1,888 research outputs found
Rapport d'activité de la section Sciences de la Terre
No full textBrun Patrick. Rapport d'activité de la section Sciences de la Terre. In: Bulletin mensuel de la Société linnéenne de Lyon, 71ᵉ année, n°6, juin 2002. p. 232
Les collections des sciences de la terre à la Société Linnéenne de Lyon
No full textBrun Patrick. Les collections des sciences de la terre à la Société Linnéenne de Lyon. In: Bulletin mensuel de la Société linnéenne de Lyon, hors-série numéro 1, 2009. Linné et le mouvement linnéen à Lyon. pp. 135-136
J.-B. Bossuet. Politics drawn from the Very Words of Holy Scripture. Translated and edited by Patrick Riley
No full textLe Brun Jacques. J.-B. Bossuet. Politics drawn from the Very Words of Holy Scripture. Translated and edited by Patrick Riley. In: Revue de l'histoire des religions, tome 208, n°3, 1991. pp. 347-348
J.-B. Bossuet. Politics drawn from the Very Words of Holy Scripture. Translated and edited by Patrick Riley
No full textLe Brun Jacques. J.-B. Bossuet. Politics drawn from the Very Words of Holy Scripture. Translated and edited by Patrick Riley. In: Revue de l'histoire des religions, tome 208, n°3, 1991. pp. 347-348
Biological and pharmacological investigations of novel diamidines in animal models of human African trypanosomiasis
No full text"African sleeping sickness, also called human African trypanosomiasis (HAT), results from the infection of humans with either of two protozoan parasites, Trypanosoma brucei gambiense and T. b. rhodesiense. HAT is transmitted by tsetse flies (Glossina spp) and, like the vector, is found exclusively in Africa between the latitudes 14° North and 29° South. A total of 50 million people live in foci where active transmission is possible and are therefore at risk of infection; however, the annual incidence and estimated prevalence currently stand at 7139 and 30 000 cases respectively. When trypanosomes are inoculated into a human host, the resulting clinical disease is classified into a first (early) stage in which trypanosomes are localised within the haemo-lymphatic system and a second (late) stage in which trypanosomes have crossed the blood brain barrier (BBB) and invaded the central nervous system (CNS). Currently, pentamidine and suramin are used to treat the first stage of T. b. gambiense and T. b. rhodesiense HAT, respectively. On the other hand, eflornithine and the nifurtimox eflornithine combination therapy (NECT) are the prefered treatments for second stage T. b. gambiense HAT. The organoarsenic drug melarsoprol may be used for both forms of HAT but is mainly used against T. b. rhodesiense. Clearly, the therapeutic options for HAT are very limited. In addition, available drugs are associated with different levels of toxicity, especially melarsoprol which causes a post treatment reactive encephalopathy (PTRE) in 5-10% of treated patients, up to 50% of PTRE patients may die. There are also reports of high melarsoprol treatment failure rates in some foci and there is a lack of easy to use oral formulations for all the drugs. We have carried out biological and pharmacological investigations of potential new drug candidates in animal models of HAT with the objective of contributing to the development of safe, efficacious and easy to use treatments for HAT. The studies were carried out in the context of a PhD programme at the Swiss TPH/University of Basel and were anchored onto an ongoing diamidines development project of the Consortium for Parasitic Drug Development (CPDD). Vervet monkeys (Chlorocebus [Cercopithecus] aethiops) were the main model for this study. To prepare for the studies in monkeys, one prodrug (DB289) was evaluated in mouse models of first stage HAT. We obtained good activities against different trypanosome isolates, including the one that is used in the monkey model, T. b. rhodesiense KETRI2537. We further evaluated the metabolism of the prodrugs in monkey liver microsomes. In all cases, prodrugs were metabolized to generate expected intermediate and active metabolites, thus allowing us to proceed to test the compounds for safety in un-infected monkeys. We determined that in monkeys: i) diamidine toxicity was dependent on the dose and duration of dosing, ii) the plasma concentrations of active metabolites were potentially therapeutic for HAT, and iii) the dose level at which there were no observed adverse effects (NOAEL). Three prodrugs (DB289, DB844 and DB868) and one active compound (DB829) were subsequently evaluated for efficacy at dose rates that were equal or below NOAEL. In general, the prodrugs were highly active against first stage HAT after oral administration and one prodrug (DB844) had additionally an improved activity (43%) in the second stage monkey HAT model in comparison with pentamidine (0%). The intramuscularly administered parent compound DB829 was fully curative in the second stage HAT model at 2.5 mg/kg x 5 days. Our findings suggest that the two compounds (oral DB868 and intramuscular DB829) should be recommended to enter the regulatory phase of development as potential HAT drugs. Oral DB868 cured the first stage HAT model at a daily dose of 3 mg/kg for 7 days (cumulative dose, CD = 21 mg/kg) compared to a maximum tolerated daily dose of 30 mg/kg for 10 days (CD = 300 mg/kg). The efficacy, safety and pharmacokinetic profiles suggest that this compound would be a useful clinical candidate using an optimal dosing duration of 5-7 days. The second compound, intramuscular DB829, cured the second stage HAT model at a daily dose of 2.5 mg/kg for 5 days and was tolerated at 5 mg/kg for 5 days (CD = 25 mg/kg). Pharmacokinetic analysis indicated the intramuscular administration of DB829 resulted in better systemic bioavailability, thus accounting for the improved efficacy in comparison with oral dosing.
Testing regimes: introducing cross-national perspectives on language, migration and citizenship
No full textOne of the most pressing issues in contemporary European societies is the need to promote integration and social inclusion in the context of rapidly increasing migration. A particular challenge confronting national governments is how to accommodate speakers of an ever-increasing number of languages within what in most cases are still perceived as monolingual indigenous populations. This has given rise to public debates in many countries on proposals to impose a requirement of competence in a ‘national’ language and culture as a condition for acquiring citizenship. These debates in turn have revealed an urgent need to develop a fuller conceptual and theoretical basis than is currently available for the widespread public discussion of the linguistic and cultural requirements being proposed as elements in the gate-keeping process leading to the achievement of citizenship in many EU member states. The controversial nature of such policy proposals and their potentially far-reaching consequences are often highlighted in public debates on social inclusion and integration. This however is frequently conducted almost entirely at a national level within each state, with little if any attention paid either to the broader European context or to comparable experience in other parts of the world. At the same time, further EU enlargement and the ongoing rise in the rate of migration into and across Europe suggest that the salience of these issues is likely to continue to grow. This volume focuses on these debates and seeks to problematise many existing definitions regarding language and citizenship and to challenge some of the assumptions underlying the new ‘testing regimes’. The introductory chapter constructs a context and a framework for the discussion in the following chapters
In vitro studies and in vivo evaluation of novel diamidines for 2nd stage sleeping sickness
No full textSummary:
African sleeping sickness is one of the most neglected tropical diseases. Transmitted by the tsetse fly it exclusively occurs in sub-Saharan Africa. It is caused by two different parasite subspecies causing two different forms of African sleeping sickness. Trypanosoma brucei gambiense is prevalent in West and Central Africa while Trypanosoma brucei rhodesiense is prevalent in East and South Africa. Sleeping sickness is classified in two main stages. In the first stage, the parasites reside in the lymph and blood system. In the second stage, the parasites additionally infect the brain. Untreated sleeping sickness is fatal. Drugs are available for this fearsome disease, however, most of them are old and have many drawbacks, such as severe adverse effects, treatment failures and complicated treatment schedules, which is a problem in remote rural areas where the disease primarily occurs.
African sleeping sickness is a communicable disease that can be controlled. In 1998, there were an estimated 300,000 cases. By 2012 the prevalence has decreased to about 30,000, by different control measures such as vector control, improved surveillance and free drug distribution. Elimination seems possible, but safe and effective drugs are needed to reach this goal. One of the current drugs is the diamidine pentamidine which is in use since the early 1940s. However, it works only in patients with first stage disease and it has to be injected.
The Consortium for Parasitic Drug Development (CPDD) was founded in the year 2000 to find novel diamidines with better characteristics than the existing drugs. We improved oral absorption, which makes it possible to use pills instead of injections, and central nervous system (CNS) penetration. One compound (pafuramidine) has been tested in patients with first stage infections. It was the first compound that cured sleeping sickness orally, which is of great help for rural areas. Unfortunately, pafuramidine caused kidney and liver problems, and it did not cure second stage infections. In the meantime, we have identified superior compounds especially for the second stage.
As described in Chapter 3, two compounds, the prodrugs DB868 and DB844, given orally, cured all mice with CNS infections. However, both prodrugs were too toxic at the high doses required to cure both stages in monkeys. Nevertheless, DB868 is a good candidate drug to cure first stage sleeping sickness by an oral treatment, as demonstrated in mice and monkeys with first stage infections. Chapter 4 shows data of another CNS potent prodrug, DB1227 which was, however, less effective than DB868 in CNS infected mice.
Chapters 3, 7, 8 and 9 deal with two unmasked diamidines, DB829 and 28DAP010, which were highly effective in mice with second stage infections after i.p. injection. This was unexpected since diamidines are rather unlikely to cross the blood brain barrier in sufficient concentrations by diffusion. These two diamidines may penetrate into the brain by specific transporter proteins. The advantage of the two diamidines is that both cure with a short treatment course which could shorten the time of hospitalization of the patients. We have already tested DB829 in monkeys with promising results. It was safe and effective at low doses and a short treatment schedule in monkeys with second stage disease. 28DAP010 seems to be similarly effective as DB829 on both T. brucei subspecies in vitro and in mouse models.
In Chapter 6 we established a new in vitro method to measure the kinetics of drug action on pathogenic protozoa on a real time basis. We exploited the capacity of viable cells to produce heat and measured the heat flow using microcalorimetry. 28DAP010 inhibited the heat production of trypanosome cultures faster than DB829. The parasite clearance time of 28DAP010 was also faster than of DB829 in mice. The required effective treatment duration was still similar in mice with single dose for first stage and 5 days for second stage infections.
Upcoming efficacy studies will reveal if 28DAP010 is as curative in monkeys as DB829 and toxicity studies of 28DAP010 and DB829 side by side will shed light on their toxicity profile. These studies will help to select the better of these two compounds as a clinical drug candidate for the treatment of second stage sleeping sickness. ---------- Zusammenfassung: Die Afrikanische Schlafkrankheit ist eine Tropenkrankheit, welche durch die Tsetsefliege übertragen wird und daher ausschliesslich im tropischen Afrika vorkommt. Sie gehört zu den vernachlässigsten Krankheiten überhaupt und wird deshalb auch “vergessene Seuche“ genannt. Der Erreger ist ein einzelliger Parasit. Es gibt zwei verschiedene Unterarten, die zu etwas unterschiedlichen Schlafkrankheitsformen führen. Ohne wirksame Medikamentenbehandlung sind beide Formen tödlich. Trypanosoma brucei gambiense kommt nur in West- und Zentralafrika vor, während Trypanosoma brucei rhodesiense in Ost- und Südafrika zu finden ist. Der Krankheitsverlauf kann in zwei Stadien unterteilt werden. Im ersten Stadium findet man die Parasiten im Blut- und Lymphsystem und im zweiten Stadium zusätzlich im Gehirn. Zwar gibt es für diese Krankheit Medikamente, jedoch sind die meisten davon veraltet, haben ausgeprägte Nebenwirkungen und sind wegen Rückfällen oder der komplizierten und aufwendigen Behandlung problematisch.
Die Bekämpfung der Afrikanischen Schlafkrankheit ist möglich. 1998 gab es geschätzt etwa 300.000 Krankheitsfälle. Durch verbesserte Überwachung mit anschliessender medizinischer Behandlung der Infizierten, kostenlose Medikamentenverteilung und Vektorkontrolle, liess sich die Krankheit auf etwa 30.000 Krankheitsfälle im Jahr 2012, eindämmen. Für eine Eliminierung sind wirksame und verträgliche Medikamente notwendig. Ein Diamidin, das schon seit den frühen 40-er Jahren eingesetzt wird ist Pentamidin. Es wirkt noch heute, aber nur in Patienten die sich im ersten Stadium befinden, zudem muss es injiziert werden.
Im Jahr 2000 wurde das Konsortium CPDD, für die Entwicklung neuer Wirkstoffe zur Behandlung parasitärer Erkrankungen, vor allem für die Schlafkrankheit, gegründet. Neuartige Diamidine mit verbesserten Eigenschaften wurden gesucht und es war uns möglich, die orale Bioverfügbarkeit und die Bluthirnschrankengängigkeit, chemisch zu verbessern. Pafuramidin, war einer der neuen Wirkstoffe, das erste oral einzunehmende Medikament gegen Schlafkrankheit, das im Menschen getestet wurde. Ein orales Medikament hat grosse Vorteile für diese Krankheit, die hauptsächlich in abgelegenen Gebieten Afrikas vorkommt, wo ein ausgebautes Gesundheitssystem oft fehlt.
Pafuramidin heilte nur das erste Schlafkrankheitsstadium und dabei wurden Leber- und Nieren-Unverträglichkeiten festgestellt. Während der klinischen Studie testeten wir weitere Diamidine und fanden verbesserte Substanzen, vor allem bezüglich der Wirksamkeit des zweiten Krankheitsstadiums. Kapitel 3 und 4 beschreibt die wirksamsten Moleküle, die das Zweitstadium bei oraler Verabreichung heilten. Diese Moleküle, DB844, DB868, DB1227, aber auch das Pafuramidin sind Medikamenten-vorstufen (Prodrugs). Diese wurden entwickelt, um die orale Aufnahme und Gehirn-gängigkeit zu verbessern. Die aktivsten waren DB868 und DB844 in Mäusen, jedoch zeigten beide Moleküle toxische Wirkungen im Affen ohne dabei ausreichend die Gehirninfektion zu heilen. Dennoch war DB868 im Affenmodell deutlich besser verträglich als Pafuramidin und ist somit ein guter Ersatzkandidat für eine orale Wirkstoffentwicklung fürs erste Stadium.
Unerwartet konnten wir jedoch zwei Diamidine (ohne Vorstufenergänzung) identifizieren, die ebenfalls Mäuse mit Gehirninfektionen heilten. Da Diamidine unter physiologischen Bedingungen protoniert sind, ist es unwahrscheinlich, dass sie durch die Bluthirnschranke diffundieren. Möglicherweise werden sie über spezifische Mechanismen ins Gehirn transportiert. Kapitel 3, 7, 8 und 9 befassen sich mit den beiden aktivsten Diamidinen, DB829 und 28DAP010. Ihre hohe Wirkung und die kurze Behandlungszeit nach parenteraler Verabreichung (i.p. oder i.m) sind vielversprechend. DB829 war gut verträglich und wirksam bei niedrigen Dosen und heilte die infizierten Affen mit dem zweiten Krankheitsstadium bereits bei einer 5-tägigen Behandlung. In vitro und im Mausmodel war 28DAP010 auf beide Trypanosomen Unterarten ähnlich wirksam wie DB829.
Um die Wirkungszeit neuer Substanzen auf Trypanosomen zu testen, entwickelten wir eine neue Methode, die in Kapitel 6 beschrieben wird. Dabei nutzten wir die Eigenschaft der Zellen, Wärme zu produzieren und massen diese mit einem Kalorimeter auf Echtzeit. 28DAP010 reduzierte die Wärmeentwicklung einer Trypanosomenkultur deutlich schneller als DB829. Auch in infizierten Mäusen wirkte 28DAP010 schneller. Die Behandlungsdauer und Dosierung war bei beiden Diamidinen trotzdem vergleichbar. Eine Einzeldosis heilte das erste und eine 5-tägige Behandlung das zweite Stadium in Mäusen.
Weitere Studien sind nötig, um die Wirksamkeit von 28DAP010 im Affenmodel zu überprüfen und die Verträglichkeit beider Diamidine zu analysieren. Diese Ergebnisse werden zeigen, welches der bessere klinische Kandidat für die Behandlung des zweiten Schlafkrankheitsstadiums sein wird
Charles-Augustin Sainte-Beuve, Le Cahier brun (1847-1868)
No full textPatrick Labarthe presenta in questo volume un’accurata edizione critica del Deuxième cahier o Cahier brun di Sainte-Beuve, pubblicato qui per la prima volta nella sua interezza, riproducendo il manoscritto del Fond Lovenjoul della Biblioteca dell’Institut de France. «Ensemble d’observation prenant la suite du Cahier vert, s’étendant sur plus de vingt ans», il testo presenta una cronologia irregolare, con ellissi e concentrazioni che seguono – come scrive Labarthe nella préface (Les Meubles du..
Os guerreiros do imaginário: Entrevista de Abdellatif Chaouite com Patrick Chamoiseau
No full textTradução de uma entrevista com Patrick Chamoiseau, por Abdellatif Chaouite realizada na ação « Fazer o mundo com o Outro », iniciada pela Maison des Passages (Lyon) no contexto do Contrato Urbano de Coesão Social, publicada no periódico Ecarts d'identité, Grenoble: n°112, p. 25-34, junho, 2008.</jats:p
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