Bioprospecting in Ecuador, current situation analysis and future opportunities

Bioprospecting in Ecuador, current situation analysis and future opportunities : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자	임이슬	카테고리	전문가 인사이트
작성일	2017-08-01	조회수	4,363
원문
출처

글 Esteban Ortiz-Prado: 에콰도르 GPKOL위원

세부 전문분야 및 컨설팅 내용

R&D 기획(R&D Planning/Clinical Trial/GMP, GCP and Regulatory Affairs/Project management)
OneResearch Group, Faculty of Medicine, Universidad de las Americas, Quito, Ecuador; Department of Medicine and Center for Global Health and Translational Science, State University of New York Upstate Medical University, Syracuse, NY, USA, Global Pharma Key Opinion Leader) position at the KHIDI (Korea Health Industry Development Institute).

Introduction:

The panorama of the actual pharmaceutical sector is characterized by an increase in the demand for medicines to meet medical needs that have not yet been effectively treated. This panorama is widely distributed, not only at national and regional level but actually it’s a worldwide trend. Undoubtedly, in Ecuador there are still neglected medical needs, which reduce the quality of life of its inhabitants, causing important health problems as well as economic losses to the public and private health system, not only for the high costs of medicines but also due to the year life lost (YYL) and the reduction in productivity. For these reasons it is necessary to search for strategies that allow to attend to these neglected medical needs, and that in turn promote the sovereignty and sustainability of the rational use of our natural resources; in other words, develop our own products (medicines and related products) to treat the main causes of national morbidity and mortality will improve the quality of health of our population and also will improve our economy.
In this sense, a highly dependent economy such as the Ecuadorian will receive important benefits from the research, especially the one that intends to promote bio-discovery and bioprospecting natural resources, playing a crucial role in the development of pharmaceutical industry in Ecuador.

RESEARCH AND BIOPROSPECTING

Historically, humans have used the resources that nature offers to improve their living conditions and to cure their illness. Discovering new substances and their potential uses and benefits found in nature it has been an important factor in the evolution of mankind, allocating resources to the community including natural therapies, remedies and nutrients(Ortiz-Prado, Ponce-Zea, & Galarza-Maldonado, 2013).
In Ecuador there is not only biodiversity, but also important ethnopharmacological knowledge that has been guarded by indigenous tribes, information that its invaluable and constitutes an important source of potentially rentable information to whoever require to undertake studies of pharmaceutical bioprospecting.
The challenge of promoting bio-discovery based on the principle of finding and testing molecules intended to be use as human, veterinary or agricultural products comes from the fact that millions of natural products can have some activity and lower down that search to the most promising is a must.
In Ecuador in the last ten years the government has implemented new regulations that tries to encourage researchers to perform experimental analysis with products that came from the mega biodiversity of Ecuador. According to one of the most important books about pharmacology and botany in Ecuador states that 3 out of 10 plans in Ecuador has some sort of medicinal activity either as a human medicine, agricultural biodegradable product, eatable substances or as a cosmetic primary ingredient(Ríos, Koziol, Pedersen, & Granda, 2007).
The process of obtaining new drugs will depend on who invest in monetary and infrastructural resources within this sector. The most indicated should be the industry however in Ecuador the government is the most important funder of this type of projects. The role of local and international pharmaceutical companies operating in Ecuador as funders it has been very scarce, demonstrating that most of their interests fall in selling their products rather than investing in bio-discovery.
The process of obtaining molecules with potential therapeutic value require scientific validation, meaning that most of the studies will be experimental in vivo and in vitro designs, requiring a lot of resources and time before getting any economical Another pitfall in the race to discover products with therapeutic potential, the diagnose of the current situations as well as the role of all the actors involved in the research process, needs to be regulated by the country's higher education, science and technology institution, in this case Senescyt.

CURRENT SITUATION

In Ecuador, many of the universities do not have the necessary infrastructure and equipment to develop this type of research. In this sense, most of the projects are carrying by international institutions, situation that is not always positive since most of the samples obtained in Ecuador are usually shipped abroad for genetic testing and several analyses, putting in risk the opportunity to lose a potentially profitable molecule. Another pitfall from this practice is that costs are usually higher and the ancestral knowledge misinterpreted, putting our sovereignty in discussion.
As a country in the middle of an industrialization and economic development process we cannot be relegated to the world scientific and technological career, for these reasons it is imperative to establish a Scientific Research Plan for Drug Development at the governmental level.
As is generally known, research for drug development is a series of complex and costly processes. Not only are large amounts of economic resources and infrastructure required, but highly skilled human talent working in multidisciplinary teams. In addition, today, R & D productivity has declined as costs skyrocket which has led to the development of new models for research into new drugs.
It should be considered more than anything that bioprospecting cannot be done as it did 20 years ago based mostly on experiments of trial and error, which many times led to false positives and false negatives, the research done must be systematized and create a collective knowledge regarding to the natural resources that are possessed, that is to say to create virtual libraries, databases and other tools that accelerate and diffuse the investigations so far carried out, the knowledge that does not spread does not construct.
In this sense, the use of technological tools and the training of human talent must also be updated. If possible, make strategic alliances with international institutions, ensuring the establishment of win-win agreements, in which all parties involved get benefit, guaranteeing an equitable distribution of the benefits obtained.
It should be taken into account the national legal and normative aspects regarding the use of traditional knowledge and access to biological and genetic resources, having clear rules of the game, it will be possible to give security to the researcher as to the communities possessing the traditional knowledge, which entails to an equitable distribution of benefits.

CURRENT SITUATION

For thousands of years, biological diversity has been a source of useful materials and materials from which to obtain food, energy, habitation, medicines and services for the environment. Bioprospecting it’s a well-known technique that is been around for centuries. The development of this type of science of analyzing natural compounds arrives from the old ancestry technique of alchemy. Those practicing the extraction of molecules from nature were called alchemists, most of them were philosophers, truth-seekers and ancient thinkers. Centuries ago these people were considered a very important part of the kingdoms and past civilizations.

BIO-DISCOVERY OR BIO-PROSPECTION

The procedure of discovery new molecules, especially those coming from natural products due to a systematic exploration, examination and identification of potentially useful substances that were originally biological natural species(Salazar Fernández, 2017). This identification consist in the classification and identification of new chemical compounds, genes, proteins, microorganisms and other products with current or potential economic value, which are part of biodiversity(Cartaxo, de Almeida Souza, & de Albuquerque, 2010; Hoareau & DaSilva, 1999). This technique can be also summarized as the process of extracting active substances from the nature to transform then in useful molecules(Bravo, 2007).
The global economic value of biodiversity is unknown. However, a recent attempt yielded an estimated economic value of more than $ 2900 billion USD worldwide. This interesting benefit comes from several sources of money related with the analysis of biomolecules from nature. 500 million USD will be made from ecotourism and related activities, 200 million USD from pollination and their products, 90 million USD from nitrogen fixation and a little more than 135 million USD for global CO2 retention(Carrioza, 2000).
According to some reports, nature agglomerates more than 400,000 plant species which have given rise to thousands of active ingredients with potential therapeutic use and about one hundred of these have already been marketed as medicines(Table 1)(Tle PLant List, 2017).

Table 1 Some examples of bio prospection worldwide
Product	Mechanism of action	Plant specie
Acetildigoxina	Cardiotonic	Digitalis lanata
Adonisida	Cardiotonic	Adonis vernalis
Atropine	Anticholinergic	Atropa belladonna
Benzilbenzoato	Scabicide	Various Species
Caffeine	CNS Stimulant	Camellia sinensis (te, café y cocoa)
Canfor	Cough	Cinnamomum camphora (canfor)
Cocaine	Local Anaesthetic	Erythroxylum coca (coca)
Codeine	Analgesic, antitussive	Papaver somniferum (Opium)
Colchicine	Antitumor, anti-gout	Colchicum autumnale
Digoxin	Cardiotonic	Digitalis purpurea
Hiosciamina	Anticholinergic	Hyoscyamus niger
Morphine	Analgesic	Papaver somniferum (Opium)
Papaverina	Muscle relaxant	Papaver somniferum (Opium)
Fisostigmina	Inhibitor of the Cholinesterase	Physostigma venenosum
Pilocarpine	Parasimpaticomimético	Pilocarpus jaborandi
Quinine	Anti-malária	Cinchona ledgeriana (Quinine)
Scopolamine	Sedative	Datura species
Silimarina	Liver protective	Silybum marianum
Tetrahydrocannabinol(THC)	Antiemetic, anti-glaucomatous	Cannabis sativa (marihuana)
Theobromine	Diuretic, vasodilator	Theobroma cacao (cocoa)
Theophylline	Diuretic, bronchodilator	Theobroma cacao (cocoa, tea)
Tubocurarina	Muscle relaxant	Chondodendron tomentosum (curare)
Vinblastina	Antitumor, oncologic	Catharanthus roseus
Vincristina	Antitumor, oncologic	Catharanthus roseus

If we review the origin of the patented product, most of them have been discovered in tropical countries, however the economic benefit goes to industrialized countries, a negative procedure specially for those countries that buy the final product (Zhong & Xiao, 2009).

ECUADOR PHARMACEUTICAL POTENTIAL

The Ecuadorian territory has 256 370 km2 and is estimated to have 20,000 to 30,000 vascular plants. The value of drugs derived from the biodiversity of tropical forests to be discovered was estimated at $ 147 billions of dollars in 1994, so with an average global inflation rate of 3.9% per annum ("Indicators | Data"), it would be equivalent to approximately current $328 billions of dollars. Significant efforts have been made to compile existing information on medicinal plants in Ecuador, the book Useful Plants of Ecuador, applications, challenges and perspectives, Where 46% of the records correspond to medicinal plants(Ríos et al., 2007).

Figure 1 Main potential uses of plants in Ecuador
Although there is so much wealth in medicinal plants, little has been scientifically validated on the use of medicinal plants in Ecuador. Despite this, some are marketed and have a sanitary registration as a natural product, 797 sanitary registries granted to natural products. however, since regulation does not require natural products to submit clinical trials to register, almost all do not have studies demonstrating its efficacy (figure 2) (ARCSA, 2017).

Figure 2 Principal sources of natural products in Ecuador

There are natural products marketed in Ecuador who import raw material or finished product, showing that there is still an important sector to develop the potential in our plant, natural resources.
The risks existing in bioprospecting consist mainly in association with bio piracy and the depletion of natural resources. As international instrument exists, the Convention of the biological diversity (CBD) and the program of the United Nations for environment (UNEP), which is a legally binding international treaty with three main goals: the conservation of biological diversity, the sustainable use of its components and the fair and equitable sharing of benefits arising from the utilization of genetic resources(Rivadeneira Redín, 2007).
On the protection of genetic resources, Ecuador is also on the Nagoya protocol established by the United Nations, however has not yet been approved by the plenary of the National Assembly. It is hoped that once the regulations have been established by the governing bodies, they will give impetus to research and that these will not be transformed into bureaucratic practices that delay it, or that are exclusive and not an incentive for investment in research and development.
On the other hand, another risk exists is that the lack of socialization of environmental norms and poor management of biodiversity, causes in many cases species of wild medicinal plants to risk disappearing, since there are no programs that promote the cultivation of plants Medicinal plants, and rather people living in areas close to wild growth zones are overexploiting the resource.
Without a doubt, many investigations have been carried out within the bioprospecting of molecules with potential pharmaceutical use in Ecuador. However, it is the opinion of the authors that in order to achieve a greater impact than the current one, the coordination and collaboration of the Main actors involved. In addition, the focus should be changed to why bioprospecting is necessary, the main objective should be to generate products to reduces and treat neglected medical needs rather than to obtain economic benefits from the use and exploitation of natural resources, the main objective should be to generate products to alleviate and treat unmet medical needs rather than to obtain economic benefits from the use and exploitation of natural resources. It should also focus on specific therapeutic areas where we find the causes of prevalent morbidity and mortality. As well as developing projects with a systematic and collaborative approach, rather than isolated research within hermetic academic circles. The pharmaceutical industry can reap great benefits from collaborations with academia and communities with ethno-pharmacological knowledge, but for this, clear agreements on intellectual property and equitable benefit sharing must be generated.

HARMACEUTICAL DEVELOPMENT IN ECUADOR

Ecuador is one of the most biodiverse countries worldwide(Cincotta, Wisnewski, & Engelman, 2000). The geographical location of Ecuador and the topographical conditions have produced a very rich ecological mosaic of plants, animals and insects. The differences in climate and environmental conditions generates an impressive diversity of eco-natural systems and sub-systems where thousands of species with unexplored bioprospecting potential emerge(Dorsey, 2003).
Most of the biodiversity in Ecuador comes from the Amazon basin, the cloud forest and the Galapagos Islands in the Pacific Ocean of Ecuador. Several decades ago the country started to host scientists from all over the world to explore our diversity. In Ecuador several reports suggest that some pharmaceutical products have been discovered thanks to studies completed in Ecuador(Humble, 1982).
Although several pharmaceutical products that have been commercialized worldwide came directly or indirectly from Ecuador or the Amazonian forest, none of the benefits has returned to the country or the indigenous people who actually discovered those products several decades ago. This unfair contribution has lead the local industry in Ecuador to be underdeveloped, with very few patents in the pharmaceutical field and almost none scientific reports published (by the industry). The industry in Ecuador has no invested in research and development, they have not financed researchers, scientific projects, student scholarships or continual education programs for those working in their plants.
This historical conduct has lead the pharmaceutical industry in Ecuador to be primarily dependent of imports with very low relative exportations and with very mediocre productive line, focusing almost completely in solid easy-to-synthetize molecules.

ECUADORIAN POSITIVE EXPERIENCES

Although there is so much wealth in medicinal plants, little has been scientifically validated on the therapeutic use of these Products by Ecuadorians. In Our country we have always offered the biodiversity and the natural resources but very few times we have created a product that reached the market. Independently of how effective could be or what are the indications, one of the best commercial experiences of a product entirely developed in Ecuador is the case of the natural plant extract called and patented as BIRM ™(Dandekar, Lokeshwar, Cevallos-Arellano, Soloway, & Lokeshwar, 2003; Ravalji et al., 2015; Shamaladevi et al., 2016). The history of this product is quit exiting. A physician from Ecuador start testing this natural extract very rudimental at least 25 years ago. Due to its apparently good results, the owner of the patent started to commercialized the product, acquiring more technological capabilities as the years passed. This type of effort is what is needed in Ecuador, bringing natural products to the entire cycle of pharmaceutical development is remarkable. Nowadays this product have reached an interesting reputation, it’s being sold in every local pharmacy in Ecuador and has created jobs and expertise to a very immature industry in Ecuador(Dandekar et al., 2003; Ravalji et al., 2015; Shamaladevi et al., 2016).

PHARMACEUTICAL DEVELOPMENT AND BIOPIRACY

Bio-piracy, the act of obtaining resources without the legit permit of the true owners and beneficiaries of those resources. This undesirable conducts its been around for centuries, however, scientific piracy it has been demonstrated recently in several locations around the globe. Although this type of conduct is now regulated, before scientific missions came to Ecuador in order to obtain and export natural resources, looking to find new molecules. In the context of research, the exploration of natural resources needs to be separated from the term exploitation, term that reflects the benefits obtained from those who came to explore but obtained economic or financial successes without the recognition or retribution to the people that through the traditional knowledge allowed the discovery of those molecules(Bejarano, 1997; Carrioza, 2000; Cartaxo et al., 2010).
One of the most iconic case in the one of curare and its active principle d-tubocurarine. This molecule was obtained thanks to the observation of indigenous tribes from Ecuador hunt their pray with poisoned arrows(Humble, 1982). The observation of this tribe lead to the discovery of a well-known and commonly used muscle relaxant, commercialized under the name of Rocuronio, product that Ecuador imports greatly every year(Drews, 2000). Another example widely criticized among Ecuadorians was the one regarding the use Cinchona genus plant(Madsen, 2002). This plant lead to the discovery of the highly effective Quinine, a drug used to treat Malaria. In this case, the researchers obtained this plant from Loja, the southern province in Ecuador where the leafs were used to treat and relieve febrile symptoms.
In any of the cases described, neither the country of the indigenous people obtained any benefit, leading the government to recently emit a widely recognized public policy that lookout for ethical research behavior among scientist in order to establish good bioprospecting practices.

ECUADOR, A COUNTRY OF OPPORTUNITIES

In Ecuador, the pharmaceutical market its growing significantly. In the last 6 years the market went from less than 600 million US dollars a year to more than 1.5 US Billions(Durán, Lucio, & Rovira, 2017; Ortiz-Prado, Galarza-Maldonado, Cornejo, L, & Ponce, 2014). This market analysis included all the registered drugs in the the National Agency for Health Regulation and Control, ARCSA, for products intended to be used in humans. Although this list is vast, including more than 10.000 products registered, the list of natural products and their market it’s never been studied. The only available information is the number of sanitary registrations granted to natural products by ARCSA(ARCSA, 2017). The list has included up to 794 natural products, however more of them are imported (figure 1).

Figure 3 Country of origin of the natural products registered in Ecuador (2015) Source ARCSA

Although the process of obtaining sanitary registries did not require Clinical trials for natural products at least until 2014. This condition permitted that several products can be commercialized without any regulation.
The author of this manuscript consider that Ecuador is a country with several strengths, including the great biodiversity. Investing in the development of new products should be level one priority for local or international industries due to the possibilities to discover products with potential positive effects to treat cancer, diabetes, infections and other chronic diseases.

CONCLUSIONS

Although the intention to make a rational use of our biodiversity is more than valid, we must first know the capacities available at the national level, from which a suitable strategy and mechanisms for the scientific and technological development in this field are selected, so that the resources invested in the development of medicines bear fruit, which in turn allow to invest again in research and development.
Finally, we wish to emphasize that, to carry out scientific research on natural resources from Ecuadorian biodiversity to treat diseases prevalent at national and regional level, with proper coordination between the academic and industrial sectors; Would constitute, one of the pillars for the development of the pharmaceutical in the country.

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