Expansion of the Middle Class, Consumer Credit Markets and Volatility in Emerging Countries:

Thesis advisor: Peter IrelandThe literature on real business cycles finds that one reason why emerging economies are more volatile than developed small open economies is that they face greater financial frictions. Indeed, according to several measures of financial depth and access, financial systems in emerging countries are on average less developed than those in developed small open economies. Despite the lag in financial development, private credit, particularly unsecured credit to households, has been steadily increasing during the last two decades in emerging countries in Latin America. During this period of rising credit, various countries in the region observed an increase in the size of their middle income class population and the emergence of the vendor financing channel in their consumption credit market. Estimates by the World Bank suggest that the share of middle class households increased from 20.9 % in 1995 to 40.7 % in 2010. In addition, the share of poor households was approximately halved and reached 23.4 % at the end of this 15 year period. This phenomenon not only increased credit demand but also motivated the entry of new suppliers in the consumer credit market in countries like Mexico, Colombia, Chile and Brazil. In spite of a significant decline in unemployment in recent years, the lack of formal employment and poor credit history were still impeding many individuals from gaining access to consumer finance from traditional financial institutions. In order to enable new middle class shoppers access items typically offered by large retail stores, the retailers themselves started offering credit. In this dissertation, I study the relationship between middle class size, unsecured credit markets and aggregate consumption volatility in emerging countries. In the first chapter of this thesis, we examine the link between middle class size and consumption growth volatility using a sample of middle income countries. In the second chapter, we study the effect of an expansion of the middle class on vendor financing incentives and unsecured credit supply on its extensive margin. In the third chapter, I study business cycle implications of a reduction in the share of financially excluded households in an emerging economy. In the first chapter, I empirically examine the effect of middle income class size on consumption growth volatility in emerging countries. Using a panel data of middle income countries, I find that a larger middle class size tends to increase aggregate consumption growth volatility, particularly at lower levels of financial system depth. Financial development plays a significant role in determining the sign of the marginal effect of middle class size on aggregate volatility. Unlike emerging countries, the effect of the size of the middle class and the role of financial development on consumption volatility in developed countries is ambiguous. The key message of this analysis is that as more households escape poverty thresholds and reach the middle income class status in developing and emerging economies, it becomes more important to deepen financial systems from the perspective of aggregate consumption volatility. In the second chapter, I explore through the lens of a theoretical model, potential reasons triggering an increase in credit supplied by the non traditional financial sector, i.e vendors, at the extensive margin. I find that a reduction in the average risk of default and an increase in the market size of credit customers raise vendor financing incentives. This model rationalizes the observation that the improvement of economic conditions of the low-income and financially constrained households potentially led to increased credit supply by vendors in several countries of Latin America. In the third chapter, I study business cycle implications of a decline in household financial exclusion in a dynamic general equilibrium model suitable for emerging economies. Using Mexico as a case study, I estimate the model with Bayesian methods for the period 1995 to 2014. Standard measures of predictive accuracy suggest that the extended business cycle model with limited credit market participation outperforms a model with zero financial exclusion. The results of the estimation suggest that a rise in credit market participation in an emerging economy increases aggregate volatility of key macroeconomic aggregates, and that financial frictions play a key role in this relationship. I confirm this prediction by re-estimating the model for Mexico after splitting the sample into two non- overlapping decades. A key implication derived in this chapter is that a reduction of financial exclusion within an emerging country may lead to higher consumption growth volatility and trade balance volatility, and that fewer financial frictions dampen the marginal effect. As household financial access increases in these countries, a greater need for improving broad financial development measures arises

Los “doce roles del docente de medicina”: un estudio piloto de tres universidades públicas de Paraguay

Reconocer los múltiples roles que tienen los docentes de medicina es importante para prepararlos para la compleja tarea de enseñar la ciencia médica. El objetivo de este trabajo fue determinar la importancia que dan los docentes de medicina de 3 universidades públicas de Paraguay a los “Doce roles de un docente de medicina” planteados por Harden y Crosby. Fue un estudio observacional, descriptivo, de corte transversal, con muestreo por conveniencia. Los participantes fueron docentes de Medicina, de la Universidad Nacional de Asunción, Nacional del Este y Nacional de Itapúa, con al menos 2 años de experiencia, que completaron un cuestionario que midió la importancia que dan a los doce roles del docente de medicina. Para ese fin, se utilizó una versión en español de la teoría de Harden y Crosby, traducida con autorización de sus autores. Participaron del estudio 73 docentes. La mayoría percibió su papel más importante como proveedor de información en las prácticas o en la clínica (4,68±0,57), como modelo de rol en el ámbito laboral (4,53±0,60) y en la enseñanza (4,45±0,67), y como planificador o participante en las evaluaciones del estudiante (4,41±0,62). Estos resultados nos permiten afirmar que el docente de medicina de Paraguay se ve a sí mismo como más que un instructor de clases teóricas o prácticas clínicas, sino cumpliendo muchos diferentes roles al mismo tiempo. Los docentes de medicina pueden desempeñar un papel importante en la realización de estudios de investigación pedagógica que permitan mejorar las prácticas de enseñanza y aprendizaje de la medicina

Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam.

BACKGROUND: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. METHODS: This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. RESULTS: Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. CONCLUSIONS: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00651066

Influence de la fixation protéique des inhibiteurs de la protéase du VIH (amprénavir et atazanavir) sur la variabilité de leur pharmacocinétique et conséquences pharmacodynamiques

Les inhibiteurs de la protéase du virus de l immunodéficience humaine (VIH) sont des médicaments fortement fixés aux protéines plasmatiques (orosomucoïde et albumine). L amprénavir et l atazanavir, dont l efficacité et la tolérance ont été évaluées dans les essais cliniques ANRS 104 (Puzzle-1) et ANRS 107 (Puzzle-2), ont été sélectionnés comme modèles. D une part, leur fixation protéique a été étudiée in vitro en déterminant leur pourcentage de fixation, le nombre de sites et les constantes d affinité pour les protéines fixatrices. Les sources de variation telles que les déplacements par des médicaments associés, les concentrations ou le polymorphisme de l orosomucoïde ont été analysées. D autre part, nous avons étudié l influence de la fixation protéique de l amprénavir et de l atazanavir sur leurs paramètres pharmacocinétiques et pharmacodynamiques.Protease inhibitors are highly bound to plasma proteins (orosomucoid and albumin). Amprenavir and atazanavir, which are studied in clinical trials ANRS104 (Puzzle-1) and ANRS 107 (Puzzle-2) were chosen as models. First in vitro protein binding was characterized (number of sites, constant of the drug association). The influence of combined drug and the implications of polymorphism and concentrations of orosomucoid were analysed. Second we evaluate whether plasma protein binding influence the pharmacokinetics of atazanavir and amprenavir. The virological consequences were analysed.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Place des antagonistes du co-récepteur CCR5 dans l'optimisation de la prise en charge thérapeutique des patients infectés par le VIH-1 et atteints de troubles neurocognitifs

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Niveau de preuve du suivi thérapeutique pharmacologique du lopinavir

Le lopinavir, inhibiteur de la protéase du virus de l’immunodéficience humaine (VIH), présente une variabilité pharmacocinétique importante, du fait d’un métabolisme hépatique et intestinal par le CYP3A. Les données de la littérature ont été analysées pour évaluer le niveau de preuve du suivi thérapeutique du lopinavir. Chez les patients naïfs ou prétraités, la relation entre concentrations et efficacité virologique n’a pas été mise en évidence, les concentrations obtenues chez un patient adhérent sont probablement supérieures aux concentrations virales inhibitrices. La survenue d’hyperlipidémie semble associée à des concentrations résiduelles de lopinavir > 8 000 ng/mL. Ces données permettent de proposer un niveau de preuve pour le suivi thérapeutique du lopinavir, recommandé chez les enfants, la femme enceinte, les patients en échec virologique, sous réserve que le nombre de mutations sur la protéase du virus soit < 5, en cas d’association avec des inducteurs enzymatiques, et en cas de toxicité

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

International audienceBackground and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and theABCB1 3435 C>T(rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation

Influence of Alpha-1 Glycoprotein Acid Concentrations and Variants on Atazanavir Pharmacokinetics in HIV-Infected Patients Included in the ANRS 107 Trial▿

Atazanavir is an HIV-1 protease inhibitor with high protein binding in human plasma. The objectives were first to determine the in vitro binding characteristics of atazanavir and second to evaluate whether plasma protein binding to albumin and alpha-1 glycoprotein acid (AAG) influences the pharmacokinetics of atazanavir in HIV-infected patients. For the in vitro study, atazanavir protein binding characteristics were determined in AAG- and albumin-containing purified solutions. Atazanavir was found to bind AAG on a high-affinity saturable site (association constant, 4.61 × 105 liters/mol) and albumin on a low-affinity nonsaturable site. For the in vivo study, blood samples from 51 patients included in trial ANRS 107—Puzzle 2 were drawn prior to drug intake at week 6. For 10 patients included in the pharmacokinetic substudy, five additional blood samples were collected during one dosing interval at week 6. Atazanavir concentrations were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Albumin concentrations, AAG concentrations, and phenotypes were also measured in these patients. Concentrations of atazanavir were modeled using a population approach. A one-compartment model with first-order absorption and elimination best described atazanavir pharmacokinetics. Atazanavir pharmacokinetic parameters and their interindividual variabilities were as follows: absorption rate constant (ka), 0.73 h−1 (139.3%); apparent clearance (CL/F), 13.3 liters/h (26.7%); and apparent volume of distribution (V/F), 79.7 liters (27.0%). Atazanavir CL/F decreased significantly when alanine aminotransferase and/or AAG levels increased (P < 0.01). The ORM1*S phenotype also significantly increased atazanavir V/F (P < 0.05). These in vivo results indicate that atazanavir pharmacokinetics is moderately influenced by its protein binding, especially to AAG, without expected clinical consequences