Doctor Pharmaceuticae - Dpharm / The use of efavirenz (EFV) in the first trimester of pregnancy remains controversial. In South Africa, the use of EFV-containing antiretroviral therapy (ART) as part of a Fixed Dose Combination (FDC) during the first trimester of pregnancy started in April, 2013. Literature to date has reported conflicting outcomes following the use of EFV-containing ART during the first trimester of pregnancy. The objectives of the study were to determine the prevalence of adverse pregnancy outcomes among HIV-positive pregnant women treated with EFV-containing ART and compare these results with those of pregnant women treated with NVP-containing ART and HIV-negative pregnant women in resource-limited settings. In addition, the study also aimed to determine the effect of the time of initiation of ART on the prevalence of adverse pregnancy outcomes.

Submitted by Paulo Junior (paulo.jr@fgv.br) on 2010-05-13T21:02:37Z No. of bitstreams: 1 Cláudia Hoirisch.pdf: 1193444 bytes, checksum: 18921b0201a6008cb606c1dcc39797a0 (MD5) / Approved for entry into archive by Paulo Junior(paulo.jr@fgv.br) on 2010-05-13T21:03:02Z (GMT) No. of bitstreams: 1 Cláudia Hoirisch.pdf: 1193444 bytes, checksum: 18921b0201a6008cb606c1dcc39797a0 (MD5) / Made available in DSpace on 2010-05-14T12:29:32Z (GMT). No. of bitstreams: 1 Cláudia Hoirisch.pdf: 1193444 bytes, checksum: 18921b0201a6008cb606c1dcc39797a0 (MD5) Previous issue date: 2010-03-24 / The scope of this study is to evaluate the implementation process of the Compulsory License in the case of the antiretroviral efavirenz. This research is descriptive in nature and the medium of investigation was the case study. It was conducted during the months of October through December 2009 with semi-structured interviews containing open-ended questions with a group of Public Health policy makers and managers residing in the states of Rio de Janeiro, Sao Paulo and the Federal District who participated in the compulsory license process. These individuals were allowed to express themselves without any constraints in such a way that they could produce discourses. The Collective Subject Discourse (CSD) technique was then used for analysis of the discourses. The results revealed that Brazil has the technological capability to develop and produce antiretrovirals within a reasonably short period of time. The results further showed that the Compulsory License helped to curb spending on antiretrovirals and that the measure can be used to ensure access by the public to high-cost and strategic antiretroviral drugs for the Brazilian public health service (Unified Health System – SUS) in an environment with limited funds, whenever an impasse is reached in negotiations for price reductions with transnational pharmaceutical laboratories. / O objetivo deste estudo é avaliar o processo de implementação da Licença Compulsória no caso do anti-retroviral efavirenz. Esta pesquisa é de caráter descritivo, o meio de investigação foi o estudo de caso e foi conduzido com entrevistas semi-estruturadas contendo questões abertas para um conjunto de atores representativos da área da Saúde Pública que participaram do processo da licença compulsória residentes nos estados do Rio de Janeiro e São Paulo e no Distrito Federal durante os meses de outubro a dezembro de 2009. Permitiu-se que esses indivíduos se expressassem mais ou menos livremente de forma que eles produzissem discursos. Para a análise dos discursos, utilizou-se a técnica do Discurso do Sujeito Coletivo (DSC). Os resultados demonstraram que o Brasil possui capacitação tecnológica para desenvolver e produzir anti-retrovirais em um prazo relativamente curto. Os resultados mostram ainda que a Licença Compulsória ajudou a refrear os gastos com anti-retrovirais e que o instrumento pode ser utilizado para garantir o acesso da população a medicamentos anti-retrovirais de alto custo e estratégicos para o Sistema Único de Saúde em um ambiente de recursos limitados sempre que se chegar a um impasse na negociação para redução de preços com os laboratórios farmacêuticos transnacionais.

Bakgrund: Det finns läkemedel som ger ökad risk för vitamin D-brist. En kartläggningsstudie av hur patientgrupper med olika riskläkemedel hanteras i Landstinget i Kalmar län har inte gjorts tidigare. En sådan studie är önskvärd, för att få en nulägesanalys och öka medvetenheten bland hälso-och sjukvårdspersonal om hur läkemedel påverkar D-vitaminstatus. Syfte: Syftet var att undersöka omfattningen av ordinerade riskläkemedel hos samtliga patienter, samt hos patientgruppen ≥75år och hur dessa handläggs avseende ordination av supplementering (samtidig behandling med läkemedel innehållande vitamin D3 / kalcium och vitamin D3,), provtagning och analysresultat avseende kalcidiol i serum. Metod: Riskläkemedel för vitamin D-brist identifierades. Inklusionskriterier för studien var patienter med de fördefinierade riskläkemedlen med ordinationer under 2012 och/eller 2013. Populationen som ingick i studien var patienter i Landstinget i Kalmar län. Data hämtades från patientdatasystemet Cambio Cosmic. Utifrån dessa data analyserades förekomst av supplementering, provtagning för S-25(OH)D kalcidiol och analyssvar. Materialet strukturerades efter respektive läkemedel avseende kön och ålder (≥75 år.) Resultat: 9118 individer ordinerades något av riskläkemedelen orlistat, sevelamer, kolestyramin, kolestipol, efavirenz, prednison, prednisolon, fenytoin, fenobarbital eller karbamazepin. 31% av patienterna som ordinerats riskläkemedel var ≥75 år. Totalt behandlades 22% med supplementationspreparat av de som ordinerats riskläkemedel. I åldersgruppen ≥75 år behandlades 43% med supplement. 61% av de supplementerade patienterna var ≥75 år. Totalt provtogs enbart 4,1% avseende kalcidiol av de som ordinerats riskläkemedel. Av dessa hade 37% av de provtagna en bristnivå av S-25(OH)D (≤50 nmol/L) vid första provtillfället. 57% av de som visade brist supplementerades. Endast 8,3% av de som hade en brist följdes upp med ytterligare en eller flera provtagningar. Av patienterna ≥75 år provtogs 4,1% av patienterna i åldersgruppen. Detta innebär att 31% av de som provtogs var ≥75år. 39% led brist. Av de patienter ≥75 år som hade led brist supplementerades 65% av individerna. Konklusion: Det finns förbättringsutrymme för implementering av kunskap kring riskläkemedel i Landstinget i Kalmar län. / Introduction: Some drugs increase the risk for vitamin D deficiency. To date, no survey has been performed in Kalmar County about how patients medicated with risk pharmaceuticals are handled. Such a survey would be desirable in order to increase knowledge among healthcare workers about how substances interfere with vitamin D status. Aim: The aim was to examine the extent to which risk pharmaceuticals are prescribed among all patients and among patients aged ≥75, and to investigate how these patients are treated with respect to supplementation (drugs containing vitamin D3 / Calcuim and vitamin D3), blood sampling and analysis of serum calcidiol levels. Method: Drugs interfering with vitamin D were identified. Inclusion criteria for the survey were patients that had been prescribed the pre-defined risk pharmaceuticals during 2012 and/ or 2013. The surveyed population was residents in Kalmar County. Data were collected from the patient database Cambio Cosmic. From these data analyzes were made about the occurrence of: supplementation, sampling of S-25(OH)D calcidiol and test results. The collected data were arranged by substance, gender and age (elderly aged ≥75). Results: 9118 patients were prescribed at least one of the risk pharmaceuticals; orlistat, sevelamer, cholestyramine, colestipol, efavirenz, prednisol, prednison, phenytoin, phenobarbital or carbamazepine. 31% of these were aged ≥75. Overall, 22% of the patients were prescribed supplements. Out of these, 61% were elderly. Among the patients that had been prescribed risk pharmaceuticals a minority, 4,1% of the patients were sampled for calcidiol. 37% of these had deficiency in S-25(OH)D (≤50 nmol/L). 8.3% of patients with a vitamin D deficiency were sampled more than once. Out of the patients with deficiency 57% were treated with supplements. Out of the elderly patients prescribed risk pharmaceuticals, 4.1% of the patients were tested for calcidiol. This means that 31% of the tested patients were aged ≥75 and 39% of these had a deficiency. Out of the elderly patients with deficiency, 65% were treated with supplements. Conclusion: In Kalmar County, much can be done in order to better implement the existing knowledge about drugs that increase the risk for vitamin D deficiency. / Betydelsen av bra D-vitaminstatus för äldres hälsa – Hur stor är förekomsten av D-vitaminbrist hos äldre i Kalmar län och hur påverkar läkemedel D-vitaminstatus

Indiana University-Purdue University Indianapolis (IUPUI) / The antiretroviral drug efavirenz remains a cornerstone for treatment-naïve HIV patients. Subsequent to the demonstration that efavirenz is a substrate of cytochrome P450 (CYP) 2B6, a number of clinical studies found that the CYP2B6*6 allele is significantly associated with higher efavirenz exposure and/or adverse reactions. However, the mechanism of reduced efavirenz metabolism by this genetic variant is not fully understood and whether this variant exhibits differential susceptibility to metabolic inhibition is also unknown. Ths use of efavirenz is further complicated by the drug interactions associated with it. Therefore, I hypothezised that 1) the CYP2B6*6 allele reduces efavirenz metabolism by altering catalytic properties of CYP2B6; 2) efavirenz alters the pharmacokinetics of co-administered drugs by inhibiting drug metabolizing enzymes. A series of studies was carried out in hepatic microsomal preparations to determine the functional consequences of the CYP2B6*6 allele and to assess inhibition potency of efavirenz on 8 CYPs. The major findings for these studies include: 1) the CYP2B6*6 allele reduces efavirenz metabolism by decreasing substrate binding and catalytic efficiency; 2) functional consequences of the CYP2B6*6 allele appear to be substrate- and cytochrome b5-dependent; 3) the CYP2B6*6 allele confers increased susceptibility to metabolic inhibition; and 4) efavirenz inhibits the activities of CYP2B6, 2C8, 2C9 and 2C19 at therapeutically relevant concentrations. In addition, I explored the hypothesis that the incorporation of in vitro mechanism by which the CYP2B6*6 allele reduced efavirenz metabolism predicts the genetic effect of this allele on efavirenz clearance after a single oral dose by modeling approach. A pharmacogenetics-based in vitro-in vivo extrapolation (IVIVE) model was developed to predict human efavirenz clearance. Taken together, results from this dissertation provide new mechanistic information on how the CYP2B6*6 allale alters substrate metabolism and drug interactions; demonstrate new mechanisms of efavirenz-mediated inhibition interactions; and demonstrate the utility of a pharmacogenetics-based predictive model that can serve as a basis for future studies with efavirenz and other CYP2B6 substrates. Overall these data provide improved understanding of genetic and non-genetic determinant of efavirenz disposition and drug interactions associated with it.

PhD. (Department of Biotechnology, Faculty of Applied and Computer Sciences), Vaal University of Technology. / South Africa utilises more antiretroviral (ARV) compounds per capita than any other nation in the fight against Human Immune Deficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS). Considering the main entrance pathways of antiviral drugs into the urban water cycle, excretions via urine or faeces from treated individuals play a dominant role. Due to the limited efficiency of conventional biological treatment (activated sludge), ARVs were detected in South African wastewater treatment plant effluents and surface waters. This poses a threat to aquatic environments due to the toxicity of ARVs and can be a potential contributor to ARV resistance due to persistent low level ARV exposure in the general population. This study investigated the efficacy of a moving bed biofilm reactor (MBBR) for ctybtri8nthe elimination of five ARV compounds i.e., tenofovir, emtricitabine, nevirapine, ritonavir and efavirenz from synthetic wastewater. Furthermore, the study also looked at the shift in microbial community compositions of biofilms in the MBBR due to exposure to the ARV compounds. Lastly, the ecotoxicity of the MBBR’s influent and effluent along with the actual ARV compounds were examined. The capacity of ARV degradation by the MBBR was investigated by spiking synthetic wastewater influent with 10 μg/L of five ARV compounds. Actual removal during treatment was assessed by sampling the inlets and outlets of the reactor. A targeted solid phase extraction method with Ultra High Pressure Liquid Chromatography coupled to quadrupole time of flight mass spectrometry (LC-MS/MS) was used to quantify the five ARV compounds. Microbial diversity (alpha-diversity) of seeded sludge from a full-scale municipal WWTP and biofilm samples from a laboratory scale MBBR system during pre- and post-introduction of ARV compounds was investigated by Illumina sequencing of the 16S rRNA gene. Ecological toxicity of the MBBR’s influent and effluent along with the five ARV compounds was determined using the Vibrio fischeri, Daphnia magna and Selenastrum capricornutum toxicity test kits and measured as EC50. After MBBR treatment; Nevirapine, Tenofovir, Efavirenz, Ritonavir and Emtricitabine all showed marked reduction in concentration between the influent and effluent of the MBBR. On average, the percentage removed for Nevirapine, Tenofovir, Efavirenz, Ritonavir and Emtricitabine was 62.31%, 74.18%, 93.62%, 94.18% and 94.87% respectively. Microbial diversity results demonstrated that the introduction of antiretroviral drugs affects the bacterial community composition and diversity considerably. For instance, Nitrosomonas, Nitrospira and Alicycliphilus were found to be higher in post introduction of ARV compounds biofilm samples than in biofilm samples before the introduction of ARV compounds. The EC50 for Tenofovir, Emtricitabine, Nevirapine, Ritonavir and Efavirenz were 82.5, 41.7, 39.3, 60.3 and 0.21 mg/L respectively for S. capricornutum; 81.3, 50.7, 49, 87.1 and 0.43 mg/L respectively for D. magna; and 73.5, 55.1, 41.3, 83.6 and 0.55 mg/L respectively for V. fischeri. The EC50 of the influent and effluent were found to be above 100% concentration, therefore they could not be specifically determined. The ecotoxicity results show that ARV compounds are potentially toxic to the environment, with efavirenz being more toxic than the other four ARV compounds tested. Since there were no toxic effects observed from the effluent, it can be assumed that mineralisation has occurred, or the transformation products are of less or equal toxicity to the influent (because the influent did not show any toxic effects to the model organisms tested).