Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica

OBJECTIVES: The pharmacokinetic (PK) parameters of artesunate, recently discovered to possess promising trematocidal activity, and its main metabolite dihydroartemisinin (DHA) were determined in rats infected with hepatic and biliary stages of Fasciola hepatica and compared with uninfected rats after single intragastric and intravenous (iv) doses. METHODS: Rats infected with F. hepatica for 25 and 83 days and uninfected rats were cannulated in the right jugular vein and blood samples were withdrawn at selected timepoints following 10 mg/kg of iv and a single 100 mg/kg oral dose of artesunate. Plasma was analysed for artesunate and DHA by liquid chromatography coupled to tandem mass spectrometry. RESULTS: Rats harbouring juvenile and adult F. hepatica infections revealed considerable changes in PK parameters of artesunate and DHA. Following oral administration, maximum plasma concentrations (C(max)) of artesunate and DHA were 1.8-2.3-fold higher in infected rats [artesunate: 1334 +/- 1404 ng/mL (no infection) versus 2454 +/- 1494 ng/mL (acute infection) and 2768 +/- 538 ng/mL (chronic infection); DHA: 3802 +/- 2149 ng/mL (no infection) versus 6507 +/- 3283 ng/mL (acute infection) and 9093 +/- 884 ng/mL (chronic infection)]. The AUCs of artesunate and DHA were 2.1-4.4-fold greater in infected rats. An opposite trend was observed after iv injection. C(max) and AUC of artesunate and DHA following iv dosing were 5784 +/- 3718 and 140 938 +/- 128 783 ng.min/mL and 3849 +/- 3060 and 86 107 +/- 41 863 ng.min/mL, respectively, in uninfected rats versus 2623 +/- 1554 and 21 617 +/- 12 230 ng.min/mL and 2835 +/- 980 and 64 290 +/- 29 057 ng.min/mL, respectively, in rats harbouring a chronic infection. The elimination half-lives (t(1/2)) of artesunate and DHA were considerably altered in infected rats following oral and iv administration of artesunate. CONCLUSIONS: F. hepatica infections strongly influence the disposition kinetics of artesunate and its metabolite in rats. The clinical implications of this finding need to be carefully studied.

Kiista kansallisesta identiteettiprojektista

Abstract: Debating the Finnish National Identity Project

Genetic diversity of cultivated accessions and wild species of rubber tree using EST‑SSR markers

The objective of this work was to evaluate the efficiency of EST‑SSR markers in the assessment of the genetic diversity of rubber tree genotypes (Hevea brasiliensis) and to verify the transferability of these markers for wild species of Hevea. Forty‑five rubber tree accessions from the Instituto Agronômico (Campinas, SP, Brazil) and six wild species were used. Information provided by modified Roger's genetic distance were used to analyze EST‑SSR data. UPGMA clustering divided the samples into two major groups with high genetic differentiation, while the software Structure distributed the 51 clones into eight groups. A parallel could be established between both clustering analyses. The 30 polymorphic EST‑SSRs showed from two to ten alleles and were efficient in amplifying the six wild species. Functional EST‑SSR microsatellites are efficient in evaluating the genetic diversity among rubber tree clones and can be used to translate the genetic differences among cultivars and to fingerprint closely related materials. The accessions from the Instituto Agronômico show high genetic diversity. The EST‑SSR markers, developed from Hevea brasiliensis, show transferability and are able to amplify other species of Hevea.

Kansainvälisten yhtiöiden yritysostot Venäjän elintarviketeollisuudessa

Tässä työssä tutkittiin Venäjän elintarviketeollisuuteen vuosina 1992 - 2004 investoineitakansainvälisiä yhtiöitä, niiden käyttämiä investointitapoja ja yritysostojen motiiveja. Viime vuosina Venäjän bruttokansantuote kasvoi yli 4 % vuodessa. Venäjän ostovoima kasvoi talouden mukana. Venäjän elintarviketeollisuudella on vieläkin kasvupotentiaalia. Paikallinen elintarvikevalmistus on varteenotettava vaihtoehto, jota kannattaa harkita. Vuosina 1992 - 2004 meijeri- ja virvoitusjuomateollisuudessa uusien tehtaiden rakentajia oli enemmän kuin tehtaiden ostajia. Panimoteollisuudessa oli enemmän yritysostojen käyttäjiä kuin uuden tehtaan rakentajia. Konditoriateollisuudessa ja kaikilla tutkituilla sektoreilla yhteensä yritysostojen käyttäjiä oli saman verran kuin uusien tehtaiden rakentajia. Tärkeimmät ulkoiset syyt yritysostoihin Venäjällä olivat markkinoiden koko, hallituspolitiikka ja säädökset, ostettavan kohdeyrityksen tuotemerkki ja kohdeyrityksen markkinaosuus. Tärkeimmät sisäiset syyt yritysostoihin olivat ulkomaan markkinoiden rooli strategiassa, tuotteen sopeuttamisen tarve ja yrityksen omat vapaat resurssit.

Luoteis-Venäjän metsävaratja niiden hyödyntämismahdollisuudet

Suomen metsäteollisuuden käyttämästä puusta neljännes on tuontipuuta, josta Venäjän tuonnin osuus on hyvin merkittävä. Suomen metsäteollisuus on riippuvainen etenkin Luoteis-Venäjän metsien puusta. Venäjä pyrkii nostamaan metsäteollisuuden jalostusastetta ja hyödyntämään voimallisemmin omia metsävaroja, mikä merkitsee suuria haasteita suomalaiselle metsäteollisuudelle ja sen raaka-ainehuollolle. Tässä raportissa tarkastellaan Luoteis-Venäjän metsävaroja, metsänkäyttöä ja sen ongelmia sekä metsien hallinnointia. Lisäksi käsitellään Luoteis-Venäjän metsäsektoria ja siihen tehtyjä suoria ulkomaisia investointeja. Lopuksi kuvataan Luoteis-Venäjän kuljetusinfrastruktuuria sekä arvioidaan Luoteis-Venäjän metsävarojen käytön potentiaalia.

Three essays in dynamic corporate finance

The three essays constituting this thesis focus on financing and cash management policy. The first essay aims to shed light on why firms issue debt so conservatively. In particular, it examines the effects of shareholder and creditor protection on capital structure choices. It starts by building a contingent claims model where financing policy results from a trade-off between tax benefits, contracting costs and agency costs. In this setup, controlling shareholders can divert part of the firms' cash ows as private benefits at the expense of minority share- holders. In addition, shareholders as a class can behave strategically at the time of default leading to deviations from the absolute priority rule. The analysis demonstrates that investor protection is a first order determinant of firms' financing choices and that conflicts of interests between firm claimholders may help explain the level and cross-sectional variation of observed leverage ratios. The second essay focuses on the practical relevance of agency conflicts. De- spite the theoretical development of the literature on agency conflicts and firm policy choices, the magnitude of manager-shareholder conflicts is still an open question. This essay proposes a methodology for quantifying these agency conflicts. To do so, it examines the impact of managerial entrenchment on corporate financing decisions. It builds a dynamic contingent claims model in which managers do not act in the best interest of shareholders, but rather pursue private benefits at the expense of shareholders. Managers have discretion over financing and dividend policies. However, shareholders can remove the manager at a cost. The analysis demonstrates that entrenched managers restructure less frequently and issue less debt than optimal for shareholders. I take the model to the data and use observed financing choices to provide firm-specific estimates of the degree of managerial entrenchment. Using structural econometrics, I find costs of control challenges of 2-7% on average (.8-5% at median). The estimates of the agency costs vary with variables that one expects to determine managerial incentives. In addition, these costs are sufficient to resolve the low- and zero-leverage puzzles and explain the time series of observed leverage ratios. Finally, the analysis shows that governance mechanisms significantly affect the value of control and firms' financing decisions. The third essay is concerned with the documented time trend in corporate cash holdings by Bates, Kahle and Stulz (BKS,2003). BKS find that firms' cash holdings double from 10% to 20% over the 1980 to 2005 period. This essay provides an explanation of this phenomenon by examining the effects of product market competition on firms' cash holdings in the presence of financial constraints. It develops a real options model in which cash holdings may be used to cover unexpected operating losses and avoid inefficient closure. The model generates new predictions relating cash holdings to firm and industry characteristics such as the intensity of competition, cash flow volatility, or financing constraints. The empirical examination of the model shows strong support of model's predictions. In addition, it shows that the time trend in cash holdings documented by BKS can be at least partly attributed to a competition effect.

Business model design: an evaluation of paper-based and computer-aided canvases

In recent years, Business Model Canvas design has evolved from being a paper-based activity to one that involves the use of dedicated computer-aided business model design tools. We propose a set of guidelines to help design more coherent business models. When combined with functionalities offered by CAD tools, they show great potential to improve business model design as an ongoing activity. However, in order to create complex solutions, it is necessary to compare basic business model design tasks, using a CAD system over its paper-based counterpart. To this end, we carried out an experiment to measure user perceptions of both solutions. Performance was evaluated by applying our guidelines to both solutions and then carrying out a comparison of business model designs. Although CAD did not outperform paper-based design, the results are very encouraging for the future of computer-aided business model design.

Visualizing Business Model Evolution with the Business Model Canvas: Concept and Tool

The Business Model Canvas (BMC) assists in the design of companies' business models. As strategies evolve so too does the business model. Unfortunately, each BMC is a standalone representation. Thus, there is a need to be able to describe transformation from one version of a business model to the next as well as to visualize these operations. To address this issue, and to contribute to computer-assisted business model design, we propose a set of design principles for business model evolution. We also demonstrate a tool that can assist in the creation and navigation of business model versions in a visual and user-friendly way

Ilmatotieteeseenkin kuuluu skeptisyys

Keskustelua

Venäläisvetoinen yrittäjyys Suomessa

Venäjän maantieteellinen läheisyys ja kasvavat markkinat ovat yhä edelleen tärkeimpiä syitä suomalaisyritysten Venäjä-toiminnoille. Vuorovaikutus rajan yli ei kuitenkaan ole yksipuolista, vaan maantieteellisen läheisyyden vuoksi myös venäläisyritysten voisi olettaa pitävän Suomea luonnollisena vaihtoehtona kansainvälistymiselleen. Suomessa toimivissa venäläisyrityksissä on havaittavissa ominaispiirteitä, jotka erottavat ne kotimaisesta yritystoiminnasta. Samalla kuitenkin venäläisyritysten piirteet eivät ole yhteneviä muualla maailmassa havaittujen etnisten yritysten ominaisuuksien kanssa. Toisin kuin etniset yritykset yleensä, venäläiset yritykset eivät ole syntyneet julkisen tuen avustuksella, eivätkä ne toimi matalan kannattavuuden aloilla. Venäläisen yritystoiminnan rooli on merkittävä Suomen ja Venäjän välisessä kaupassa, ja samalla se tuo lisämausteensa suomalaiseen pienyrityskenttään.

Lehtrid / Embudos

Postprint (published version)