Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review.

PURPOSE: Older people are at risk of anticholinergic side effects due to changes affecting drug elimination and higher sensitivity to drug's side effects. Anticholinergic burden scales (ABS) were developed to quantify the anticholinergic drug burden (ADB). We aim to identify all published ABS, to compare them systematically and to evaluate their associations with clinical outcomes. METHODS: We conducted a literature search in MEDLINE and EMBASE to identify all published ABS and a Web of Science citation (WoS) analysis to track validation studies implying clinical outcomes. Quality of the ABS was assessed using an adapted AGREE II tool. For the validation studies, we used the Newcastle-Ottawa Scale and the Cochrane tool Rob2.0. The validation studies were categorized into six evidence levels based on the propositions of the Oxford Center for Evidence-Based Medicine with respect to their quality. At least two researchers independently performed screening and quality assessments. RESULTS: Out of 1297 records, we identified 19 ABS and 104 validations studies. Despite differences in quality, all ABS were recommended for use. The anticholinergic cognitive burden (ACB) scale and the German anticholinergic burden scale (GABS) achieved the highest percentage in quality. Most ABS are validated, yet validation studies for newer scales are lacking. Only two studies compared eight ABS simultaneously. The four most investigated clinical outcomes delirium, cognition, mortality and falls showed contradicting results. CONCLUSION: There is need for good quality validation studies comparing multiple scales to define the best scale and to conduct a meta-analysis for the assessment of their clinical impact.

Comparative assessment for rat strain differences in metabolic profiles of 14 drugs in Wistar Han and Sprague Dawley hepatocytes.

Knowledge of inter-strain and inter-gender differences in drug metabolism studies is important for animal selection in pharmacokinetic and toxicological studies. The effects of rat strain and gender in in vitro metabolism were investigated in Sprague Dawley (SD) and Wister Han (WH) rats based on the hepatocyte metabolic profiles of 14 small molecule drugs. Similarities were found between the hepatocyte metabolic clearances of SD and WH strains, suggesting that only one strain can be confidently used for the evaluation of hepatic clearance. Neither strain of rat was preferable over the other to cover human metabolites. Higher similarities in metabolic pathways were found between the same gender than the same strain. Differences in metabolite identities, metabolite formation rates and potential biotransformation pathways were observed between SD and WH rat strains. Eleven metabolites from six drugs were "disproportionally" formed between SD and WH rats. The use of a specific rat strain model and gender for ADME and toxicity testing should, therefore, be carefully considered as metabolic profiles may differ, even though metabolic clearance was similar between SD and WH rats.

Pharmacokinetic considerations in pediatric pharmacotherapy.

PURPOSE: The changes in physiological functions as children grow and organ systems mature result in pharmacokinetic alterations throughout childhood. These alterations in children result in absorption, distribution, metabolism, and excretion of drugs that are different from those seen in the typical adult diseased population. SUMMARY: Changes in gastrointestinal motility and gastric pH in neonates and infants affect the absorption rate and bioavailability of drugs. Skin absorption rate and extent can be altered by different skin structures and perfusion in young children. Intramuscular and rectal absorption become less predictable in children due to erratic absorption site perfusion and other factors. Children's body compositions also differ greatly from that in adults. Water-soluble drugs distribute more extensively in newborns due to larger water content than in older children and adults. Drug elimination and excretion are also affected in pediatric population due to differences in liver and renal function. Immature enzyme development and renal function result in reduced clearance of drugs in young children. There are limited pharmacokinetic data available for many drugs used in children. CONCLUSION: Considering the changes in pharmacokinetics in children can help pharmacists optimize the dosing and monitoring of drugs and do the best they can to help this vulnerable population.

Assessment of the Biotransformation of Low-Turnover Drugs in the HµREL Human Hepatocyte Coculture Model.

Metabolic profiles of four drugs possessing diverse metabolic pathways (timolol, meloxicam, linezolid, and XK469) were compared following incubations in both suspended cryopreserved human hepatocytes and the HµREL hepatocyte coculture model. In general, minimal metabolism was observed following 4-hour incubations in both suspended hepatocytes and the HµREL model, whereas incubations conducted up to 7 days in the HµREL coculture model resulted in more robust metabolic turnover. In the case of timolol, in vivo human data suggest that 22% of the dose is transformed via multistep oxidative opening of the morpholine moiety. Only the first-step oxidation was detected in suspended hepatocytes, whereas the relevant downstream metabolites were produced in the HµREL model. For meloxicam, both the hydroxymethyl and subsequent carboxylic acid metabolites were abundant following incubation in the HµREL model, while only a trace amount of the hydroxymethyl metabolite was observed in suspension. Similar to timolol, linezolid generated substantially higher levels of morpholine ring-opened carboxylic acid metabolites in the HµREL model. Finally, while the major aldehyde oxidase-mediated mono-oxidative metabolite of XK469 was minimally produced in hepatocyte suspension, the HµREL model robustly produced this metabolite, consistent with a pathway reported to account for 54% of the total urinary excretion in human. In addition, low-level taurine and glycine conjugates were identified in the HµREL model. In summary, continuous metabolite production was observed for up to 7 days of incubation in the HµREL model, covering cytochrome P450, aldehyde oxidase, and numerous conjugative pathways, while predominant metabolites correlated with relevant metabolites reported in human in vivo studies.

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly (P < 0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin [area under the plasma concentration-time curve (AUC) ratio ∼21-39]. Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (P < 0.05) impacted the renal clearance of rosuvastatin (∼8-fold). In vitro, rifampicin (10 µM) inhibited uptake of pitavastatin, rosuvastatin, and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP, whereas talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions.

Simultaneous Assessment In Vitro of Transporter and Metabolic Processes in Hepatic Drug Clearance: Use of a Media Loss Approach.

Hepatocyte drug depletion-time assays are well established for determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition to metabolism. Using experimental procedures consistent with a high throughput, a selection of 12 compounds with a range of uptake and metabolism characteristics (atorvastatin, cerivastatin, clarithromycin, erythromycin, indinavir, pitavastatin, repaglinide, rosuvastatin, saquinavir, and valsartan, with two control compounds-midazolam and tolbutamide) were investigated in the presence and absence of the cytochrome P450 inhibitor 1-aminobenzotriazole and organic anion transporter protein inhibitor rifamycin SV in rat hepatocytes. Data were generated simultaneously for a given drug, and provided, through the use of a mechanistic cell model, clearance terms characterizing metabolism, active and passive uptake, together with intracellular binding and partitioning parameters. Results were largely consistent with the particular drug characteristics, with active uptake, passive diffusion, and metabolic clearances ranging between 0.4 and 777, 3 and 383, and 2 and 236 µl/min per milligram protein, respectively. The same experiments provided total and unbound drug cellular partition coefficients ranging between 3.8 and 254 and 2.3 and 8.3, respectively, and intracellular unbound fractions between 0.014 and 0.263. Following in vitro-in vivo extrapolation, the lowest prediction bias was noted using uptake clearance, compared with metabolic clearance or apparent clearance from the media loss assay alone. This approach allows rapid and comprehensive characterization of hepatocyte drug disposition valuable for prediction of hepatic processes in vivo.

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study.

BACKGROUND: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. METHODS: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. RESULTS: Large inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). CONCLUSIONS: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01793012 . Registered on 24 January 2013.

Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections.

We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC0-24/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m2, respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h; volume in the central compartment, 72.50 ± 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h-1; and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h-1 A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus for an AUC0-24/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC = 56 and 69%, fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC ≥ 82%, fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance.

BACKGROUND: Aminoglycoside clearance depends on kidney function, but the Australian Therapeutic Guidelines for antibiotics (version 14, 2010) recommend initial dosing based on weight without consideration of kidney function. Other guidelines that modify dosing based on kidney function estimates often use the Cockroft-Gault equation, but the role of the estimated glomerular filtration rate equations for this purpose is unclear. AIM: To determine the performance of current guideline dosing in achieving target area-under-the-curve and examine the relative precision of the estimated glomerular filtration rate equations compared with traditional Cockroft-Gault creatinine clearance in predicting aminoglycoside clearance. METHODS: We analysed 496 aminoglycoside treatment episodes involving 1377 infusions in adult patients. Conformity with antibiotic guideline dosing was achieved if the discrepancy between prescribed and recommended dose was less than 15%. Aminoglycoside clearance was determined from linear regression using a one compartment model with the Aminoglycoside Levels and Daily Dose Indicator programme. We assessed the precision of the Cockroft-Gault, Modification of Diet in renal Disease Study and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in predicting aminoglycoside clearance by correlation and linear regression. RESULTS: Conformity with guideline dosing was not associated with achieving target area-under-the-curve. The CKD-EPI estimated glomerular filtration rate adjusted for body surface area showed the highest correlation (gentamicin, r = 0.66; tobramycin, r = 0.82) and best predictive model for aminoglycoside clearance. CONCLUSION: Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.

Aldehyde oxidase activity in donor-matched fresh and cryopreserved human hepatocytes and assessment of variability in 75 donors.

Studies were conducted to evaluate the impact of time and cryopreservation on aldehyde oxidase (AO) activity in human hepatocytes isolated from 10 donor livers, using O(6)-benzylguanine as a probe substrate. In addition, variability in activity was assessed using cryopreserved hepatocytes from 75 donors. Substantial donor-dependent loss in AO activity within 24 hours after isolation of hepatocytes was observed (average loss of 42%, range 15%-81%). Meanwhile, AO activity in cryopreserved hepatocytes more closely represented the activity observed in fresh hepatocytes that were incubated immediately after isolation for the same donors (within 81% of fresh, range 48%-100%). Activity of AO in cryopreserved hepatocytes from 75 donors varied by at least 17-fold (≤ 5.4 to 90 ml/minute per kilogram of body weight), with 63% of the donors having higher activity than a pooled 19-donor lot (34.2 ml/minute per kilogram). Comparison of demographics such as gender, body mass index, age, and ethnicity showed no statistically significant correlations with activity. Evaluation of medical histories revealed that three of the five donors with no measurable activity had immediate histories of extensive alcohol abuse. Meanwhile, two single nucleotide polymorphisms (SNPs) for AOX1 (rs3731772 and rs55754655) were detected in our donor pool and showed allelic frequencies similar to those reported from other cohort studies. However, these SNPs did not correlate with a statistically significant difference in intrinsic clearance compared with wild-type donors. With a general lack of clarity about what causes highly variable AO activity, prescreening donors for AO activity and creating a custom high-activity pooled lot of cryopreserved hepatocytes are advised to minimize underpredictions of clearance.

Estimation of the interindividual variability of cytochrome 2D6 activity from urinary metabolic ratios in the literature.

Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its intrinsic metabolic activity (CL(int,CYP2D6,app)) relative to extensive metabolizers (EM) and its variability were estimated by analyzing the urinary metabolic ratios (MR) based on the well-stirred model. Sparteine and debrisoquine were considered to be appropriate probes for our methodology, whereas dextromethorphan was not appropriate since the formation of its metabolite of interest is not described by the well-stirred model. From the analysis of MRs of sparteine and debrisoquine for Caucasian subjects in the literature, CL(int,CYP2D6,app) for intermediate metabolizers (IM) was estimated to be approximately 15% of that for EM. The coefficient of variability (CV) of CL(int,CYP2D6,app) was estimated to be approximately 60% for both EM and IM and 100% for the combined population of ultrarapid metabolizer, EM and IM [i.e., the non-poor metabolizer (non-PM) population]. Simulation of exposure in the non-PM population showed that the CV of exposure was 140% for dextromethorphan and 71% for metoprolol, which reflected the reported values of 110% and 53% for dextromethorphan and metoprolol, respectively. The present study should be useful for predicting the interindividual variability in exposure to investigational drugs that are metabolized by CYP2D6.

Prescribing and monitoring clozapine in Christchurch.

OBJECTIVE: The aim of the study was to identify the pattern of usage of clozapine in Christchurch, New Zealand, including daily dose, indication and use of drug concentration monitoring. METHOD: Patients (n=353) were identified retrospectively from the pharmacy computer system. Data gathered included patient demographics, the daily clozapine dose and the number of occasions that clozapine drug concentration monitoring occurred. In addition, each psychiatrist who had prescribed clozapine was surveyed, regarding their indications for the use of clozapine and their use of clozapine drug concentration monitoring. RESULTS: The majority (63%) of patients on clozapine were male. The mean age of the patients was 43 years (range 15-88 years). The mean daily dose of clozapine was 325 mg (range 12.5-900 mg). Patients over the age of 65 years were on a significantly lower dose (mean=143 mg, 95% CI=103-183 mg) compared with those under 65 years of age (mean=350 mg, 95% CI=330-370 mg). The median duration of treatment on clozapine was 4 years. Fifty-one percent of patients had undergone drug concentration monitoring, the majority on multiple occasions. In females, increasing age correlated with an increase in dose-corrected plasma clozapine concentrations (r(2)=0.29, p<0.001). This was not demonstrated in the male population. Of the psychiatrists surveyed, 44% prescribed clozapine for unlicensed indications and 79% used clozapine drug concentration monitoring in their patients. This was most commonly performed to assess compliance or confirm toxicity. CONCLUSIONS: The mean daily dose of clozapine of 325 mg was similar to that found in other studies. An age-related decline in dose was observed, probably due to different indications, with many of the elderly patients receiving clozapine for Parkinsonian related symptoms. There was also an age-related decline apparent in clearance in females. Clozapine was often used for unlicensed indications, and a clear majority of psychiatrists use drug concentration monitoring.

Familial influences and obesity-associated metabolic risk factors contribute to the variation in resting energy expenditure: the Kiel Obesity Prevention Study.

BACKGROUND: A low metabolic rate may be inherited and predispose to obesity, whereas a higher metabolic rate in obesity may be acquired by obesity-associated cardiometabolic risk. OBJECTIVE: We aimed to explain the interindividual variation in resting energy expenditure (REE) by assessing 1) the association between REE and body composition, thyroid hormones, and obesity-related cardiometabolic risk factors, and 2) the familial (genetic and environmental) contribution to REE. DESIGN: REE and metabolic risk factors (ie, blood pressure and plasma insulin, glucose, and C-reactive protein concentrations) were assessed in 149 two- or three-generation families, including at least one overweight or obese member. Heritability of REE, respiratory quotient (RQ), thyroid hormones [thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)], and body composition (fat-free mass and fat mass) were estimated by using variance components-based quantitative genetic models. RESULTS: REE adjusted for body composition, sex, and age (REEadj) significantly correlated with systolic and diastolic blood pressure, plasma insulin and glucose concentrations, and the homeostasis model assessment (HOMA) (r = 0.14-0.31, P < 0.05). Thyroid hormones had a modest influence on REE variance only. Heritability was 0.30 +/- 0.07 for REEadj and 0.29 +/- 0.08 for REE after additional adjustment for thyroid hormones and metabolic risk. Furthermore, heritability was estimated to be 0.22 +/- 0.08 for RQ, 0.37 +/- 0.08 for TSH, 0.68 +/- 0.06 for FT4, and 0.69 +/- 0.05 for FT3 (all significantly larger than zero). CONCLUSIONS: Obesity-related cardiometabolic risk factors contribute to interindividual variation in REE, with hypertension and insulin resistance being associated with a higher REE. REE was moderately heritable, independent of body composition, sex, age, thyroid function, and cardiometabolic risk.

Neurocognitive costs and benefits of psychotropic medications in older adults.

Psychotropic medications are widely used in older adults and may cause neurocognitive deficits. Older adults are at increased risk of developing adverse effects because of age-related pharmacodynamic and pharmacokinetic changes. This article provides a comprehensive review of the undesirable, and at times beneficial, effects of psychotropic medications. The review covers a wide range of medications that impair executive function, memory, and attention, as well as a much smaller group of medications that lead to improved neurocognitive function. Some of the most commonly used psychotropic medications in older adults, namely, antidepressants, sedatives, and hypnotics, are among the drugs that most consistently lead to cognitive impairments. Medications with anticholinergic properties almost invariably lead to neurocognitive dysfunction, despite symptom improvement. The neurocognitive costs and benefits of psychiatric medications should be considered in the context of disease treatment in older adults.

Avaliação do ritmo de filtração glomerular / Assessment of glomerular filtration rate

A medida do ritmo de filtração glomerular (RFG) é a prova laboratorial mais utilizada na avaliação da função renal. Para tanto, usam-se marcadores indiretos, como as determinações de creatinina e cistatina C no sangue, ou procede-se à determinação do RFG propriamente dito, com indicadores como inulina; contrastes iodados, marcados ou não; e outras substâncias. O exame mais solicitado para avaliação do RFG no laboratório de patologia clínica é a dosagem da creatinina sérica. Em algumas condições, entretanto, o resultado encontrado da creatinina sérica deve ser corrigido (através da utilização de fórmulas que levam em consideração características próprias do indivíduo) para ser devidamente interpretado. De fato, a inulina ainda é vista como marcador ideal de filtração glomerular, mas seu uso não se destina à prática clínica, de modo que ainda hoje persiste a busca por testes adequados para uso rotineiro.

Glomerular filtration rate (GFR) determination is the most frequently used laboratorial test to evaluate renal function. Indirect markers as blood determination of creatinine and cystatin C are used with this purpose, as well as the direct determination of GFR, with indicators like inulin; iodated contrasts, radioactive or not; and others. Serum creatinine is the test that is most commonly performed in order to evaluate GFR in the clinical pathology laboratory. However, in some conditions, aiming at the adequate interpretation of the test, the result of serum creatinine must be corrected (by using formulas that include individual characteristics of the subjects). In fact, inulin is still seen as the ideal marker of glomerular filtration, but its use is not directed to clinical practice; then the search for appropriate tests for routine use continues.

Prescribing medications in pediatrics: concerns regarding FDA approval and pharmacokinetics.

Prescribing medications "off-label" is a common practice in pediatric health care since many medications lack U.S. Food and Drug Administration (FDA) approval for pediatric drug labeling due to insufficient drug testing in children. This clinical paper reviews the FDA laws regarding approval of medications in children and the pharmacokinetic differences in absorption, distribution, metabolism and excretion between children and adults. Two commonly used pharmacology resources were reviewed to determine their identification of FDA approved indications in children and dosing recommendations by age or weight in children. Adhering to the "community's standard of care" is a common guideline for prescribing "off-label" in pediatrics, but must be used in combination with multiple respected pediatric resources and with full knowledge of pharmacokinetics in children, particularly in young children.

Renal evaluation in the healthy green iguana (Iguana iguana): assessment of plasma biochemistry, glomerular filtration rate, and endoscopic biopsy.

Plasma biochemistry, iohexol clearance, endoscopic renal evaluation, and biopsy were performed in 23 clinically healthy 2-yr-old green iguanas (Iguana iguana). Mean (+/- SD) values for packed cell volume (30 +/- 3%), total protein (62 +/- 7 g/L, 6.2 +/- 0.7 g/dl), albumin (25 +/- 2 g/L, 2.5 +/- 0.2 g/dl), globulin (37 +/- 6 g/L, 3.7 +/- 0.6 g/ dl), total calcium (3.0 +/- 0.2 mmol/L, 12.0 +/- 0.7 mg/dl), ionized calcium (1.38 +/- 0.1 mmol/L), phosphorus (1.32 +/- 0.28 mmol/L, 4.1 +/- 0.9 mg/dl), uric acid (222 +/- 100 micromol/L, 3.8 +/- 1.7 mg/dl), sodium (148 +/- 3 mmol/L or mEq/ L), and potassium (2.6 +/- 0.4 mmol/L or mEq/L) were considered within normal limits. Values for urea were low (< 1.4 mmol/L, < 4 mg/dl) with 70% of samples below the detectable analyzer range. After the i.v. injection of 75 mg/ kg iohexol into the caudal (ventral coccygeal or tail) vein, serial blood collections were performed over 32 hr. Iohexol assays by high-performance liquid chromatography produced plasma iohexol clearance graphs for each lizard. A three-compartment model was used to fit area under the curve values and to obtain the glomerular filtration rate (GFR) using regression analysis. The mean GFR (SD) was 16.56 +/- 3.90 ml/kg/hr, with a 95% confidence interval of 14.78-18.34 ml/kg/hr. Bilateral endoscopic renal evaluation and biopsy provided tissue samples of excellent diagnostic quality, which correlated with tissue harvested at necropsy and evaluated histologically. None of the 23 animals demonstrated any adverse effects of iohexol clearance or endoscopy. Recommended diagnostics for the evaluation of renal function and disease in the green iguana include plasma biochemical profiles, iohexol clearance, endoscopic examination, and renal biopsy.

Voltammetric assessment of dopamine clearance in the absence of the dopamine transporter: no contribution of other transporters in core or shell of nucleus accumbens.

Cocaine elevates dopamine (DA) in the nucleus accumbens (NAc) by blocking the uptake of DA through the DA transporter (DAT). It is commonly believed that the reinforcing properties of cocaine depend upon interaction with the DAT, however, cocaine is still reinforcing in mice with a genetic deletion of the DAT (DAT-KO mice). Although cocaine continues being able to elevate DA in the NAc of these mice, this mechanism is unclear. The present voltammetric study in brain slices was designed to examine the role of the norepinephrine and serotonin transporters in removing DA from the extracellular space in the NAc of DAT-KO mice. We found no effects of any monoamine uptake inhibitors, including cocaine (10 microM), desipramine (10 microM) or fluoxetine (10 microM) on the clearance of DA in these mice. Therefore, it appears that there is no compensatory uptake of DA by alternative transporters either in core or shell of the nucleus accumbens of DAT-KO mice.