Efeito da sistematização sobre atributos físicos, químicos e biológicos de um solo de várzea no Rio Grande do Sul.

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A Simultaneous D-Optimal Designed Study for Population Pharmacokinetic Analyses of Mycophenolic Acid and Tacrolimus Early After Renal Transplantation86

Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients&#039; demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and TAC were obtained from 65 stable adult renal allograft recipients on a single occasion (ie, day 15 after transplantation). A sampling schedule was estimated based on the D-optimality criterion with the POPED software, using parameter values from previously published studies on MPA and TAC modeling early after transplantation. Subsequently, a population PK model describing MPA and TAC concentrations was developed using nonlinear mixed-effects modeling. Optimal blood-sampling times for determination of MPA and TAC concentrations were estimated to be at 0 (predose) and at 0.24, 0.64, 0.98, 1.37, 2.38, and 11 hours after oral intake of mycophenolate and TAC. The PK of MPA and TAC were best described by a 2-compartment model with first-order elimination. For MPA, the absorption was best described by a transit compartment model, whereas first-order absorption with a lag time best described TAC transfer from the gastrointestinal tract. Parameters were estimated with good precision and accuracy. While hematocrit levels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation and MRP2 genetic polymorphism were retained as significant covariates on MPA absorption and elimination, respectively. The prospective use of the simultaneous D-optimal design approach for MPA and TAC has allowed good estimation of MPA and TAC PK parameters in the early period after transplantation characterized by a very high unexplained variability. The influence of some relevant covariates could be shown</p

Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in liver biopsies after hepatic transplantation: correlation with histopathologic staging of rejection.

The aims of this work were both to validate a sensitive and specific method to quantify tacrolimus (TAC) in liver biopsies after hepatic transplantation and to evaluate the predictive value of either tissue or blood TAC concentrations for rejection in 146 adult patients under a TAC-based immunosuppression. Trough blood levels were monitored daily during the hospital stay by immunoassay. Liver biopsies were routinely performed at day 7 posttransplantation. The tissue assay was developed by liquid chromatography-mass spectrometry. The limit of quantification was 5 pg/mg, with intra- and interassay precision ranging from 3.9% to 14.3% and 4.7% to 15.9%, respectively. The extraction efficiency was approximately 80%. TAC found in liver biopsies ranged from less than 5 up to 387 pg/mg. Blood TAC levels ranged from 2.7 to 19.3 ng/mL. Tissue levels displayed excellent correlation with liver histopathologic BANFF rejection score, whereas blood levels did not. Clinically significant rejections (BANFF scores &gt; or = 6) were characterized by mean TAC tissue and blood concentration of 13.1 pg/mg and 7.6 ng/mL, respectively, whereas these mean values became, respectively, 74.9 pg/mg (P &lt; 0.05) and 7.1 ng/mL (not significant) for nonclinically significant rejection episodes (BANFF &lt; 6). In this study, hepatic tissue TAC concentrations were distributed in a wider range and displayed a significantly better correlation with the severity of the organ rejection than predose blood levels. A tissue TAC concentration less than 30 pg/mg is 89% sensitive and 98% specific to discriminate clinically significant cellular rejection. Further studies are required to better understand the factors affecting TAC distribution within liver tissue (such as carrier proteins and cytochrome genetic polymorphism, liver function, age, hepatic blood flow, type of organ transplanted, time posttransplantation) and to define its value in the treatment of liver allograft&nbsp;rejection.</p

Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock89

INTRODUCTION: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum beta-lactam concentrations when standard dosages are administered. Previous studies on beta-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. METHODS: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. RESULTS: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T &gt; 4 x MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 mug/mL), 45% for ceftazidime (MIC = 32 mug/mL), 34% for cefepime (MIC = 32 mug/mL), and 33% for piperacillin-tazobactam (MIC = 64 mug/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam. CONCLUSIONS: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock</p

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60 countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V