Metabolic Clearance Rate

Alzheimer's disease (AD) is the most common type of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and clearance of Aβ from the brain becomes a main therapeutic strategy for AD. Recent studies found that Aβ clearance in the periphery contributes substantially to reducing Aβ accumulation in the brain. Therefore, understanding the mechanism of how Aβ is cleared in the periphery is important for the development of effective therapies for AD. In this review, we summarized recent findings on the mechanisms of Aβ efflux from the brain to the periphery and discuss where and how the brain-derived Aβ is cleared in the periphery. Based on these findings, we propose future strategies to enhance peripheral Aβ clearance for the prevention and treatment of AD. This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.

BackgroundCorrect antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.MethodsThis was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system.ResultsWe obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% fT>MIC), of which almost 80% had a measured creatinine clearance>130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance>130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% fT>MIC.ConclusionsIn this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance>130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration.

IntroductionImproved methods to optimize drug dosing in the critically ill are urgently needed. Traditional prescribing culture involves recognition of factors that mandate dose reduction (such as renal impairment), although optimizing drug exposure, through more frequent or augmented dosing, represents an evolving strategy. Elevated creatinine clearance (CLCR) has been associated with sub-therapeutic antibacterial concentrations in the critically ill, a concept termed augmented renal clearance (ARC). We aimed to determine the prevalence of ARC in a cohort of septic and traumatized critically ill patients, while also examining demographic, physiological and illness severity characteristics that may help identify this phenomenon.MethodsThis prospective observational study was performed in a 30-bed tertiary level, university affiliated, adult intensive care unit. Consecutive traumatized and septic critically ill patients, receiving antibacterial therapy, with a plasma creatinine concentration ≤110 μmol/L, were eligible for enrolment. Pulse contour analysis (Vigileo / Flo Trac system, Edwards Lifesciences, Irvine, CA, USA), was used to provide continuous cardiac index (CI) assessment over a single six-hour dosing interval. Urinary CLCR measures were obtained concurrently.ResultsSeventy-one patients contributed data (sepsis n = 43, multi-trauma n = 28). Overall, 57.7% of the cohort manifested ARC, although there was a greater prevalence in trauma (85.7% versus 39.5%, P ConclusionsDiagnosis, illness severity and age, are likely to significantly influence renal drug elimination in the critically ill, and must be regularly considered in future study design and daily prescribing practice.

PurposeEvaluation of distribution kinetics is a neglected aspect of pharmacokinetics. This study examines the utility of the model-independent parameter whole body distribution clearance (CLD) in this respect.MethodsSince mammillary compartmental models are widely used, CLD was calculated in terms of parameters of this model for 15 drugs. The underlying distribution processes were explored by assessment of relationships to pharmacokinetic parameters and covariates.ResultsThe model-independence of the definition of the parameter CLD allowed a comparison of distributional properties of different drugs and provided physiological insight. Significant changes in CLD were observed as a result of drug-drug interactions, transporter polymorphisms and a diseased state.ConclusionTotal distribution clearance CLD is a useful parameter to evaluate distribution kinetics of drugs. Its estimation as an adjunct to the model-independent parameters clearance and steady-state volume of distribution is advocated.