Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 μM) and the more potent and specific P-gp inhibitor valspodar (5 μM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 μM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

The knowledge about diagnostic imaging methods among primary care and medical emergency physicians

Objective To evaluate the knowledge about diagnostic imaging methods among primary care and medical emergency physicians. Materials and Methods Study developed with 119 primary care and medical emergency physicians in Montes Claros, MG, Brazil, by means of a structured questionnaire about general knowledge and indications of imaging methods in common clinical settings. A rate of correct responses corresponding to ≥ 80% was considered as satisfactory. The Poisson regression (PR) model was utilized in the data analysis. Results Among the 81 individuals who responded the questionnaire, 65% (n = 53) demonstrated to have satisfactory general knowledge and 44% (n = 36) gave correct responses regarding indications of imaging methods. Respectively, 65% (n = 53) and 51% (n = 41) of the respondents consider that radiography and computed tomography do not use ionizing radiation. The prevalence of a satisfactory general knowledge about imaging methods was associated with medical residency in the respondents' work field (PR = 4.55; IC 95%: 1.18-16.67; p-value: 0.03), while the prevalence of correct responses regarding indication of imaging methods was associated with the professional practice in primary health care (PR = 1.79; IC 95%: 1.16-2.70; p-value: 0.01). Conclusion Major deficiencies were observed as regards the knowledge about imaging methods among physicians, with better results obtained by those involved in primary health care and by residents.

Internet, Law and Politics. A decade of transformations.

Proceedings of Internet, Law and Politics. A decade of transformations.

Oncobiguanides: Paracelsus" law and nonconventional routes for administering diabetobiguanides for cancer treatment

The dose makes the poison, the common motto of toxicology first expressed by Paracelsus more than 400 years ago, may effectively serve to guide potential applications for metformin and related biguanides in oncology. While Paracelsus' law for the dose-response effect has been commonly exploited for the use of some anti-cancer drugs at lower doses in non-neoplastic diseases (e.g., methotrexate), the opposite scenario also holds true; in other words, higher doses of non-oncology drugs, such as anti-diabetic biguanides, might exert direct anti-neoplastic effects. Here, we propose that, as for any drug, there is a dose range for biguanides that is without any effect, one corresponding to"diabetobiguanides" with a pharmacological effect (e.g., insulin sensitization in type 2 diabetes, prevention of insulin-dependent carcinogenesis, indirect inhibition of insulin and growth factor-dependent cancer growth) but with minimal toxicity and another corresponding to 'oncobiguanides' with pharmacological (i.e., direct and strong anticancer activity against cancer cells) as well as toxic effects. Considering that biguanides demonstrate a better safety profile than most oncology drugs in current use, we should contemplate the possibility of administering biguanides through non-conventional routes (e.g., inhaled for carcinomas of the lung, topical for skin cancers, intravenous as an adjunctive therapy, rectal suppositories for rectal cancer) to unambiguously investigate the therapeutic value of high-dose transient biguanide exposure in cancer. Perhaps then, the oncobiguanides, as we call them here, could be viewed as a mechanistically different type of anti-cancer drugs employed at doses notably higher than those used chronically when functioning as diabetobiguanides

Repensando la relación entre la ley y la violencia hacia las mujeres. Una aproximación a los discursos de los/las agentes del ámbito judicial en relación a la ley integral de violencia de género en España = Rethinking the relationship between law and violence against women. an approach to the juridical agents' discourses in relation to the integral law of gender-based violence

Of the many dimensions of the problem of violence exercised by men toward women in the context of the relations of partner or ex partner, this article deals with the analysis of the discursive productions of the institutional actors that are part of the judicial process. Our intention is to investigate the relationship between criminal law and gender-based violence starting from the implementation of the Law of Integral Gender-based Violence in Spain (LO. 1 / 2004) from a theoretical perspective which includes contributions from social psychology, and socio-legal feminism. We have approached the legal instrument - the Law of Integral Gender-based Violence - through the discourse of legal officers with a perspective that questions the values, so often proclaimed, of universality, objectivity and neutrality of the law

Epistemological anarchism of Paul Karl Feyerabend and medical education

The thoughts of the philosopher Paul Karl Feyerabend brought important contributions to the debate on Science in the 20th century. Most recently his views about non-existence of a single method for doing science have been employed to rethink science education and propose the use of multiple methods for effective teaching-learning process. This article employs the theoretical framework of the author expressed in the book Against Method, 1977, about the epistemological anarchism and the methodological pluralism and uses it in the contemporary discussion of medical education.

Pierre Bourdieu and medical education

The contemporary discussion about the transformation of the training of health professionals has focused primarily on the change in method. This article discusses this issue in the light of Pierre Bourdieu's theoretical contributions - habitus, field, symbolic capital, symbolic violence and reproduction. The conclusion is drawn that pedagogical change alone is not enough to change the profile of medical graduates.

The history of Lapland : wherein are shewed the original manners, habits, marriages, conjurations, &c. of that people : written by John Scheffer, professor of law and rhetoric at Upsal in Sweden.

Added engraved title page: The history of Lapland.

Essays on Business and Leadership Ethics

As this is a dissertation, an academic thesis, it is important to define the objectives of my research, even if ex post facto, explicitly: - To define, develop and study the concept of business and leadership ethics. - To empirically study the phenomena associated with business and leadership from an ethical perspective. - To create a new framework for the development of responsible business. - To create an “acid test” for my body of works, i.e. a test and an evaluation on how well my research and ideas hold up under academic philosophical reflection. The utilitarian reasoning had the most support when the actors justified their actions regarding economic benefit. (=instrumental good). Duty and benefit were often mixed up in people’s speech. Their meaning contents were blurred and the argumentation lines created by the actors were broken. This can be interpreted in a way that supports Frankena’s mixed deontological philosophy as a frame of reference. Deontologica reasoning was used e.g. in describing the personnel management processes of a company. Virtue ethics is a favourable starting point for studying management and leadership ethics. All the actors studied could name virtues for their operations, towards which to aspire to. They also named professional practices already in use that they considered to be virtuous. Finally, I wish to state that normative ethics is an important branch of philosophical ethics, if also very important in applied ethics especially. From the normative standpoint, the results of this dissertation want to lead nations, communities and individuals towards the virtues of democratic leadership and sustainable economic development.

Opportunistisen sopimusrikkomuksen ongelmasta, erityisesti Suomen vahingonkorvaus- ja rikoslainsäädännön näkökulmasta tarkasteltuna. Law and Economics -näkökulma.

Tämä pro gradu -tutkielma käsittelee opportunistisen sopimusrikkomuksen ongelmaa erityisesti Suomen vahingonkorvaus- ja rikoslainsäädännön näkökulmasta tarkasteltuna. Tutkielman lähestymistapa on oikeustaloustieteellinen (engl. Law and Economics). Opportunistisella sopimusrikkomuksella tarkoitetaan toimintaa, jossa sopimusosapuoli rikkoo sopimuksen tarkoituksellisesti, pyrkimyksenään tällä toiminnalla saavuttaa enemmän hyötyä kuin sopimuksessa pysymällä. Opportunistinen sopimusrikkomus on mahdollista toteuttaa tilanteessa, jossa sopimusasetelma itsessään antaa mahdollisuuden enemmän hyödyn saavuttamiseen rikkomus toteuttamalla kuin sopimus asianmukaisesti täyttämällä. Suomalaisessa vahingonkorvausj��rjestelmässä sovelletaan sopimusrikkomusten osalla positiivisen sopimusedun mukaista vahingonkorvausta, joka hyvittää rikotulle osapuolelle sopimussuhteeseen ryhtymisestä syntyneet kustannukset sekä sopimusrikkomuksen johdosta saamatta j��äneen tuoton. Positiivisen sopimusedun soveltaminen ei kuitenkaan ole opportunistisen sopimusrikkomuksen ehkäisemiseksi riittävää, sillä opportunistisesti toimiva sopimusosapuoli voi j��ädä rikkomuksensa johdosta voitolle vielä sen j��lkeenkin, kun kärsineelle osapuolelle on jo positiivista sopimusetua noudattaen korvattu sopimussuhteessa syntyneet kustannukset sekä rikkomuksen johdosta saamatta j��änyt tuotto. Keskeinen ongelma koskien opportunististen sopimusrikkomustilanteiden syntyä onkin juuri vallitsevan sääntelyn liiallinen keskittyminen rikotun osapuolen kärsimän vahingon kompensoimiseen, ei rikkomustilanteiden synnyn ennaltaehkäisemiseen. Suomen vahingonkorvausj��rjestelmää tulisi kehittää suuntaan, jossa j��rjestelmä paremmin ennaltaehkäisisi opportunististen sopimusrikkomustilanteiden syntyä. Common law -oikeusj��rjestelmässä käytössä olevan disgorgement principle -suuntaisen ajattelun, jossa korvauksen perustana toimisi rikkomuksella saatu hyöty kärsityn vahingon sijaan, omaksuminen olisi yksi mahdollinen kehityskulku. Olennaista olisi kuitenkin se, että j��rjestelmää kehitettäisiin suuntaan, jossa rikkomus ei enää voisi tulla rikkojalle kannattavaksi. Opportunistisen toiminnan kannustimet tulisi lainsäädäntöä tarkistamalla poistaa. Tällä olisi sekä sopimusinstituutiota turvaavaa että vaihdantaa edistävää vaikutusta.

Is All Fair in Law and War? The Ambiguous Principle of Proportionality of Collateral Damage and the CIA Drone Attacks in Pakistan

Tutkielma käsittelee Yhdysvaltain CIAn miehittämättömiä lennokki-iskuja Pakistanissa kansainvälisen humanitaarisen oikeuden suhteellisuusperiaatteen näkökulmasta. Suhteellisuusperiaatteen mukaan aseellisista iskuista saatavan sotilaallisen hyödyn tulee olla suhteellinen verrattuna siviileille aiheutuvaan haittaan. CIAn iskuja Pakistanissa on kritisoitu, että ne eivät täytä suhteellisuusperiaatteen asettamia vaatimuksia. Tutkielmassa perehdytään ensinnäkin selvittämään ne velvollisuudet, jotka suhteellisuusperiaate asettaa hyökkääjille. Sen j��lkeen CIAn lennokki-iskuja tutkitaan näiden velvollisuuksien valossa. Tutkielmassa pyritään selvittämään antaako suhteellisuusperiaatteen luomat oikeudelliset velvollisuudet riittävää suojaa Pakistanin siviileille lennokki-iskujen tuhoja vastaan. Lisäksi pyritään selvittämään, onko lennokki-iskuissa viitteitä suhteellisuusperiaatteen vastaisista iskuista. Tutkimusmenetelmänä käytetään positivistista lainopin metodia, jonka avulla selvitetään voimassa olevaa kansainvälisen humanitaarisen tapaoikeuden suhteellisuusperiaatteen sisältöä. Oikeudellisina lähteinä käytetään pääasiassa humanitaarista tapaoikeutta, mutta tulkinnallisena apuna myös kansainvälisiä sopimuksia sekä oikeuden päätöksiä. Lisäksi oikeudellinen kirjallisuus on tutkimuksessa tärkeässä asemassa. Tutkimuksessa päädytään siihen, että suhteellisuusperiaatteen asettamat velvollisuudet hyökkääj��lle ovat niin epämääräiset, että ne eivät anna riittävää suojaa siviileille. Ensinnäkin hyökkääj�� voi määrittää sotilaallisen hyödyn omien päämääriensä mukaisesti suhteellisuusanalyysissä. Lisäksi kynnys sille, mikä katsotaan suhteellisuusperiaatteen vastaisuudeksi on hyvin epämääräinen ja korkea. Tämän vuoksi varotoimenpiteet iskujen suunnittelussa ovat hyvin tärkeässä asemassa myös suhteellisuusanalyysissä. Kuitenkin jos hyökkääj�� edes jossain määrin osoittaa, että on tehnyt iskut hyvässä uskossa niiden laillisuudesta, iskujen katsotaan yleensä olevan suhteellisuusperiaatteen mukaisia. CIAn lennokki-iskuissa Pakistanissa on viitteitä suhteellisuusperiaatteen vastaisuudesta erityisesti ”tunnusmerkki-iskujen” osalta. ”Tunnusmerkki-iskut” johtavat yleensä vain vähäiseen sotilaalliseen hyötyyn aiheuttaen silti siviiliuhreja. Lisäksi erityisesti tunnusmerkki-iskuissa edellytetään korkeampaa tarkkuutta varotoimenpiteissä. Kuitenkin useat siviiliuhrit voivat merkitä sitä, että näitä varotoimenpiteitä ei ole noudatettu iskuissa.

Utilitarianism and Buddist ethics: a comparative approach to the ethics of animal research

This thesis explores the comparison utilitarianism and Buddhist ethics as they can be applied to animal research. It begins by examining some of the general discussions surrounding the use of animals in research. The historical views on the moral status of animals, the debate surrounding their use in animals, as well as the current 3R paradigm and its application in Canadian research are explored. The thesis then moves on to expound the moral system of utilitarianism as put forth by Jeremy Bentham and John Stuart Mill, as well as contemporary additions to the system. It also looks at the basics of Buddhist ethics well distinguishing the Mahayana from the Therevada. Three case studies in animal research are used to explore how both systems can be applied to animal research. It then offers a comparison as to how both ethical systems function within the field of animal research and explores the implications in their application on its practice.

Fitness to stand trial : how discourses of rationality, reasonableness and culpability inform the law and psychiatry to create standards of normal

The objective of this thesis is to demonstrate the importance of the concepts of rationality, reasonableness, culpability and autonomy that inform and support our conception of both the person and the punishable subject. A critical discourse analysis tracing these concepts through both the law and psychological tools used to evaluate the fitness of a person reveals that these concepts and their implied values are inconsistently applied to the mentally disordered who come into conflict with the law. I argue that the result of this inconsistency compromises a person's autonomy which is a contradiction to this concept as a foundational principle of the law. Ultimately, this thesis does not provide a solution to be employed in policy making, but its analysis leaves open possibilities for further exploration into the ways legal and social justice can be reconciled.