Antibiotic treatment causes an ecological disturbance on the human microflora. Four commensal bacteria: E. coli, enterococci, a-streptococci and coagulase-negative staphylococci, from patients with extensive, high antibiotic usage were investigated with regard to resistance pattern and mutation frequency. Among 193 investigated strains it was found that high antibiotic usage selected for resistant bacteria and enriched for bacteria with a small but significantly increased mutation frequency. The relative biological fitness cost of resistance in Staphylococcus epidermidis was assessed in a human in vivo model where the indigenous flora was present. In vitro data of the bacterial growth rate correlated well to in vivo fitness assayed in the competition experiments on skin. An in vitro kinetic model was shown to be a useful tool to establish the pharmacokinetic and pharmacodynamic (PK/PD) indices for efficacy of antibiotics. It was confirmed that the time, when the concentration exceeds the minimal inhibitory concentration (MIC), correlates with efficacy for b-lactam antibiotics. To achieve maximal killing for penicillin-resistant pneumococci, with an MIC of 2 mg/L, the peak concentration was also of importance. Suboptimal dosing regimen facilitates selection of resistance. Penicillin-resistant pneumococci were easily selected in a mixed population with penicillin-sensitive, -intermediate and -resistant pneumococci in an in vitro kinetic model. The selection of the resistant strain was prevented when the benzylpenicillin concentration exceeded the MIC for approximately 50% of 24 h.

Vertical flow constructed wetlands (VF CWs) are becoming increasingly popular for onsite wastewater treatment due to their high oxygen transfer capacity and high nitrification rates. However, there are still some question marks regarding (1) how the treatment performance of VF CWs is affected by design and operational parameters, and (2) the treatment processes happening inside the wetland bed as the wastewater percolates through. In this study, we investigated the effects of filter media (coarse sand or fine gravel), dosing regime (hourly with 4 mm or bi-hourly with 8 mm) and plant presence (with or without Phragmites australis) on the  treatment performance and concentration depth profiles of pollutant removal in six pilot-scale VF CWs treating primary treated domestic wastewater. Grab samples of wastewater were collected every 2-3 weeks during 5 months and analyzed for organic matter, suspended solids, nitrogen and E. coli. We found that sand beds performed better than gravel beds for removal of all pollutants except total nitrogen, although for long term operation gravel may be less susceptible to clogging. The overall treatment performance was not affected by different dosing regimes, but the concentration depth profiles showed that smaller and more frequent doses led to more pollutant removal in the upper part of the beds. The presence of plants was moderately important for the removal of ammonium, but had no effect on other pollutants.

Mathematical models provide unique insights to real-world problems. Within the context of infectious diseases, models are used to explore the dynamics of infections and control mechanisms. Human papillomavirus (HPV) globally infects about 630 million people, many of these infections develop into cancers and genital warts. Vaccines are available to protect against the most prevalent and devastating strains of HPV. The introduction of this vaccine as part of a national immunization program in Canada is a complex decision for policy-makers in which mathematical models can play a key role. We use the current recommendations provided by the World Health Organization to explore the integral role mathematical models have in the decision to incorporate the HPV vaccine within a national immunization program. We then provide a review of the literature discussing the role of mathematical models in the decision to include a vaccine in a national immunization program within the context of the HPV vaccine. Next, we evaluate the current standing of mathematical models used within the context of HPV immunization, to highlight the types of models used, underlying assumptions and general recommendations made about these immunization programs. Then, we create and analyze a model to explore the possibility of bettering the current HPV vaccine strategy in Canada. We focus on the effects of the grade of vaccination and the number of doses required to eradicate the targeted strains of HPV.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua. / A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis.

A papaína é uma enzima utilizada em formulações tópicas como agente proteolítico debridante, no tratamento de lesões abertas de grande extensão e queimaduras. Também empregada como agente promotor da permeação cutânea, peeling químico e como agente depilatório progressivo. A estabilidade de formulações contendo enzimas não é facilmente alcançada. No presente trabalho realizou-se a modificação da papaína com polietilenoglicol, visando maior estabilidade. O Teste de Estabilidade Normal de formulações cosméticas incorporadas de papaína não modificada e modificada apresentou um perfil diferenciado para a atividade da enzima modificada, nas diferentes condições de temperatura (5 ± 1 °C; 22 ± 2 °C, 40 ± 2 °C), sendo que a mais adequada para a papaína não modificada foi de 5 ± 1 °C e para a modificada foi de 22 ± 2,0 °C. Estes resultados confirmam o aumento da estabilidade da papaína modificada e o seu potencial de aplicação em formulações de uso tópico. / Papain is an enzyme used in formulations for local application as proteolitic debridant agent, treatment of wound exposed in large extension and burns. It is also applied as promotor agent of cutaneous permeation, chemical peeling and as progressive depilatory agent. The stability of formulations with enzymes is not easily obtained. In this work modification of papain with polyethylenglycol was made in order to obtain more stability. The Test of Normal Stability of cosmetic formulations incorporated with papain not-modified and modified, showed a differentiated profile for modified enzyme in different conditions of temperature (5 ± 1 °C; 22 ± 2 °C, 40 ± 2 °C), being that, the most adequated for papain not-modified was 5 ± 1°C and for modified was 22 ± 2,0 °C. These results confirm the increase of stability of papain modified and its potential application in formulations for local application.

The introduction of artemisinin-based combination therapy (ACT) substantially reduced malaria-related mortality and morbidity during the past decade. Despite the widespread use of ACT, there is still a considerable knowledge gap with regards to safety, efficacy and pharmacokinetic properties of these drugs, particularly in vulnerable populations like children and pregnant women. In addition, there is growing evidence of widespread artemisinin-resistance across the Greater Mekong Subregion. Expedited delivery of novel antimalarial drugs with different mechanisms of action to the clinical setting is still far off; therefore, it is crucial to improve the use of existing antimalarial drugs for optimal outcome in order to prolong their therapeutic life span. This thesis focuses on utilizing pharmacometric tools to support this effort for malaria prevention and treatment. An extensive simulation framework was used to explore alternative malaria chemopreventive dosing regimens of a commonly used ACT, dihydroartemisinin-piperaquine. Different monthly and weekly dosing regimens were evaluated and this allowed an understanding of the interplay between adherence, loading dose and malaria incidence. A weekly dosing regimen substantially improved the prevention effect and was less impacted by poor adherence. This is also expected to reduce selection pressure for development of resistance to piperaquine. Population pharmacokinetics-pharmacodynamic models were developed for artesunate and the active metabolite dihydroartemisinin, effect on parasite clearance, in patients with artemisinin-resistant and -sensitive malaria infections in Southeast Asia. The modeling identified an association between parasite density and drug bioavailability. It predicted the presence of high levels of artemisinin resistant infection among patients in Cambodia and its spread into Myanmar. A nomogram to identify patients with artemisinin resistant infections was developed. Furthermore, the model was used to demonstrate the need for extended treatment duration to treat patients with artemisinin resistant infections. A population pharmacokinetic model developed from data on pregnant women in East Africa allowed further understanding of artemether-lumefantrine exposure in pregnant populations. It also suggested that the lumefantrine exposure in this population is not compromised. In summary, the results presented in this thesis demonstrate the value of pharmacometric approaches for improving antimalarial drug treatment and prevention. This ultimately contributes to overcoming the prevailing challenges to malaria control.

Mathematical models provide unique insights to real-world problems. Within the context of infectious diseases, models are used to explore the dynamics of infections and control mechanisms. Human papillomavirus (HPV) globally infects about 630 million people, many of these infections develop into cancers and genital warts. Vaccines are available to protect against the most prevalent and devastating strains of HPV. The introduction of this vaccine as part of a national immunization program in Canada is a complex decision for policy-makers in which mathematical models can play a key role. We use the current recommendations provided by the World Health Organization to explore the integral role mathematical models have in the decision to incorporate the HPV vaccine within a national immunization program. We then provide a review of the literature discussing the role of mathematical models in the decision to include a vaccine in a national immunization program within the context of the HPV vaccine. Next, we evaluate the current standing of mathematical models used within the context of HPV immunization, to highlight the types of models used, underlying assumptions and general recommendations made about these immunization programs. Then, we create and analyze a model to explore the possibility of bettering the current HPV vaccine strategy in Canada. We focus on the effects of the grade of vaccination and the number of doses required to eradicate the targeted strains of HPV.

The aim of the diploma thesis is to design the technical solution of minimization of frictional losses, which occur when using a sine pump at position of the shaft locking and on the impeller wheel. The losses originating from the frictional forces have a negative influence on the lifetime of individual parts and economy of the pump. In the first part the author describes sine pumps from the constructional point of view and the main producers are mentioned. The second part contains suggestions on the parameters of the pump and various possibilities of solutions. The last part covers the experiment and conclusions.