IntroductionExtracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits.MethodsFour identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays.ResultsFour hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26).ConclusionsSequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.

IntroductionVital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits.MethodsFour identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables.ResultsFour hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R2 = 0.88, P <0.001).ConclusionsRecovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

Calibration curve is a regression model used to predict the unknown concentrations of analytes of interest based on the response of the instrument to the known standards. Some statistical analyses are required to choose the best model fitting to the experimental data and also evaluate the linearity and homoscedasticity of the calibration curve. Using an internal standard corrects for the loss of analyte during sample preparation and analysis provided that it is selected appropriately. After the best regression model is selected, the analytical method needs to be validated using quality control (QC) samples prepared and stored in the same temperature as intended for the study samples. Most of the international guidelines require that the parameters, including linearity, specificity, selectivity, accuracy, precision, lower limit of quantification (LLOQ), matrix effect and stability, be assessed during validation. Despite the highly regulated area, some challenges still exist regarding the validation of some analytical methods including methods when no analyte-free matrix is available.

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BackgroundGiven the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO.Methods/DesignThis is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO.DiscussionThe evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure.Trial registrationACTRN12612000559819

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

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BackgroundMigraine is a common neurovascular condition that may be linked to hyperhomocysteinemia. We have previously provided evidence that reduction of homocysteine with a vitamin supplementation can reduce the occurrence of migraine in women. The current study examined the occurrence of migraine in response to vitamin supplementation with a lower dose of folic acid.MethodsThis was a 6 month randomised, double blinded placebo controlled trial of daily vitamin supplementation containing 1 mg of folic acid, 25 mg of Vitamin B6 and Vitamin B12, on reduction of homocysteine and the occurrence of migraine in 300 female patients diagnosed with migraine with aura.ResultsVitamin supplementation with 1 mg of folic acid, did not significantly decrease homocysteine levels (P = 0.2). The treatment group did not show a significant decrease in the percentage of participants with high migraine disability, severity or frequency at the end of the 6 month intervention (P > 0.1).Conclusion1 mg of folic acid in combination with vitamin B6 and B12 is less effective in reducing migraine associated symptoms compared to the previously tested dosage of 2 mg folic acid in combination with 25 mg of vitamin B6 and 400 μg of vitamin B12.