failure corresponding to NYHA class II.

Publication Types: Clinical Trial. Randomized Controlled Trial

15: Phytomedicine. 2001 Jan;8(1):47-52.

MeOH extracts, fractions and pure substances from Musanga cecropioides, Cecropia species and Crataegus oxyacantha /C. monogyna were screened by using an in vitro bio-assay based on the inhibition of Angiotensin Converting Enzyme (ACE), as measured from the enzymatic cleavage of the chromophore-fluorophore-labelled substrate dansyltriglycine into dansylglycine and diglycine. Phenolic acids showed no significant ACE-inhibition whereas flavonoids and proanthocyanidins demonstrated inhibitory activity at 0.33 mg/ml using this test system.

16: Indian J Exp Biol. 2000 May;38(5):509-11.

The present study was carried out to study the effect of antioxidants on oxidised LDL + VLDL and found that vitamin E, eugenol and tincture of crataegus (antioxidants) inhibited oxidation of (LDL + VLDL) similar to standard antioxidant (butylated hydroxy toluene). Vitamin C acted as an antioxidant at lower concentration, and prooxidant at higher concentration.

17: Phytother Res. 2000 Dec;14(8):612-6.

The antioxidant capacity of extracts of Crataegus oxyacantha, Hamamelis virginiana, Hydrastis canadensis, plants native to Europe and North America which have long been used in herbal medicine for the treatment of cardiac and circulatory functions, has been investigated. The total antioxidant potential conferred by all hydrogen donating antioxidants present in these extracts has been assessed by the ABTS assay and the relative order of antioxidant potential has been established. Gas chromatography coupled to mass spectrometry (GC-MS) has been used for the chemical identification of the antioxidant volatile compounds present in the extracts. The GC-MS data were related to the results obtained using the ABTS assay.

18: Eur J Heart Fail. 2000 Dec;2(4):431-7.

Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)--rationale, study design and study protocol.

Holubarsch CJ, Colucci WS, Meinertz T. Medizinische Klinik und Poliklinik, Abt. Innere Medizin III - Kardiologie und Angiologie, Freiburg, Germany.

SPICE is the first, international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug Crataegus Special Extract WS 1442 (hawthorn leaves with flowers) on mortality of patients suffering from congestive heart failure. BACKGROUND: In vitro and experimental animal studies have suggested the following pharmacological modes of action of standardized Crataegus extracts: (1) cAMP-independent positive inotropy; (2) peripheral and coronary vasodilation; (3) protection against ischemia-induced ventricular arrhythmias; (4) antioxidative properties; and (5) anti-inflammatory effects. STUDY DESIGN: In this randomized, placebo-controlled, double-blind, international trial (approximately 120 investigational centers in seven European countries), up to 2300 patients with congestive heart failure, New York Heart Association class II and III and markedly impaired left ventricular function, will be enrolled and treated over a period of 24 months. During this time patients receive either two film-coated tablets of 450 mg of the Special Extract WS 1442 standardized to 84.3 mg of oligomeric procyanidines or matched placebo per day in addition to standard therapy for congestive heart failure, such as diuretics, digoxin or digitoxin, beta-adrenoceptor blockers and angiotensin-converting-enzyme inhibitors. The primary outcome variable is the combined endpoint of cardiac death, non-lethal myocardial infarction, and hospitalization due to progression of heart failure. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life as well as pharmacoeconomic parameters. The first patient was included in October 1998. The trial is expected to be completed at the end of 2002.

Publication Types: Clinical Trial. Multicenter Study. Randomized Controlled Trial

19: Life Sci. 2000;67(2):121-31.

The extract of Crataegus, a mixture of flavonoids and procyanidins extracted from hawthorn, Crataegus oxyacantha, L. and C. monogyna Jacq., relaxed vascular tone or increased production of cyclic GMP in the rat aorta, but flavonoid components of Crataegus extract, hyperoside, rutin and vitexin, did not affect the vascular tone. The aim of the present study was to characterize the endothelium-dependent relaxation elicited by procyanidins fractionated from Crataegus extract in isolated rat aorta. Procyanidins caused endothelium-dependent relaxation which was associated with the production of cyclic GMP. Both responses to these procyanidins were inhibited by methylene blue or N(G)-nitro-L-arginine, but not by indomethacin. Relaxation in response to procyanidins was not affected by atropine, diphenhydramine, [D-Pro2,D-Trp7,9]substance P, propranolol, nifedipine, verapamil and glibenclamide, but were markedly reduced by tetraethylammonium. These findings showed that procyanidins in Crataegus extract may be responsible for the endothelium-dependent nitric oxide-mediated relaxation in isolated rat aorta, possibly via activation of tetraethylammonium-sensitive K+ channels.

20: J Cardiovasc Pharmacol. 2000 May;35(5):700-7.
Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently.

Schwinger RH, Pietsch M, Frank K. Laboratory of Muscle Research and Molecular Cardiology, Clinic III of Internal Medicine, University of Cologne, Germany.

The mode of action of Crataegus extracts in the treatment of heart failure is still under examination. WS 1442, a standardized special extract from Crataegus leaves with flowers, exerts direct positive inotropic effects. This study was designed to investigate the mode of inotropic action of WS 1442 in human myocardium from patients with congestive heart failure (left ventricular myocardium from explanted hearts; NYHA IV, n = 8) as well as in nonfailing controls (right auricular trabeculae from patients with coronary heart disease, n = 8). WS 1442 effectively displaced specifically bound 3H-ouabain but did not influence the activity of adenylate cyclase [control, + Gpp(NH)p (10(-4) microM) 3,500 pmol cyclic adenosine monophosphate (cAMP)/20 min). In isolated left ventricular papillary muscle strips, WS 1442 significantly increased the force of contraction [basal, 1.8+/-0.2 mN; WS 1442 (50 microg/ml), 2.4+/-0.1 mN (130%)] and improved the frequency-dependent force generation (0.5 vs. 2.5 Hz: control, +0.1+/-0.01 mN; WS 1442, +0.9+/-0.3 mN) even in failing human myocardium. In fura-2-loaded muscle strips (right atrial trabeculae), WS 1442 increased both the Ca2+-transient and force generation. These effects also were observed in the lipophilic ethyl acetate-soluble fraction A, enriched in flavone derivatives. In conclusion, these findings suggest a pharmacologic mechanism of WS 1442 similar to the cAMP-independent positive inotropic action of cardiac glycosides. In addition, WS 1442 improves the force-frequency relation in failing human myocardium.

21: Herz. 1999 Oct;24(6):465-74.
High-dose Crataegus extract WS 1442 in the treatment of NYHA stage II heart failure

Tauchert M, Gildor A, Lipinski J. Klinikum Leverkusen. Germany.

The efficacy and tolerance of the standardized hawthorn (crataegus) extract WS 1442 were tested in a multicenter utilization observational study. We monitored 1,011 patients with cardiac insufficiency stage NYHA II, treated with this extract (Crataegutt novo 450, 1 tablet b.i.d.) over a period of 24 weeks. During and at the end of the observation period a significant improvement in clinical symptoms (reduced performance in the exercise tolerance test, fatigue, palpitation and exercise dyspnea) was observed. Ankle edema and nocturia disappeared by 83%, and by half of the patients respectively manifesting these symptoms before treatment. The improvement and economization of cardiac performance were additionally shown by a reduction in blood pressure, an increased maximal exercise tolerance and a reduction in the difference in the pressure/heart rate product (PHRP). The positive effects of WS 1442 were further demonstrated by an improved ejection fraction and an increased percentile shortening fraction measured using M-mode echocardiography. The stabilizing effect of the hawthorn extract on the heart rate was shown by a slower rest pulse, as well as by an increase in the number of day and night normorhythmic patients, as documented by long-term ECG. The reduction in the number of patients showing ST depressions, arrhythmias and ventricular extrasystoles at the maximum exercise level is regarded as an indication for an improved myocardial perfusion. Fourteen side effects were noted. In two cases (abdominal discomfort and facial pains accompanied by tachycardia) a possible relationship with the hawthorn therapy, was postulated which however was considered unlikely by the treating physicians. Almost 2/3 of the patients felt better or much better following the 24 weeks of treatment. More than 3/4 of the participating physicians noted a good or a very good efficacy, and 98.7% noted a good or a very good tolerance. High-dose hawthorn therapy is an efficient, well-tolerated and easily regulated therapeutic alternative for patients suffering from cardiac insufficiency stage NYHA II.

22 : Wien Med Wochenschr. 1999;149(8-10):226-8.

Phytogenic drugs in heart diseases exemplified by Crataegus

Loew D. Abteilung fur Klinische Pharmakologie, Klinikums der Johann-Wolfgang-Goethe-Universitat, Frankfurt, Deutschland.

According to the results, standardized extracts differ from other inotropic drugs used for treatment of chronic heart insufficiency. Crataegus extracts have positive inotropic, positive chronotropic, positive dromotropic but negative bathmotropic effects, increase coronary and myocardial perfusion, lower periphere resistance and has anti-arrhythmic and economizing effects. In randomized double-blind clinical trials, key surrogates for efficacy in chronic heart insufficiency were improved. Standardized Crataegus-extracts represent an alternative to synthetic drugs in patients with NYHA II in chronic heart insufficiency.

Publication Types: Review. Review, Tutorial

23: Planta Med. 1999 May;65(4):335-9.

Crataegus extract is used in cardiology for the treatment of mild to moderate heart failure (NYHA II) in Germany. However, little is known about the electrophysiological actions of Crataegus extract in the heart. Recently, it was shown that Crataegus extract prolongs the refractory period in isolated perfused hearts and increases action potential duration in guinea pig papillary muscle. It was the aim of this study to find out the mechanism of the increase in action potential duration caused by Crataegus extract. Using the patch-clamp technique, we measured the effects of Crataegus extract (10 mg/l; flavonoid content: 2.25%, total procyanidin content: 11.3 +/- 0.4%) on the inward rectifier and the delayed rectifier potassium current in isolated guinea pig ventricular myocytes. To get some insight into the mechanism underlying the positive inotropic effect of Crataegus extract, we also looked for effects on the L-type calcium current. Crataegus extract slightly blocked both the delayed and the inward rectifier potassium current. The inhibition amounted to 25% and about 15%, respectively. This amount of inhibition of these repolarising currents is sufficient to explain the prolongation of action potential duration caused by Crataegus extract. To our surprise we could not detect any influence of Crataegus extract on the L-type calcium current. In summary, our results show that Crataegus extract blocks repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrhythmic effects described for Crataegus extract. Our measurements of the L-type calcium current indicate that Crataegus extract's positive inotropic effect is not caused by phosphodiesterase inhibition or a beta-sympathomimetic effect.

24: Basic Res Cardiol. 1999 Apr;94(2):71-7.

The protective effect against reperfusion arrhythmias of a 3-month oral pretreatment with a dried extract of Crataegus oxyacantha (LI 132)(standardized to 2.2% flavonoids) was studied with the Langendorff heart of the rat after global no-flow ischemia. The heart was perfused with a modified Krebs-Henseleit solution in which the K+ content was reduced to 3.4 mmol/l in order to lower the fibrillation threshold. According to pilot experiments which considered various durations of global no-flow ischemia ranging from 10 to 20 minutes, two durations were chosen for the present study: 20 minutes (group 20) in which ventricular fibrillation (VF) was the predominant form of arrhythmias, and 18 minutes (group 18) in which the prevalence of VF was markedly lower despite the small difference in the duration of ischemia. Crataegus pretreatment significantly (p = 0.02) reduced the average prevalence of malignant arrhythmias (VF + Flutter) as observed during the 20-min-period of reperfusion as follows: group 20: from 89% (control, n = 9) to 51% (LI 132, n = 7), group 18: from 48% (control, n = 8) to 8% (LI 132, n = 8). In group 20, ventricular tachycardia (VT) could be observed only in the treated group, because of the predominance of VF in the control group. LI 132 pretreatment reduced the average prevalence of VT in group 18 in spite of the identical percentage of occurrence (6 out of 8 rats, with and without treatment) due to a shorter duration of the VT episodes. Thus, under the conditions of our experiments, effective prevention against reperfusion arrhythmias by Crataegus pretreatment was evident.

25: Altern Med Rev. 1998 Dec;3(6):422-31.

Botanical influences on cardiovascular disease.

Miller AL. Alternative Medicine Review, Dover, ID, USA.

Several botanicals, including Crataegus oxycantha, Terminalia arjuna, Inula racemosa, and Astragalus membranaceus, have been found to have therapeutic benefit for the treatment of cardiovascular disease. Crataegus oxycantha has been used traditionally as a cardiac tonic and current uses include treatment for angina, hypertension, arrhythmias, and congestive heart failure. Animal studies have also indicated that Crataegus extracts may also have potential use as anti-ischemic and lipid-lowering agents. The bark of the Terminalia arjuna tree has a long history of use as a cardiac tonic as well, and has been indicated in the treatment of coronary artery disease, heart failure, hypercholesterolemia and for relief of anginal pain. Additionally, it has been found to have antibacterial and antimutagenic properties. Inula racemosa, also known as Pushkarmoola, is another traditional Ayurvedic botanical that has potential cardioprotective benefit. In human trials, a combination of Inula racemosa and Commiphora mukul was shown to be superior to nitroglycerin in reducing the chest pain and dyspnea associated with angina. Astragalus membranaceus, a Chinese herb, is often used as a "Qi tonifier" and has been studied for its therapeutic benefit in treatment of ischemic heart disease, myocardial infarction, heart failure, and relief of anginal pain. Clinical studies have indicated that its in vitro antioxidant activity is the mechanism by which it affords its cardioprotective benefit.

Publication Types: Review. Review, Tutorial

26: Arzneimittelforschung. 1997 Jul;47(7):821-5.

In vitro and in vivo studies on the cardioprotective action of oligomeric procyanidins in a Crataegus extract of leaves and blooms

Chatterjee SS, Koch E, Jaggy H. Pharmakologische Abteilung, Dr. Willmar Schwabe Arzneimittel GmbH, Karlsruhe. Germany.

Cardioprotective effects of a standardized extract from leaves with flowers of Crataegus (WS-1442; content of oligomeric procyandins [OPC]: 18.75%) have recently been demonstrated in an ischemia-reperfusion model in rats. Further studies were now conducted to clarify the mechanism of action and to identify active constituents involved in these effects of WS-1442. Exhausting partitioning between ethyl acetate/water and successive ultrafiltration of the aqueous layer led to the quantitative recovery of three fractions, which were tested for their in vitro radical scavenging (RS) and human neutrophil elastase (HNE) inhibitory activity. The lipophilic ethylacetate-soluble fraction A, enriched in flavone derivatives and constituting 14.9% of WS-1442, was as active as WS-1442 in inhibiting HNE. However, its RS activity was only about half that of the primary extract. Although 67.9% of WS-1442 was recovered in a water-soluble low molecular weight fraction B, this fraction displayed only weak RS and HNE inhibiting activity. In contrast, the RS and HNE inhibiting potencies of an essentially flavone-free and OPC-rich fraction C (21.3% of WS-1442) were significantly higher (inhibition of lipid peroxidation: IC50 0.3 microgram/ml; inhibition of HNE: IC50 0.84 microgram/ml) as those of WS-1442. The RS and HNE inhibitory activities of the extract and those of its fractions correlated well with their OPC-content but not with their concentration of flavonols. These results demonstrate that OPCs of Crataegus extracts possess stronger radical scavenging activities than flavone derivatives or other constituents. In addition, the oligomeric components are potent inhibitors of HNE. Oral administration of 20 mg/kg/d of the OPC-rich fraction C to rats afforded similar protection against ischemia-reperfusion induced pathologies as treatment with WS-1442 at a dose of 100 mg/kg/d. These observations indicate that radical scavenging and elastase inhibitory activities could indeed be involved in the observed cardioprotective effects of WS-1442, and demonstrate that OPCs are major orally active constituents of WS-1442. Thus, Crataegus extracts used therapeutically for cardiovascular diseases should be analyzed and standardized for their OPC-content.

27: Pharmazie. 1997 Jan;52(1):60-4.

Antioxidant activities of polyphenolic extracts from flowers, in vitro callus and cell suspension cultures of Crataegus monogyna.

Rakotoarison DA, Gressier B, Trotin F. Laboratoire de Pharmacologie, Pharmacocinetique et Pharmacie Clinique, Universite des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.

Numerous plants synthesize among their secondary metabolites phenolic compounds which possess antioxidant effects. The aim of the present work was to assay the antioxidant activities of phenolics from Crataegus monogyna Jacq. flowers and in vitro tissue culture (calli and cell suspensions) extracts. In the case of tissue culture extracts, the phenolic production is studied at three different stages of one subculture period (initial growth period, increasing and maximal phenolic synthesis phases). Attention was paid to the main categories: flavonoids and proanthocyanidins, and to the principal individual components. Total phenolic amounts decrease in the order: fresh flowers > cell suspension cultures > callus cultures. The antioxidant activities of these different extracts against H2O2 and HOCl, have been determined in vitro. All the extracts are efficient and the scavenging capacity is clearly related to the total phenol content. The scavenging effects of the cell suspension extracts are similar to those of the flowers. Among individual compounds, the flavanol-type derivatives, specially the proanthocyanidin B2, are more efficient. Thus, in vitro plant tissues could be an interesting source of bioactive molecules.

28: Arzneimittelforschung. 1996 Nov;46(11):1086-9.

29: Fortschr Med. 1996 Aug 30;114(24):291-6.

[Crataegus Special Extract WS 1442. Assessment of objective effectiveness in patients with heart failure (NYHA II)]

Weikl A, Assmus KD, Neukum-Schmidt A. Hauptkrankenhaus Deggendorf. Germany.

METHOD: In a multicenter, placebo-controlled double-blind study, the efficacy of the Crataegus-Specialextrakt WS 1442 in patients with NYHA stage II cardiac insufficiency was investigated. A total of 136 patients with this diagnosis were admitted to the study and, following a 2-week run-in phase, treated with Crataegus-Specialextract or placebo over a period of 8 weeks. The primary target parameter was the change in the difference of the pressure, heart rate product (systolic blood pressure x heart rate/100) (PHRP 50 W load vs. rest) measured at the beginning and end of treatment. RESULTS: On the basis of this variable, a clear improvement in the performance of the heart was shown in the group receiving the test substance, while the condition of the placebo group progressively worsened. The therapeutic difference between the groups was statistically significant. The positive result for the objective efficacy parameter was confirmed by a statistically obvious superiority of Crataegus in the patient's own assessment of improvement in the main symptoms (reduced performance, shortness of breath, ankle edema etc.). In addition, active treatment led, in comparison with placebo, to a considerably better quality of life for the patient, in particular with respect to mental well-being. The tolerability of the active substance proved to be very good-as shown by comprehensive laboratory investigations and the recording of undesirable events. CONCLUSION: All in all, the results of the present clinical investigation confirm those of previous studies showing that Crataegus-Specialextrakt WS 1442 is an effective and low-risk phytotherapeutic form of treatment in patients with NYHA II cardiac insufficiency.

Publication Types:

•  Clinical Trial

•  Randomized Controlled Trial

30: Fortschr Med. 1996 Jan 20;114(1-2):27-9.

Therapeutic effectiveness of Crataegus

Weihmayr T, Ernst E. Homoopathie-Naturheilverfahren, Munchen. Germany.

Hawthorn (crataegus) has been used since antiquity for medicinal purposes. More recent research suggests it to be useful in congestive heart failure. Rigorous clinical trials show benefit concerning objective signs and subjective symptoms of congestive heart failure stage NYHA-II. No adverse drug reactions have been reported. It is therefore concluded that crataegus is an effective and safe therapeutic alternative for this indication.

Publication Types: Clinical Trial. Multicenter Study. Randomized Controlled Trial. Review. Review, Tutorial

31: Arzneimittelforschung. 1996 Jan;46(1):25-7.

Myocardial protection by pretreatment with Crataegus oxyacantha: an assessment by means of the release of lactate dehydrogenase by the ischemic and reperfused Langendorff heart.

Al Makdessi S, Sweidan H, Mullner S. Institute of Physiology II, University of Tubingen, Germany.

The effect of the pretreatment with the powder of crataegus oxyacantha on the release of lactate dehydrogenase (LDH) during ischemia and reperfusion was studied in an isolated rat heart model. Male Wistar rats were divided into control and crataegus group (for which the standard diet was mixed with a 2% crataegus powder standardized to 2.2% flavonoids). The investigations started 3 months after commencing the treatment. The hearts were isolated and a retrograde perfusion was performed at constant pressure according to the technique of Langendorff. The experimental protocol comprised 10 min equilibration, according to the technique of Langendorff. The experimental protocol comprised 10 min equilibration, according to the technique of Langendorff. The experimental protocol comprised 10 min equilibration, 110 min occlusion of the left anterior descending coronary artery, and 30 min reperfusion. The coronary effluent was sampled for the LDH determination after 5, 30, 90, 120 and 150 min. The LDH activity, which was initially very low in both groups (control, 16.5 +/- 4.3; crataegus, 26.0 +/- 8.8 mU/min) increased slightly during the ischemia, and very strongly as soon as the heart was reperfused. However, the increase in the crataegus group was significantly lower (1777.3 +/- 451.9 vs control 3795.3 +/- 511.9 mU/min, p = 0.01). At the end of the reperfusion period, LDH activity decreased markedly but did not reach the ischemic values. The attenuation of the LDH release by crataegus pretreatment suggests a preservation of the cell membrane and a protection from myocardial damage.

32: Arzneimittelforschung. 1995 Dec;45(12):1261-5.

Pharmacologic action profile of crataegus extract in comparison to epinephrine, amirinone, milrinone and digoxin in the isolated perfused guinea pig heart.

Joseph G, Zhao Y, Klaus W. Institut fur Pharmakologie, Universitat zu Koln. Germany.

Using isolated perfused guinea pig hearts experiments were performed to investigate the influence of crataegus extract LI 132 (Faros 300, CRA) in comparison to other inotropic drugs--epinephrine (adrenaline, ADR), amrinone (AM), milrinone (MIL) and digoxin (DIG)--on different functional parameters, with special emphasis on the effective refractory period of the myocardium. The simultaneous registration of appropriate parameters allowed to relate the effect on the refractory period to the inotropic, chronotropic, dromotropic and coronary actions of these compounds at each concentration level. All substances--with the exception of CRA--shortened the effective refractory period concentration-dependently besides their known other functional effects (max.: 1 x 10(-5) mol/l ADR by 38%, 7 x 10(-7) mol/l DIG by 26%, 1 x 10(-4) mol/l MIL by 13% and 5 x 10(-4) mol/l AM by 1.6%). Related to the positive inotropy the shortening was most effective under MIL (1.32 ms/mN), followed by AM (0.65 ms/mN), DIG (0.40 ms/mN) and ADR (0.28 ms/mN). On the contrary, CRA produced a prolongation of the effective refractory period by maximally 10% resp. by 2.54 ms/mN. Thus, the pharmacologic profile of CRA differs from that of other inotropic compounds mainly in this parameter (with potentially reduced arrhythmogenic risk).

33: Arzneimittelforschung. 1995 Nov;45(11):1157-61.

Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes.

Popping S, Rose H, Ionescu I, Institute of Physiology, Medical Faculty, Rheinisch-Westfalische Technische Hochschule, Aachen, Germany.

The hawthorn extract LI 132 (crataegus), prepared from leaves and flowers, and standardised to 2.2% flavonoids, was investigated with respect to its effect on (1) the contraction, (2) the energy-turnover and (3) the apparent refractory period (t(ref)) of isolated cardiac myocytes from adult rats. (1) The contractile behaviour of attached myocytes was analyzed by an image processing system. (2) The energy turnover was calculated from the decrease in oxygen content in the myocyte suspension, brought about by cellular respiration. It was differentiated between energy turnover related to cell shortening and that required for ionic transport processes by application of the contraction-inhibiting agent 2,3-butanedione monoxime. (3) The apparent refractory period (t(ref)) was evaluated by pacing the myocytes with increasing stimulation rates and determining the frequency at which failure of single contractions occurred. For these purposes, the myocytes were incubated in a stimulation chamber, which is part of a computer-assisted system allowing to simultaneously evaluate the mechanics and energetics of electrically induced contraction. Within a range of 30-180 microg/ml, the hawthorn extract exhibited a positive inotropic effect on the contraction amplitude accompanied by a moderate increase of energy turnover both for mechanical and ionic processes. In comparison with other positive inotropic interventions, such as application of the beta-adrenergic agonist isoprenaline, or of the cardiac glycoside ouabain (g-strophantin), or elevation of the extracellular Ca++-concentration, the effects of the hawthorn extract were significantly more economical with respect to the energetics of the myocytes. Furthermore the extract prolonged the apparent refractory period in the presence and the absence of isoprenaline, which be indicative for an antiarrhythmic potential.

34: Arzneimittelforschung. 1995 Aug;45(8):842-5.

35: Planta Med. 1994 Aug;60(4):323-8.

Interesting antioxidant activities of extracts from different vegetative and reproductive organs of Crataegus monogyna harvested at different stages of growth have been determined by the malondialdehyde-thiobarbituric acid (MDA) test on hepatic microsomal preparations and compared to the contents in total phenolics, proanthocyanidins, catechins, flavonoids, and phenolic acids. The best correlations were established with total phenols while activities in leaves seem to be influenced by flavonoids and in flowers and fruits by proanthocyanidins and catechins.

36: Indian J Biochem Biophys. 1994 Apr;31(2):143-6.

Hypolipidemic activity of tincture of Crataegus in rats.

Shanthi S, Parasakthy K, Deepalakshmi PD. Department of Biochemistry, University of Madras. India.

Tincture of Crataegus (TCR), an alcoholic extract of the berries of Crataegus oxyacantha, when administered to rats fed a hyperlipidemic diet (HLD), could prevent the elevation in plasma lipid levels. A significant decrease in lipid deposits in liver and aorta was also observed. Analysis of the plasma lipoprotein profile showed that TCR produced remarkable reduction in the increased levels of cholesterol, triglycerides and phospholipids in the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) fractions in hyperlipidemic rats. Histological examination showed severe fatty vacuolation and degeneration of liver of HLD fed rats. TCR administration had an ameliorating effect on these changes. Agarose gel electrophoretic pattern of plasma lipoproteins also indicated that the drug brought down the raised levels of the atherogenic beta-lipoproteins in hyperlipidemic rats.

37: Arzneimittelforschung. 1993 Sep;43(9):945-9.

38: Fortschr Med. 1993 Jul 20;111(20-21):352-4.

Crataegus Special Extract WS 1442 in NYHA II heart failure. A placebo controlled randomized double-blind study

Leuchtgens H.

In 30 patients with stage NYHA II cardiac insufficiency, a placebo-controlled randomized double-blind study was carried out to determine the efficacy of the Crataegus special extract WS 1442. Treatment duration was 8 weeks, and the substance was administered at a dose of 1 capsule taken twice a day. The main target parameters were alteration in the pressure-x-rate product (PRP) under standardised loading on a bicycle ergometer, and a score of subjective improvement of complaints elicited by a questionnaire. Secondary parameters were exercise tolerance and the change in heart rate and arterial blood pressure. The active substance group showed a statistically significant advantage over placebo in terms of changes in PRP (at a load of 50 W) and the score, but also in the secondary parameter heart rate. In both groups, systolic and diastolic blood pressure was mildly reduced. No adverse reactions occurred.

Publication Types:

•  Clinical Trial

•  Randomized Controlled Trial

39: Fortschr Med. 1992 May 30;110(15):290-2.

The fact that the effectiveness of numerous phyto-preparations, so-called, has been demonstrated to the satisfaction of traditional medicine has led to increasing interest in phytotherapy. This also applies to Crataegus (whitethorn), the effects of which have been demonstrated in numerous pharmacological studies. These effects, produced mainly by the flavonoids, indicate a simultaneous cardiotropic and vasodilatory action, as confirmed clinically in controlled double-blind studies. This means that Crataegus can be employed for cardiological indications for which digitalis is not (yet) indicated. Prior to use, however, a Crataegus preparation must meet certain preconditions with respect to dosage, pharmaceutical quality of the preparation, and an accurate definition of the later.

40: Arzneimittelforschung. 1977 Jul;27(7):1407-10.

Reaction of local myocardial blood flow in non-anesthetized dogs and anesthetized cats to the oral and parenteral administration of a Crateagus fraction (oligomere procyanidines)

Roddewig C, Hensel H.

Local blood flow in the myocardium of the left ventricle in unanesthetized dogs was measured by chronically implanted heat-conduction probes. Oral administration of a fraction of Crataegus (oligomere procyanidines) led to a significant rise in blood flow for several hours depending on the dose, the highest increase reaching an average value of about + 70% of the resting flow. In dogs regularly fed with this substance for a longer period of time, a rising tendency of the matutinal resting values of myocardial blood flow towards a maximum was seen. Intravenous application of oligomere procyanidines in anesthetized cats led to a dose-dependent increase in myocardial blood flow for several minutes and a slight decrease in arterial blood pressure.

41: Acta Physiol Pharmacol Bulg. 1977;3(4):53-7.

On the coronary and cardiotonic action of crataemon.

Taskov M.

Crataemon contains the purified flavonoid mixture of Crataegus monogyna. Flowmetric studies of dog coronary blood flow show that it increases after intravenous application of 2 mg/kg crataemon. This increase is statistically significant and lasts about 30 min, with no significant changes in the heart rate and ECG. In experiments on cats it has been found that only the high crataemon doses have a bradycardic effect. Influence on the blood pressure is insignificant and brief. The minute cardiac volume and the cardiac index increase after all doses tested. The work of the left ventricle is also increased, which is considered to be favourable under conditions of operative shock. The general peripheral resistance is much less inhibited, most active being the highest dose tested.