Lipase-catalyzed Approaches towards Secondary Alcohols: Intermediates for Enantiopure Drugs

The use of enantiopure intermediates for drug synthesis is a trend in pharmaceutical industry. Different physiological effects are associated with the enantiomers of chiral molecules. Thus, the safety profile of a drug based on an enantiopure active pharmaceutical ingredient is more reliable. Biocatalysis is an important tool to access enantiopure molecules. In biocatalysis, the advantage of selectivity (chemo-, regio- and stereoselectivity) is combined with the benefits of a green synthesis strategy. Chemoenzymatic syntheses of drug molecules, obtained by combining biocatalysis with modern chemical synthesis steps usually consists of fewer reaction steps, reduced waste production and improved overall synthetic efficiency both in yields and enantio- and/or diastereoselectivities compared with classical chemical synthesis. The experimental work together with the literature review clearly indicates that lipase catalysis is highly applicable in the synthesis of enantiopure intermediates of drug molecules as the basis to infer the correct stereochemistry. By lipase catalysis, enantiopure secondary alcohols used as intermediates in the synthesis of Dorzolamide, an antiglaucoma drug, were obtained. Enantiopure _-hydroxy nitriles as potential intermediates for the synthesis of antidepressant drugs with 1-aryl-3- methylaminopropan-1-ol structure were also obtained with lipases. Kinetic resolution of racemates was the main biocatalytic approach applied. Candida Antarctica lipase B, Burkholderia cepacia lipase and Thermomyces lanuginosus lipase were applied for the acylation of alcohols and the alcoholysis of their esters in organic solvents, such as in diisopropyl ether and tert-butyl methyl ether. Candida Antarctica lipase B was used under solvent free conditions for the acylation of ethyl 3-hydroxybutanoate.

Lääkevaihdon ja viitehintajärjestelmän vaikutukset patenttisuojattujen lääkevalmisteiden kohtuullisen tukkuhinnan vahvistamismenettelyyn

Pro gradu-tutkielman ensisijaisena tavoitteena oli selvittää, millaisia muutoksia lääkevaihto ja lääkkeiden viitehintajärjestelmä ovat aiheuttaneet patenttisuojattujen lääkevalmisteiden kohtuullisen tukkuhinnan vahvista-mismenettelyyn. Tätä menettelyä koskevat säännökset sisältyvät sairausvakuutuslain 6. lukuun, joten tutkimuksessa pyrittiin selvittämään kyseisen luvun soveltamista ja siinä mahdollisesti tapahtuneita muutoksia. Lääkevaihto otettiin Suomessa käyttöön 1.4.2003 ja viitehintajärjestelmä 1.4.2009. Lääkevalmisteiden hinnat ovat laskeneet niiden myötä merkittävästi. Tutkimusaineiston muodostivat 241 lääkkeiden hintalautakunnan sairausvakuutuskorvattavuutta ja kohtuullista tukkuhintaa koskevaa päätöstä vuosilta 2000-2010. Lisäksi käytössä oli muita päätöksiin liittyviä dokumentteja. Tutkimusaineisto lääkevaihdon käyttöönottoa edeltäneeltä ajalta jäi niukaksi. Tutkimuksen keskeiset havainnot liittyvätkin nimenomaan viitehintajärjestelmän käyttöönottoon. Nämä havainnot kuvaavat sitä, millaiset muutokset kohtuullisen tukkuhinnan vahvistamisessa ovat johtaneet patenttisuojattujen lääkevalmisteiden hintojen laskuun.

Fractionation of Hen Egg and Oat Lipids with supercritical Fluids Chemical and functional Properties of Fractions

Hen eggs and oats (Avena Sativa) are important materials for the food industry. Today, instead of merely satisfying the feeling of hunger, consumers are asking for healthier, biologically active and environmentally friendly products. The growing awareness of consumers’ increasing demands presents a great challenge to the food industry to develop more sustainable products and utilise modern and effective techniques. The modification of yolk fatty acid composition by means of feed supplements is well understood. Egg yolk phospholipids are polar lipids and are used in several applications including food, cosmetics, pharmaceuticals, and special nutrients. Egg yolk phospholipids are excellent emulsifiers, typically sold as mixtures of phospholipids, triacylglycerols, and cholesterol. However, highly purified and characterised phospholipids are needed in several sophisticated applications. Industrial fractionation of phospholipids is usually based on organic solvents. With these fractionation techniques, some harmful residues of organic solvents may cause problems in further processing. The objective of the present study was to investigate the methods to improve the functional properties of eggs, to develop techniques to isolate the fractions responsible for the specific functional properties of egg yolk lipids, and to apply the developed techniques to plant-based materials, too. Fractionation techniques based on supercritical fluids were utilised for the separation of the lipid fractions of eggs and oats. The chemical and functional characterisation of the fractions were performed, and the produced oat polar lipid fractions were tested as protective barrier in encapsulation processes. Modifying the fatty acid compositions of egg yolks with different types of oil supplements in feed had no affect on their functional or sensory properties. Based on the results of functional and sensory analysis, it is evident that eggs with modified fatty acid compositions are usable in several industrial applications. These applications include liquid egg yolk products used in mayonnaise and salad dressings. Egg yolk powders were utilised in different kinds of fractionation processes. The precipitation method developed in this study resembles the supercritical anti-solvent method, which is typically used in the pharmaceutical industry. With pilot scale supercritical fluid processes, non-polar lipids and polar lipids were successfully separated from commercially produced egg yolk powder and oat flakes. The egg and oat-based polar lipid fractions showed high purities, and the corresponding delipidated fractions produced using supercritical techniques offer interesting starting materials for the further production of bioactive compounds. The oat polar lipid fraction contained especially digalactosyadiacylglycerol, which was shown to have valuable functional properties in the encapsulation of probiotics.

A Farewell to Flat Biology. Three-dimensional Cell Culture Models in Cancer Drug Target Identification and Validation

Cells of epithelial origin, e.g. from breast and prostate cancers, effectively differentiate into complex multicellular structures when cultured in three-dimensions (3D) instead of conventional two-dimensional (2D) adherent surfaces. The spectrum of different organotypic morphologies is highly dependent on the culture environment that can be either non-adherent or scaffold-based. When embedded in physiological extracellular matrices (ECMs), such as laminin-rich basement membrane extracts, normal epithelial cells differentiate into acinar spheroids reminiscent of glandular ductal structures. Transformed cancer cells, in contrast, typically fail to undergo acinar morphogenic patterns, forming poorly differentiated or invasive multicellular structures. The 3D cancer spheroids are widely accepted to better recapitulate various tumorigenic processes and drug responses. So far, however, 3D models have been employed predominantly in the Academia, whereas the pharmaceutical industry has yet to adopt a more widely and routine use. This is mainly due to poor characterisation of cell models, lack of standardised workflows and high throughput cell culture platforms, and the availability of proper readout and quantification tools. In this thesis, a complete workflow has been established entailing well-characterised 3D cell culture models for prostate cancer, a standardised 3D cell culture routine based on high-throughput-ready platform, automated image acquisition with concomitant morphometric image analysis, and data visualisation, in order to enable large-scale high-content screens. Our integrated suite of software and statistical analysis tools were optimised and validated using a comprehensive panel of prostate cancer cell lines and 3D models. The tools quantify multiple key cancer-relevant morphological features, ranging from cancer cell invasion through multicellular differentiation to growth, and detect dynamic changes both in morphology and function, such as cell death and apoptosis, in response to experimental perturbations including RNA interference and small molecule inhibitors. Our panel of cell lines included many non-transformed and most currently available classic prostate cancer cell lines, which were characterised for their morphogenetic properties in 3D laminin-rich ECM. The phenotypes and gene expression profiles were evaluated concerning their relevance for pre-clinical drug discovery, disease modelling and basic research. In addition, a spontaneous model for invasive transformation was discovered, displaying a highdegree of epithelial plasticity. This plasticity is mediated by an abundant bioactive serum lipid, lysophosphatidic acid (LPA), and its receptor LPAR1. The invasive transformation was caused by abrupt cytoskeletal rearrangement through impaired G protein alpha 12/13 and RhoA/ROCK, and mediated by upregulated adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A, and Rac/ PAK pathways. The spontaneous invasion model tangibly exemplifies the biological relevance of organotypic cell culture models. Overall, this thesis work underlines the power of novel morphometric screening tools in drug discovery.

Tuotanto- ja pakkausmateriaalien varastojen nykytila ja kehittäminen lääkeannostelijoita valmistavassa tehtaassa

Diplomityön tarkoituksena oli selvittää lääkeannostelijoita valmistavan tehtaan materiaalivarastojen nykytila. Varaston nykytila-analyysi jaettiin pääoma- ja operatiivisen tehokkuuden arviointiin. Työssä haluttiin kartoittaa toimenpide-ehdotuksia varastonohjauksen tehostamiseksi. Diplomityön tarkoituksena oli myös lisätä avainhenkilöiden ymmärrystä koskien varastojen pidon vaikutuksia yrityksen liiketoimintaan. Varastojen nykytila voitiin kiteyttää suureen pääoman sitoutumiseen, hitaisiin kiertoaikoihin sekä tehokkaan työskentelyn kannalta liian pieniin ja ahtaisiin varastoihin. Kustannuksia ei ole otettu kokonaisuudessaan huomioon tilattaessa ja varastoitaessa materiaalia. Varaston hitaita kiertonopeuksia ei ole tunnistettu vaikuttajina yrityksen tulokseen ja kannattavuuteen. Jotta varastonohjaus- ja hankintaprosesseja voitaisiin tehostaa, pitäisi ostotoimintoihin tehdä muutoksia. Tilausrytmiä ja –määriä täytyisi harkita uudelleen, jotta voitaisiin vähentää varastoihin sitoutuvan pääoman määrää. Informaationvirtaa tehtaalla sekä organisaatiorajojen yli pitäisi parantaa, jotta voitaisiin vähentää kysynnän heilahteluja sekä siihen varautumista. Varmuusvarastojen pidosta saatavien korvausten olisi katettava koko materiaalin kiertoajan aikana syntyvät varastoinnin kustannukset.

Aineeton pääoma lääkekehitysalalla: kuinka institutionaaliset sijoittajat huomioivat aineettoman pääoman päätöksenteossaan

The thesis presents the concept of intellectual capital and its effect on pharmaceutical industry and insitutional investors' decision making. Intellectual capital is also demonstrated by examples from two cases.

Reseptilääkkeiden markkinoinnin eettisyys

Tutkielmassa tarkastellaan reseptilääkkeiden markkinointia Suomessa alan toimijoiden päätöksenteon ja eettisten ohjeiden kautta. Tutkimuksen keskeisimpänä tavoitteena on esitellä lääkealan eri toimijoiden näkökulmia heidän eettisen tai epäeettisen päätöksentekonsa kautta. Mahdollisesti vaikuttavista tekijöistä tavoitteena on myös esitellä eettisiä ohjeita ja pohtia millainen rooli niillä on toimijoiden päätöksenteossa. Tutkimuksessa pyritään myös tuomaan ilmi eettisiä ongelmia lääketeollisuudessa ja avaamaan alan toimijoiden yleistä näkemystä reseptilääkkeiden markkinointiin liittyen. Lisäksi tutkimuksessa tutustutaan lääketeollisuuteen toimialana.

Terpenoid transformations over gold catalysts

Nowadays biomass transformation has a great potential for the synthesis of value-added compounds with a wide range of applications. Terpenoids, extracted from biomass, are inexpensive and renewable raw materials which often have a biological activity and are widely used as important organic platform molecules in the development of new medicines as well as in the synthesis of fine chemicals and intermediates. At the same time, special attention is devoted to the application of gold catalysts to fine chemical synthesis due to their outstanding activity and/or selectivity for transformations of complex organic compounds. Conversion of renewable terpenoids in the presence of gold nanoparticles is one of the new and promising directions in the transformation of biomass to valuable chemicals. In the doctoral thesis, different kinds of natural terpenoids, such as α-pinene, myrtenol and carvone were selected as starting materials. Gold catalysts were utilized for the promising routes of these compounds transformation. Investigation of selective α-pinene isomerization to camphene, which is an important step in an industrial process towards the synthesis of camphor as well as other valuable substrates for the pharmaceutical industry, was performed. A high activity of heterogeneous gold catalysts in the Wagner-Meerwein rearrangement was demonstrated for the first time. Gold on alumina carrier was found to reach the α-pinene isomerization conversion up to 99.9% and the selectivity of 60-80%, thus making this catalyst very promising from an industrial viewpoint. A detailed investigation of kinetic regularities including catalyst deactivation during the reaction was performed. The one-pot terpene alcohol amination, which is a promising approach to the synthesis of valuable complex amines having specific physiological properties, was investigated. The general regularities of the one-pot natural myrtenol amination in the presence of gold catalysts as well as a correlation between catalytic activity, catalyst redox treatment and the support nature were obtained. Catalytic activity and product distribution were shown to be strongly dependent on the support properties, namely acidity and basicity. The gold-zirconia (Au/ZrO2) catalyst pretreated under oxidizing atmosphere was observed to be rather active, resulting in the total conversion of myrtenol and the selectivity to the corresponding amine of about 53%. The reaction kinetics was modelled based on the mechanistic considerations with the catalyst deactivation step incorporated in the mechanism. Carvone hydrogenation over a gold catalyst was studied with the general idea of investigating both the activity of gold catalysts in competitive hydrogenation of different functional groups and developing an approach to the synthesis of valuable carvone derivatives. Gold was found to promote stereo- and chemoselective carvone hydrogenation to dihydrocarvone with a predominant formation of the trans-isomer, which generally is a novel synthetic method for an industrially valuable dihydrocarvone. The solvent effect on the catalytic activity as well as on the ratio between trans- and cis-dihydrocarvone was evaluated.

Lääke- ja sairaalatarvikelogistiikka Suomessa: markkinapotentiaali ja skenaariotarkastelu case yrityksen avulla

Työn tavoitteena oli kuvata kotimaisia lääkemarkkinoita koko arvoketjun alueelta, lähtien lääketehtaista ja päättyen vähittäismyyntiin tai sairaalajakeluun. Lisäksi työssä kuvattiin julkisen terveydenhuollon ostopalveluiden tilaa erityisesti logistiikkapalveluiden osalta. Markkinoiden kuvausta hyödynnettiin työssä Suomalaisen logistiikkayrityksen markkinapotentiaalin määrittämisessä kyseisille markkinoille. Työn toinen tavoite oli tarkastella markkinoita tulevaisuustutkimuksen työkaluja käyttämällä, ja luoda kyseisille markkinoille skenaarioita 10–15 vuoden päähän nykyhetkestä. Skenaarioiden ja markkinapotentiaaliselvityksen perusteella on työn lopputulemana luotu toimintaehdotuksia asiakasyritykselle koskien selvityksen alla olevien markkinoiden houkuttelevuutta yrityksen kannalta. Selvityksessä käytettävä tieto on kerätty julkisten raporttien ja selvitysten pohjalta, sekä tuottamalla laajamittainen haastattelututkimus yksityisten ja julkisten toimijoiden kautta läpi kotimaisen lääkkeen ja sairaalatarvikkeen arvoketjun. Haastattelututkimus on työn kannalta merkittävin tiedon lähde ja työssä hyödynnetty hiljaisten signaalien tulkinta perustuu haastatteluiden kautta saatuihin tietoihin.

The Cycle Times of Working Capital: Financial Value Chain Analysis Method

Interest towards working capital management increased among practitioners and researchers because the financial crisis of 2008 caused the deterioration of the general financial situation. The importance of managing working capital effectively increased dramatically during the financial crisis. On one hand, companies highlighted the importance of working capital management as part of short-term financial management to overcome funding difficulties. On the other hand, in academia, it has been highlighted the need to analyze working capital management from a wider perspective namely from the value chain perspective. Previously, academic articles mostly discussed working capital management from a company-centered perspective. The objective of this thesis was to put working capital management in a wider and more academic perspective and present case studies of the value chains of industries as instrumental in theoretical contributions and practical contributions as complementary to theoretical contributions and conclusions. The principal assumption of this thesis is that selffinancing of value chains can be established through effective working capital management. Thus, the thesis introduces the financial value chain analysis method which is employed in the empirical studies. The effectiveness of working capital management of the value chains is studied through the cycle time of working capital. The financial value chain analysis method employed in this study is designed for considering value chain level phenomena. This method provides a holistic picture of the value chain through financial figures. It extends the value chain analysis to the industry level. Working capital management is studied by the cash conversion cycle that measures the length (days) of time a company has funds tied up in working capital, starting from the payment of purchases to the supplier and ending when remittance of sales is received from the customers. The working capital management practices employed in the automotive, pulp and paper and information and communication technology industries have been studied in this research project. Additionally, the Finnish pharmaceutical industry is studied to obtain a deeper understanding of the working capital management of the value chain. The results indicate that the cycle time of working capital is constant in the value chain context over time. The cash conversion cycle of automotive, pulp and paper, and ICT industries are on average 70, 60 and 40 days, respectively. The difference is mainly a consequence of the different cycle time of inventories. The financial crisis of 2008 affected the working capital management of the industries similarly. Both the cycle time of accounts receivable and accounts payable increased between 2008 and 2009. The results suggest that the companies of the automotive, pulp and paper and ICT value chains were not able to self-finance. Results do not indicate the improvement of value chains position in regard to working capital management either. The findings suggest that companies operating in the Finnish pharmaceutical industry are interested in developing their own working capital management, but collaboration with the value chain partners is not considered interesting. Competition no longer occurs between individual companies, but between value chains. Therefore the financial value chain analysis method introduced in this thesis has the potential to support value chains in improving their competitiveness.

Tuoteportfolion hallinnointiprosessin erityispiirteet lääketeollisuusyrityksessä – tapaustutkimus

Tämän pro gradu -tutkielman tarkoituksena oli selvittää, miten lääketeollisuusyritys toteuttaa tuoteportfolioidensa hallinnointia ja miten tämän caseyrityksen portfolioprosessi vastaa kirjallisuuden näkemystä tuoteportfolion hallinnoinnista. Tutkimusongelmaa lähestyttiin tapaustutkimuksella caseyrityksen portfolioprosessista, ja tätä prosessia verrattiin kirjallisuuden näkemykseen aiheesta. Empiiristä aineistoa kerättiin pääosin teema- ja lomakehaastatteluilla caseyrityksen projektin avainhenkilöiltä. Tutkimuksessa havaittiin portfolioprosessin olevan vaiheittainen toimintamalli, jonka tavoitteena on hankkia mahdollisimman kannattava tuotevalikoima. Caseyrityksen portfolioprosessi vastasi pääosin aiheen teorian kuvaamaa mallia, mutta prosessia ja etenkin karsintakriteereitä monipuolistamalla voidaan tulevaisuudessa saavuttaa parempia tuloksia. Lääketeollisuudella toimialana on tiettyjä ominaispiirteitä, mutta nämä eivät suoraan näy varsinaisessa portfolioprosessissa. Kuitenkin esimerkiksi erityyppisten liiketoimintayksiköiden tarpeet olisi syytä huomioida tuoteportfolion hallinnointiprosessissa.

The corporate bias and the molding of prescription practices: the case of hypertension

Drug management of hypertension has been a noticeable example of the influence of the pharmaceutical industry on prescription practices. The worldwide leading brands of blood pressure-lowering agents are angiotensin receptor-blocking agents, although they are considered to be simply substitutes of angiotensin-converting enzyme (ACE) inhibitors. Commercial strategies have been based on the results of clinical trials sponsored by drug companies. Most of them presented distortions in their planning, presentation or interpretation that favored the drugs from the sponsor, i.e., corporate bias. Atenolol, an ineffective blood pressure agent in elderly individuals, was the comparator drug in several trials. In a re-analysis of the INSIGHT trial, deaths appeared to have been counted twice. The LIFE trial appears in the title of more than 120 reproductions of the main and flawed trial, as a massive strategy of scientific marketing. Most guidelines have incorporated the corporate bias from the original studies, and the evidence from better designed studies, such as the ALLHAT trial, have been largely ignored. In trials published recently corporate influences have touched on ethical limits. In the ADVANCE trial, elderly patients with type 2 diabetes and cardiovascular disease or risk factors, allocated to placebo, were not allowed to use diuretic and full doses of an ACE inhibitor, despite the sound evidence of benefit demonstrated in previous trials. As a consequence, they had a 14% higher mortality rate than the participants allocated to the active treatment arm. This reality should be modified immediately, and a greater independence of the academy from the pharmaceutical industry is necessary.

In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

Multinational drug corporations, intellectual property rights and the Canadian state : a historical and critical analysis

This study critically analyzes the historical role and influence of multinational drug cotpOrations and multinational corporations in general; the u.s. government and the Canadian state in negotiating the global recognition ofIntellectual Property Rights (IPR) under GATT/NAFTA. This process began in 1969 when the Liberal government, in response to high prices for brand-name drugs amended the Patent Act to introduce compulsory licensing by reducing monopoly protection from 20 to seven years. Although the financial position ofthe multinational drug industry was not affected, it campaigned vigorously to change the 1969 legislation. In 1987, the Patent Act was amended to extend protection to 10 years as a condition for free trade talks with the u.s. Nonetheless, the drug industry was not satisfied and accused Canada of providing a bad example to other nations. Therefore, it continued to campaign for global recognition ofIPR laws under GATT. Following the conclusion of the GATTI Trade-Related aspects of Intellectual Property Rights agreement (TRIPS) in 1991, the multinational drug industry and the American government, to the surprise of many, were still not satisfied and sought to implement harsher conditions under NAFTA. The Progressive Conservative government readily agreed without any objections or consideration for the social consequences. As a result, Bill C-91 was introduced. It abandoned compulsory licenses and was made retroactive from December 21, 1991. It is the contention of this thesis that the economic survival of multinational corporations on a global scale depends on the role and functions of the modem state. Similarly, the existence of the state depends on the ideological-political and socioeconomic assistance it gives to multinational corporations on a national and international scale. This dialectical relation of the state and multinational corporations is explored in our theoretical and historical analysis of their role in public policy.

The placebo effect: international patent law and the protection of traditional plant medicine

Une préoccupation essentielle traverse cette thèse: l'indifférence systémique de la Loi internationale sur la propriété intellectuelle a l'égard des savoirs traditionnels autochtones. De manière générale, un écart semble d'ailleurs croissant entre l'importance des accords internationaux sur les questions d'intérêt commercial et ceux de nature sociale. Les savoirs traditionnels autochtones sur les plantes médicinales sont particulièrement désavantagés dans ce système dichotomique puisqu'ils sont non seulement à l'origine d'énormes profits commerciaux mais se trouvent aussi au cœur de multiples croyances propres à ces sociétés. L'Accord sur les aspects des droits de propriété intellectuelle qui touchent au commerce (ADPIC) de l'Organisation mondiale du commerce (OMC) a cristallisé le souci de la législation internationale à l'égard d'une protection efficace des intérêts commerciaux. Deux années auparavant, la Convention sur la diversité biologique (CDB) était signée, traduisant une préoccupation à l'égard du développement durable, et elle devenait le premier accord international à tenir compte des savoirs traditionnels autochtones. On considère souvent que ces deux accords permettent l'équilibre du développement commercial et durable, requis par l'économie internationale. Après plus ample examen, on a plutôt l'impression que l'idée d'une CDB défendant, avec succès et efficacité, la nécessité du développement durable et des savoirs traditionnels autochtones contre les pressions opposées de l'ADPIC et de l'OMC est, au mieux, simpliste. La thèse explore également la fonction de la Loi sur les brevets dans la création d’industries, notamment pharmaceutique, et la manière dont ces industries influencent la législation nationale et en particulier internationale. De même, elle traite du rôle que jouent les brevets dans l'affaiblissement et la dépossession des peuples autochtones dotés de savoirs traditionnels sur les plantes médicinales, conduisant à une situation ou ces savoirs sont marginalisés ainsi que leurs détenteurs. La thèse aborde les failles institutionnelles du système juridique international qui permet une telle situation et indique l'urgente nécessité d'examiner attentivement les inégalités économiques et sociales au Nord comme au Sud, et non seulement entre eux. Finalement, la thèse suggère que la législation internationale gagnerait à s'inspirer des diverses traditions juridiques présentes à travers le monde et, dans ce cas particulier, peut être les détenteurs des connaissances traditionnelles concernant les plantes médicinales seront mieux servi par le droit des obligations.