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REVIEW

Neotropics and Natural Ingredients forPharmaceuticals: Why isnt South American

Biodiversity on the Crest of the Wave?

Cristian DesmarchelierNeoTropico Medicinal Plants Consultants, Buenos Aires, Argentina

Despite the advent of biotechnology and modern methods of combinatorial chemistry and rational drug design,nature still plays a surprisingly important role as a source of new pharmaceutical compounds. These are mar-keted either as herbal drugs or as single active ingredients. South American tropical ecosystems (or the Neo-

tropics) encompass one-third of the botanical biodiversity of the planet. For centuries, indigenous peoples havebeen using plants for healing purposes, and scientists are making considerable efforts in order to validate these

uses from a pharmacological/phytochemical point of view. However, and despite the unique plant diversity inthe region, very few natural pharmaceutical ingredients from this part of the world have reached the marketsin industrialized countries. The present review addresses the importance of single active ingredients and herbaldrugs from South American flora as natural ingredients for pharmaceuticals; it highlights the most relevant

cases in terms of species of interest; and discusses the key entry barriers for these products in industrializedcountries. It explores the reasons why, in spite of the regions competitive advantages, South American biodi-versity has been a poor source of natural ingredients for the pharmaceutical industry. Copyright 2010 John

Wiley & Sons, Ltd.

Keywords: Neotropics; South American medicinal plants; herbal drugs; active ingredients.

INTRODUCTION

For thousands of years, man has relied on nature as asource of medicines in order to treat and cure illnesses.Only in the twentieth century has the pharmaceuticalindustry turned to modern methods of combinatorialchemistry and rational drug design as a means of obtain-ing new chemical structures with potential drug uses.But these technologies proved to be limited when itcame to synthesizing compounds with the complexity ofthose in nature, developed through millions of years ofbiological evolution. The limitation of these methods,together with the new technologies for extraction andidentification of compounds from complex mixturessuch as plant extracts, is drawing the pharmaceuticalindustrys interest back toward nature.

In 2001, and in the eight most industrialized countries Canada, France, Germany, Italy, Japan, Russia, UKand USA extracts formulations derived from 1350plants were widely commercialized. Of these, 202 wereformulations of single pure compounds, whereas therest were extracts prepared according to various phar-macopeias (Bombardelli, 2001). And these figures donot include the nutraceuticals and cosmetics industries,both of which rely heavily on natural products.

South American tropical ecosystems (or the Neo-tropics) encompass one-third of the botanical biodiver-sity of the planet. For centuries, indigenous peopleshave been using plants for healing purposes, creating astrong tradition which becomes a challenge for scien-tists to validate the folkloric medicinal use of herbs.However, and despite the unique plant diversity in theregion, very few pharmaceutical ingredients from thispart of the world have reached the markets in industri-alized countries.

The present review has a dual purpose since itaddresses the actual and potential importance of singleactive ingredients and herbal drugs from South Ameri-can flora as natural ingredients for pharmaceuticals, anddiscusses the key entry barriers for Neotropical prod-ucts in industrialized countries. It explores the reasonswhy in spite of the regions competitive advantages,South American biodiversity has been a poor source ofnatural ingredients for the pharmaceutical industry.

THE MARKET OF NATURAL INGREDIENTSFOR PHARMACEUTICALS

The market of natural ingredients for pharmaceuticalscan be classified into two major segments: (1) herbal

drugs, and (2) single active ingredients.

Herbal drugs. Herbal medicine products are dietarysupplements that people take to improve their health:

Correspondence to: Cristian Desmarchelier, NeoTropico MedicinalPlants Consultants, Santa Fe Av. 3553, second floor 8, Buenos Aires,Argentina.E-mail: [email protected]

Received 19 November 2009Copyright 2010 John Wiley & Sons, Ltd. Accepted 17 December 2009

PHYTOTHERAPY RESEARCHPhytother. Res.24: 791799 (2010)Published online 2 February 2010 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/ptr.3114


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Copyright 2010 John Wiley & Sons, Ltd. Phytother. Res.24: 791799 (2010)

792 C. DESMARCHELIER

many herbs have been used for a long time for claimedhealth benefits. They are sold as tablets, capsules,powders, teas, extracts, and fresh or dried plants. Incontrast to single active ingredients, such drugs usuallycontain more than one active principle. Accurate statis-tics for the herbal market are difficult to obtain, becausemany herbal products are sold in the health and naturalfood trade, through direct sales and multilevel market-ing organizations, and through alternative healthcarepractitioners. These channels of distribution are usuallynot well measured by the leading organizations thattrack retail sales in the mainstream channels (Anony-mous, 1999). After a boom in the late 1990s, total esti-mated herb sales in all marketing channels leveledaround $4,500 million a year in the USA (Cavaliere etal., 2009). The data also shows that the top ten herbssold in the USA market account for about 80% of thetotal sales for this country, leaving all the rest of the

products within the remaining 20%. As in the case ofsingle active ingredients, none of the top ten herbs men-tioned are original or native to South America. Thisscenario is not very different in Europe, where SouthAmerican herbs (or products manufactured with them)also capture a very small share of the market.

Single active ingredients. From a chemistry point ofview, natural products are single and pure substancesthat are synthesized via secondary metabolism in plants,insects, fungi, and many other living organisms. Fromthe data presented in a study published by Newman etal. (2003), between 1981 and 2002, 48 of 65 drugsapproved for cancer treatment where natural products,based on natural products, or mimicked natural prod-ucts in one form or another. An updated version of thereferred study (Newman and Cragg, 2007) states that atthe time this survey was completed 47% of all the com-pounds studied in the area of cancer were actuallynatural products or directly derived from them. Thispattern is also similar in other pharmacological fieldssuch as the case of antihypertensive and antimigrainedrugs. On the other hand, the authors pointed out thatno de novo combinatorial compounds have beenapproved as a drug in this timeframe. Natural productsthus continue to play a dominant role in the discoveryof leads for the development of drugs for the treatment

of human diseases. Another interesting fact is that theoverall percentage of new medicines derived fromnatural products in excess of 35% remained constantduring half a century despite relatively lower levels of

investment in this field of R&D (Kursar et al., 2007).Table 1 shows some reputed natural products obtainedfrom plants and currently approved as drugs. None ofthese drugs have been isolated from Neotropical plants.

NEOTROPICAL PLANTS AND THEIR ROLE ININDUSTRIALIZED COUNTRIES MARKETS

So far, a case is being made for natural products andtheir importance to the pharmaceutical industry, andfor the fact that a major proportion of global biodiver-sity is currently found in Latin America. Althoughfigures regarding the importance of Neotropical plantsseem to be discouraging, its important to note thatsome names are already gaining popularity, mostly inthe field of herbal drugs. Once again, accurate data are

not available for these products, although a quickmarket survey using secondary sources can provide apicture of the most renowned South American herbs(Table 2) whose main scientific studies are summarizedas follows:

Aai. Euterpe oleracea (Arecaceae) is a species nativeto the Amazon Basin. The fruit of this palm tree hasbecome reputed for its high antioxidant activity, mostlydue to the presence of a complex mixture of antioxidantpolyphenolic compounds, namely anthocyanins (DelPozo-Insfran et al., 2004; Lichtenthler et al., 2005;Rodrigues et al., 2006; Chin et al., 2008; dos Santos etal., 2008; Mertens-Talcott et al., 2008; Pacheco-Palenciaet al., 2008).

Boldo. Peumus boldus (Monimiaceae) is a shrub nativeto Chile. The leaves of Boldo are traditionally used asa hepatoprotective. Boldo leaves are rich in severalaporphine-like alkaloids, of which boldine is the mostabundant. This compound has shown antioxidant, cyto-protective, antitumor promoting, anti-inflammatory,antidiabetic and anti-atherogenic actions (OBrien etal., 2006). Regarding antioxidant activity, boldine hasbeen reported to protect intact red cells against thehaemolytic damage induced by free radical initiators ina dose-dependent manner (Jimnez et al., 2000). Based

on the TEAC assay, 150 mL of tea prepared from P.boldus would be equivalent to around 200 mg of Trolox,a synthetic analogue of vitamin E (Speisky et al., 2006).More recently, Fernndez et al. (2009) showed that

Table 1. Single active ingredients isolated from plants and approved as drugs

Generic name Indication Common name Scientific name Origin

Artemisinin Malaria Wormwood Artemisia annua China

Curcumin Cancer, inflammation Turmeric Curcuma longa Far East

Digoxin Heart conditions Digitalis Digitalis purpurea Europe

Galantamine Alzheimers disease Snowdrop Galanthus worownii East Europe

Guggulsterone Sterol Guggul plant Commiphora wightii Africa, Asia

Indole-3-carbinol Cancer Crucifers Brassicaspp. Europe

Paclitaxel (Taxol) Cancer Yew Tree Taxus brevifolia USA

Resveratrol Cancer Red grapes Vitisspp. Europe

Salicylic acid (aspirin) Analgesic Willow tree Salixspp. Europe

Silymarin Liver disease, etc Milk Thistle Silybum marianum Europe

Vincristine, Vinblastine Cancer Periwinkle Catharanthus roseus Madagascar


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Boldo infusion (5%) and boldine (50 mg/kg) acted as aprotector with respect to the oxidative hepatic damagecaused by cisplatin in mice liver. Antioxidant activitycould also be involved in the anti-atherogenic actionclaimed for boldine, since in vivo studies have shownthat 15 mg of this compound per day for 12 weeksinduces a 40% decrease on atherosclerotic lesion for-mation in LDLR(-/-) mice (Santanam et al., 2004).

Brazil Nut. Bertholletia excelsa (Lecythidaceae) iswidely reputed and used as a food supplement due toits high content of selenium (36.1 microg per gram) andfatty acids such as palmitic, oleic, linoleic, myristic andstearic acids, and phytosterols (Moodley et al., 2007;

Strunz et al., 2008; Thompson et al., 2008).

Camu-Camu. Myrciaria dubia (Myrtaceae) is mostlyfound in countries from the Western Amazon Basinsuch as Peru. Its fruit is considered to be one of therichest sources of vitamin C (2.4 to 3.0 g/100 g in thepulp) (Justi et al., 2000). One recent clinical trial hasshown that Camu-Camu juice may have powerful anti-oxidative and anti-inflammatory properties, comparedto vitamin C tablets containing equivalent vitamin Ccontent, suggesting the existence of unknown antioxi-dant substances besides vitamin C or unknown sub-stances modulating in vivo vitamin C kinetics in the fruit(Inoue et al., 2008).

Cats Claw. Uncaria tomentosa (Rubiaceae) is a largeand woody vine that grows in the rainforests of theWestern Amazon Basin in Peru, Bolivia and Ecuador.Cats Claw is perhaps the Neotropical medicinal plantthat has been subject of the largest number of studies,with more than one hundred publications in the fieldsof pharmacology and phytochemistry alone. Heitzmanet al. (2005) published an extensive review as an attemptto cover the more recent developments in the ethno-botany, pharmacology, and phytochemistry of thisspecies, explaining that 53 novel structures had alreadybeen reported for the genus Uncaria including alka-

loids, terpenes, quinovic acid glycosides, flavonoids, andcoumarins. The review describes pharmacologicalstudies on U. tomentosa according to cytotoxicity, anti-inflammatory, antiviral, immunostimulation, antioxi-

dant, CNS-related response, vascular, hypotensive,mutagenicity, and antibacterial properties.

Copaiba Oil. The resin extracted from large rainforestCopaifera officinalis (Fabaceae) trees has been used forcenturies for internal and external inflammations. Clini-cal research has validated the resins anti-inflammatoryeffects against various laboratory-induced inflamma-tions in animal models, and has been linked to the pres-ence of sesquiterpenes, diterpenes and terpenic acids(caryophyllene, calamenene, and copalic, coipaiferic,copaiferolic, hardwickic, and kaurenoic acids) (Basile etal., 1988; Veiga et al., 2001; 2006; 2007; Paiva et al., 2002;Gomes et al., 2007). Copaiba oil is the highest known

natural source of caryophyllene, a well-documentedanti-inflammatory compound.

Dragons Blood. This red viscous latex is obtained fromthe bark ofCroton lechleri (Euphorbiaceae), and usedas a wound-healing, anti-inflammatory, antiviral andantitumor agent in the westernmost part of the AmazonValley. Several compounds have been isolated duringthe 1990s from this sap, including the alkaloid taspineand the lignan 3,4-O-dimethylcedrusin considered asthe active principles responsible for the anti-inflamma-tory activity and wound-healing properties (Vaisberg etal., 1989; Pieters et al., 1993). Pharmacological studieshave demonstrated that polyphenols, which account for90% of the dried weight of Dragons Blood (Cai et al.,1991), also play an important role in the wound-healingproperties of the latex (Spencer et al., 1988), probablydue to their oxygen free radical scavenging activity(Desmarchelier et al., 1997). More recently, clinicalstudies have focused on the use of the sap and its pro-anthocyanidins in the treatment of travelers and waterydiarrhea. For instance, standardized proanthocyanidinextracts have been shown to act as antisecretory agentsin human colonic epithelial cells by inhibiting the actionof structurally unrelated prosecretory chloride channels(Fischer et al., 2004; Tradtrantrip et al., 2010).

Graviola. The Annonaceae family has been reported topossess a large number of acetogenins, a group of com-pounds that can only be found in this botanical family.Acetogenins are of extreme interest in cancer chemo-

Table 2. Most popular South American herbs in industrialized countries

Common name Scientific name Uses Active principles

Aai Euterpe oleracea Antioxidant Phenolic compounds

Boldo Peumus boldus Hepatoprotective Boldine

Brazil Nut Bertholletia excelsa Food supplement Selenium, fatty acids, etc

Camu-Camu Myrciaria dubia Antioxidant Vitamin C

Cats Claw Uncaria tomentosa Anti-inflammatory Quinovic acid glycosides, alkaloids

Copaiba Oil Copaifera officinalis Anti-inflammatory Copalic acid

Dragons Blood Croton lechleri Cicatrizant, anti-ulcerative Proantocyanidins, taspine

Graviola Annona muricata Antitumor Acetogenins

Guaran Paullinia cupana Stimulant Caffeine

Maca Lepidium meyenii Stimulant Isothiocyanates

Mate Ilex paraguariensis Stimulant, tonic, etc Caffeine, polyphenols, xanthine alkaloids

Stevia Stevia rebaudiana Low caloric sweetener Stevioside

Pau dArco, Lapacho Tabebuia impetiginosa Antitumor Lapachol

Yacn Smallanthus sonchifolius Diabetes Fructooligosaccharides


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therapy, mostly due to their ability to inhibit multi-drugresistance in cancer cells. At least 300 studies have beenperformed so far regarding the chemistry and pharma-cology of acetogenins, many of which have been iso-lated from Graviola ( A. muricata) (Rieser et al., 1993;1996; Wu et al., 1994; 1995a; 1995b; 1995c; Zeng et al.,1996; Kim et al., 1998a; 1998b; Chang and Wu, 2001;Liaw et al., 2002).

Guaran. Paullinia cupana (Sapindaceae) is an AmazonRainforest plant with caffeine-rich fruit. Guaran haslong been used as a tonic and medicinal plant, and inrecent years it has also emerged as an ingredient inenergy drinks and sodas; more recently it has also beenclaimed to boost libido, either taken alone or in combi-nation with other herbs (Smith and Atroch, 2007).Guaran seeds are considered to be the highest sourceof caffeine in nature with levels from 2 to 7.5%, or aboutfour times as much as coffee (Beck, 2005). Theobro-mine, theophyline and other alkaloids from the xan-thine group have also been reported in this species(Pizza et al., 1999).

Maca. Lepidium meyenii (Brassicaceae) is also knownby some as the Peruvian or Andean Ginseng due to itsalleged stimulant properties. The hypocotyl of this plantthat grows at 4000 meters above sea level in the Andeshas been used for centuries, not only as energy booster,but it is also believed to enhance fertility in man. Valen-tov and Ulrichov (2003) have published a review thatdeals with the botany and the composition, the structureof main constituents, and the biological activity of Maca,explaining that alkaloids, steroids, glucosinolates, iso-thicyanates, and macamides are probably responsiblefor its aptitude to act as a fertility enhancer, aphrodisiac,

adaptogen, immunostimulant, and anabolic and to influ-ence hormonal balance. More recently, some clinicaltrials have also confirmed that the consumption of Macaat ranges of 3.03.5 g of powdered root per day canmodify certain sexual physiological and psychologicalparameters in man (Gonzales et al., 2001; 2002; 2003;Gasco et al., 2007; Brooks et al., 2008; Dording et al.,2008; Valentov et al., 2008; Zenico et al., 2009).

Mate. Ilex paraguariensis (Aquifoliaceae) is native tonorth-eastern Argentina, southern Brazil, and Para-guay. The leaves of this shrub, traditionally used by theancient Guarani inhabitants of the region as a social andmedicinal infusion, are extensively cultivated and takenorally either alone or in combination with other herbs.In recent years, the use of mate is being rapidly intro-duced to the world market, either as a tea itself or as aningredient in formulated foods or dietary supplements,gaining public attention namely in the United Statesand Europe, and research on this tea has been expand-ing. Heck and de Mejia (2007) have reviewed the scien-tific literature of this plant, which has been shown to behypocholesterolemic and hepatoprotective, a centralnervous system stimulant, a diuretic, an antioxidant,beneficial to the cardiovascular system, and effective forobesity management.

Pau dArco-Lapacho. Tabebuia impetiginosa (Bigno-niaceae) is a canopy tree indigenous to the AmazonRainforest and other parts of South America. The innerbark of the tree is usually taken as a decoction to treat

numerous conditions, but during the 1970s, Lapachobecame very popular in the treatment of cancer, andthis led to the isolation of two bioactive componentsknown as lapachol and beta-lapachone, the latter beingconsidered as the main antitumor compound. Althoughthe isolated compounds showed interesting activity,side-effects of the treatment during clinical trials wereundesirable, and to date the use of Lapacho is still

restrained to the botanical drug.

Stevia. Stevia rebaudiana (Asteraceae) is a native herbfrom the Amamba region in Paraguay that has becomewell known for the presence of stevioside in its leaves,an intense non-caloric sweetener used in foods and bev-erages in several countries. Rebaudoside A (also knownby the common name of rebiana), is the second mostabundant component of S. rebaudiana leaves, and hasalso shown similar properties to those reported for ste-vioside (Prakash et al., 2008). Although the safety of theuse of stevioside and rebiana has been questioned in thepast, several mutagenicity, carcinogenicity, acute andsub-acute toxicity, fertility, and teratogenicity studieshave concluded that Stevia, stevioside and rebiana aresafe when used as a sweetener (Geuns, 2003; Brusick,2008; Carakostas et al., 2008). Stevioside, along withrelated compounds, may also offer therapeutic benefits,as they have antihyperglycemic, antihypertensive,anti-inflammatory, antitumor, antidiarrhoeal, diuretic,and immunomodulatory actions (Chatsudthipong andMuanprasat, 2008).

Yacn. Smallanthus sonchifolius (Asteraceae) is a cropthat has been grown and used for centuries by the nativepopulations that live in the temperate valleys of thetropical Andes. Although mostly used as food, the

tubers are also considered effective in the treatment ofhyperglycemia and kidney problems, and for skin reju-venation, mostly due to the presence of oligofructansand phenolic compounds. However, probably the mostinteresting aspect of Yacn is related to the high contentof fructo-oligosaccharides in the tubers, since thesecompounds have a favorable influence on the humanintestinal flora and can modify some hyperlipidemias,therefore being classified as prebiotics. Probablythrough this action they also modulate lipid metabo-lism, calcium absorption, childhood immune systemsand gut function (Valentov and Ulrichov, 2003).These facts have made Yacn popular in the functionalfoods and dietary supplements markets in industrializedcountries.

KEY ENTRY BARRIERS FOR NEOTROPICALPRODUCTS IN INDUSTRIALIZED COUNTRIES

So far, a case is being made for natural products andtheir importance to the pharmaceutical industry, andfor the fact that a major proportion of global biodiver-sity is currently found in Latin America. However,several barriers are yet to be overcome in order to allowtranslation of the enormous biodiversity and traditionalknowledge of the region into new products for the

Northern Hemisphere.

History and cultural barriers. Contrary to most of thedeveloping world, the Neotropics are also known as the


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New World, that is to say that they were discoveredby western civilization only about five centuries ago. Assuch, a certain lag in the uptake of its culture is under-standable. This is in contrast to African and Asian cul-tures that have been in contact with Europe forthousands of years. For instance, many of the plant-based agents used in traditional Ayurvedic and Chinesemedicine including ginseng, soy, gingko and ginger have

gone through a long process of cultural acceptance inindustrialized countries, gaining competitive advan-tages and in consequence an important share of theirmarkets.

Thus, a natural process of initial awareness has led toa slow but constant increase in the demand of theseproducts that has taken several centuries. Probably thesame process is taking place with South American rain-forest remedies, but since this process started later inhistory, it will take a while for them to overcome cul-tural barriers and reach parity with Old World herbs.

Regulatory barriers. Once cultural barriers have beenovercome and the market is ready to absorb a product,regulatory issues have to be complied with either forraw materials or end products. In this sense, regulatoryauthorities in Europe and the USA increasingly demanddetailed documentation concerning safety, efficacy, andstability of drugs based on compounds of natural origin,regardless of the nature of them being single activedrugs or multi-active complexes in herbal drugs. Therealso is a trend toward increasing efforts in follow up onmedical claims made by synergistic actions betweenmultiple compounds, or multiple pharmacologicalactions of single active principles. Mucke and Aschauer(2001) have presented a comprehensive outlook of theregulatory scenario in industrialized countries.

Regarding drugs consisting of a single active ingredi-ents obtained from natural sources, regulatory authori-ties from both sides of the Atlantic are more or lessconsistent in their attitudes in the sense that they arenot, in principle, concerned with the origin of the activecompounds, provided that production methods are vali-dated and result in a standardized product criteria thatalso apply to synthetic ingredients. However, there aredifferent attitudes of the US Federal Drug Agency(FDA) and the European Medicines Agency (EMEA)concerning herbal drugs, which are unlikely to be rec-onciled in the near future.

As stated by Mucke and Aschauer (2001), drugsbased on standardized extracts present health authori-ties with complex regulatory and quality control prob-lems, which have been addressed in quite different wayson either side of the Atlantic. While phytotherapy hasbeen part of the medical tradition for many years inEurope, there is no such tradition or practice in theUSA. Medicinal plants in Europe, their extracts,active components, and finished products have beendescribed in many national pharmacopeias that haveultimately lead to a unified European Pharmacopeia(EP), setting the standards for these products in theregion regarding their use as drugs. More recently, andin the UK in particular, new regulations from the Medi-cines and Healthcare products Regulatory Agency

(MHRA) will come into force in 2011. However, in theUSA, the scenario is somewhat different in the sensethat herbals are regulated by the FDA as food ratherthan as drugs.

Adding to the complex regulatory issues that naturalproducts have to confront in order to enter the marketsin industrialized countries, businesses and scientists inLatin America have to overcome additional (local)regulatory barriers regarding export of their products.This is because until 1992 the worlds genetic resourceshad been regarded as a common heritage of mankind.However, this situation was reverted when the Conven-

tion on Biological Diversity (CBD, 1992) came intoforce, and developing countries successfully achievedthe right to exploit their own resources pursuant to theirown environmental policies. As a consequence, and inorder to protect their green gold, particularly tightlegal restrains were introduced in several South andCentral American countries such as Costa Rica, Colom-bia, Peru, and Brazil, adding difficulties for scientistsfrom outside the region carrying out research in Southand Central America. For example, removal of plantmaterial, even just for herbarium specimens, has beenprohibited in many cases. This discourages bothresearchers from investigating the plants and companiesfrom investing in such research, and has become a majorbarrier to research and development.

Scientific barriers. One of the most important problemsis the fact that there is very little scientific informationon Neotropical plants, in comparison to medicinalplants from other parts of the world. For instance, it iswidely believed that only 1% of the plants that gracethe Earth have been subject to exhaustive pharmaco-logical and phytochemical research. But when it comesto South American plants, this figure is probably over-stated by one order of magnitude: from the 50,000100,000 plants that are native to the region, maybe nomore than 50 (0.1%) have been subject to exhaustive

scientific investigation (Desmarchelier and WittingSchaus, 2001). This fact makes it even harder for SouthAmerican natural products to compete in overseasmarkets, since both consumers and regulatory agenciesnot only expect empiric information but also scientificvalidation in order to embrace new products.

This is in sharp contrast to many Asian and Europeanmedicinal plants. For instance, while many SouthAmerican plants claimed to be effective in the treat-ment of some types of cancers have only been subjectto scattered preclinical studies, there is strong evidenceindicating that many of the plant-based agents used intraditional Ayurvedic and Chinese medicine indeedsuppress multiple pathways that have been implicatedin tumorigenesis (Aggarwall et al., 2007)

Obviously, encouraging ongoing research on medici-nal plants in local universities and pharmaceutical com-panies is the most logical way to overcome this hurdle.Several international projects have also tackled thisissue. For instance, the International Cooperative Bio-diversity Groups (ICBG) from the National Institutesof Health (NIH) has been working for several years onresearch of the pharmacological potential of Panama-nian plants. The Institute de Recherche pour le Dvel-oppment (IRD) of France has also entered severalcollaborative agreements with local universities inBolivia, Paraguay, French Guyana, and more recently

Peru, in order to uncover the pharmaceutical potentialof these countries biodiversity. Perhaps one of the mostrenowned examples is that of the National BiodiversityInstitute of Costa Rica (INBIO), who in the 1990s


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entered a collaborative agreement with Merck in orderto study the countrys rainforests. More recently, theGlobal Institute for Bio-Exploration (GIBEX) is alsoshowing a particular interest in the region.

The role of pharmaceutical companies and theirinvolvement in research activities in the region is lessclear. Several local companies have R&D projects,although they are mostly focused on herbal drugs. Prod-

ucts are based on ethnobotanical information, andusually (but not always) this information is validated tosome extent by scientific research. However, privatebio-exploratory activities in pursuit of new single activecompounds usually remain undisclosed. One high-pro-file case was that of Shaman Pharmaceuticals, a UScompany developing antiviral agents based on a mole-cule isolated from Dragons Blood. However, thecompany got into financial trouble earlier this decadedue to lack of cash for financing clinical trials, and nowtheir lead product Crofelemer, indicated for HIV-asso-ciated acute infectious diarrhea, has been transferred toNapo Pharmaceuticals (NAPL.L), a publicly tradedcompany on the London Stock Exchange. Crofelemeris currently in Phase III clinical trials for the treatmentof chronic diarrhea in people living with HIV/AIDS.

Economic barriers. Last but not least, economicbarriers play a major role in this field. The key issue inthis sense is the low levels of direct investments andtechnology in local companies that provide raw materi-als and finished products. South American companiesfocus their efforts in exporting raw materials (such asdried and ground leaves, etc.) to be used in manufactur-ing herbals in the industrialized countries. However,raw material cost is said to be only 3% of the finalmanufactured drug price. Less often, standardized

extracts are also manufactured, and only in very fewcases finished products (i.e., tablets) are producedlocally for export.

Regarding raw materials in the region, agronomicproduction of medicinal plants is mostly represented byintroduced species rather than native plants, obviouslydue to market requirements. For example, in the Stateof Paran in Brazil alone, in 2008 Bellini reported thatmedicinal plants production yields approximately 19million Brazilian Reals annually (US$10.7 million).Adding the gains of herb varieties harvested in theParan forests 2600 tons to the mentioned produc-tion total we arrive at 22 million Reals (US$ 12.4million). Chamomile is amongst the most cultivatedspecies as is ginger, whose exports represent an impres-sive 95% of the overall production of medicinal plantsin that state (Bellini, 2008). Neither of these species isnative to South America.

Regarding transformed (further processed) materi-als, standardized extracts are amongst the most commonin terms of exports. In most industrialized countries,buyers are not interested in plant material, but in plantextracts. Usually, standardized extracts are the rawmaterials used in manufacturing final products such astablets, capsules, etc. As in the case of raw materials,the production of standardized extracts depends on theinternational market, which is largely represented by

plants that are not native to South America. However,and when compared to the volumes of plant materialthat are exported, standardized extracts comprise a verysmall percentage.

There are only a few developing countries that areable to supply extracts conforming to the requirementsof the western industry. According to Gupta (2006) theextracts of South American plants more frequently usedin industrialized countries are Boldo (Peumus boldus),Quina (Cinchona calisaya), Carqueja (Bacharis trimeraor Baccharis spp.), Dragons Blood (Croton sp.), CatsClaw (Uncaria tomentosa, U. guianensis), Marcela

(Achyrocline saturoides) and Sarsaparilla (Smilax camp-estris). To this we should add natural colorants such asbixin, which is obtained from Bixa orellana, and curcu-min from Curcuma longa, which represent the largestshare of natural ingredients exports for some countriessuch as Peru (78%). Many of these products are believedto be at a maturity stage in terms of the product-marketcycle.

Statistical information available regarding marketshare of South American products in this sense is hardto find. For example, in a 131-page EU market surveypublished in 2005, the only information presented onthis issue was the fact that Chile is amongst the leadingdeveloping country suppliers of medicinal and aromaticplants to the EU, and that Brazil supplied more than8% of the total value of alkaloids originating in devel-oping countries (Anonymous, 2005).

These figures become bleaker when it comes to fin-ished products, especially regarding those that haverisen from local R&D. In this sense, South Americanbiotechnology and pharmaceutical industries are stillunderrepresented. However, some interesting examplesare showing that it is possible to develop effective medi-cations for a low price from plants active principles. Forexample, thanks to a vegetal polymer derived from anundisclosed Brazilian plant, Brazilian company Pele-nova Biotechnologies (www.pelenova.com.br) claims to

have developed biomembranes capable of inducingneo-angiogenesis, or the production of new bloodvessels that help multiply cells used during the wound-healing process. Pelenovas product is currently in clini-cal use and marketed under the brand BIOCURE.

CONCLUSIONS

Only a few well-known herbs account for most of thesales volume in industrialized countries and they do notbelong to the Neotropics. Thus, it could be said that thePareto Principle (or the 80-20 rule) applies to the herbalmarket (and probably also to the single active ingredi-ents market), in the sense that Neotropical plants arerepresented in the lowest segment of sales volumes(which is also shared with many other less known herbsfrom Asia and Africa). The present analysis describessome key market entry barriers that include cultural,historical, regulatory, scientific, and economic issues, allof which could account for this uneven pattern.

In the particular case of herbal drugs, and in spite ofthese discouraging figures, it is important to note thatsome names are already gaining popularity. Once again,no accurate data is available for these products, althougha quick market survey using secondary sources can

provide a picture of the most renowned South Ameri-can herbs (Table 2).Furthermore, some natural ingredients such as Yacon

(Smallanthus sonchifolius), used as a food supplement


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to reduce the risk of diabetes, Maca (Lepidium meyenii),an effective revitalizer and invigorating food, Tara Gum(Caesalpinia spinosa), anthocyanins of Purple Corn(Zea mays) and Aa (Euterpe oleracea), natural dyesfrom Genipap (Genipa americana), and vitamin C richextracts of Camu-Camu (Myrciaria dubia) are growingin recent years. Most of these new products are in anintroductory stage of the product life cycle.

As in the case of other developing countries, theeconomies in Latin America have been traditionallybased on raw material production and exports, andthis scenario does not seem to be too different inthe case of pharmaceutically active natural products.Unfortunately, and perhaps with the sole exceptionof Brazil and Chile, policy-makers have done very littlein order to change this scenario during the last fewdecades.

This historical constriction is aggravated, as men-tioned earlier, by scientific and economic issues, such aslack of investment in research and development. Tradi-tional drug discovery involves high levels of investmentand economic risk, since it is usually based on screeningof libraries of chemicals, and isolation and purificationof active compounds, two processes that are character-ized by low rates of success, high costs, and lengthytimeframes for a product to reach the market.

One alternative way to succeed in this scenario couldbe to cooperate in strategic alliances with complemen-tary organizations and thus create virtual drug develop-ment corporations (VDDCs). Such joint ventures werefirst described during the 1990s (Lightfoot, 1996) as amatrix approach capable of doing business across tradi-tional company boundaries by means of strategic alli-ances. As explained by Lightfoot, when the strategicalliance is thoroughly defined and complementary core

competencies are identified, a VDDC can achievequicker product approvals and greater profits than arepossible when a company attempts to manage the devel-opment process alone.

Unfortunately, and although the virtual companymodel is gaining acceptance in many industrializedcountries, in South America this kind of multilevelcooperation project between companies, academia andNGOs is still unpopular, mostly due to cultural issues.One interesting case in the field of pharmaceuticalproduct development from medicinal plants and worthbenchmarking is that of Phytopharm (www.phyto-

pharm.co.uk), a British virtual company whose modelis centered on a lean cash burn with all laboratory,manufacturing, and clinical work outsourced to special-ists, while core competencies such as strategy and man-agement are maintained in-house. The companysefforts are focused on Asian and African plants; it ispublicly traded on the London Stock Exchange underthe symbol PYM.L, and earlier last year had a marketcapitalization of US$10M. Although Phytopharm hassuffered commercial setbacks lately due to withdrawalof support from major development in the industry, itsproduct development model is still an example to befollowed.

While many core technologies for drug discovery anddevelopment are actually available in universities andcompanies throughout South America, a culture ofcooperation is still virtually non-existent in the region.There seems to be a vacuum at the interface of the dif-ferent organizations, which has made the orchestrationof joint activities hard to accomplish. Working at thisinterface and matching efforts in order to bring togetherthe different parts of the equation is thus essential atboth horizontal (different organizations within SouthAmerica) and vertical (South America industrializedcountries) levels. This should be accomplished by meansof small, virtual and efficient organizations (i.e., consul-tancy services) capable of acting within these interfaces,

bringing together local complementary capacities onone hand, and making the outcome of these joint ven-tures visible and available to market stakeholders inindustrialized countries on the other.

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