There are more than 100 species of hawthorn in North America, consisting of small trees
and shrubs. However, only a few are used for medicinal purposes. These include Crataegus
laevigata, C. oxyacantha, C. monogyna and, less often, C. pentagyna.1 The name
Crataegus oxyacantha is from the Greek: kratos (hard), oxus (sharp) and akantha (thorn).2
Common names for hawthorns, which are members of the Roasaceae family, include may,
mayblossom, quick, thorn, whitethorn, haw hazels, gazels, halves, hagthorn, and bread and
cheese tree. C. oxyacantha or C. monogyna are usually multibranched 2–5 meter shrubby
trees that can reach a height of up to 10 meters. They prefer the forest margin at lower
and warmer areas. The leaves are alternated, stalked, divided into 3–5 lobes and
grayish-green on the underside. The scented white flowers grow in bunches and bloom from
April to June, after which dark red, egg-shaped fruit develops. The flowering tops are
collected in late spring and early summer. Berry-collecting starts in September and ends
by late October.3
Traditionally, the berries are used for their astringent properties in heavy menstrual
bleeding and in diarrhea. The leaves also have been used as a substitute for green tea and
in making liqueurs. Both the flowers and berries act as diuretics and can be used to treat
kidney problems and dropsy.2 Recently, the flower has been widely used as a
heart tonic. While research suggests that the flower contains more cardioactive components
than do the berries, total extracts of both have been recommended to treat cardiac
failure, arteriosclerosis, hyperlipidemia, hypertension, angina pectoris, and a variety of
geriatric conditions. Chinese medicine employs the berries of C. pinnatifida as a
digestive and circulatory stimulant.
Chemical Composition and Pharmacology
Flowers and leaves contain mixtures of chlorogenic acid and flavonoids such as quercin,
hyperoside (quercetin 3-galactoside), vitexin and vitexin 4’-rhamnoside.4,5
Chlorogenic acid and caffeic acid have some analgesic effects.6,7 Quercetin has
multiple actions: antiarrhythmic, antihepatotoxic and inhibitor of cAMP-phosphodies.8-10
Other flavonoids identified in Crataegus species are luteolin, luteolin-3’-7
diglucosides, apigenin, apegenin-7-O-glucoside and rutin.11 Luteolin is an
effective smooth muscle relaxant and protects the heart lipids against doxorubicin-induced
lipid peroxidation.12,13 In addition, luteolin 5-rutinoside has achieved a
marked antidiabetic activity in streptozocin-induced diabetes.14 Apigenin and
luteolin inhibit tumor formation. Luteolin decreases aromatase enzyme activity; apigenin
showed inhibitory effect on TPA-mediated tumor promotion and is antimutagenic.15-17
Hawthorn contains amygdalin; it has been tested in cancer, but provided no substantive
benefits. In fact, several patients experienced symptoms of cyanide toxicity with
amygdalin therapy.18 The other major constituents are triterpenoids, e.g.,
oleanolic acid, ursolic acid and crataegus acid. Ursolic acid induced apoptosis in human
leukemia cells, perhaps triggered by enhanced intracellular Ca2+ levels.
Lowering Ca2+ levels inhibited the apoptotic action of ursolic acid.19
The antiproliferative action of ursolic acid was also indicated in a mouse melanoma cell
line.20 Oleanolic acid and ursolic acid also have anti-inflammatory and
antihyperlipidemic properties. Oleanolic acid is marketed in China as an oral drug for
human liver disorders.21
Therapeutic Actions
Cardiac Activity: Hawthorn extracts prepared from leaves and flowers were investigated for
their effects on contraction, energy turnover, and the apparent refractory period in
isolated cardiac myocytes from an adult rat heart. The hawthorn extract exhibited a
positive inotropic effect accompanied by a moderate increase of oxygen consumption.22
This research compared the hawthorn extract with other known positive inotropic drugs,
such as the beta-adrenergic agonist isoprenaline or the cardiac glycoside ouabain
(gamma-strophantin); the effects of the hawthorn extract were significantly more
economical with respect to the energy of the myocytes. Furthermore, the extract prolonged
the apparent refractory period in the presence and absence of isoprenaline, which was
indicative of an antiarrhythmic action as well.
Guinea pig hearts also were used to compare the influence of Crataegus extract to that of
other inotropic drugs, such as epinephrine, milrinon and digoxin. Different functional
parameters were measured, focusing on the effective refractory period of the myocardium.23
Several cardiac parameters were measured to test the effect of the extract on the
refractory period. All of the drugs except the Crataegus extract shortened the effective
refractory period in a concentration-dependent manner. However, the Crataegus extract
prolonged the effective refractory period by a maximum of 10%.
The main flavonoids of Crataegus species were tested on isolated guinea pig heart.
O-glycosides, luteolin-7-glucoside, hyperoside and rutin increased the coronary flow
(186%, 66%, and 66%, respectively) and the relaxation velocity. A slight, positive
inotropic effect and a rise in the heart rate were also seen.9 The
C-glycosides—vitexin, vitexin-rhamnoside and monoacetyl-vitexin-rhamnoside—had
similar, but less dramatic, effects. A possible beta-adrenergic effect of the glycosides
was eliminated by propranolol treatment. Also, reserpine did not influence the myocardial
action of hyperoside. These results and former experiments showed that an inhibition of
3’, 5’-cAMP phosphodiesterase may be underlying the possible mechanism of the
glycosides of the species.
Lactate dehydrogenase (LDH) is released from damaged heart cells and is used as a marker
of myocardial injury following myocardial infarction. Rats were treated for three months
with C. oxyacantha. When the coronary effluent was sampled for LDH content, the Crataegus
group showed significantly lower LDH activity after reperfusion, indicating a preservation
effect on the plasma membrane and protection from myocardial damage.24
The effects of garlic (Allium sativum) and Crataegus were examined on isoprenaline-induced
heart, liver and pancreas damage in rats.25 Hawthorn extract in combination
with garlic powder showed protective effects in a dose-dependent manner. Clinical signs,
histological and histoenzymatical findings, and determination of activities of succinate
dehydrogenase (SDH), NADH-NBT reductase, acid phosphatase and glucose-6-phosphate
dehydrogenase (G-6-DPH) were evaluated. Heart, hepatic and pancreatic tissue pretreated
with 0.5 g/kg Allium sativum and 0.3 g/kg Crataegus showed a marked protective effect
against tissue necrosis. Evaluation of hepatic and heart SDH in isoprenaline-treated
animals given the drug combination mentioned above yielded significant enhancement of
enzyme activity. In evaluating the other key enzyme activity G-6-DPH, the composition of
0.5 g/kg garlic and 0.3 g/kg Crataegus had a significant protective effect against
necrosis induced by isoprenaline. The G-6-DPH activity increase was more pronounced in the
heart, providing excellent protection against isoprenaline-induced myocardial lesions.25
In a multicenter trial of 80 patients with heart problems originating from ischemia or
hypertension, the group taking the hawthorn extract showed statistically significant (p
< 0.01) improvement in cardiac function, palpitations, cardiac edema and shortness of
breath. However, ECG results did not improve for the treated or placebo group.26
In a study
utilizing hawthorn and other herbs,
87% of treated subjects had lower total serum cholesterol. |
Another placebo-controlled, double-blind study involved 30 patients aged
50 to 70 years, who had New York Heart Association classification stage II cardiac
insufficiency. Subjects were treated with either 80 mg dry extract or placebo twice a day
for 8 weeks. Physical parameters tested patients’ performances on a standardized
bicycle exercise program and evaluated responses to a questionnaire regarding
patients’ assessments of their conditions. The active substance group showed a
statistically significant improvement (p < 0.05) over the placebo group. No adverse
effects were observed.27
The efficacy of 60 mg of standardized Crataegus extract was tested in a double-blind,
placebo-controlled, clinical study involving 36 multimorbid elderly patients
(62–84 years of age) suffering from decreasing cardiac performance.28
Hemodynamic data were measured before and after exercise, and the patients’
subjective well-being was assessed. The pressure heart rate product (a measure of cardiac
stress) significantly decreased under the active substance both in exercise and recovery
phase; the blood pressure and heart rate also dropped. Fewer prematurely terminated
exercise sessions also indicated the patients’ well-being, including psychological
parameters.
In a meta-analysis of eight clinical studies evaluating heart failure, Crataegus extract
improved both objective and subjective symptoms. The researchers concluded that hawthorn
is safe and an effective therapeutic alternative for the treatment of heart failure.29
Hypotensive Action: A water-alcoholic extract of a procyanidin isolated from C. oxyacantha
has been tested on cats. An injected dosage of 3 mg/kg lowered the blood pressure of the
cats from 160 to 110 mmHg.30 Stepka and Winters investigated 39 known Crataegus
species and found 15 with mild to significant hypotensive activity.31
Myocardial blood flow and arterial blood pressure were tested on nonanesthetized dogs and
anesthetized cats. Oral administration of Crataegus (12–70 mg/kg) in the dogs and an
injection of 15–35 mg/kg in the cats led to a significant increase in blood flow for
several hours depending on the dose. A maximum 70% increase over resting flow was reached
in the dogs. In cats, a similar result was associated with a slight decrease in arterial
blood pressure.32
Hypolipidemic Action: An alcoholic extract prepared from the berries of C. oxyacantha was
tested on hyperlipidemic rats, and a significant decrease in lipid deposits in liver and
aorta was observed. The reductions of cholesterol and triglycerides were progressive in
the low density (LDL) and very low-density (VLDL) lipoprotein fractions. Further study
revealed that the drug lowered the level of the atherogenic component, beta-lipoprotein.33
A similar study in rats fed an atherogenic diet showed that Crataegus tincture increased
the LDL receptor-binding capacity in the liver and enhanced bile acid secretion. These
observations indicated that Craetegus possibly up-regulates cholesterol influx into the
liver and enhances cholesterol degradation to bile acid while suppressing cholesterol
biosynthesis.34 A Chinese clinical trial conducted on 130 hyperlipidemic
subjects also achieved an impressive result with a combination of Chinese herbs, including
C. pinnatifida. After the treatment, 87% of subjects had lower total serum cholesterol,
and 80.8% also had lower triglyceride level.35
Antioxidant Activity: While oxidation is part of a normal biological reaction, overloading
the cells with free radicals could initiate the pathogenesis of many diseases.36
Some Crataegus constituents are predicted to be good antioxidants. The flower and fruit
constituents responsible for free radical scavenging activity are epicatechin, hyperoside
and chlorogenic acid. They are also among the best antilipoperoxidants.37-38
Phenolic compounds of Crataegus also have antioxidant activity. The flowers contain the
most phenolic compounds, and the antioxidant activity of these extracts was clearly
related to the phenolic contents.39
Research supports the suggestion that Crataegus extracts used therapeutically for
cardiovascular diseases should be standardized for oligomeric procyanidins (OPC) content.40
Anti-inflammatory Action: Recent research showed that macrophage-derived
mediators—cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF)—play a
crucial role in inflammatory and immune responses. Therefore, inhibition of IL-1 and TNF
could be criteria of anti-inflammatory activity. Extracts of the root of C. tanacetifolia
showed inhibitory effect depending upon the concentration applied on IL-1 alpha and beta,
and TNF alpha.41
A hydroalcoholic extract from the flower heads of C. oxyacant has inhibited thromboxane A2
biosynthesis in vitro. Further analysis showed that the following ingredients may be
responsible for the action: vitexin, vitexin-2’-O-rhamnoside, quercetin and
hyperoside from the flavonoid class. Also, significant inhibitions were observed with
catechin and epicatechin from the flavonoid class.42
A triterpene fraction isolated from C. monogyna, which contained mainly cycloartenol, was
tested against paw edema in rats. A 40 mg/kg oral dose had significant inhibition (61.5%)
after 3 hours of administration. A similar action was observed in mice, measured with an
inflammation test of the peritoneum. The triterpene fraction given orally to mice (40
mg/kg) inhibited peritoneal leukocyte infiltration by 89.4%. The fraction also showed weak
inhibition of phospholipase A2 in vitro.43
CNS Actions: The alcoholic extract of C. oxyacantha has shown direct influence on the CNS,
having sedative, hypothermic and hypotensive actions.30
Dosage and Toxicity
No toxicity has been directly related to Crataegus preparations. The acute parenteral
toxicity (LD50), tested in different animals, was found in a range of 18–34 mL/kg,
with that of individual constituents ranging from 50-2,600 mg/kg. The acute oral toxicity
was reported to be in a range of 18.5–33.8 mL/kg and 6 g/kg, respectively.44
In humans, therapeutic doses of hawthorn did not have adverse effects. However, drug
interactions are likely with other cardiovascular agents, generating unwanted synergetic
effects. Hawthorn can potentiate cardiac glycoside action of digitalis (or other related
drugs, such as digitoxin, digoxin, or gitalin). Patients who take these drugs should
consult with a medical professional before taking hawthorn.45
The recommended daily dosage is 0.3–1 g, or by infusion 2 teaspoonfuls three times
daily, liquid extract 0.5–1.0 mL three times daily (1:1 in 25% alcohol) or tincture
1–2 mL three times daily (1:5 in 45% alcohol).46 Tincture combinations are
available, such as hawthorn-cactus-motherwort-ginger, 15–30–40 drops, given
three times daily. Hawthorn and its extracts can take up to two weeks to produce effects.
For maximum benefit, they must be taken for at least 4–8 weeks.
Conclusion
The German Commission E made a positive recommendation about the flower and leaf extract
of hawthorn. The combined pharmacological effects are positively inotropic, chronotropic
and dromotropic. Its negative bathmotropic effect makes this herb unique among
anti-arrhythmic drugs, with few adverse effects. The herb enhances coronary and myocardial
circulation by dilating coronary vessels, relieving cardiac hypoxemia. Additional benefits
are its hypotensive and hypolipidemic effects. In Europe, Crataegus extract gained full
recognition in the treatment of age-related degenerative heart diseases.
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45. Alternative herbal health product Cactus-hawthorn compound HYPERLINK http://www.herbsinfo.com/pages/cact.htm
by Herbal Resources Inc.
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London: The Pharmaceutical Press 1996. |
