Mulheres com obesidade são mais propensas a complicações médicas, cirúrgicas e obstétricas, tais como maiores índices de indução do trabalho de parto e falha na indução. O misoprostol é um análogo sintético da prostaglandina E1 utilizado para a indução do trabalho de parto. O presente trabalho visa avaliar os efeitos da obesidade materna sobre a farmacocinética do misoprostol em parturientes, bem como a avaliação da influência da obesidade na resposta clínica da indução do trabalho de parto. Foram investigadas 40 parturientes, assim distribuídas, Grupo 1: 10 parturientes não obesas, Grupo 2: 10 com obesidade grau 1, Grupo 3: 10 com obesidade grau 2 e Grupo 4: 10 com obesidade grau 3. Após a internação das pacientes, leitura e assinatura do Termo de Consentimento Livre e Esclarecido, foi avaliado o comprimento do colo do útero, o índice de Bishop foi determinado e uma amostra de sangue foi colhida para avaliação dos exames laboratoriais, genótipo e tempo zero da farmacocinética. Após a administração do comprimido de misoprostol 25µg via vaginal, foram colhidas amostras seriadas de sangue nos tempos 15 a 360 minutos. As concentrações plasmáticas do ácido misoprostólico foram analisadas em plasma empregando UPLC-MS/MS. Os parâmetros farmacocinéticos foram calculados com base nas curvas de concentração plasmática total versus tempo empregando o programa Winnonlin. Todas as parturientes realizaram o pré-natal satisfatoriamente e nenhuma havia se submetido a cesárea anterior. As parturientes do grupo 1 apresentaram uma taxa de sucesso de indução de 60%, com uma média de 1,10 dias de indução e 2,50 comprimidos de misoprostol. No grupo 2, houve uma taxa de sucesso de 70%, em 1,40 dias de indução, utilizando 2,80 comprimidos. No grupo 3, a taxa de sucesso foi de 60%, em 1,70 dias de indução e também utilizou 2,80 comprimidos. Entretanto no grupo 4, a taxa de sucesso foi de apenas 30%, em 2,40 dias e utilizando quase o dobro de comprimidos (4,80). Houve uma diferença significativa da falha de indução entre os grupos, a taxa de falha de indução no grupo 4 foi de 70%, enquanto nos demais grupos foi de apenas 10%. O método para análise do ácido misoprostólico em plasma seguiu o preconizado pela legislação vigente, com LIQ de 2,0 pg/mL. Não houve diferença significativa entre os parâmetros farmacocinéticos dos grupos. A AUC variou de 56,77 a 83,89 pg.h/mL; o Cmax de 14,29 a 21,89 pg/mL; o tmaxde 2,25 a 4,5 h; o t1/2 de 0,96 a 1,31 h. Não houve diferença entre o IMC e os parâmetros farmacocinéticos, entretanto houve influência do peso na AUC. Também houve uma relação entre a baixa exposição ao misoprostol (AUC) e maior taxa de falha de indução. Conclui-se que A obesidade influencia a biodisponibilidade (AUC) do fármaco, sugerindo que o regime posológico do misoprostol possa ser alterado. A obesidade também influenciou a taxa de falha de indução, quanto maior o IMC, maior a taxa de falha de indução, maior o tempo de internação, maior o número de comprimidos utilizados / Women with obesity are more prone to medical, surgical and obstetric complications, such as higher rates of labor induction and failure to induce. Misoprostol is a synthetic analogue of prostaglandin E1 used to induce labor. The present study aims to evaluate the effects of maternal obesity on the pharmacokinetics of misoprostol in parturients, as well as the evaluation of the influence of obesity on the clinical response of labor induction. Group 1: 10 non-obese parturients, Group 2: 10 with obesity grade 1, Group 3: 10 with obesity grade 2 and Group 4: 10 with obesity grade 2. After the patients\' hospitalization, reading and signing of the Informed Consent Term, the length of the cervix was evaluated, the Bishop\'s index was determined and a sample was collected to evaluate the laboratory tests, genotype and time of pharmacokinetics. Following administration of the 25?g misoprostol vaginal tablet, serial blood samples were collected at times of 15 to 360 minutes. Plasma concentrations of misoprostolic acid were analyzed in plasma using UPLC-MS / MS. Pharmacokinetic parameters were calculated based on the total plasma concentration versus time curves using the Winnonlin program. All the parturients performed prenatal satisfactorily and none had undergone previous caesarean section. The parturients of group 1 had an induction success rate of 60%, with a mean of 1.10 days of induction and 2.50 tablets of misoprostol. In group 2, there was a success rate of 70%, at 1.40 days of induction, using 2.80 tablets. In group 3, the success rate was 60% at 1.70 days of induction and also used 2.80 tablets. However, in group 4, the success rate was only 30%, in 2.40 days and using almost twice as many tablets (4.80). There was a significant difference in induction failure between groups, the rate of induction failure in group 4 was 70%, while in the other groups it was only 10%. The method for the analysis of misoprostolic acid in plasma followed the prevailing legislation, with LIQ of 2.0 pg / mL. There was no significant difference between the pharmacokinetic parameters of the groups. AUC ranged from 56.77 to 83.89 pg.h / mL; C max from 14.29 to 21.89 pg / mL; or tmax of 2.25 to 4.5 h; or t1 / 2 from 0.96 to 1.31 h. There was no difference between BMI and pharmacokinetic parameters, however, there was weight influence in AUC. There was also a relationship between low misoprostol exposure (AUC) and higher rate of induction failure. It is concluded that obesity influences the bioavailability (AUC) of the drug, suggesting that the dosage regimen of misoprostol can be altered. Obesity also influenced the rate of induction failure, the higher the BMI, the higher the rate of induction failure, the longer the hospital stay, the greater the number of tablets used

Orientador: Daniela Ponce / Resumo: Introdução: Peritonite é complicação grave nos pacientes em diálise peritoneal (DP) e a principal causa de transição para hemodiálise. O uso intraperitoneal (IP) de aminoglicosídeo e vancomicina é opção para o tratamento empírico. No entanto, a absorção sistêmica dessas drogas é controversa e pouco estudada. Objetivo: Descrever os níveis plasmáticos e do dialisato de amicacina e vancomicina administrados IP em pacientes com peritonite em DP nos momentos de 30 e 120 min após administração, após 24h da administração da amicacina e 48h da vancomicina e associá-los com o desfecho da peritonite. Metodologia: Estudo observacional realizado de novembro/2017 a abril/2019, que incluiu 32 episódios de peritonites. Análise de amostras foi realizada no 1º, 3º e 5º dias. No momento de pico, foram consideradas concentrações terapêuticas de amicacina valores entre 25 e 35 mg/L e no vale (antes da infusão do dialisato) concentrações de 4-8 mg/L ; e de vancomicina no vale de 15–20 mg/L. Resultados: A idade foi de 60 ± 11,3 anos, a principal causa da doença renal foi diabetes (42,4%) e 63,3% eram homens. Entre as culturas 39,4% foram gram negativos, 36,3% gram positivos e 21,2% negativas. Houve cura em 84,8% dos episódios. Vancomicina foi administrada IP a cada 72h e amicacina diariamente. Avaliando-se os períodos antes e depois da peritonite, não houve mudanças no tipo de transporte peritoneal (p=0,76), mas houve diferenças na função renal residual (p=0,05) e redução do débito urinário (p=0,0... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Peritonitis is a serious complication in patients on peritoneal dialysis and the main cause of transition to hemodialysis. The intraperitoneal use of aminoglycoside and vancomycin is an option for empiric treatment. However, the systemic absorption of these drugs is controversial and little studied. Objectives: Describe intraperitoneal amikacin and vancomycin dialysate levels in patients with peritonitis on peritoneal dialysis at 30 and 120 minutes after administration, 48 hours after vancomycin and 24 hours after amikacin and associating them with the peritonitis outcome. Methodology: Observational study conducted from August 2017 to April 2019, which included 32 episodes of peritonitis. Samples were analyzed on the 1st, 3rd and 5th days. At peak moment, therapeutic concentrations of amikacin were considered to be between 25 and 35 mg/L and at baseline concentrations of 4-8 mg/L; and vancomycin at the valley moment of 15-20 mg/L. Results: Age was 60 ± 11.3 years, the main cause of kidney disease was diabetes (42.4%) and 63.3% were men. Among the cultures 39.4% were gram negative, 36.3% gram positive and 21.2% negative. There was cure in 84.8% of the episodes. Vancomycin was administered intraperitoneal every 72 hours and amikacin daily. There were no changes in the peritoneal transport type (p = 0.76), but there were differences in residual renal function (p = 0.05) and reduction in urinary output (p = 0.02). Regarding the outcomes of cure and non-cure, there w... (Complete abstract click electronic access below) / Mestre

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Ondřej Martinec Supervisor: Assoc. Prof. PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretroviral drugs with membrane transporters Oral delivery is the most common, convenient, and economical form of drug administration. Absorption of orally administered drugs occurs mainly in the intestine. Intestinal absorption can be reduced by the activity of efflux drug ABC transporters, mainly p-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), located in the apical membrane of the intestinal epithelium. HIV-infected patients are dependent on lifelong pharmacotherapy, which includes a combination of three or more antiretroviral drugs. Hepatitis C (HCV) is a common co-infection of HIV. In addition, the HIV-positive population is aging, which is associated with burden of other comorbidities. This results in an indication of polypharmacy and thus an increased risk of drug-drug interactions. Many antiretroviral drugs used are substrates, inhibitors and /or inducers of ABCB1, so they might quantitatively affect the intestinal absorption of co-administered drugs (ABCB1 substrates), thereby affecting the efficacy/safety of treatment. As part of this...

Background: Antiretroviral therapy (ART), notably lopinavir and nevirapine substantially reduces Human immune-deficiency virus (HIV) associated morbidity and mortality in HIVinfected children. Low concentrations of nevirapine and lopinavir have been linked to inferior virological outcomes; it is recommended that lopinavir and nevirapine concentrations are maintained above 1 mg/L and 3 mg/L, respectively, in order to maintain viral suppression. Adherence to both lopinavir and nevirapine ART, respectively has long known to be a crucial contributor to HIV treatment success. Lopinavir and nevirapine pharmacokinetics demonstrate considerable inter-individual variability, which may affect treatment outcomes. At least part of this variability may be explained by host genetic factors. Associations between human genetic variants and exposure to lopinavir and nevirapine are incompletely understood, and have not been studied in a South African paediatric population. Data in this thesis were from a clinical trial conducted at Rahima Moosa Mother and Child Hospital in Johannesburg to assess whether NVP can be re-used (Post-randomization Phase) among 323 children exposed to NVP for PMTCT if they are first suppressed on ritonavir-boosted lopinavir based regimen (Pre-randomization Phase). This thesis assessed the relationship between serial clinic visits lopinavir (Pre-and-Post-randomization) and nevirapine (Postrandomization) concentrations and/or percentage adherence(Pre-and-Post-randomization) and virological outcomes in children. Moreover, population pharmacokinetics models were used to characterise lopinavir and nevirapine parameters. From the final models parameters were derived and were used to assess the relationship between lopinavir and nevirapine pharmacokinetics and genetic polymorphism relevant to both drugs Methods: Cox proportional hazard regression modelling for multiple failure events was used to estimate the crude and adjusted hazard effect of lopinavir (Pre-and Post-randomization) and nevirapine(Post-randomization) concentrations and/or percent adherence(Pre-and Post-randomization) of viral load>400 copies/mL (Pre-randomization) and >50 copies/mL (Post-randomization), respectively. The population means and variances of lopinavir and nevirapine pharmacokinetic parameters at steady state were estimated using non-linear mixed-effects regression. The final models of lopinavir and nevirapine were used to derive individual clearances (CL/F), minimum concentrations (Cmin) and area under the concentration time curves (AUC). The associations between model-derived pharmacokinetic parameters and genotypes in selected genes relevant to lopinavir or nevirapine were explored. Results: In 237 children pre-randomization with viral loads and lopinavir concentrations, the crude and adjusted Cox models revealed significant associations between virologic failure (viral load>400 copies/mL) and both lopinavir plasma concentrations (<1/mg/L) and pretreatment height-for-age z-scores but not percent adherence. In 99 children postrandomization, lopinavir concentrations >1 mg/L reduced the risk of viremia (viral load >50 copies/mL) with about 40%, compared to children with LPV <1 mg/L. No association was found with percent adherence in this group. In 95 children on nevirapine post-randomization, nevirapine concentrations were not significantly associated with increased hazard of viremia (viral load >50 copies/mL). Similarly, there was no significant association with percent adherence in this group. Lopinavir and nevirapine pharmacokinetics were both separately best described with a one compartment models with absorption lag time and transit compartment absorption models, respectively. There was an age driven effect on lopinavir and nevirapine relative bioavailability, respectively. After adjusting for multiple testing, there was no significant association between lopinavir CL/F, Cmin and AUC and genetic polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1. CYP2B6 516G→T and CYP2B6 983T→C were associated with NVP CL/F. CYP2B6 983T→C was associated with NVP Cmin and AUC. Additionally, polymorphisms in the ABCB1 and CYP3A5 were independently associated with NVP CL/F, Cmin and AUC. Conclusions: Lopinavir concentrations <1mg/L were associated with the increased hazard of viremia (viral load >400 copies/mL or >50 copies/mL). The results suggest that lopinavir plasma concentration monitoring at a routine clinic visit may be a useful tool in identifying sub-therapeutic antiretroviral concentrations in children, and this could be used as a guide to therapeutic drug monitoring in children. There was no statistically significant association between polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1 and lopinavir pharmacokinetics. Polymorphisms in the ABCB1, CYP2B6 CYP3A4 and CYP3A5 predicted nevirapine pharmacokinetics.

Objective: Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP). Materials and Methods: Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma and urine were assessed based on 100 g body weight. Using tissues collected 24 hrs post-treatment, gastrointestinal inflammation was estimated through duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) levels; while kidney tissue was examined for dilatation and necrosis. CEL concentration was assayed in renal tissue and plasma utilizing high-performance liquid chromatography. Results: Although there were significant changes when comparing CEL and CEL-NP to VEH in plasma sodium concentration and potassium excretion rate, there was no significant variation between CEL and CEL-NP. There was a significant reduction of protective duodenal PGE2 in CEL compared to VEH (p = 0.0088) and CEL-NP (p = 0 .02). In the C EL-NP formulation, t1/2, Cmax, AUC0-∞, and Vd/F increased significantly when compared to CEL. Conclusions: At the observed dosage and duration, CEL-NP may not affect CEL-associated electrolyte parameters in either plasma or urine; however, it does provide increased systemic exposure while potentially alleviating some gastrointestinal outcomes related to inflammation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal and renal side effects. Rebamipide is a mucoprotective agent that reduces gastrointenstinal side effects when administered concomitantly with NSAIDs. In this study, we investigated the pharmacokinetic drug interactions of rebamipide with two selected NSAIDs, celecoxib or diclofenac. Rats were randomly divided into five groups. Two groups received placebo and three groups were administered rebamipide (30 mg/kg) orally twice daily for two days. On day 3, the animals treated with placebo received celecoxib (40 mg/kg) or diclofenac (10 mg/kg) and rats receiving rebamipide were administerd rebamipide followed by a single dose of placebo, celecoxib, or diclofenac. To investigate drug protein interactions, blank rat plasma was spiked with known concentrations of rebamipide, diclofenac plus rebamipide, or celecoxib plus rebamipide then dialyzed through a Rapid Equilibrium Dialysis device. AUC (139.70 ± 24.97 μg h/mL), C max (42.99 ± 2.98 μg/mL), and CLoral (0.08 ± 0.02 L/h/kg) values of diclofenac in diclofenac plus rebamipide group altered when compared to those of diclofenac treated groups. Treatment with rebamipide showed no significant change in pharmacokinetic parameters of celecoxib treated rats. Cmax (7.80 ± 1.22 μg/mL), AUC (56.46 ± 7.30 μg h/mL), Vd/F (7.55 ± 1.37 L/kg), and CLoral (0.58 ± 0.09 L/h/kg) of rebamipide were significantly altered when diclofenac was co-administered with rebamipide. Pharmacokinetic parameters of rebamipide plus celecoxib group were not significantly different from those of rebamipide group. Plasma protein binding was not affected by concomitant administration of another drug. These results indicate alteration of pharmacokinetic parameters of both rebamipide and diclofenac when co-administered and cannot be explained by a variation in plasma protein binding.

Background: Moxifloxacin is a new fourth-generation 8-methoxy fluoroquinolone developed primarily for the treatment of community-acquired pneumonia and upper respiratory tract infections. The aim of the study was to investigate the plasma pharmacokinetics characteristic of moxifloxacin in calves, after intravenous, intramuscular and subcutaneous administration of a single dose. Meanwhile, plasma protein binding and bioavailability of moxifloxacin were also estimated. Methods: Plasma concentrations of moxifloxacin were measured using a modified HPLC method, and the extent of plasma protein binding was determined in vitro using ultrafiltration. Results: Following intravenous administration, the half life of elimination, the volume of distribution at steady state and the area under the curve were 3.29 h, 0.94 l/kg and 24.72 μg·h/ml, respectively. After intramuscular and subcutaneous administration of moxifloxacin at the same dose, the peak plasma concentrations were 2.41 and 2.20 μg/ml and were obtained at 1.54 and 1.59 h, respectively. The systemic bioavailabilities were 87.19 and 75.94%, respectively. The in vitro plasma protein binding of moxifloxacin in plasma of calves was 27%. Conclusion: A high peak plasma concentration, area under the curve, rapid absorption and bioavailability following intramuscular and subcutaneous administration characterize the pharmacokinetics of moxifloxacin in calves.

Background: Trimebutine maleate is a prokinetic agent that acts directly on the smooth muscle of the GI tract. A bioequivalence (BE) study of 2 oral formulations of 100 mg trimebutine maleate (TMB) was carried out in 24 healthy male Korean volunteers according to a crossover-randomized design. Methods: Subjects were given a single dose of 2 100 mg tablets of each formulation. The test and reference formulations were Recutin™ (Hutax Co., South Korea) and Polybutin™ (Samil Co., South Korea), respectively. Each set of tablets was administered with 240 ml of water to subjects after 10 h overnight fasting on 2 treatment days separated by a 1 week washout period. After dosing, serial blood samples were collected for a period of 36 h. Plasma was analyzed for the main metabolite of TMB, N-monodesmethyl trimebutine (nor-TMB), by a validated LC with MS/MS detection capacity for nor-TMB in the range 5-1500 ng/ml, with a lower limit of quantification (LLOQ) of 5 ng/ml. Several pharmacokinetic (PK) parameters (including AUCt, AUCinfinity, Cmax, Tmax, T1/2, and Ke) were determined from the plasma concentrations of nor-TMB of both formulations. AUCt, AUCinfinity, and Cmax were tested for BE after log-transformation of the data. Results: No significant difference was found based on ANOVA; 90% confidence intervals (98.98%112.03% for AUCt; 98.60%-113.20% for AUCinfinity; 90.85%-107.87% for Cmax) for the test and reference were found within KFDA acceptance range of 80-125%. Conclusions: Based on these statistical inferences, it was concluded that Recutin™ is bioequivalent to Polybutin™ and can be used interchangeably in a clinical setting.

Study Design: A single-blind, 2-factor (4 treatments by 8 time points) repeated-measures study design. Objective: To analytically determine dexamethasone and dexamethasone phosphate concentrations in plasma derived from proximal effluent venous blood, following cathodic iontophoresis. Methods and Measures: Six volunteers received the following dexamethasone phosphate (2.5 ml, 4 mg/ml) treatments to their wrists on separate occasions: cathodic iontophoresis (4 mA, 10 minutes or 4 mA, 20 minutes), passive application (10 or 20 minutes). Plasma samples from the ipsilateral antecubital vein were obtained 10 minutes prior to and half way through the treatment (5 or 10 minutes), at the end of the treatment (10 or 20 minutes), and posttreatment (15, 30, 60, 90, and 120 minutes). The present investigation examined: (1) the sensitivity and linearity of extraction and analysis of dexamethasone and dexamethasone phosphate; (2) the necessity for determining both; and (3) the plasma levels from proximal effluent venous blood following cathodic iontophoresis. Results: The aggregate (n= 18) of the 6-point standard curves were linear for dexamethasone (r > 0.974) and dexamethasone phosphate (r > 0.829). In vitro dephosphorylation of dexamethasone phosphate to dexamethasone occurred in plasma at 37°C and during freeze-thaw. Measurable dexamethasone or dexamethasone phosphate concentrations were absent at all time points and under all conditions in the human subjects. Conclusions. These results demonstrate the sensitivity of the current assay and the need for evaluating both forms of the drug, as in vitro dephosphorylation results in the presence of dexamethasone and dexamethasone phosphate in samples. Absence of measurable dexamethasone or dexamethasone phosphate in the proximal effluent venous blood may require re-evaluation of the extent of drug delivery during the clinical iontophoresis of dexamethasone phosphate.

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