Acquired Immunodeficiency Syndrome (AIDS) is characterized by the progressive destruction of a person’s immune system and is the latest and most serious stage of Human Immunodeficiency Virus (HIV) infection. Botswana currently has the highest estimated prevalence of HIV infection in the world. Botswana has a relatively young population structure, with about 60% of the approximately 1,8 million people aged less than 45 years. HIV prevalence for pregnant women aged 15–45 years in Botswana did, however, decrease marginally from 36,2% in 2001 to 35,4% in 2002. It is estimated that about 258 000 Botswana are now living with HIV and AIDS, and high morbidity and mortality rates due to HIV/AIDS have seen Botswana slip down the United Nations Development Plan (UNDP) Human Development Index rankings from 71 in 1996, to 122 in 1999/2000. In 2002 Botswana initiated public antiretroviral therapy (ART) at four sites initially to provide treatment to HIV/AIDS patients before expanding the programme to the rest of the country. The specific objective of the study was to investigate the prescribing patterns of ARV drugs at Sekgoma Memorial Hospital ARV therapy clinic (SMH–IDCC) in the central district of Botswana for a two–year period from 2005 to 2006. Data from 1717 patients were obtained from the SMH–IDCC electronic database regarding ARV drugs prescribed during the study period, CD4–Tcell count (cells/?L) at the commencement of therapy and after six months from the commencement of therapy and side effects necessitating change of therapy for the study period 2005 until 2006. The study showed that there were eight antiretroviral therapy (ART) regimens prescribed: zidovudine plus lamivudine plus efavirenz (AZT/3TC/EFV), zidovudine plus lamivudine plus nevirapine (AZT/3TC/NVP), Combivir® plus efavirenz (CBV/EFV), Combivir® plus nelfinavir (CBV/NFV), Combivir® plus nevirapine (CBV/NVP), stavudine plus lamivudine plus efavirenz (D4T/3TC/EFV), stavudine plus lamivudine plus nelfinavir (D4T/3TC/NFV), and stavudine plus lamivudine plus nevirapine (D4T/3TC/NVP). The most prescribed ART regimen for adult patients was Combivir® plus efavirenz (CBV/EFV) (51,37%). This was broken down as 17,20% of females and 34,17% of males. The second most prescribed ART regimen was Combivir® plus nevirapine (CBV/NVP)(36% of the total study population (N=1717). This represented 34,17% of females and 1,98% of males. The most prescribed ART regimen in children was zidovudine plus lamivudine plus efavirenz (AZT/3TC/EFV) (3,73% of the total population), broken down as 1,05% of females and 2,68% of males. The second most prescribed regimen in this group was zidovudine plus lamivudine plus nevirapine (ZDV/3TC/NVP) (3,50% of total population). The findings from this study indicated that all eight the ART regimens prescribed at the study site were in accordance with the Botswana national ART guidelines. There were thirteen different types of side effects necessitating change of therapy, including pregnancy, treatment failure and poor adherence. The average CD4–Tcell count change (155.63 cells/?L, ± 204.08 cells/?L) for the study population was more than 100% after six months from commencement of therapy, indicating success of therapy in terms of CD4–Tcell count. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Acquired Immunodeficiency Syndrome (AIDS) is characterized by the progressive destruction of a person’s immune system and is the latest and most serious stage of Human Immunodeficiency Virus (HIV) infection. Botswana currently has the highest estimated prevalence of HIV infection in the world. Botswana has a relatively young population structure, with about 60% of the approximately 1,8 million people aged less than 45 years. HIV prevalence for pregnant women aged 15–45 years in Botswana did, however, decrease marginally from 36,2% in 2001 to 35,4% in 2002. It is estimated that about 258 000 Botswana are now living with HIV and AIDS, and high morbidity and mortality rates due to HIV/AIDS have seen Botswana slip down the United Nations Development Plan (UNDP) Human Development Index rankings from 71 in 1996, to 122 in 1999/2000. In 2002 Botswana initiated public antiretroviral therapy (ART) at four sites initially to provide treatment to HIV/AIDS patients before expanding the programme to the rest of the country. The specific objective of the study was to investigate the prescribing patterns of ARV drugs at Sekgoma Memorial Hospital ARV therapy clinic (SMH–IDCC) in the central district of Botswana for a two–year period from 2005 to 2006. Data from 1717 patients were obtained from the SMH–IDCC electronic database regarding ARV drugs prescribed during the study period, CD4–Tcell count (cells/?L) at the commencement of therapy and after six months from the commencement of therapy and side effects necessitating change of therapy for the study period 2005 until 2006. The study showed that there were eight antiretroviral therapy (ART) regimens prescribed: zidovudine plus lamivudine plus efavirenz (AZT/3TC/EFV), zidovudine plus lamivudine plus nevirapine (AZT/3TC/NVP), Combivir® plus efavirenz (CBV/EFV), Combivir® plus nelfinavir (CBV/NFV), Combivir® plus nevirapine (CBV/NVP), stavudine plus lamivudine plus efavirenz (D4T/3TC/EFV), stavudine plus lamivudine plus nelfinavir (D4T/3TC/NFV), and stavudine plus lamivudine plus nevirapine (D4T/3TC/NVP). The most prescribed ART regimen for adult patients was Combivir® plus efavirenz (CBV/EFV) (51,37%). This was broken down as 17,20% of females and 34,17% of males. The second most prescribed ART regimen was Combivir® plus nevirapine (CBV/NVP)(36% of the total study population (N=1717). This represented 34,17% of females and 1,98% of males. The most prescribed ART regimen in children was zidovudine plus lamivudine plus efavirenz (AZT/3TC/EFV) (3,73% of the total population), broken down as 1,05% of females and 2,68% of males. The second most prescribed regimen in this group was zidovudine plus lamivudine plus nevirapine (ZDV/3TC/NVP) (3,50% of total population). The findings from this study indicated that all eight the ART regimens prescribed at the study site were in accordance with the Botswana national ART guidelines. There were thirteen different types of side effects necessitating change of therapy, including pregnancy, treatment failure and poor adherence. The average CD4–Tcell count change (155.63 cells/?L, ± 204.08 cells/?L) for the study population was more than 100% after six months from commencement of therapy, indicating success of therapy in terms of CD4–Tcell count. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

The objective of this study was to assess levels of HAART adherence and factors affecting it. An observational, analytic, cross-sectional and quantitative study using IMB model was conducted on a randomly selected 349 HIV/AIDS patients on a HAART regimen. Data collection was done by interviewing respondents using a structured questionnaire. Both descriptive and inferential statistics used in the study. Only 80.2% of the total sample population reported a HAART adherence rate of more than or equal to 95% in this study. The findings highlight the need for on-going educational, informational and other interventions to address the knowledge, motivation and adherence behavioural skills of patients in order to improve the current levels of HAART adherence behaviour. The study also suggested the need for research into objective measures of adherence as well as longitudinal studies on adherence behaviour because strict adherence to treatment is a long-term process and not a one-time activity. / Health Studies / M.A. (Public health)

Thesis (MA )--Stellenbosch University, 2011. / ENGLISH ABSTRACT: The purpose of this thesis is to assess the impact of HIV and AIDS on democratic consolidation in two democracies in Southern Africa: Botswana and South Africa. Mattes (2003), Barnett and Whiteside (2006) and others warned that in states with high HIV infection levels, the negative impact of the pandemic - especially in terms of socio-economic conditions, budgetary pressures and a loss of human capital in the state and the economy - was potentially so great that it may affect democracy detrimentally. In contrast, some scholars, particularly Anthony Butler (2005a) and Alex de Waal (2006), contended that although the pandemic had negative effects, democracies might survive it and that in some specific ways, democratic consolidation might even benefit from the its consequences. For instance, they argued that in South Africa, the civil society response to the government’s controversial HIV and AIDS policy deepened the institutional framework of democracy. The methodology for the above comparative analysis is based on the application of a minimalist multivariate model which, following the thinking of Bratton and Van de Walle (1997) consists of both institutional and socio-economic factors. Factors are selected for their relevance to democratic consolidation, as argued by scholars such as Linz and Stepan (1996), Przeworski, Alvarez, Cheibub and Limongi (1996), Bratton and Van de Walle (1997) and Leftwich (2000). The chosen factors are the system of government (the relationship between the branches of government); the electoral system; political rights and civil liberties; economic indicators (affluence, economic growth and the reduction of inequality); human development (as measured by the United Nations Development Program) and civil society. This is a descriptive, qualitative, desktop study, using secondary literature in books, as well as articles. There is no empirical component, such as fieldwork, surveys or questionnaires. As stated below, such methodology may be used for further elaboration and refining of the findings of this desktop-based comparative analysis. The main finding is that currently, despite the cost and human implications of the disease, there are no indications that it is directly threatening to destroy the democracies of Botswana or South Africa. This finding differs from the more negative expectations of the scholars mentioned above. It is suggested that the increasing provision and effectiveness of antiretroviral treatment (ART) enables these democracies and their economies to avoid some of the ravages of the disease that seemed inevitable a few years ago. Furthermore, it is suggested that the comparative affluence of the two states in question shields them from some negative effects of HIV and AIDS and that this may be different in poorer Southern African states. This is an issue for further research. Such research should go beyond desktop research to include fieldwork and questionnaires. / AFRIKAANSE OPSOMMING: Die doel van hierdie tesis is om die impak van MIV en VIGS op demokratiese konsolidering in twee Suider-Afrikaanse demokrasieë, Botswana en Suid-Afrika, vas te stel. Mattes (2003), Barnett en Whiteside (2006) en ander het gewaarsku dat die negatiewe uitwerking van die pandemie - veral in terme van sosio-ekonomiese toestande, begrotingsdruk en ’n verlies aan menslike hulpbronne in die staat en ekonomie - potensieel so groot is dat dit demokrasie nadelig sou beïnvloed. In teenstelling hiermee het ander akademici, soos Anthony Butler (2005a) en Alex de Waal (2006), geredeneer dat demokrasieë die pandemie mag oorleef ten spyte van die negatiewe effekte wat dit wel het en dat demokrasieë selfs op sekere wyses by die gevolge daarvan mag baatvind. Byvoorbeeld, het hulle geargumenteer, in Suid-Afrika het die burgerlike samelewing se reaksie op die Mbeki-regering se kontroversiële MIV en VIGSbeleid die institusionele raamwerk van demokrasie verdiep. Die metodologie vir hierdie vergelykende analise is gebaseer op die toepassing van ’n minimalistiese multiveranderlike model. Soos gepostuleer deur Bratton en Van de Walle (1997), wat beide institusionele en sosio-ekonomiese faktore insluit. Faktore is gekies op grond van hulle relevansie tot demokratiese konsolidering (volgens vakkundiges soos Linz en Stepan (1996), Przeworski, Alvarez, Cheibub en Limongi (1996), Bratton en Van de Walle (1997) en Leftwich (2000), asook vir dié se moontlike relevansie tot demokrasieë wat spesifiek deur MIV en VIGS geaffekteer word. Die gekose faktore is die regeringstelsel (die verhouding tussen die uitvoerende, wetgewende en regsprekende gesag), die verkiesingstelsel, politieke regte en burgerlike vryhede, ekonomiese aanwysers (welvaart; ekonomiese groei en die vermindering van ongelykheid), menslike ontwikkeling (soos gemeet deur die Verenigde Nasies se Ontwikkelingsprogram) en die burgerlike samelewing. Hierdie tesis is ’n literatuurstudie van ’n beskrywende, kwalitatiewe aard. Daar is gebruik gemaak van sekondêre literatuur in boeke, asook van artikels. Daar is geen empiriese komponent soos veldwerk en meningspeilings nie. Soos hieronder beklemtoon word, kan empiriese metodes in toekomstige studies gebruik word om op die bevindinge wat hierdie navorsing opgelewer het, uit te brei en dit te verfyn. Die hoofbevinding is dat daar tans, ten spyte van die finansiële en menslike koste van MIV en VIGS, geen aanduiding is dat die siekte ‘n direkte bedreiging inhou vir die voortbestaan van demokrasie in Botswana en Suid-Afrika nie. Hierdie bevinding verskil van die meer negatiewe verwagtinge hierbo uitgespreek. Dit word voorgestel dat die toenemende voorsiening en effektiwiteit van antiretrovirale behandeling hierdie demokrasieë en hulle ekonomieë daartoe in staat stel om gedeeltelik die verwoesting van hierdie pandemie te vermy, iets wat enkele jare gelede nog as onvermydelik beskou is. Verder word die voorstel gemaak dat die impak van die pandemie op armer Suider-Afrikaanse state vergelyk behoort te word met die bevindinge wat hier aangebied word. Sulke toekomstige navorsing behoort nie net literatuurstudie in te sluit nie, maar ook veldwerk en meningsopnames.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Introduction: Since the South African public sector antiretroviral roll-out programme started in 2004, the success of antiretroviral combination therapy (cART) has been experienced in terms of survival, prevention of mother-to-child transmission (PMTCT) and quality of life. However, as the programme matures, viral resistance to the constituent drugs will increase. Monitoring antiretroviral drug resistance (ARVDR) should therefore be a priority in the public health approach to HIV treatment. Methods: A cross-sectional investigation of genotypic antiretroviral drug resistance in: a) HIV-infected mothers who were exposed to a PMTCT regimen of short course azidothymidine (AZT) with single dose nevirapine (NVP) during labour. b) HIV-infected adults and children who were cART-naïve (transmitted or initial resistance). c) HIV-infected adults and children who were failing cART (drug-induced or acquired resistance). In case of adults, this includes patients on a first-line, non-nucleoside reverse transcriptase (NNRTI)-based regimen, or on a second-line, protease inhibitor (PI)-based regimen, and in case of children, this includes patients on a first-line PI-based regimen. Results: In mothers who received a PMTCT-regimen that combined AZT and NVP the prevalence of NNRTI resistance mutations was 17.1% (95% CI: 8.7-25.6%). The prevalence of transmitted ARVDR in adults was low, as was initial ARVDR in young children (mostly PMTCT-exposed), except for NNRTI resistance in children who had received NVP as part of PMTCT. Drug-induced resistance was found in adults failing first-line NNRTI-based cART, with 83% having resistance to ≥1 drug. In contrast, adult patients failing second-line PI-based cART had a low prevalence of PI resistance; the predominant reason for failure was poor drug exposure, as detected by measuring lopinavir concentrations in blood plasma and hair samples. In contrast, PI resistance in children was not rare, largely due to historic exposure to un-boosted PIs. This resulted in extensive resistance to PIs and reverse transcriptase inhibitors (RTI) in some children. Conclusions: A combined regimen of short course AZT with intrapartum NVP for PMTCT may, in addition to reducing the risk of neonatal infection, also reduce the risk of NVP resistance in the mothers compared to a regimen of NVP only. In South Africa, the prevalence of transmitted ARVDR remains low relative to industrialised countries, probably as comparatively little time has elapsed since the scale-up of cART. Adults failing first-line cART are likely to respond to second-line cART, without failure due to resistance. However some children with PI and RTI resistance cannot be adequately treated with drugs currently available through the roll-out programme. This emphasizes the urgent need for a rational and science-based approach to managing cART-experienced children, including access to additional drugs to form a third-line paediatric cART regimen. / AFRIKAANSE OPSOMMING: Inleiding: Sedert die begin van die Suid Afrikaanse publieke sektor antiretrovirale uitrol program in 2004 is die sukses van antiretrovirale kombinasie-behandeling (k-ARB) ervaar in terme van oorlewing, voorkoming van moeder na kind oordrag (VMKO) en lewenskwaliteit. Nietemin, sal weerstandigheid teen die middels wat in die antiretrovirale program gebruik word toeneem soos wat die program gevestig raak. Die monitoring van antiretrovirale middel-weerstandigheid is derhalwe ‘n prioriteit in gemeenskap-gesondheid benadering tot MIV behandeling. Metodes: ‘n Deursnit ondersoek van genotipiese antiretrovirale middel-weerstandigheid in: a) MIV-geïnfekteerde moeders wat blootgestel is aan VMKO regimen bestaande uit ‘n kort kursus AZT met ‘n enkeldosis nevirapien (NVP) tydens kraam. b) MIV-geïnfekteerde volwassenes en kinders wat komibinasieterapie-naïef (oorgedraagde of inisiële weerstandigheid) is. c) MIV-geïnfekteerde volwassenes en kinders wat k-ARB faal (middel-geïnduseerde weerstandigheid). In geval van volwassenes, sluit dit pasiënte op ‘n eerste-linie, non-nucleosied tru-transkriptase inhibitor (NNRTI)-regimen, en tweede-linie protease inhibitor (PI)-gebaseerde regimen, en in geval van kinders, sluit dit pasiënte in op ‘n eerste-linie PI-gebaseerde regimen. Resultate: In moeders wat ‘n gekombineerde AZT en NVP VMKO-regimen ontvang het, was die voorkoms van NNRTI weerstandigheid 17.1% (95%-vertrouensinterval: 8.7-25.6%). Die voorkoms van oorgedraagde ARVMW in MIV-geïnfekteerde volwassenes en kinders wat kombinasieterapie-naïef is, was laag, so ook ARVMW in jong kinders (meestal VMKO-blootgestel), behalwe vir non-nukleosied tru-transkriptase inhibitor (NNRT) weerstandigheid in kinders wat NVP ontvang het deur VMKO. Middel-geïnduseerde weerstandigheid was gevind in volwassenes wat die eerste-linie NNRTI-gebaseerde k-ARB gefaal het, met 83% wat weerstandigheid teen ≥1 middel het. Volwassenes wat ‘n tweede-linie protease inhibitor (PI) –gebaseerde k-ARB gefaal het , het ‘n lae voorkoms van PI weerstandigheid, met die oorwegenede oorsaak, swak middel-bloostelling, soos bepaal deur van lopinavir-konsentrasies in bloed plasma en hare. In teenstelling hiermee was PI weerstandigheid nie skaars in kinders nie, hoofsaaklik weens historiese blootstelling an ongeskraagde PI-behandeling. Dit het tot uitgebreide weerstandigheid tot PIs en tru-transkritptase inhibitors (RTI) in sommige kinders gelei. Gevolgtrekkings: ‘n Gekombineerde regimen van ‘n kort kursus AZT met NVP tydens kraam vir VKMO, mag bykomend tot die vermindering die risiko van pasgebore infeksie, ook die kans vir weerstandigheid teen NVP in die moeders verlaag in vergelyking met ‘n regimen van NVP-alleen. Die voorkoms van oorgedraagde ARVMW is tans laag in vergelyking met geïndustrialiseerde lande, waarskynlik aangesien daar nog betreklik min tyd verloop het sedert k-ART wyd beskikbaar gemaak is. Volwassenes wat eerstelyn kombinasie terapie faal sal waarskynlik goed reageer op tweede-linie terapie, sonder terapie faling weens middelweerstandigheid. Daarenteen kan sommige kinders met protease inhibitor en tru-transkriptase weerstandigheid nie voldoende behandel word met die huidig-beskikbare middels in die uitrol program nie. Dit beklemtoon die dringende noodsaaklikheid van ‘n rasionele en wetenskaplike benadering tot k-ART in kinders, met ‘n lang terapie geskiedenis, wat toegang tot bykomende medikasie behels om `n derde-linie regimen saam te stel.

Este documento de Tese é o resultado de um trabalho de pesquisa voltado à análise cristalográfica de novas formas sólidas cristalinas derivadas de fármacos antirretrovirais, diante do contexto da engenharia de cristais para o desenho das novas formas sólidas, e principalmente diante da ótica da análise das densidades de carga, o que permitiu um entendimento mais acurado da estrutura eletrônica molecular desta classe de compostos. Compostos farmacêuticos antirretrovirais do tipo inibidores nucleosídeos da transcriptase reversa (INTRs), são de grande importância, uma vez que são amplamente usados na terapêutica antirretroviral, principalmente contra o vírus HIV. Nesse contexto, são conhecidos alguns problemas associados na manufatura destes fármacos, principalmente aos processos de extração e purificação dos fármacos Lamivudina (3TC) e Emtricitabina (FTC). Diante desta problemática, a engenharia de cristais fornece uma solução, mediante o planejamento racional de formas sólidas (sais, cocristais, solvatos, polimorfos, etc.) que apresentam maior estabilidade e facilitem principalmente o processo de purificação em grande escala. Daí surge a importância de estudar a estrutura molecular das diferentes formas sólidas derivadas destes fármacos, sendo uma das principais técnicas para este estudo a difração de raios X em monocristais (DRXM). Neste trabalho um total de nove novas formas sólidas foram avaliadas e reportadas, com uma discussão detalhada das conformações moleculares e supramoleculares. Entretanto, é realizada uma análise das densidades de carga mediante métodos experimentais, uma vez que foram conduzidos experimentos de DRXM em alta resolução, em virtude da boa qualidade dos cristais que algumas das formas sólidas apresentaram. Desta maneira foi possível propor modelos de densidade de carga experimentais construídos mediante o formalismo de Hansen & Coppens, utilizando refinamento por mínimos quadrados baseados nos dados de difração em alta resolução. Por último, com o intuito de ter um estudo mais completo e detalhado da estrutura eletrônica, foram realizados cálculos teóricos de primeiros princípios em condições gasosas e periódicas de contorno. Desta forma, é apresentada uma sinergia entre os resultados obtidos pelas análises das distribuições de densidade de cargas de algumas formas sólidas, com os resultados gerais da engenharia de cristais e, portanto, concluir e extrapolar alguns aspectos importantes, principalmente no que se refere às energias associadas com as interações intermoleculares. A sinergia dos estudos de engenharia de cristais e de densidade de carga, é um tipo de pesquisa pouco publicada dentro da área da cristalografia de pequenas moléculas. / This Thesis is the result of the research proposal aimed to the crystallographic analysis of new crystalline solid forms derived from antiretroviral drugs, in the context of the crystal engineering for the design of the new solid forms, mainly since the viewpoint of the charge density analysis, which allowed an accurate comprehension of the molecular electronic structure of this kind of compounds. Antiretroviral drug compounds of nucleoside analog reverse-transcriptase inhibitors (NRTI) type, are of great importance once they are large used in the antiretroviral therapy, mainly against the HIV. In this context, some problems are known regard to the manufacture process of these drugs, mainly in the extraction and purification procedures of the lamivudine (3TC) and emtricitabine (FTC) drugs. On this issue, the crystal engineering provides an answer, through the rational planning of solid forms (salts, cocrystals, solvates, polymorphs, etc.) that exhibit an increased stability and facilitate mainly the large-scale purification process. Hence is important to study the molecular structure of the diverse solid forms derived from these drugs, mainly through the single-crystal X-ray diffraction (SCXD) experiments. In this research a total of nine new solid forms were assessed and reported, along with a detailed discussion of the molecular and supramolecular conformations. Meantime, it was carried out an analysis of the experimental charge density, once it was performed high-resolution SCXD experiments, since some of the solid forms showed good quality single crystals. In this way, it was possible to propose models of experimental charge density through the Hansen & Coppens formalism, using least-square refinement against high-resolution X-ray diffraction data. Finally, with the aim to have a more complete and detailed study of the electronic structure, it was also carried out first principles theoretical calculations in gas-phase and periodic boundary conditions. Thus, it is shown a synergy between the results obtained by the analysis of the charge density distributions of some solid forms and the crystal engineering results and, therefore, to conclude and to extrapolate some important aspects, mainly involved with the intermolecular interaction energies. The synergy of the crystal engineering and charge density studies is a kind of research little published, within the small molecule crystallography area.

A Enfuvirtida(ENF), único inibidor de fusão disponível, representa uma opção interessante aos pacientes com infecção pelo HIV quando utilizada em combinação com outros antirretrovirais, principalmente no tratamento de multiexperimentados com falha virológica e poucas opções terapêuticas. Sua eficácia já comprovada em ensaios clínicos esbarra nas barreiras impostas por sua administração parenteral. Impulsionado por estes dados, avaliamos durante 48 semanas a resposta virológica, a evolução de células T CD4 a possível resistência primária a ENF e o impacto para a adesão do uso subcutâneo da droga em dez pacientes que fazem acompanhamento ambulatorial no Hospital Universitário Pedro Ernesto e que tinham história de mais de dez anos de infecção pelo HIV e uso de ENF no seu esquema terapêutico sugerido por teste de resistência. Todos os pacientes alcançaram ao final do seguimento sucesso terapêutico, mantendo carga viral não detectada, e um incremento médio significativo de linfócitos T CD4. Em relação a uma possível resistência primária, em nenhum dos testes, genotipagem da glicoproteína 41, foi visualizado mutações naturais que pudessem diminuir a ação da ENF. Sobre o manejo do medicamento, preparo e aplicação, observamos que é imprescindível um apoio multidisciplinar para que não haja descontinuação na sua utilização / Enfuvirtide (ENF) is the only fusion inhibitor available. It is an interesting option for patients with HIV infection when used in combination with other antiretroviral drugs, especially in the treatment of multi-experienced patients with virological failure and few therapeutic options. Its effectiveness confirmed in clinical trials finds the barriers in its parenteral administration. Using these data, we evaluated, for 48 weeks, the virological response, evolution of CD4 T cells, the possible primary resistance to ENF and the impact to the subcutaneous use of the drug in ten patients undergoing outpatient monitoring at Hospital Universitário Pedro Ernesto with a history of more than ten years of HIV infection and use of ENF in their therapy, as suggested by resistance testing. All patients have successfully completed the therapy by the end of follow-up with an undetected viral load and a significant average increase of CD4 T lymphocytes. As for a possible primary resistance, neither the genotyping nor the glycoprotein 41 revealed natural mutations that could diminish the effect of ENF. Concerning the management, preparation and application of the drug, we found that a multidisciplinary support is essential to avoid that the drug be discontinued

Propriedades de estado sólido estão diretamente relacionadas ao desempenho de um fármaco. Entre todas as propriedades físicas e químicas dependentes da fase cristalina de um fármaco, estabilidade e solubilidade são as que mais alteram sua biodisponibilidade. Neste sentido, a engenharia de cristais moleculares é uma estratégia para aperfeiçoar as propriedades de estado sólido relacionadas às eficácias dos fármacos. Neste trabalho, nove novas formas cristalinas de fármacos antirretrovirais inibidores nucleosídeos de transcriptase reversa, a saber, lamivudina, zalcitabina e didanosina, foram preparadas e suas estruturas cristalinas foram elucidadas por difração de raios X por monocristal. Parte das modificações cristalinas preparadas foi também caracterizada por microscopia eletrônica de varredura, difração de raios X por pó, espectroscopia vibracional no infravermelho e Raman, calorimetria exploratória diferencial e termogravimetria. As solubilidades aquosas e purezas das modificações cristalinas de lamivudina preparadas como amostras monofásicas foram determinadas por espectrofotometria de absorvância no ultravioleta e cromatografia líquida de alta eficiência, respectivamente. A solubilidade de lamivudina nas modificações cristalinas preparadas pode ser tanto aumentada quanto reduzida quando comparada com a solubilidade da fase cristalina do fármaco incorporada em formulações farmacêuticas. As solubilidades foram também correlacionadas às características estruturais e calorimétricas, o que permitiu o estabelecimento de relações entre estrutura/energia de rede cristalina e propriedade de estado sólido. Ainda, duas modificações cristalinas de lamivudina, em que moléculas do fármaco estão pareadas através de seus fragmentos de citosina, sendo estes pares helicoidalmente sobrepostos, mimetizando uma estrutura polimérica de ácido desoxirribonucléico, revelaram que nucleosídeos têm a informação estrutural necessária para arquitetar duplas hélices de ácidos nucléicos. / Solid state properties are directly related to drug performance. Among all physical and chemical properties dependent on the crystal phase of a drug, stability and solubility are the main ones that alter its bioavailability. In this way, molecular crystal engineering is a strategy to improve solid state properties of drugs related to their efficacies. In this work, nine new crystal forms of antiretroviral nucleoside reverse transcriptase inhibitor drugs, namely, lamivudine, zalcitabina and didanosine, were prepared and their crystal structures were elucidated by single crystal X-ray diffraction. Some of the prepared crystal modifications were also characterized by scanning electron microscopy, powder X-ray diffraction, infrared and Raman vibrational spectroscopy, differential scanning calorimetry and thermogravimetry. The water solubilities and purities of the lamivudine crystal modifications prepared as monophasic samples were determined by ultraviolet absorbance spectrophotometry and high performance liquid chromatography, respectively. The solubility of lamivudine in the prepared crystal modifications can be either increased or decreased when compared to the solubility of the drug crystal phase incorporated into pharmaceutical formulations. The solubilities were also correlated to calorimetric and structural features, which allowed the establishment of relationships between crystal lattice energy/structure and solid state property. In addition, two crystal modifications of lamivudine, in which drug molecules are paired through their cytosine fragments, being these pairs helically stacked, mimicking a polymeric structure of deoxyribonucleic acid, have revealed that nucleosides possess the structural information necessary to assemble double stranded helices of nucleic acids.

This thesis describes bioanalytical methods for measuring melatonin and some anti-infective drugs in biological fluids. Solid-phase extraction (SPE) or protein precipitation was used for enrichment and purification of the analytes and Liquid Chromatography (LC) was used to analyze the samples. Developed methods were validated according to international guidelines. Melatonin is a hormone secreted by the pineal gland with a robust circadian rhythm. Bioanalytical methods for determination of melatonin in plasma and saliva have been developed which were used for monitoring melatonin levels in volunteers and patients suffering from sleep related diseases. Eflornithine (DFMO) is a chiral drug used for the treatment of human African trypanosomiasis. A bioanalytical method for determination of the DFMO enantiomers in plasma, after precolumn derivatization with o-phtalaldehyde and N-acetyl-L-cystein has been developed. The method has been used to study the L- and D-DFMO pharmacokinetics, in order to investigate the possible development of an oral treatment of DFMO. A method for simultaneous determination of three antiretroviral drugs i.e. Lamivudine (3TC), Zidovudine (AZT) and Nevirapine (NVP) in dried blood spots (DBS) was developed. The method was used for drug determination in two subjects after receiving standard antiretroviral treatment. The method seemed well suitable for the determination of 3TC and NVP and in some extent for AZT. Lumefantrine (LF) is one of the active components in a new fixed drug combination recommended by the WHO as a replacement to older drugs that has lost their effect. A method for the determination of LF in DBS was developed. The method is suitable for monitoring of drug treatment in rural settings. Tafenoquine is a new promising antimalarial drug under development. A method for the determination of Tafenoquine in plasma and in DBS is described. The method may be useful in future clinical studies in laboratory environment as well as in rural settings. / Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 703

A Enfuvirtida(ENF), único inibidor de fusão disponível, representa uma opção interessante aos pacientes com infecção pelo HIV quando utilizada em combinação com outros antirretrovirais, principalmente no tratamento de multiexperimentados com falha virológica e poucas opções terapêuticas. Sua eficácia já comprovada em ensaios clínicos esbarra nas barreiras impostas por sua administração parenteral. Impulsionado por estes dados, avaliamos durante 48 semanas a resposta virológica, a evolução de células T CD4 a possível resistência primária a ENF e o impacto para a adesão do uso subcutâneo da droga em dez pacientes que fazem acompanhamento ambulatorial no Hospital Universitário Pedro Ernesto e que tinham história de mais de dez anos de infecção pelo HIV e uso de ENF no seu esquema terapêutico sugerido por teste de resistência. Todos os pacientes alcançaram ao final do seguimento sucesso terapêutico, mantendo carga viral não detectada, e um incremento médio significativo de linfócitos T CD4. Em relação a uma possível resistência primária, em nenhum dos testes, genotipagem da glicoproteína 41, foi visualizado mutações naturais que pudessem diminuir a ação da ENF. Sobre o manejo do medicamento, preparo e aplicação, observamos que é imprescindível um apoio multidisciplinar para que não haja descontinuação na sua utilização / Enfuvirtide (ENF) is the only fusion inhibitor available. It is an interesting option for patients with HIV infection when used in combination with other antiretroviral drugs, especially in the treatment of multi-experienced patients with virological failure and few therapeutic options. Its effectiveness confirmed in clinical trials finds the barriers in its parenteral administration. Using these data, we evaluated, for 48 weeks, the virological response, evolution of CD4 T cells, the possible primary resistance to ENF and the impact to the subcutaneous use of the drug in ten patients undergoing outpatient monitoring at Hospital Universitário Pedro Ernesto with a history of more than ten years of HIV infection and use of ENF in their therapy, as suggested by resistance testing. All patients have successfully completed the therapy by the end of follow-up with an undetected viral load and a significant average increase of CD4 T lymphocytes. As for a possible primary resistance, neither the genotyping nor the glycoprotein 41 revealed natural mutations that could diminish the effect of ENF. Concerning the management, preparation and application of the drug, we found that a multidisciplinary support is essential to avoid that the drug be discontinued