Cinchona (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

Cinchona L.

Protologue: Sp. pl. 1: 172 (1753); Gen. pl. ed. 5: 79 (1754).

Family: Rubiaceae

Chromosome number: x= 17; C. officinalis, C. pubescens: 2n= 34

• Cinchona officinalis L.,
• C. pubescens Vahl.

• Cinchona, quinine (En).
• Quinquina (Fr)
• Indonesia: kina
• Malaysia: kuinin
• Cambodia: kini:n
• Thailand: quinin
• Vietnam: canh ki na.

Cinchona comprises about 50 species. The centre of diversity lies along the Andes mountains of Bolivia, Peru, Ecuador, Colombia and Venezuela. There the species and natural hybrids flourish on the misty and humid eastern slopes at 800-3000(-3700) m altitude.

The collection of Cinchona germplasm for dispersal outside its centre of origin started in 1848. Hasskarl's expeditions to South America (1852-1854) provided the Dutch in Java (Indonesia) with plant material. A British expedition under Markham did likewise for India and Sri Lanka (1859). In both cases, the plant material adapted to the local conditions with no problems. However, the bark of the vigorously growing trees appeared to contain such small amounts of quinine that it was not profitable to start cultivation. Seeds Ledger (1864) collected in Bolivia produced weakly growing seedlings in Java, some of which had an unusually high percentage of quinine in the bark. Meanwhile, seed samples from South America and from importations from surrounding countries had arrived in nearly every country of South-East Asia.

Cinchona started to be distributed worldwide in the second part of the 19th Century. Around 1880, Sri Lanka had become a major producer of cinchona bark, albeit of low quality. By 1895 it had been superseded by the Dutch East Indies (Indonesia) as the main producer, mainly because of the better quality of the bark (C. officinalis). The crop was introduced into West and East Africa (Guinea, Cameroon, Kenya, Tanzania) and Central Africa (Congo Kinshasa, Rwanda) in the 1930s. In all of these countries, except for Congo Kinshasa, production has dwindled. After the rapid decline of bark production in South America around 1880, interest revived in Latin America around 1940, especially in Guatemala, but declined sharply after 1945.

In Asia, Cinchona cultivation is still important in Indonesia and India. The plantations in Burma (Myanmar), the Philippines, Sri Lanka and Vietnam have been abandoned, as have those in Australia (Queensland) and Papua New Guinea.

The Spanish conquerors of Central and South America reported the use of cinchona bark by Indian miners in the Andes to suppress shivering from the cold in the mines. Later, Jesuits found that shivering was caused by fever. This led to the discovery of cinchona bark as a remedy against malaria. Anti-malarial drinks containing small quantities of quinine, one of the major alkaloids found in cinchona bark, were developed for use in the tropics especially in India; they are still very popular (e.g. tonic water).

Malaria is a disease mostly found in tropical areas, where it constitutes a major medical problem. It is characterized by attacks of severe fever, which recur at regular intervals. There is also a form with irregular attacks of severe fever. The disease is caused by a parasitic protozoan of the genus Plasmodium, which uses mosquitos of the genus Anopheles as an intermediary host. When an infected mosquito bites a person, sporozoites enter the blood, but they disappear rapidly from the circulation to localize in the parenchymal cells of the liver in which they grow and segment. On reaching maturity these merozoites are released from the liver cells and penetrate erythrocytes where further division and development takes place. When this process is complete, the erythrocytes burst open and the merozoites enter the blood stream. It is this periodic breaking of erythrocytes that induces the chill so characteristic of malaria. The fever following the chill is the body's response to the liberated foreign protein and cell products.

Some of the merozoites infect new blood corpuscles, while others develop into the sexual form, called gametes. The gametes can pass to a healthy mosquito when it bites a person suffering from malaria. The gametes conjugate in the mosquito, forming sporozoites, and the circle is complete. Quinine acts by killing the merozoites in the blood, except for those in the reproductive stages.

Quinine has largely been replaced by synthetic anti-malarials (e.g. chloroquine), which have fewer side-effects. In recent years, however, renewed interest has arisen in quinine and related alkaloids because of the growing resistance of malaria-causing agents (Plasmodium spp.) to industrial anti-malarial drugs currently in use. Additionally, large amounts of quinine are used as a bitter flavouring in soft drinks and in innumerable other products, such as hair oils and shampoos, sun-tan oil, insecticides, as a vulcanizing agent in the rubber industry, and in the preparation of certain metals.

Another cinchona alkaloid, quinidine (a stereoisomer of quinine) is also active against malaria, but is nowadays mainly employed as an anti-arrhythmic. Minor uses of cinchona alkaloids include the treatment of ophthalmia, internal haemorrhoids and hiccups. A tincture has been used as a bitter to stimulate appetite and digestion. The alkaloids are also used in insecticides and moth repellants. Other applications of cinchona alkaloids are in the asymmetrical catalysis of chemical reactions. After extraction of alkaloids, the bark is still useful for tanning leather.

Indonesia maintained an almost total monopoly on the production of cinchona bark for nearly 50 years, up to the Second World War. In terms of ready product, this amounted to roughly 800 t/year of quinine sulphate. Since the Second World War, Indonesia has been gradually caught up and surpassed by Congo Kinshasa, although substantial quantities of quinine sulphate are still being produced in Indonesia, Guatemala, Tanzania and other countries.

International trade figures are often difficult to interpret because of the varying ways the quinine content of cinchona bark is indicated. In the past SQ2 and SQ7 were used most frequently, indicating 2 and 7 water molecules respectively. Nowadays, percentages are generally indicated as QAA, the anhydrous form of quinine salts: 1% QAA = 1.206% SQ2 = 1.345% SQ7.

At present, world production of cinchona alkaloids is estimated at about 600 t/year of QAA, for which about 10 000 t of bark are extracted, with Congo Kinshasa producing about 55%, Indonesia 30%, India 8% and the other countries 7%. Stripe canker (Phytophthora cinnamomi) is a threat to production in East and Central Africa.

Although there are factories in bark-producing countries (Indonesia, India, Guinea, Congo Kinshasa and Rwanda) that extract alkaloids, most of the end-products are still manufactured in Europe (West Germany, the Netherlands, France). About 60% of the production is used for pharmaceuticals, most of the remaining 40% in the food and beverage industry.

More than 36 different alkaloids have been reported as constituents of various Cinchona barks, the most important being quinine, quinidine, cinchonine and cinchonidine. Biosynthetically, these alkaloids are derived from the amino acid tryptophan and a monoterpenoid skeleton of the Corynanthe type. Quinine and quinidine are stereoisomers, their difference being the configurations at C-8 and C-9. Cinchonine and cinchonidine form another set of stereoisomers which lack the methoxy group at the C-6' position. Quinine and quinidine are of medicinal value; they are used to treat malaria and cardiac arrhythmias, respectively. Approximately 30-50% of the quinine produced is chemically converted to quinidine. The other alkaloids are not used medicinally, although they show effects similar to quinine and quinidine. Cinchonine showed inhibition of human platelet aggregation.

The composition and content of alkaloids vary with species, genotype, environment and age of the bark. Generally, the alkaloid concentration is higher in bark from the bole than in branch bark. Selected clones of C. officinalis have been reported to yield as much as 14-16% quinine from dry bark. Normally, Cinchona bark has a total alkaloid content of 3-15%, and pharmaceutical bark must contain at least 6%. The quinidine content is generally low: about 1% of the total amount of alkaloids. Quinine can be converted into quinidine by means of a rather complicated chemical process. Alkaloids known as the cinchophyllines have been isolated from leaves of C. officinalis; they may be regarded as indole analogues of emetine and have shown in vitro amoebicidal activity. Research on the anti-microbial activity of a series of quasi-dimeric alkaloids found activity against gram-positive bacteria, but no activity against gram-negative bacteria, yeast and several fungi. A weak local anesthetic activity was found for cinchophyllamine, as well as some analgesic activity.

Numerous plant resources have been used and are still used in traditional medicine to treat malaria. One of the most important alternatives to cinchona is the herb Artemisia annua L. (or its isolated active compound artemisinin), which is widely used in Vietnam and China ("Quinghaosu"). Other species used in traditional medicine to treat malaria that have recently shown in vitro antiplasmodial activity are Azadirachta indica A.H.L. Juss., Brucea javanica (L.) Merr., Cyclea barbata Miers and Dichroa febrifuga Lour.

• Evergreen woody shrubs or small to medium-sized trees, 8-16 m, occasionally up to 30 m tall; bark thick, greyish-brown to brown.
• Leaves opposite, oblong-elliptical, simple and entire; stipules interpetiolar, deciduous and leaving a characteristic scar.
• Inflorescence a terminal panicle, many-flowered.
• Flowers 1-2 cm long, fragrant, 5-merous, heterodistylous, pink or yellowish; calyx small, with pointed lobes; corolla tubular with spreading lobes with a fringe of hairs along the margins; stamens alternating with the corolla lobes and inserted in the corolla tube; ovary inferior, bilocular, style at the base with a circular disk, ending in a bifid stigma.
• Fruit a 1-3 cm long capsule containing 40-50 seeds.
• Seeds flat, winged, 4-5 mm × 1 mm.

Freshly harvested Cinchona seeds include varying numbers of immature and deteriorated ones. After these have been removed the germination percentage is usually more than 90% after 2-3 weeks of incubation. The seeds remain viable over a year if stored dry, cool and dark. Light promotes the germination.

The tiny seedlings develop slowly at first but then speed up: after about 2 months 2-3 pairs of leaves have formed. Flowering starts after 4-7 years or even earlier under stress conditions. There is a periodicity in flowering which has not been fully investigated. Cross-pollination is by insects, mainly bees, butterflies and flies. Fruits mature about 7-8 months after flowering.

Most Cinchona cultivated in South-East Asia is known under the name C. ledgeriana, and most probably are high-yielding selections of C. officinalis. Cinchona known under the name C. succirubra belongs to C. pubescens.

The majority of the species and hybrids from the centre of diversity do not produce valuable chemical compounds, but might nevertheless be of interest for breeding.

In the natural habitat of Cinchona, high, evenly distributed annual rainfall (up to 4000 mm) and high relative humidity prevail. Cinchona grows optimally with a rainfall of 2500-3800 mm well distributed throughout the year. Nevertheless, Cinchona is known to grow under drier conditions as well (1500 mm, with distinct dry season) and it can stand an annual precipitation of 5000 mm, provided this is well distributed throughout the year. Low irradiation (misty slopes, forest canopy) is frequently encountered in regions where Cinchona occurs naturally.

In Asia, Cinchona grows well in areas with an average minimum temperature of 14 °C and an average maximum temperature of 21 °C. Growth is hampered severely below 7 °C and above 27 °C. Altitudinal range is largely determined by the prevailing climatic conditions, but generally lies between 800-2000 m. It has been reported that the yield of quinine is low in plants cultivated under 800 m altitude, and that the plants are susceptible to diseases. Growth is slow at elevations above 2000 m. Cinchona cannot stand waterlogging.

Favourable soil types are slightly acid, well drained, with a good water-retaining capacity. Cinchona grows well on soils of volcanic origin. The most important species, C. officinalis, is very vulnerable to weed competition; C. pubescens is more competitive.

Cinchona is propagated by seed as well as by vegetative means. Seedbeds are carefully prepared to give a fine tilth. The small seeds are broadcast on the soil surface (3000-12 000/m² corresponding with 1-4 g/m²) and protected against wind, rain and direct sunlight. Germination starts within 2-3 weeks; after 4-6 months plantlets are 5-10 cm tall and are moved to nursery beds where they stay 6-7 months. The seedlings require temperature, light and ventilation to be carefully controlled, to avoid damping-off and other hazards. Young plants can be transplanted to the field when 1-1.5 years old. The rather delicate C. officinalis is often grafted on the more robust and vigorous C. pubescens. Seedlings of the latter reach the proper size for grafting after about 1 year. The scion is usually inserted by side-tongue grafting, but green-budding is also applied. Cuttings are difficult to root; cuttings taken from shoots formed after topping give better results.

The isolation and multiplication of high-yielding or disease-tolerant trees by in vitro culture techniques is a promising new method that may result in high-yielding and disease-resistant clones being available for planting in the near future. In vitro micro-grafting of C. officinalis on C. pubescens has proved to be successful and is comparatively simple.

Cinchona is almost exclusively grown as an estate crop, except in Congo Kinshasa where smallholders occasionally grow it. It is mostly grown as a sole crop, although in Congo Kinshasa it is occasionally intercropped with beans. Cinchona is planted in the field in holes of 50 cm × 50 cm × 50 cm, 80-150 cm apart, in rows or in a triangular arrangement depending mainly on the topography of the field. Before planting, the plants are pruned back about one-third, or defoliated by 50%. The planting out takes place at the beginning of the rainy season. Leguminous cover crops may be planted between the rows (e.g. Desmodium in Congo Kinshasa, Crotalaria trichotoma Bojer or Shuteria vestita Wight & Arnott in Indonesia) or on the contour to prevent erosion (e.g. Leucaena leucocephala (Lamk) de Wit).

In recent decades, much attention has been paid to the biosynthesis of cinchona alkaloids in in vitro cell, tissue and organ cultures. Fine cell suspensions do not produce alkaloids, and only cultures showing some form of differentiation produce alkaloids in reasonable amounts. Studies of possible biotechnological production of alkaloids with plant cell cultures are in progress, but have not yet led to large-scale processes.

Hypocotyl explants from seedlings can be induced to form callus on solid Gamborg B5 medium (0.7% agar), containing 2,4-dichlorophenoxyacetic acid (1 ppm) and kinetin (0.2 ppm). Alkaloid production is low and growth slow in cell and tissue cultures. It has been found that growth and indole alkaloid production (e.g. cinchonamine) was improved by increasing the auxin concentration in callus cultures, but anthraquinone production and quinoline alkaloid levels (e.g. quinidine) were highest when auxin concentrations were reduced. Low and medium cytokinin concentrations benefit the production of quinoline alkaloid. Adding the precursor tryptophan increases the amount of alkaloids produced, but reduces growth. The best growth was obtained in the light, although many media resulted in no growth at all in the light. From the results of the experiments with tissue culture it was concluded that the pathways leading to the various secondary products (anthraquinones, indole alkaloids and quinoline alkaloids) are, at least partly, regulated independently.

Two systems of cultivation are applied:

• A short-term, intensive, high-production system with a relatively short production cycle of about 10 years from planting to harvesting. It is practised mainly in Congo Kinshasa. Planting is at densities of 10 000-12 000 plants/ha. Weeding is mostly by hand, although the use of herbicides is increasing. Around the third year after planting, weeds are shaded out because of the development of the canopy. At the same time pruning and thinning starts, producing the first harvest of low-quality bark. Thinning continues until, around 10 years after planting, a stand of 3000 well-shaped trees is left. These are then harvested completely, producing a minimum of 3.5 kg of high-quality bark per tree.

• A long-term, extensive, intermediate-production system with a longer occupation period. It is practised in Indonesia and Guatemala. Planting is at a density of 5000 plants/ha. Weeding is necessary over a longer period, while pruning is only carried out to shape the trees. After 7-8 years, when competition for light becomes a limiting factor, all trees are coppiced to a height of 15-20 cm. In maintaining a maximum of 2-3 shoots per stool, a new cycle is started which is treated in the same way as the first one. If proper care is taken and mortality after coppicing is not too high, this system of production can be maintained for several decades. It is also suitable for Cinchona cultivation under the shade of rainforest trees, which are left to prevent serious erosion.

A combination of both systems is practised in West Bengal (India), where C. officinalis seedlings are first coppiced and then after completion of the second cycle, harvested completely. Modifications of these 2 systems have been developed to meet local conditions. One involves grafting clonal C. officinalis or hybrids on a rootstock of C. pubescens, giving uniform planting material, better growth and tolerance or resistance to Phytophthora cinnamomi. This method is practised in Indonesia and Guatemala.

Composite fertilizers such as NPK (20-10-10 or 15-15-15) are widely applied, although other compounds such as phosphates and oligo-elements are used as well, depending on the local conditions. In general, a final dressing of nitrogenous fertilizer (100-600 kg/ha of the above-mentioned NPK) about 6 months prior to harvest increases the alkaloid content of the bark. Where soils are low in organic matter, Cinchona responds well to the mulching.

Mechanization is not widespread in Cinchona cultivation, partly because of the fields are often undulating. For the time being, it is mainly limited to the application of herbicides and insecticides and, to a lesser extent, to the harvest and stripping of the trees. However, mechanization is becoming more important where labour is scarce.

Seedlings are susceptible to Pythium spp., Rhizoctonia solani (causing damping-off), Fusarium solani (causing wilt), Phytophthora cinnamomi, Sporotrichium and Verticillium species (causing stem blight) and Sclerotium rolfsii (causing seedling blight). Attacks can easily be overcome by chemically sterilizing the seedbed, and by regularly shifting the nursery site. In later stages, Cinchona is vulnerable to Phytophthora cinnamomi, P. parasitica (causing top blight and girdle canker), Corticium salmonicolor (dieback of branches), and Armillaria sp. (root rot). Other fungi (Alternaria, Cercospora and Sclerotium spp.) are of little economic importance. In areas with Phytophthora cinnamomi and P. parasitica, a combination of cropping techniques (e.g. cover crops) should be practised to avoid infestation, because once these diseases have taken hold the application of fungicides is almost impossible and too expensive. Phytophthora cinnamomi can also be avoided by grafting on a C. pubescens rootstock. The outbreak of Corticium salmonicolor can be avoided by timely pruning of trees, and of Armillaria sp. and Fomes noxius by consistent removal of old stumps. There are indications that insufficient drainage and planting too deep may favour the incidence of a physiological canker.

The main pest in Cinchona is Helopeltis spp., which can cause considerable damage by sucking young shoots and leaves. Helopeltis outbreaks can be avoided by timely application of insecticides. Occasional outbreaks of other pests such as various caterpillars (e.g. Delephila nerii) and borers occur, but are only of local importance.

In general, two phases of harvest can be distinguished: pruning and thinning in the early years and the final harvest.

The bark is removed in various ways. In Indonesia and Congo Kinshasa, bark is removed by clubbing, but in Tanzania and Guatemala knives are used. Bark peeling machines are used occasionally.

Pruning and thinning result in relatively low yields of bark and alkaloids. At the final harvest, yields of at least 10 t/ha of dry bark are obtained with the short-term production system. The bark from selected planting material may contain at least 7% QAA on average, resulting in more than 700 kg/ha of QAA. Both bark yield and alkaloid content vary considerably, as they are affected by various factors.

Yields from the long-term production system are generally lower in terms of production per ha per year. However, this system can be more advantageous in terms of return on investment.

As a guideline, industrial Cinchona plantations should produce an average of 50-100 kg/ha per year of QAA to give a safe return on investment. A plantation should be at least 300 ha in size to sustain the initial and overhead costs involved.

The stripped bark is left to dry, preferably in the shade, or dried artificially. Drying in the open air has to be well supervised, because heating of wet bark may result in substantial losses of alkaloids. The bark should be spread thinly and turned over regularly. It is ready for further treatment when its moisture content is about 10%. Properly dried bark can be kept for several months without deterioration. It can be milled before packing, to facilitate shipment over long distances. Extraction and processing of the alkaloids to either totaquina, quinine bisulphate, quinine sulphate, quinine HCl or quinidine is mainly carried out in western Europe.

The dispersal of Cinchona seeds in the mid-19th Century is well documented. However, the limited survival rate of seeds and the destruction of earlier, low-yielding introductions have resulted in a very limited genetic variation in the germplasm available outside the centre of diversity. Care should be taken to preserve the germplasm present in the centre of diversity for future use. Most work on breeding has been carried out in Indonesia. At an early stage it was concluded that besides a high quinine content, other parameters such as bark production, tree shape and vegetative growth were also important in determining yield. The "ring method" was developed; this involves calculating the amount of quinine (in g) in a ring of bark 1 dm in width, at a height of 1 m, by multiplying the girth (in dm) at that height by the amount (in g) of water-free bark/dm²and the average quinine content of the bark. However, since the girth of a tree is a function of the plant density, this method proved insufficiently reliable for judging the amount of bark.

In 1931, some C. officinalis seeds of Indonesian origin had reached Congo Kinshasa to start a selection programme at the Mulungu experimental station near Bukavu. Elite trees were selected from the original population, vegetatively propagated, and planted in isolation. Seeds from these plots were harvested and distributed to local farmers and plantation enterprises. This policy resulted in rapid progress in bark production in Congo Kinshasa and neighbouring countries. Quinine percentages of up to 15% QAA were found in trees of about 10 years. However, there has been little further progress since the mid 1960s.

In India, breeding work has focused on selection of elite types, vegetative propagation of these types for industrial plantings, and controlled crosses between selected parents. Various methods of vegetative propagation have been tried: cuttings, air layering, budding, grafting, inarching. Budding and the production of cuttings by top-working have been most successful. This breeding programme has not been very successful, as the quality of the bark has not improved over the years. In the 1940s and 1950s a breeding programme was undertaken in Guatemala: hybrids of C. pubescens and C. officinalis were grafted on a C. pubescens rootstock or planted as cuttings. However, this programme was short-lived. Most breeding programmes have been abandoned (Congo Kinshasa, Guatemala) or give disappointing results (India, Indonesia). However, progress could be achieved for instance, by producing and distributing selected plant material, selecting suitable C. pubescens rootstocks to be used for grafting, and breeding for appropriate rooting architecture and disease resistance in C. officinalis. Although not much progress is to be expected in obtaining higher quinine content in selected individuals, there is potential to increase QAA production per ha per year by at least 50%. In Indonesia, over 300 clones of C. officinalis and C. pubescens are maintained in germplasm collections.

Interest in Cinchona has recently been increasing. Vegetative propagation by means of tissue culture has provided a tool for more effective breeding programmes. It will play an increasingly important role in future plantings. The introduction of high-yielding, multi-line cultivars may improve productivity significantly. Improved cropping techniques (e.g. mechanization) will play an important role in the economics of the crop. Research has also been focused on the production of alkaloids by means of cell culture. Although stable cultures have been successfully established and small quantities of QAA have been produced, this method is still far removed from industrial application. Cinchona alkaloids have played a useful role in human life for more than 350 years. There are encouraging prospects of obtaining higher production levels at lower costs. This may be an important contribution in future malaria treatment, since the need for a cheap, effective therapy is becoming more important because of the increasing occurrence of this disease.

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• Cinchona officinalis
• Cinchona pubescens

• G. Staritsky, E. Huffnagel, A. Dharmadi & S.L. Dalimoenthe