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Background: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza.Methods: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose.Results: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8-14.9) microg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257-900) microg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2=0.00, p=0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2=0.27, p<0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function.Interpretation: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prescription claims data have been used to estimate refill medication adherence through calculations of cumulative medication acquisition (CMA) and cumulative medication gap (CMG) values. Few studies have assessed the validity of these calculated rates. OBJECTIVES: We sought to assess the validity of CMA and CMG calculated from the Manitoba prescription claims database (DPIN) against pill count medication adherence, targeting overall medications and angiotensin converting enzyme inhibitors (ACEIs). METHODS: Using a survey of a convenience sample of subjects recruited through community pharmacies, subjects who were eligible for study (ie, 65 years or older, noninstitutionalized, taking 2 or more 'discrete' prescribed medications, including an ACEI, and willing to provide informed consent) were studied. Pill counts were conducted on all prescribed medicines during 3 home interviews over the course of 4 months. Ten months of DPIN data also were collected on each subject. RESULTS: The concordance between CMA and pill count for overall medications was 411/522 (79%) and for ACEIs was 89/101 (88%) with no systematic differences (McNemar's P = 0.68 and P = 0.097, respectively). CMG and pill count showed even better concordance of 438/514 (85%) for overall medications and 96/101 (95%) for ACEIs, although systematic differences were noted for overall medications (McNemar's P = 0.0012) but not for ACEIs (McNemar's P = 0.500). Spearman's rank correlations were weak for all comparisons. CONCLUSIONS: The high concordance between prescription claims database and pill counts suggested that the rate with which patients refill their medications usually is consistent with the rate they consume them. DPIN is not accurate for nondiscrete dosage forms or medications prescribed for 'as-required' use. [ABSTRACT FROM AUTHOR]

Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharmacokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CL(d) with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary. [ABSTRACT FROM AUTHOR]

Background: Although gentamicin is used extensively within the first week of life for suspected sepsis in neonates, little is known about the performance of gentamicin dosing nomograms in this population.Objective: The goal of our study was to retrospectively assess the performance of a gentamicin dosing nomogram in neonates given gentamicin during the first week after birth.Methods: In this retrospective study, gentamicin therapeutic drug monitoring data were collected during routine clinical care for all neonates who were born in St. Boniface General Hospital (Winnipeg, Manitoba, Canada) between January 1999 and April 2001 and given gentamicin during the first week after birth. We used Bayesian pharmacokinetic analysis to retrospectively assess the performance of our gentamicin dosing nomogram in neonates born at gestation ages <32 weeks, between 32 and 34 weeks, and >34 weeks. Bayesian pharmacokinetic values for parameters within groups were compared and used to explore predicted peak and trough serum gentamicin concentrations based on the institutional dosing nomogram.Results: In a total of 58 neonates, those neonates born at +/- 34 weeks' gestation had a weight-normalized apparent volume of gentamicin distribution 1.6 times larger than infants born after 34 weeks' gestation (P<0.001), as identified by Bayesian analysis. Weight-normalized gentamicin clearance was 22% lower in the youngest age category (P<0.01). Only 33% of predicted peak serum gentamicin concentrations were >6 mg/L for neonates born at 34 weeks' gestation, whereas 90% were therapeutic in neonates born at

The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM-derived parameters were a total body clearance of 2.12 +/- 0.28 L/kg/h, distributional clearance of 8.43 +/- 4.58 L/kg/h, central volume of distribution of 1.22 +/- 0.21 L/kg, and peripheral volume of distribution of 1.81 +/- 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics. [ABSTRACT FROM AUTHOR]

Objective: To conduct a meta-analysis of randomized controlled trials of antibiotic treatment of acute otitis media in children to determine whether outcomes were comparable in children treated with antibiotics for less than 7 days or at least 7 days or more.Data Sources: MEDLINE (1966-1997), EMBASE (1974-1997), Current Contents, and Science Citation Index searches were conducted to identify randomized controlled trials of the treatment of acute otitis media in children with antibiotics of different durations.Study Selection: Studies were included if they met the following criteria: subjects aged 4 weeks to 18 years, clinical diagnosis of acute otitis media, no antimicrobial therapy at time of diagnosis, and randomization to less than 7 days of antibiotic treatment vs 7 days or more of antibiotic treatment.Data Extraction: Trial methodological quality was assessed independently by 7 reviewers; outcomes were extracted as the number of treatment failures, relapses, or reinfections.Data Synthesis: Included trials were grouped by antibiotic used in the short course: (1) 15 short-acting oral antibiotic trials (penicillin V potassium, amoxicillin [-clavulanate], cefaclor, cefixime, cefuroxime, cefpodoxime proxetil, cefprozil), (2) 4 intramuscularceftriaxone sodium trials, and (3) 11 oral azithromycin trials. The summary odds ratio for treatment outcomes at 8 to 19 days in children treated with short-acting antibiotics for 5 days vs 8 to 10 days was 1.52 (95% confidence interval [CI], 1.17-1.98) but by 20 to 30 days outcomes between treatment groups were comparable (odds ratio, 1.22; 95% CI, 0.98 to 1.54). The risk difference (2.3%; 95% CI,-0.2% to 4.9%) at 20 to 30 days suggests that 44 children would need to be treated with the long course of short-acting antibiotics to avoid 1 treatment failure. This similarity in later outcomes was observed for up to 3 months following therapy (odds ratio, 1.16; 95% CI, 0.90-1.50). Comparable outcomes were shown between treatment with ceftriaxone or azithromycin, and at least 7 days of other antibiotics.Conclusion: This meta-analysis suggests that 5 days of short-acting antibiotic use is effective treatment for uncomplicated acute otitis media in children. [ABSTRACT FROM AUTHOR]

1 The kinetic disposition of a novel xanthine bronchodilator, enprofylline, was determined in young healthy male volunteers in the presence and absence of amoxycillin or erythromycin. These data were compared to those derived from a similar study of theophylline disposition in the presence and absence of erythromycin. 2 Erythromycin inhibited theophylline disposition only in those subjects in whom the control kinetic study was done after antibiotic ingestion, but the effect was modest. Erythromycin had no effect on enprofylline disposition. 3 Amoxycillin reduced the renal clearance of enprofylline, but the change was not statistically significant. [ABSTRACT FROM AUTHOR]

1 To compare classical linear regression techniques and a Michaelis- Menten elimination model eight normal human volunteers each received three intravenous doses (0.375, 0.5, and 0.75 g/kg) of ethanol and four of the subjects each received four oral doses (0.5, 0.65, 0.95, 1.25 g/kg) of ethanol. 2 Computerized analysis of the time-plasma concentration profiles using a two-compartment Michaelis-Menton elimination model yielded a median absorption constant of 1.29 h-1; volume of distribution of 0.47 l/kg; Vmax of 0.12 g h-1 kg-1; and Km of 0.03 g/l. Classical techniques resulted in a slope of 0.20 g l-1 h-1, volume of distribution of 0.55 l/kg, and a B60 of 0.11 g h-1 kg-1. 3 Transient post-prandial decreases in elimination slope occurred at higher oral doses. A trend of increasing slope with increasing oral dose was seen at concentrations well above the Km. Time to sobriety (0.8 g/l) increased nonlinearly with increasing peak concentration. 4 Maximal ethanol elimination rates are determined equally well by the two techniques. Classical analyses overestimate the volume of distribution of ethanol by 17%. Neither technique helps explain the post-prandial changes in slope or increasing slope with dose at high concentrations. [ABSTRACT FROM AUTHOR]

The kinetic disposition and diuretic effect of frusemide was assessed in 16 patients with acute pulmonary oedema utilizing a specific gas- liquid chromatographic assay for the drug. Serum frusemide concentrations decayed biexponentially with wide variation in both alpha half-life (range 15-79 min) and beta half-life (range 127-1190 min). The beta phase half-life was inversely related to creatine clearance. The apparent volume of distribution varied greatly among the patients (range 0.085-0.818 l/kg), and patients with an acute myocardial infarction had a larger peripheral kinetic compartment. Patients with acute myocardial infarction excreted less unchanged drug and had a lesser urinary excretion of sodium and volume compared to patients without infarction. The urinary excretion of sodium, chloride, calcium and volume was linearly related to the urinary excretion of unchanged frusemide. [ABSTRACT FROM AUTHOR]

Spermidine/spermine N1-acetyltransferase 1 ( SAT1 ) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-si SAT1 ) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-si SAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-si SAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood-brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-si SAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-si SAT1 . These results suggest LNP-si SAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.

Aim: The assessment of tumor response to therapy is of critical importance as it permits for a prospective end point evaluation and provides a guide to clinicians for making future treatment decisions. However, current practices in early evaluation of chemotherapy are insufficient. Amantadine is a substrate for SSAT-1 . The present pilot study tests the hypothesis that SSAT-1 activity within the tumor, as measured by plasma acetylamantadine concentrations, can be used to monitor patient response to therapy., Results: In cases with evidence of disease response, there was a reduction in the plasma acetylamantadine concentration at 4 h by approximately 32%. There was a mean increase of approximately 34% at the 4 h collection in the nonresponders., Conclusion: Although large-scale studies are required these findings suggest that the amantadine test could allow for determination of the efficacy of therapeutic interventions earlier, providing an effective test to assess response to treatment and for better management of patients., Competing Interests: Financial & competing interests disclosure RA Bux is the President and CEO of BioMark Diagnostics Inc. D Moyer is Clinical Research Manager at BioMark Diagnostics Inc. G Huang is Project Director at BioMark Diagnostics Inc. AW Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics Inc. This study was supported, in part, by Biomark Diagnostics Inc. (BC, Canada), Maunders-McNeil Foundation (AB, Canada) and the University of Manitoba. Biopharmaceutical Research Inc. (BC, Canada) completed the LC/MS/MS analyses. Infrastructural support was provided by the St Boniface Hospital Foundation and the University of Manitoba. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2021 Paramjit S. Tappia, Andrew W. Maksymiuk, Rashid Ahmed Bux et al.)

The objective of this research is to use metabolomic techniques to discover and validate plasma metabolite biomarkers for the diagnosis of early-stage non-small cell lung cancer (NSCLC). The study included plasma samples from 156 patients with biopsy-confirmed NSCLC along with age and gender-matched plasma samples from 60 healthy controls. A fully quantitative targeted mass spectrometry (MS) analysis (targeting 138 metabolites) was performed on all samples. The sample set was split into a discovery set and validation set. Metabolite concentration data, clinical data, and smoking history were used to determine optimal sets of biomarkers and optimal regression models for identifying different stages of NSCLC using the discovery sets. The same biomarkers and regression models were used and assessed on the validation models. Univariate and multivariate statistical analysis identified β-hydroxybutyric acid, LysoPC 20:3, PC ae C40:6, citric acid, and fumaric acid as being significantly different between healthy controls and stage I/II NSCLC. Robust predictive models with areas under the curve (AUC) > 0.9 were developed and validated using these metabolites and other, easily measured clinical data for detecting different stages of NSCLC. This study successfully identified and validated a simple, high-performing, metabolite-based test for detecting early stage (I/II) NSCLC patients in plasma. While promising, further validation on larger and more diverse cohorts is still required.

Background : Lung cancer is the most common cause of cancer-related deaths worldwide. Early diagnosis is crucial to increase the curability chance of the patients. Low dose CT screening can reduce lung cancer mortality, but it is associated with several limitations. Metabolomics is a promising technique for cancer diagnosis due to its ability to provide chemical phenotyping data. The intent of our study was to explore metabolomic effects and profiles of lung cancer patients to determine if metabolic perturbations in the SSAT-1/polyamine pathway can distinguish between healthy participants and lung cancer patients as a diagnostic and treatment monitoring tool. Patients and Methods : Plasma samples were collected as part of the SSAT1 Amantadine Cancer Study. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and quantify metabolite concentrations in lung cancer patient and control samples. Standard statistical analyses were performed to determine whether metabolite concentrations could differentiate between healthy subjects and lung cancer patients, as well as risk prediction modeling applied to determine whether metabolic profiles could provide an indication of cancer progression in later stage patients. Results : A panel consisting of 14 metabolites, which included 6 metabolites in the polyamine pathway, was identified that correctly discriminated lung cancer patients from controls with an area under the curve of 0.97 (95% CI: 0.875-1.0). Conclusion: When used in conjunction with the SSAT-1/polyamine pathway, these metabolites may provide the specificity required for diagnosing lung cancer from other cancer types and could be used as a diagnostic and treatment monitoring tool.

Aim: Spermidine/spermine N 1 -acetyltransferase (SSAT-1) regulates cell growth, proliferation and death. Amantadine is converted by SSAT-1 to acetylamantadine (AA). In our earlier studies, although SSAT-1 was activated in patients with cancer, a number of ostensibly healthy adult volunteers had higher than expected AA concentration. This study was therefore undertaken to examine the outlier group., Materials & Methods: A follow up of urine analysis for AA by liquid chromatography-tandem mass spectrometry as well as clinical assessments and additional blood analyses were conducted., Results: In some of the outlier controls, higher than expected AA concentration was linked to increased serum carcinoembryonic antigen. Clinical and radiographic assessments revealed underlying abnormalities in other cases that could represent premalignant conditions. Hematology tests revealed elevations in white blood cells and platelets, which are markers of inflammation., Conclusion: High urine concentration of AA could be used as a simple and useful test for screening of cancer in high-risk populations., Competing Interests: Financial & competing interests disclosure RB Ahmed is the President and CEO and B Cheng is the acting CTO of BioMark Diagnostics Inc. A Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics Inc. This study was supported, in part, by BioMark Diagnostics Inc. (BC, Canada) and the Maunders-McNeil Foundation (AB, Canada). LC–MS/MS analysis was conducted by Biopharmaceutical Research Inc. (BC, Canada). Infrastructural support was provided by the St Boniface Hospital Foundation and the University of Manitoba. Part of this work was published in abstract form in the 2019 ASCO meeting proceedings (online): https://meetinglibrary.asco.org/record/177214/abstract The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Aim: Spermidine/spermine N 1 -acetyltransferase (SSAT-1) plays a critical role in cell growth, proliferation and death, and is known to be activated in human cancer cells. Amantadine, a US FDA-approved antiviral drug, is a substrate for SSAT-1 and can be used to indirectly measure SSAT-1 activity because of its conversion to acetylamantadine (AA). This study was undertaken to further validate SSAT-1 activity in breast and lung cancer patients., Results: An increase in the urinary concentration of AA in lung and breast cancer patients was observed. The 0-2 h collection time point was determined to be optimal in revealing significant differences in urinary AA concentration between healthy controls and cancer patients., Conclusion: The high urine concentration of AA could be used as a simple and useful test for the detection of breast and lung cancer., Competing Interests: Financial & competing interests disclosure This study was supported, in part, by Biomark Diagnostics, Inc. (Richmond, BC, Canada) and the Maunders-McNeil Foundation (Edmonton, AB, Canada). The study was also funded by the University of Manitoba and Biomark Diagnostics, Inc. None of the authors has conflict of interest to disclose. However, RB Ahmed is the President and CEO and B Cheng is the acting CTO of BioMark Diagnostics, Inc. A Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Aim: SSAT-1 is an enzyme that plays a critical role in cell growth. Amantadine, a FDA-approved antiviral drug, is a substrate for SSAT-1. The utility of amantadine as an agent to demonstrate elevated SSAT-1 activity linked to cancer was conducted., Results: High levels of SSAT-1 expression were measured in tumor human cell lines, and in breast, prostate and lung tumor tissue. An increase in the urinary levels of acetylated amantadine in cancer patients was observed., Conclusion: Increases in SSAT-1 contents in tumor tissue could be of value in targeting cancers with high SSAT-1 expression for confirmation/quantification. The high levels of acetylated amantadine could be used as a simple and useful screening test for the presence of cancer., Competing Interests: Financial & competing interests disclosure This study was supported by the Manitoba Tumor Bank, Winnipeg, Manitoba and a member of the Canadian Tumor Repository Network and funded in part by Cancer Care Manitoba and the Canadian Institutes of Health Research and the Maunders-McNeil Foundation. The study was also funded by the University of Manitoba and Biomark Diagnostics Inc. None of the authors has conflict of interest to disclose. R Ahmed is the president and CEO and B Cheng is the acting CTO of BioMark Diagnostics Inc. (Richmond, BC, Canada), which has partially sponsored this study. AW Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

While assessing the ability of mammalian lung tissue to metabolize theophylline, a new metabolite was isolated and characterized. The metabolite was produced by the microsomal fraction of lungs from several species, including rat, rabbit, dog, pig, sheep and human tissue. Metabolite production was blocked by boiling the microsomal tissue. This new metabolite, theophylline-7β-d-ribofuranoside (theonosine), was confirmed by several spectral methods and by comparison to an authentic synthetic compound. Tissue studies from rats, rabbits, dogs, and humans for cofactor involvement demonstrated an absolute requirement for NADP and enhanced metabolite production in the presence of magnesium ion. It remains to be demonstrated whether theonosine may contribute to the known pharmacological effects of theophylline., Competing Interests: The authors declare no conflicts of interest.

Background: Owing to its ability to form spores and toxins, Bacillus anthracis is considered a bioterror agent. Although current therapeutic strategies can be effective, treatment does not prevent sporulation and toxin production., Objectives: To quantify the combined effect of a protein synthesis inhibitor and a bactericidal agent on B. anthracis toxin production, sporulation and cell growth., Methods: Susceptibility and synergy titrations were conducted on B. anthracis Sterne and 03-0191 strains using linezolid and levofloxacin. The effect of antibiotic exposure on cell viability was evaluated using a continuous medium replacement model. In vitro static models were used to study the effect of linezolid and levofloxacin on sporulation and toxin production. Spores were quantified using the heat shock method. Toxin was quantified via commercial ELISA., Results: Synergy titrations indicated that the combination was synergistic or indifferent; however, in all models antagonism was observed. In the spore model, linezolid resulted in the lowest sporulation rates, while combination therapy resulted in the highest. In the toxin model, linezolid prevented toxin production altogether., Conclusions: This study advances our understanding of the effects of combination therapy on B. anthracis infection. Used alone, linezolid therapy abolishes toxin production and reduces sporulation. These results suggest that studies using a step-wise approach using linezolid initially to stop sporulation and toxin production followed by levofloxacin to rapidly kill vegetative B. anthracis can be recommended., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Higher doses of cefazolin are required in obese patients for preoperative antibiotic prophylaxis, owing to its low lipophilicity. An ultra high performance liquid chromatography-tandem mass spectrometry method was developed to quantify cefazolin in serum and adipose tissue from 6 obese patients undergoing cesarean delivery, and using stable-isotope labeled cefazolin as an internal standard. The method has a 2μg/g lower limit of quantitation. The concentration in adipose tissue was 3.4±1.6μg/mL, which is less than half of the reported minimum inhibitory concentration of 8μg/mL for cefazolin. Serum cefazolin concentrations were more than 30-fold higher than in adipose tissue., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Major advances produced by healthcare research have resulted in an increasing number of drugs that may be used to modify disease expression and improve quality of life. These discoveries have been used by clinical pharmacologists as a basis to identify new drug candidates and to develop strategies for their optimal delivery to maximize benefit while simultaneously minimizing adverse events. Unfortunately, many of these studies do not include sufficient older persons in whom most of these drug therapy interventions are likely to apply. This article examines selected physiological, pathological and healthcare interventional changes with age that impact clinical drug studies and the decision to use drugs as therapy in older adults. Clinical examples are provided that illustrate confounders to the accomplishment of an ideal outcome, the improved quality of life that remains for this population.

Background: Intensive sampling of patients for drugs with complex pharmacokinetic profiles is difficult to perform in the clinic or hospitalized patient setting. We seek to address whether sparse sampling can obtain pharmacokinetic parameter values similar to those with traditional modeling from a post hoc analysis of 2 previous clinical trials., Objective: This study investigated whether population-guided, sparse-sampling pharmacokinetic analysis of morphine in 14 healthy volunteers allowed for optimal characterization of concentration-time profiles for a validation population of 5 young male patients receiving morphine., Methods: Data were analyzed using nonparametric adaptive grid (NPAG) population modeling to investigate optimal compartmental structure and the influence of sparse sampling (ie, 9 versus 3 samples per subject) on parameter identification. These results were compared with traditional standard 2-stage (STS) pharmacokinetic modeling. The coefficients of determination (R(2)), mean error (ME), and root-mean-square error were used to assess the predictive performance of the various sampling models against a validation population., Results: Seventy-nine percent of the healthy volunteers were male, with a mean age of 36 (17) years and a mean weight of 68 (10) kg. NPAG modeling identified that intravenous morphine was best represented by a 3-compartment pharmacokinetic profile and that sparse sampling with a least 3 blood samples per subject resulted in virtually identical measures of central tendency as the more intensively sampled dataset. A validation cohort of 5 male patients undergoing elective surgery had a mean age of 26 (4) years and a mean weight of 80 (13) kg. Using mean parameter estimates generated from sparse sampling and the 3-compartment model structure, simulated profiles were compared against measured concentrations in this validation cohort. Sparse sampling using NPAG achieved similar values of predictive performance as mean parameter values from the more intensively sampled, with an ME of -1.0 ng/mL and precision of 26.2 ng/mL compared with 0.76 ng/mL and 25.8 ng/mL, respectively. Traditional (STS) modeling techniques resulted in the greatest degree of underprediction within the validation group (ME = 4.43 versus 0.76 ng/mL, STS and NPAG-9, respectively; P < 0.0001)., Conclusions: This post hoc analysis suggests that intensive sampling for discerning complex, 3-compartment pharmacokinetic models, such as morphine, may not be necessary. Sparse sampling achieved accurate model structure recognition and parameter identification for predicting concentrations of very complex drug-dosage regimens., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: An influenza neuraminidase inhibitor drug, oseltamivir (Os) may be prescribed to renal transplant patients to prevent and treat influenza A and B illness. A pharmacokinetic (PK) interaction between Os and immunosuppressive drugs might adversely affect the efficacy and/or toxicity of the latter agents. This study was conducted to determine whether adverse symptoms and acute drug interactions occur during their coadministration., Materials and Methods: A randomized, crossover study design was utilized to study the effect of a 75-mg dose of Os on the steady-state PK of cyclosporine A (CyA), mycophenolate mofetil, or tacrolimus (Tac) in a convenience sample of 19 adults with a renal allograft by measurement of total plasma or blood drug concentrations (C(p)) over one 12-hour dose interval. Os PK parameters were determined from its concentrations and those of its metabolite, Os carboxylate, in plasma and urine over 48 hours., Results: Of 19 volunteers, 12 were men, with age (mean ± SD) 46 ± 11 years, weight 83 ± 19 kg, and calculated Cl(creatinine) 64 ± 27 mL/min. Adverse effects were minor and transient. Os did not affect the steady-state C(max), T(max), or area under the concentration versus time curve (AUC) over a 12-hour dose interval of CyA, mycophenolic acid, or Tac or the C(trough) of CyA or mycophenolate but increased the mean C(trough) of Tac by 13%., Discussion: The increase in Tac mean C(trough) during coadministration with Os is not likely clinically important. Os and Os carboxylate PK were similar to those in subjects with native kidneys and similar renal function who have been described in the literature., Conclusions: These data from a single Os dose study suggest that coadministration is not expected to cause adverse symptoms nor alter the steady-state PK of CyA, mycophenolate mofetil, or Tac in stable adult renal transplant patients with mild renal insufficiency. The data enable a multiple-dose study that reflects clinical practice during influenza exposure and assesses the possibility that chronic exposure to Os might result in a different outcome.

Previous studies showed that amantadine transport increased while tetraethylammonium (TEA) transport decreased in kidney tissue from diabetic rats. Changes in transport activity were reversed by exogenous insulin. We hypothesized that this difference in transport regulation is due to differential regulation of different transport systems. Native human embryonic kidney cortex cells (HEK293 cell line) and rat organic cation transporter (rOCT)-transfected cells were used to test the hypothesis. In support of differential regulation, short-term glucose starvation stimulated amantadine transport and inhibited TEA transport, but the effect was bicarbonate-modulated only for amantadine. cAMP analogues inhibited TEA transport while stimulating amantadine transport. This effect was additive to the effect of insulin, and the presence of bicarbonate affected the extent of the change. Our findings indicated that regulation of rOCT 1 and 2 was mediated by transmembrane adenylyl cyclase, and regulation of amantadine transport was mediated by soluble adenylyl cyclase, suggesting that intracellular microdomains of cAMP may be important in determining overall cellular transport for organic cations. Soluble adenylyl cyclase activity is known to be modulated by bicarbonate and lactate. These observations support our hypothesis and reconcile our previous studies demonstrating increased transport affinity for amantadine in the presence of bicarbonate and decreased transport affinity in the presence of lactate.

Background: Ethical problems are quoted as a reason not to perform clinical trials in children. Little is known about the views of researchers regarding ethics., Objectives: A pilot study was conducted to assess the applicability of a questionnaire design containing trial scenarios to examine views regarding the use of children in drug trials and to elicit possible international differences., Setting: Paediatricians and researchers in the United Kingdom and Canada., Methods: Responders were presented with a questionnaire containing direct questions and six trial scenarios, each containing an ethical dilemma. Responders were asked regarding their own approval and their perceived opinion of whether an ethical review board (ERB) would approve., Results: One hundred questionnaires (50 each country) were received. Few responders had research ethics training (14% United Kingdom and 8% Canada). Most (80 and 88%) felt children could be harmed by participation in trials and half (47 and 59%) felt children should only participate if they receive direct benefit. Many (58 and 61%) disagreed with payments beyond travel expenses. In the trial scenarios, 34% of responders were willing to enter healthy children in a pharmacokinetics study of an antibiotic for cystic fibrosis and 22% considered their ERBs would approve. Only a third (33%) would enter children in an analgesia trial that was placebo-controlled., Conclusion: Using healthy children and placebos in trials caused concern. Similar views were found between the two countries. The majority had no training in research ethics. The study highlights the usefulness of a questionnaire with clinical trial scenarios to try to elicit views on the ethics of conducting research in children.

The elderly represent a very rapidly increasing segment of human society worldwide. As people age, they accumulate multiple and chronic diseases that are very often managed with drug therapy. This approach to health maintenance is reflected by the fact that the elderly use a disproportionate amount of prescribed and over-the-counter medications compared to their numbers in the population. Cardiovascular diseases, almost always managed at least in part with drug therapy, remain a leading cause of morbidity and mortality in older individuals. Although we appreciate that there are physiological changes with aging to body composition, and renal, gastrointestinal, hepatic, and cardiovascular function that potentially confound optimization of drug therapy in the elderly, we have been slow to use this knowledge to improve pharmacological therapy of geriatric patients. This overview examines the physiological changes that commonly occur as we age, and focuses on the application of this knowledge to the potential for optimization of drug therapy of cardiovascular diseases of the elderly. Representative cardiovascular drugs are presented that are commonly used, and for which there is evidence of an opportunity to alter their use and potentially to improve therapy in this cohort.

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.

Epidemiological studies support an association between perinatal cigarette smoke (CS) exposure and a number of severe pre- and postnatal complications. However, the mechanisms through which CS enhances such risks largely remain unknown. One of the reasons for our inability to discover such mechanisms has been the unavailability of a clinically relevant and physiologically concordant animal model. A number of studies have previously used nicotine (Nic) as surrogate for CS. We sought to (1) establish the amount of CS exposure to achieve plasma Nic concentrations observed among moderate to heavy smokers (20-60 ng/ml), (2) investigate the temporal changes in plasma Nic concentrations, carboxyhemoglobin, and hematocrit with advancing pregnancy, and (3) elucidate the effects of CS exposure on pregnancy outcome. Pregnant Sprague-Dawley rats were exposed to various doses of CS or room air (Sham) from days 6 to 21 of gestation. Exposure to 6000 ml/day of CS led to very high plasma Nic concentrations and increased maternal and fetal mortality (P < 0.001). The plasma Nic concentrations remained higher than those observed in moderate smokers until the CS dose was reduced to 1000 ml/day and showed dose-dependent temporal changes with advancing gestational age. Significant increases in carboxyhemoglobin and hematocrit were observed in the CS group as compared with the Sham group (P < 0.001). In addition, prenatally CS exposed fetuses had lower birth weight as compared with the Sham group (P = 0.04). Our current study establishes a newly standardized and physiologically relevant model to investigate the mechanisms of CS-mediated adverse effects during the critical period of fetal development.

A bicarbonate-dependent organic cation transporter, unique from rOCT1 and rOCT2, primarily mediates amantadine uptake into renal proximal tubules. We examined whether intracellular pH regulates bicarbonate-dependent amantadine transporter function in these tubules. NH(4)Cl treatment resulted in immediate intracellular alkalinization of tubules for up to 30s followed by gradual acidification that was maximal at 5min. Proximal tubule amantadine uptake was similarly inhibited (60%) by NH(4)Cl during both the early intracellular alkalinization and later acidification phases. Sodium propionate treatment resulted in immediate intracellular acidification of proximal tubules without inhibiting amantadine uptake. NH(4)Cl inhibition of bicarbonate-dependent amantadine uptake was dose-dependent, competitive and sex-dependent. NH(4)Cl, NH(4)NO(3), (NH(4))(2)SO(4) and (NH(4))(2)HPO(4) inhibited amantadine uptake into proximal tubules similarly. NH(4)Cl also stimulated efflux of amantadine and tetraethylammonium from preloaded proximal tubules, suggesting mediation of a facilitated process. These data suggest the potential for direct modulation of organic cation transporters by NH(4)(+) in rat kidney proximal tubules.

Minocycline reduces infarct volume measured up to 1 week after focal cerebral ischemia, but it has not been shown that this results in lasting improvement in functional outcome. This study examined behavioral outcome in rats out to 3 weeks after focal ischemia induced by injection of the vasoconstrictor endothelin (ET)-1 (400 pmol in 1 microL of saline) into the striatum. Magnetic resonance imaging confirmed reduced blood flow after administration of ET-1, and was used to determine lesion volumes at 1 and 21 days postischemia. In control rats, intraperitoneal injection of minocycline resulted in plasma levels of 6.6 +/- 2.7 microg mL(-1) between 1 and 8 hours after administration. Based on these results, intraperitoneal minocycline treatment was started either 1 hour before or 3 hours after ET-1 administration, and was repeated daily for 5 days. Outcome, assessed using a composite behavioral deficit score (days 2, 4, 7, 14, and 21) and a test of asymmetric forelimb use (days 7 and 21), was significantly better in both groups of rats treated with minocycline, and the improvement was maintained for the 3-week study period. No differences were found in infarct volumes between groups.

Dr. Dan Sitar was the recipient of the 2004 CSCP Senior Investigator Award at the First Canadian Therapeutics Congress held in June 2004. He presented a lecture highlighting some of the studies he participated in that have contributed to an increased understanding of the role of aging on drug disposition and effect.

Background: Some investigators have recommended the convenient practice of administering vancomycin doses during the last hour of the hemodialysis treatment. Accepting that a greater amount of vancomycin is lost to dialysis with this recent approach, the objective of this study is to determine the pharmacokinetics of vancomycin and assess the adequacy of this dosing regimen in maintaining therapeutic predialysis concentrations., Methods: A sampling of 22 consecutive patients administered intradialytic vancomycin, 1 g, intravenously (IV) and maintenance doses of 500 mg during the last hour of high-flux dialysis sessions was studied. A population-modeling program and Bayesian pharmacokinetic analysis were used to identify all global and unique pharmacokinetic parameters of interest based on measured vancomycin predialysis concentrations., Results: For the 22 patients studied, this regimen achieved the targeted predialysis concentration range of 5 to 20 microg/mL for 96% of levels, whereas more narrowly within 5 to 15 microg/mL for 86% of levels. Average amount of vancomycin removed during a standardized 3- to 4-hour dialytic session ranged from 30% +/- 7% to 38% +/- 8%. Average elimination half-life of vancomycin on hemodialysis treatment was 5.4 hours (interquartile range, 5.0 to 5.9 hours). Patients showed an average predialysis plasma concentration of 11 +/- 3 microg/mL for the first 7 days of therapy., Conclusion: Our results indicate that intradialytic dosing with vancomycin using a 1-g IV load and 500 mg IV with subsequent high-flux dialysis sessions conveniently maintains adequate predialysis plasma concentrations. The lack of drug accumulation with this regimen provides convincing support for a limited blood sampling approach to plasma concentration determinations.

Background: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome., Objective: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality., Methods: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome., Results: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01)., Conclusions: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

The organic cation (OC) transporters OCT1 and OCT2 are suspected of mediating substrate entry from the blood into proximal tubule cells as the first step in renal secretion of OCs. We examined the contribution of each process in different rabbit renal proximal tubule (RPT) segments, taking advantage of the fact that rabbit orthologs of OCT1 and OCT2 can be distinguished by the high affinity of the former for tyramine (TYR) and of the latter for cimetidine (CIM). We verified that TEA uptake, for which both transporters share a similar affinity, is relatively constant in all three segments (apparent inhibitory constant of 33, 74, and 30 microM and maximal rate of mediated TEA uptake of 0.8, 1.0, and 1.2 pmol x mm(-1) x min(-1) in S1, S2, and S3, respectively). In the S1 segment, TYR was a more effective inhibitor of TEA uptake than CIM (IC50 values of 39 and 328 microM, respectively), implicating OCT1 as the predominant pathway for TEA transport. The opposite profiles were noted in the S2 segment (IC50 values of 302 and 20 microM for TYR and CIM, respectively) and S3 segment (IC50 values of 2,900 and 54 microM for TYR and CIM, respectively), suggesting that OCT2 is the predominant TEA transporter in the later portion of RPT. TEA sufficient to saturate OCT1 and OCT2 blocked only 37% of mediated amantadine transport in the S2 segment, confirming the functional presence of at least one additional OC transporter (perhaps OCT3). These data indicate that renal OC transport involves the concerted activity of a suite of transport processes.

Background: Although it is a commonly held belief that the ingestion of drugs with an anticholinergic action would prolong the duration of time after drug ingestion for effective gastrointestinal decontamination, data are lacking to support this belief. The purpose of this study is to determine whether activated charcoal is more effective in the presence of concurrent anticholinergic activity., Methods: A three-limbed randomized crossover study in 10 healthy volunteers was completed to determine the ability of a 50 g dose of activated charcoal to reduce the bioavailability of a simulated overdose of acetaminophen (12 x 325 mg tablets) in the presence and absence of a concurrently present anticholinergic drug, atropine (0.01 mg/kg I. M. administered 15 min prior to the acetaminophen ingestion)., Results: After the acetaminophen ingestion, median Cmax occurred at 1 h for all three exposures but was lower in the atropine-treated study arm (31+/-19 mg/L) than in the control or charcoal alone intervention arms (49+/-13 and 51+/-16 mg/L, respectively) (P<0.05). Compared to the control area under the serum concentration vs. time curve, a single dose of activated charcoal 1 h after drug ingestion reduced acetaminophen bioavailability by 20% (95% CI 4-36%) and by 47% (95% CI 35-59%) in the presence of atropine (P<0.05 atropine plus charcoal vs. charcoal alone)., Conclusions: Our data support the belief that activated charcoal is more effective in the presence of anticholinergic activity. Additional study is required to determine whether in patients with anticholinergic drug overdose, activated charcoal is effective at times beyond the recommendation for overdoses of drugs without this pharmacodynamic effect.

Objective: We tested the hypothesis that individualized dosing of amantadine hydrochloride, based upon a patient's creatinine clearance, would maintain efficacy against influenza A infection while reducing adverse reactions to the drug., Design: A prospective cohort study, Participants: Residents of two nursing homes with a total population of 301 individuals, Intervention: Amantadine hydrochloride was administered prophylactically subsequent to a confirmed influenza A outbreak. The dose was individualized based upon the resident's calculated creatinine clearance., Results: The concentration of amantadine hydrochloride in the circulation at steady-state in patients who had doses adjusted for their estimated creatinine clearance was not different by nursing home or by sex of the resident. The mean concentration was within the 95% CI for the target concentration of 1.6 micromol/L. Side effects were modest and did not require discontinuation of amantadine hydrochloride therapy. Only the presence of concurrent influenza-like illness was significantly associated with adverse events during amantadine hydrochloride therapy., Conclusions: Adjustment of doses for estimated creatinine clearance is feasible in a long term care facility when amantadine hydrochloride is indicated for influenza A prophylaxis. These data form the basis for a definitive study of amantadine hydrochloride efficacy in patients with reduced renal function. Concurrent influenza-like illness is likely to confound attempts to associate adverse reactions to the administration of amantadine hydrochloride therapy.