Dichroa febrifuga (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

Dichroa febrifuga Lour.

Protologue: Fl. cochinch.: 301 (1790).

Family: Saxifragaceae

Chromosome number: 2n= unknown

Synonyms

• Adamia chinensis Gardner & Champ. (1849),
• Dichroa cyanea (Wallich) Schltr. (1914),
• Dichroa sylvatica (Reinw. ex Blume) Merr. (1934),
• Dichroa versicolor (Fortune) D.R. Hunt (1981).

Vernacular names

• Indonesia: gigil (Javanese, Sundanese), tataruman (Sundanese), ramram (Ayawasi, Papua)
• Cambodia: phuck mon
• Thailand: yaai khlang yai (peninsular), hom kham, hom dong (northern)
• Vietnam: thường sơn.

Origin and geographic distribution

D. febrifuga is found from northern India and the Himalayas to Burma (Myanmar), Thailand, Indo-China and China, southward to mountainous areas of Malaysia, Indonesia, the Philippines and Papua New Guinea.

Uses

In Java, the leaves of D. febrifuga are finely ground with Kaempferia galanga L. rhizomes, red onions, salt and a little water, and applied as a poultice at the beginning of a fever. In Papua, leaves softened over a fire are fed to dogs that refuse to eat. It will cause vomiting, and may dispose of worms. In Vietnam, the roots and especially the leaves have been used for the treatment of malaria in traditional medicine since time immemorial. It is one of the ingredients of a well-known antimalarial formula. An extract of the leaves was successfully used as a substitute for quinine, during World War II.

D. febrifuga has a long-standing reputation in the treatment of malarial fevers in China. The roots and leaves are credited with antipyretic, expectorant, cathartic, emetic and diuretic properties. The wood and bark are also considered medicinal.

In humans the fresh sap of the leaves and roots causes vomiting and depresses the circulation of blood. According to traditional medicine, these side effects, especially nausea and vomiting, may be controlled by heating the drug with a little vinegar, and by combination with other drugs as indicated in classic formulas. The dried drug should be steeped in alcohol and subsequently heated to achieve the same effect. The drug is contraindicated in pregnancy and senile debility.

Production and international trade

D. febrifuga is only used and traded at a local level.

Properties

The alkaloids febrifugine (= dichroin A orα-dichroine) and isofebrifugine (= dichroin B orβ-dichroine) have been isolated from the leaves and roots of D. febrifuga. Tests revealed isofebrifugine, administered intravenously, to be as equally effective as quinine in ducks infected with Plasmodium lophurae, whereas febrifugine was 100 times more effective as an antimalarial. In chickens infected with P. gallinaceum, febrifugine was 64 times more effective than quinine. Tested against tropozoites of P. cynomolgi in monkeys, febrifugine was at least 100 times more effective. The LD₅₀ of febrifugine, given orally, in white mice is about 2.5-3.0 mg/kg. It is therefore more toxic than quinine, but the toxic syndromes are different; it has an effect on respiration, urinary incontinence, sweating and a corrosive action on the gastric mucosa.

The electrophysiological effects of another alkaloid, changrolin (4- 3',5'-bis((N-pyrrolidinyl)methyl)-4'-hydroxyanilino-quinazoline), derived from D. febrifuga were examined using the whole-cell patch-clamp method on single cells isolated from guinea-pig and rabbit hearts. At a clinically relevant concentration of 50μmol/l this anti-arrhythmic compound shortened the action potential duration in both guinea-pig and rabbit ventricular cells, and significantly reduced L-type Ca²⁺ current (ICa) values in these cells. Changrolin also inhibited the transient outward current (ITO), but had little effect on fast Na⁺ current (INa). Furthermore, in vivo, changrolin exhibited significant protective and therapeutic effects against experimental arrhythmias induced by aconitine or ouabain. It raised the electrical threshold of ventricular fibrillation. Intravenous injections in dogs and rabbits caused a mild tachycardia followed by bradycardia; a prolongation of P-R interval and a widening of QRS complex in the ECG; a gradual hypotension; a slight weakening of cardiac functions; and only moderate influences on the hearts of dogs and rabbits when the rate of infusion was less than 1 mg/min. Changrolin could be well absorbed by oral administration, although absorption appeared to be more rapid and complete by intramuscular injection.

The effect of the alkaloid halofuginone on collagen α1(I) gene expression and collagen synthesis was evaluated in human skin fibroblasts from patients with chronic graft-versus-host disease (cGvHD) or scleroderma and from a normal individual. Halofuginone caused a dose-dependent inhibition in collagen α1(I) gene expression and collagen synthesis in all cultures tested, the cGvHD fibroblasts being the least sensitive. In normal and scleroderma fibroblasts, concentrations of halofuginone as low as 10^-10M and 10^-9M were sufficient to cause a significant reduction in collagen α1(I) gene expression and collagen synthesis, respectively. In addition, halofuginone also inhibited the transforming growth factorβ-induced collagen synthesis. Three days after halofuginone removal, collagen gene expression returned to control levels. The reduction of collagen mRNA transcript levels by halofuginone appeared to be dependent on new protein synthesis because simultaneous treatment of fibroblasts with protein synthesis inhibitors prevented the suppressive effect of halofuginone on collagen α1(I) mRNA gene expression. The ability of extremely low concentrations of halofuginone to inhibit collagen α1(I) synthesis specifically and transiently at the transcriptional level suggests that this material may be an important tool for studying collagen α1(I) gene regulation and maybe used as a novel and promising antifibrotic therapy.

Extracts of D. febrifuga were furthermore shown to inhibit the secretion of nitric oxide and tumour necrosis factor in lipopolysaccharide and/or interferon-γ stimulated mouse peritoneal macrophages, without affecting cell viability. By using a quite similar assay for nitric oxide production, febrifugine was isolated as the main active compound, showing a dose-dependent relationship.

Adulterations and substitutes

The alkaloid febrifugine is also present in Hydrangea spp. (Saxifragaceae).

Description

• An erect, evergreen shrub, 1-3 m tall, twigs terete, variably pubescent.
• Leaves opposite, simple, ovate, elliptical to oblong, 7.5-30 cm × 2.5-12.5 cm, base cuneate, apex short- to long-acuminate, margin serrate-dentate, variably pubescent; petiole 1.5-6 cm long; stipules absent.
• Inflorescence a terminal, erect panicle, 4-15(-20) cm long and up to 25 cm in diameter, many-flowered, axes minutely pubescent.
• Flowers bisexual, actinomorphic, pedicel 3-8 mm long, calyx tube campanulate, 2-4 mm long, with 5-6 teeth; petals valvate, 5-6(-7), 5-10 mm long, oblong, acute or obtuse, light to dark blue; stamens diplo-(poly-)stemone; ovary semi-inferior, 1-locular, many-ovuled, styles 3-5.
• Fruit a globose berry, about 5 mm in diameter, with calyx and styles persistent, blue.

Growth and development

D. febrifuga can be found flowering and fruiting throughout the year.

Other botanical information

Some prefer to retain the family of Saxifragaceae s.l. including the tribe Hydrangeae, whereas others prefer Hydrangeaceae as a separate family. Dichroa is part of the tribe Hydrangeae or the family Hydrangeaceae, respectively. Dichroa very much resembles Hydrangea. However, the outer flowers of the panicle are not sterile and the fruit is a berry, not a capsule.

Dichroa is a small genus containing about 12 species, ranging from mainland South-East Asia southward to the Pacific islands. However, most species are rather restricted in their distribution. Six species are known from China and Indo-China; 3 are confined to west and north-west New Guinea; 2 are endemic in the Philippines. Only D. febrifuga is widely distributed in South-East Asia. In this treatment D. febrifuga is considered in the broad sense. A wide range of variation exists in the size of the plants, the shape, texture and dentation of the leaves, and the number of flowers per cluster. Large-flowered plants in cultivation in Hong Kong, were raised to species rank by Hunt. Large-flowered D. sylvatica from Java was reduced in synonymy by van Steenis.

Ecology

D. febrifuga is found in forest undergrowth and forest borders, in montane forest or preferably in moist localities, e.g along rivers and streams at (200-)700-2000 m altitude.

Propagation and planting

D. febrifuga can be easily propagated by cuttings from young branches.

Harvesting

The drug is collected mostly from wild plants of D. febrifuga. To harvest the roots 3-4-year-old plants are dug up. Leafy tops are simply plucked.

Yield

Root material of D. febrifuga from China contained 0.08-0.8% crude alkaloids of which 55% consisted of febrifugine and isofebrifugine at a ratio of 6:1-1:1. The crude alkaloid content of roots from India was 0.05% of which 63% febrifugine and 2% isofebrifugine; the leaves contained 0.01-0.02% total alkaloids of which 50% was febrifugine.

Handling after harvest

The roots of D. febrifuga are separated from the shoots, washed and dried in the sun, either whole or finely chopped. Leafy tops can be simply dried for future use.

Genetic resources and breeding

D. febrifuga has a large area of distribution and does not seem to be at risk of genetic erosion. Especially the large flowered plants are locally cultivated. There are no known breeding programmes of D. febrifuga.

Prospects

Several alkaloids isolated from D. febrifuga show interesting pharmacological effects, especially concerning malaria and heart-arrhythmias. More research is needed, however, for example in the field of toxicology, to evaluate the possibilities of these compounds or their semisynthetic derivatives in future medicine.

Literature

• Halevy, O., Nagler, A., Levi-Schaffer, F., Genina, O. & Pines, M., 1996. Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone. Biochemical Pharmacology 52(7): 1057-1063.
• Hwang, S.-M., 1987. A preliminary study on Dichroa Lour. Acta Phytotaxonomica Sinica 25(5): 384-389.
• Kim, Y.H., Ko, W.S., Ha, M.S., Lee, C.H., Choi, B.T., Kang, H.S. & Kim, H.D., 2000. The production of nitric oxide and TNF-α in peritoneal macrophages is inhibited by Dichroa febrifuga Lour. Journal of Ethnopharmacology 69(1): 35-43.
• Li, L.Q., Qu, Z.X., Wang, Z.M., Zeng, Y.L., Ding, G.S., Hu, G.J. & Yang, X.Y., 1979. Studies on a new anti arrhythmic drug changrolin 4-3' 5' bis-n pyrrolidinyl methyl-4'-hydroxyanilino quinazoline. Scientia Sinica 22(10): 1220-1228.
• Lu, L.L., Habuchi, Y., Tanaka, H. & Morikawa, J., 1995. Electrophysiological effects of changrolin, an anti-arrhythmic agent derived from Dichroa febrifuga, on guinea-pig and rabbit heart cells. Clinical and Experimental Pharmacology and Physiology 22(5): 337-341.
• Murata, K., Takano, F., Fushiya, S. & Oshima, Y., 1998. Enhancement of NO production in activated macrophages in vivo by an antimalarial crude drug, Dichroa febrifuga. Journal of Natural Products 61(6): 729-733.

Other selected sources

• [74] Backer, C.A. & Bakhuizen van den Brink Jr, R.C., 1964—1968. Flora of Java. 3 volumes. Noordhoff, Groningen, the Netherlands. Vol. 1 (1964) 647 pp., Vol. 2 (1965) 641 pp., Vol. 3 (1968) 761 pp.
• [135] Burkill, I.H., 1966. A dictionary of the economic products of the Malay Peninsula. Revised reprint. 2 volumes. Ministry of Agriculture and Co-operatives, Kuala Lumpur, Malaysia. Vol. 1 (A—H) pp. 1—1240, Vol. 2 (I—Z) pp. 1241—2444.
• [215] Council of Scientific and Industrial Research, 1948—1976. The wealth of India: a dictionary of Indian raw materials & industrial products. 11 volumes. Publications and Information Directorate, New Delhi, India.
• [264] Doan Thi Nhu, Nguyen Thuong Thuc, Do Huy Bich & Vu Thuy Huyen (Editors), 1990. Les plantes médicinales au Vietnam. Livre 1. Médicine traditionelle et pharmacopée [The medicinal plants of Vietnam. Volume 1. Traditional medicine and pharmacopoeia]. Agence de coopération Culturelle et Technique, Paris, France. 201 pp.
• [312] Flore du Cambodge, du Laos et du Viêtnam [Flora of Cambodia, Laos and Vietnam](various editors), 1960—. Muséum National d'Histoire Naturelle, Paris, France.
• [407] Heyne, K., 1950. De nuttige planten van Indonesië [The useful plants of Indonesia]. 3rd Edition. 2 volumes. W. van Hoeve, 's-Gravenhage, the Netherlands/Bandung, Indonesia. 1660 + CCXLI pp.
• [458] Hunt, D.R., 1981. Dichroa versicolor. Curtis's Botanical Magazine 183(3): 107—110.
• [739] Nguyen Van Duong, 1993. Medicinal plants of Vietnam, Cambodia and Laos. Mekong Printing, Santa Ana, California, United States. 528 pp.
• [786] Perry, L.M., 1980. Medicinal plants of East and Southeast Asia. Attributed properties and uses. MIT Press, Cambridge, Massachusetts, United States & London, United Kingdom. 620 pp.
• [788] Pételot, A., 1952—1954. Les plantes médicinales du Cambodge, du Laos et du Vietnam [The medicinal plants of Cambodia, Laos and Vietnam]. 4 volumes. Centre National de Recherches Scientifiques et Techniques, Saigon, Vietnam.
• [1027] van Steenis, C.G.G.J., 1972. The mountain flora of Java. E.J. Brill, Leiden, the Netherlands. 90 pp. + 72 photographs + 57 coloured plates.
• [1079] Wongprasert, T., 1998. Hydrangeaceae. Thai Forest Bulletin, Botany 26: 25—30.

Authors

• J.L.C.H. van Valkenburg