Natural products and cardiovascular disturbances

PHYTOTHERAPY RESEARCH, VOL. 12, S121–S123 (1998)

Natural Products and Cardiovascular Disturbances N. Mascolo,1* F. Borrelli,1 R. Capasso,1 F. Capasso,1 G. Di Carlo,1 A. A. Izzo,1 L. Pinto,1 S. Castaldo2 and R. Longo3 1

Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano 49, Naples, Italy Heart Unit, INPS Nola, Naples, Italy C. Sessa Pharmaceutical Laboratories, Viale Gramsci 212, 20099 Sesto S. Giovanni Milano, Italy

2 3

Digitalis and other plants containing cardioactive glycosides are infrequently used today for congestive heart failure. Hawthorn has positive inotropic effects and accelerates the heart rate but its use is restricted to the prevention of angina. Ginkgo is employed in chronic cerebral ischaemia and intermittent claudication while horse-chestnut is effective in chronic venous insufficiency. These vegetable drugs are useful in themselves and also in association with more effective therapeutic agents. # 1998 John Wiley & Sons, Ltd. Phytother. Res. 12, S121–S123 (1998) Keywords: angina; peripheral vascular disease; hawthorn; ginkgo; horse-chestnut.

INTRODUCTION Digitalis, the dried leaves of Digitalis purpurea or D. lanata, was used for about two centuries in the treatment of congestive heart failure (CHF), but recently its efficacy has been questioned in CHF patients with sinus rhythm. The advisability of the chronic use of digitalis for long term treatment has been recently debated (Marchetti, 1993). However, digitalis is an extremely potent drug, not easily available in standardized preparations; on the other hand CHF is a serious disturbance which requires a prompt diagnosis and careful treatment with well-defined drugs. Therefore in this paper other drugs of botanical origin and proven efficacy in humans will be examined.

ANGINA The coronary blood flow adjusts the myocardial oxygen demand and therefore is very important in maintaining normal cardiac function: a transient inadequate coronary blood flow can result in a painful condition known as angina or angina pectoris. The reduced flow may be a consequence of coronary artery spasm (primary angina), may depend on a fixed (emodynamically significant) stenosis of one or more coronary arteries (secondary angina) or be a combination of both factors. Angina is treated with nitrates, compounds able to give rapid relief from acute attacks, b-adrenergic receptor antagonists, useful in effort-induced angina, and calcium channel blockers, useful in the prophylaxis and/or treatment of vasospastic and effort-induced angina. * Correspondence to: N. Mascolo, Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy

CCC 0951–418X/98/0SS121–03 $17.50 # 1998 John Wiley & Sons, Ltd.

The vegetable drugs employed today for the treatment of angina are not more effective than nitrates, b-blockers or calcium channel blockers. Therefore, their use is restricted to prevention or to follow up classical treatment (Haas, 1991). Hawthorn, recommended for this purpose, consists of the leaves with flowers and/or fruits of Crataegus laevigata Poir., C. monogyna Jacq. or C. oxyacantha Thuin. The activity of this drug is attributed to flavonoids like procyanidins, quercetin, rutin, hyperoside and vitexin. Other constituents include saponins, cyanogenetic glycosides and amines (Newall et al., 1996). Several studies carried out in animals have shown that hawthorn extracts increase coronary blood flow both in vitro (in the guinea-pig heart) and in vivo (cat, dog, rabbit) (Petkow, 1979; Ammon and Handel, 1981a) and reduce blood pressure and peripheral resistance in vivo (Petkow, 1979) via a vasodilatatory action. Hawthorn also exhibits a prophylactic antiarrhythmic activity in rabbits administered intravenous aconitine (Thompson et al., 1974) and a cardioprotective effect in an ischaemic and perfused Langendorff rat heart (Nasa et al., 1993; A1-Makdessi et al., 1996). In humans hawthorn has been reported to improve cardiac function and remove symptoms such as dyspnoea and palpitations (Iwamoto et al., 1981). It is also effective in a stable form of angina (Hanak and Bruckel, 1983), and in patients with cardiac failure (Weikl et al., 1996). It has been demonstrated that hawthorn in association with passionflower improves heart rate and diastolic blood pressure in patients with CHF. An association of hawthorn, valerian, camphor and cereus, given to patients with cardiovascular disorders also causes an improvement in 84% of treated persons (see Newall et al., 1996; Weihmayr and Ernst, 1996). Actually the daily dosage is determined either on the basis of flavone (5 mg), total flavonoids (10 mg) or procyanidins calculated as epicatechin (5 mg). However, Accepted 11 June 1997

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the difficulty in finding on the market standardized extracts providing these contents and the side effects (nausea, sweating, rash on the hands) reported in clinical trials makes hawthorn unsuitable for self-medication.

PERIPHERAL VASCULAR DISEASE This is a general term that includes cerebral circulatory disturbances and other peripheral circulatory disorders like intermittent claudication and varicosities. Cerebral circulatory disturbances are a result of abnormalities of the vessels, blood flow or blood itself. Such abnormalities may produce a reduction in the blood flow and consequently ischaemia. Depending on its severity, location and duration, it may cause symptoms like dizziness, depression, tinnitus, weakened memory and even dementia. Cerebral circulatory disturbances may respond to treatment with drugs of botanical origin like ginkgo and rosemary. Ginkgo, the leaves of Ginkgo biloba L., contains terpenoids (bilobalide, ginkgolides), flavonoids and other compounds like amino acids and proanthocyanidins. It has been demonstrated that ginkgolides inhibit the binding of platelet-activating factor (PAF) to its receptor (Braquet, 1987). PAF induces aggregation of the blood platelets, release of mediators of inflammation and chemotaxis of phagocytes (Izzo, 1996). PAF also decreases myocardial contractility and coronary flow in perfused guinea-pig heart. Ginkgolides not only block PAF activity but also improve circulation increasing blood fluidity (Tyler, 1993). Other substances like bilobalide act in concert with the ginkgolides improving cerebral circulation. The flavone rutin also reduces capillary fragility and increases the threshold of blood loss from the capillary vessels preventing brain damage. The usefulness of concentrated extract of ginkgo in chronic cerebral ischaemia has been demonstrated in several trials (Vorberg, 1985; Hindmarsh, 1984; Hopfenmuller, 1994). All results show a statistically significant regression of symptoms like vertigo, headache, tinnitus, short term memory and mood disturbance. A daily dosage of 120–160 mg of the extract causes an improvement between weeks 2 and 4 of treatment (Raabe et al., 1991; Eckmann, 1990). Ginkgo is also useful in the peripheral arterial circulatory disturbance known as intermittent claudication (Mouren et al., 1994; Blume et al., 1996); it is safe and effective, improving walking distance and reducing pain severity. An improvement of haemorheology (microcirculation, viscoelasticity of blood, etc.) has been demonstrated with ginkgo extract (Witte et al., 1992; Koltringer et al., 1993). Ginkgo is available in many countries in several pharmaceutical forms (tablets, liquids and parenteral preparations) and in a variety of dosages. There are also patented ginkgo extracts. These preparations are not recommended for self-medication because they can cause mild adverse reaction including gastrointestinal upset and headache (Pizzorno and Murray, 1985). Intermittent claudication is a condition caused by sclerosis of the arteries of the leg; it is characterized by a cramping pain in the calf muscles brought on by walking a short distance. # 1998 John Wiley & Sons, Ltd.

We have just referred to the use of gingko in this disturbance. Another drug employed in this circumstance is rosemary (Rosmarinus officinalis L.), both leaves and its volatile oil. Given internally, or applied externally (also in the form of a bath) rosemary oil seems to improve chronic circulatory weakness. However, the efficacy of rosemary when given internally is under debate (Hansel, 1991) because it is still unclear how the drug may improve the peripheral circulation. Therefore the internal use of the oil is not completely justified while, in the light of its counterirritant properties, could be of some value for external use. Varicosities are another peripheral vascular disease frequently treated with drugs of botanical origin. Varicosities are characterized by dilated, tortuous, visible veins of the extremity. There is also aching discomfort, pain and oedema. Varicose vein syndrome is largely the result of the destruction of the network of proteoglycans in the elastic tissue of the vein wall by lysosomal enzymes. This situation causes an abnormal dilatation of the vein and a passage of electrolytes, proteins and water through the venous wall and then oedema formation. Drugs used in the treatment of varicosities may provide only relief of the unpleasant symptoms by increasing capillary resistance and venous tone but not reverse changes in organic structures. In some cases these drugs may also inhibit the action of lysosomal enzymes. Substances frequently used are rutin, hesperidin, diosmin, coumarin and others. The most effective drug of botanical origin is horse chestnut, i.e. the seeds of Aesculus hippocastanum L. It contains a complex mixture of triterpenoid saponin glycosides named aescin, flavonoids like quercetin and kaempferol, tannins, allantoin, amino acids, adenine, adenosine, guanine and other constituents. Aescin possesses antiinflammatory activity in rats; however, this compound has been proven to be less potent than horse chestnut extract. This and the fact that an extract without aescin also exhibits activity suggests that horse chestnut contains antiinflammatory agents other than aescin (Tsutsumi and Ishizuka, 1967). However aescin has the ability to inhibit lysosomal enzymes activity and the transcapillary filtration of water and proteins by reducing the number and/or diameter of capillary pores. In addition aescin increases the tonus of the veins, thus improving return blood flow to the heart (Haas, 1991). A controlled double-blind trial over 4 weeks involving 137 patients with chronic venous insufficiency has shown an antioedematous effect of a horse chestnut extract (Rehn et al., 1996). Similar results have been obtained by Diehm et al. (1996) and Greeske and Pohlman (1996). All these results confirm previous human studies (see Newall et al., 1996) and show that symptoms usually registered (pain, tiredness, tension, volume of the leg, itching and tendency towards oedema) improve or disappear after treatment with horse chestnut extract. Horse chestnut extract also reduces the activity of proteoglycans, substances able to modify capillary rigidity and pore size. Horse chestnut seed extract containing from 16% to 21% triterpene glycosides, calculated as aescin, is normally used. Initial oral daily dosage is 90–150 mg of aescin but following improvement this may be reduced to 35–70 mg daily. Horse chestnut may be irritant to the gastrointestinal tract and may interfere with coagulant/anticoagulant therapy. It must be avoided by patients with existing renal or hepatic impairment. Phytother. Res. 12, S121–S123 (1998)

NATURAL PRODUCTS AND CARDIOVASCULAR DISTURBANCE

CONCLUSION Hawthorn, ginkgo and horse chestnut have been used since antiquity for medicinal purposes. More recent research suggest that they may be useful in the treatment

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of cardiovascular and venous diseases like angina, cerebrovascular disease, intermittent claudication and varicose vein syndrome. Therefore these drugs are an effective and safe therapeutic alternative for these indications. They also represent an economical therapeutic aid.

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# 1998 John Wiley & Sons, Ltd.

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Phytother. Res. 12, S121–S123 (1998)