Beatrix Wulkersdorfer

Comparison of Mucosal Pressures Induced by Cuffs of Different Airway Devices

Background:High pressures exerted by balloons and cuffs of conventional endotracheal tubes, the Combitube® (Tyco Healthcare Nellcor Mallinckrodt, Pleasanton, CA), the EasyTube® (Teleflex Ruesch, Kernen, Germany), the Laryngeal Mask Airway ™ (LMA North America, San Diego, CA), the Intubating Laryngeal Mask Airway ™ (Fastrach®; LMA North America), the ProSeal ™ (LMA North America), and the Laryngeal Tube (LT; VBM Medizintechnik, Sulz, Germany) may traumatize the pharyngeal mucosa. The aim of this study was to compare pressures exerted on the pharyngeal, tracheal, and esophageal mucosa by different devices designed for securing the patient’s airways. Methods:Nineteen fresh cadavers were included. To measure mucosal pressures, microchip sensors were fixed on the anterior, lateral, and posterior surfaces of the proximal balloon and the distal cuff of the investigated devices. Depending on the respective airway device, the cuff volume was increased in 10-ml increments at the proximal balloon starting from 0 to a maximum of 100 ml, and in 2-ml increments at the distal cuff starting from 0 up to 12 ml. Results:Tracheal mucosal pressures were significantly higher using the Combitube® compared with the endotracheal tube and the EasyTube®. Maximal esophageal pressures were significantly higher using the EasyTube® compared with the Combitube®. Using cuff volumes according to the manufacturers’ guidelines, we found the highest pharyngeal pressures with the Intubating Laryngeal Mask Airway ™ versus all other devices. At maximal volumes, the Laryngeal Mask Airway ™, the Intubating Laryngeal Mask Airway ™, and the ProSeal ™ induced significantly higher pharyngeal pressures compared with all other devices. Using a pharyngeal cuff volume of 40 ml, the Intubating Laryngeal Mask Airway ™ followed by the Laryngeal Mask Airway ™ exerted significantly higher pressures compared with the other devices. Conclusions:Although some devices exhibit a somewhat higher mucosal pressure when compared with others, the authors believe that the observed differences of the cuff pressures do not suggest a clinically relevant danger, because the investigated devices, except the endotracheal tubes, are not intended for prolonged use.

Using Positron Emission Tomography to Study Transporter‐Mediated Drug–Drug Interactions in Tissues

Drug disposition is highly regulated by membrane transporters. Some transporter‐mediated drug–drug interactions (DDIs) may not manifest themselves in changes in systemic exposure but rather in changes in tissue exposure of drugs. To better assess the impact of transporter‐mediated DDIs in tissues, positron emission tomography (PET)—a noninvasive imaging method—plays an increasingly important role. In this article, we provide examples of how PET can be used to assess transporter‐mediated DDIs in different organs.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier

ABCB1 and ABCG2 work together at the blood–brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([11C]elacridar and [11C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single‐nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high‐dose tariquidar. In contrast to the ABCB1‐selective substrate (R)‐[11C]verapamil, [11C]elacridar and [11C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [11C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Airway Management with Endotracheal Tube versus Combitube® during Parabolic Flights

Background: Training of National Aeronautics and Space Administration space shuttle astronauts revealed difficult airway management with endotracheal tubes (ETTs) under microgravity conditions. The authors performed a randomized comparative study of ETT and Combitube® (ETC; Tyco Healthcare, Pleasanton, CA). The aim of the study was to evaluate ease, time of insertion, and success rates during normogravity and parabolic flights using mannequins. Methods: After normogravity experiments, four flyers performed intubation on a mannequin during the flights. Sixty-two intubation attempts were performed using the ETC (normogravity, 29; microgravity, 33), and 58 intubation attempts were performed using the ETT (each 29 attempts, both conditions). Time to completion of the intubation procedure, success rate, and ease of insertion were recorded. Results: The ETC performed equally well between normogravity (median, 18 s; range, 17–25 s) and microgravity (median, 18.5 s; range, 17–28 s), whereas the ETT performed significantly slower under microgravity (median, 20 s; range, 17–27 s) as compared with normogravity (median, 18 s; range, 16–22 s; P = 0.019). One hundred nine of 120 (90%) were successful. The ETT and ETC were comparable with respect to successful intubations, under normogravity or microgravity, respectively. Conclusions: Both the ETC and ETT perform comparably well. Slight differences could be found with respect to time of insertion in favor of the ETC. Because this is the first experiment using the ETC on the KC-135, it is shown that there is enough time to perform the insertion procedure. Because the ETC airway requires less training and is easier to insert than an ETT, it is recommended for further study as an alternative airway to what is currently on the shuttle.

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

ABSTRACT Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fTMIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC0-τ) for free CPT in soft tissues and the AUC0-τ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fTMIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies.

Usefulness of interleukin-10 detection in lung transplant patients with human cytomegalovirus infection with respect to virus persistence

Background. Human cytomegalovirus (HCMV) infection in lung transplant patients induces an inflammatory response, including local production of cytokines involved in viral clearance. The aim of this study was to evaluate the potential value of monitoring interleukin (IL)-10 with respect to HCMV persistence in blood and/or bronchoalveolar lavage (BAL). Methods. A quantitative polymerase chain reaction assay was used for HCMV-DNA detection in plasma and BAL. IL-10 was measured with an enzyme-linked immunosorbent assay in blood and with BAL in 101 lung transplant patients. IL-10 levels were correlated with clinical outcome. Results. A total of 23 patients of 35 (66%) with detectable HCMV in plasma and/or BAL exhibited increased levels of IL-10 in plasma and/or BAL. Complete clearance of HCMV was observed after 168 (median 130) days in the IL-10-positive group (n=23) in comparison with 87 (median 58) days in the IL-10-negative group (n=12; P<0.024). In the seven HCMV-positive patients with positive IL-10 levels in BAL only, HCMV persisted in BAL for a median of 579 days without signs of systemic infection (positive plasma levels) or clinical symptoms. Conclusions. We show that in lung transplant patients with elevated levels of IL-10 in plasma and/or BAL, HCMV clearance is prolonged because of the influence of anti-inflammatory cytokines.

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR–TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug–drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

Influence of OATPs on Hepatic Disposition of Erlotinib Measured With Positron Emission Tomography

To assess the hepatic disposition of erlotinib, we performed positron emission tomography (PET) scans with [11C]erlotinib in healthy volunteers without and with oral pretreatment with a therapeutic erlotinib dose (300u2009mg). Erlotinib pretreatment significantly decreased the liver exposure to [11C]erlotinib with a concomitant increase in blood exposure, pointing to the involvement of a carrier‐mediated hepatic uptake mechanism. Using cell lines overexpressing human organic anion‐transporting polypeptides (OATPs) 1B1, 1B3, or 2B1, we show that [11C]erlotinib is selectively transported by OATP2B1. Our data suggest that at PET microdoses hepatic uptake of [11C]erlotinib is mediated by OATP2B1, whereas at therapeutic doses OATP2B1 transport is saturated and hepatic uptake occurs mainly by passive diffusion. We propose that [11C]erlotinib may be used as a hepatic OATP2B1 probe substrate and erlotinib as an OATP2B1 inhibitor in clinical drug–drug interaction studies, allowing the contribution of OATP2B1 to the hepatic uptake of drugs to be revealed.

Effect of P‐glycoprotein inhibition at the blood–brain barrier on brain distribution of (R)‐[11C]verapamil in elderly vs. young subjects

AIMSnThe efflux transporter P-glycoprotein (ABCB1) acts at the blood-brain barrier (BBB) to restrict the distribution of many different drugs from blood to the brain. Previous data suggest an age-associated decrease in the expression and function of ABCB1 at the BBB. In the present study, we investigated the influence of age on the magnitude of an ABCB1-mediated drug-drug interaction (DDI) at the BBB.nnnMETHODSnWe performed positron emission tomography scans using the model ABCB1 substrate (R)-[11 C]verapamil in five young [26xa0±xa01xa0years, (mean ± standard deviation)] and five elderly (68 ± 6xa0years) healthy male volunteers before and after intravenous administration of a low dose of the ABCB1 inhibitor tariquidar (3xa0mg kg-1 ).nnnRESULTSnIn baseline scans, the total distribution volume (VT ) of (R)-[11 C]verapamil in whole-brain grey matter was not significantly different between the elderly (VT xa0=xa00.78 ± 0.15) and young (VT xa0=xa00.79 ± 0.10) group. After partial (incomplete) ABCB1 inhibition, VT values were significantly higher (P = 0.040) in the elderly (VT xa0=xa01.08 ± 0.15) than in the young (VT xa0=xa00.80 ± 0.18) group. The percentage increase in (R)-[11 C]verapamil VT following partial ABCB1 inhibition was significantly greater (P = 0.032) in elderly (+40 ± 17%) than in young (+2xa0±xa017%) volunteers. Tariquidar plasma concentrations were not significantly different between the young (786 ± 178xa0nmol l-1 ) and elderly (1116 ± 347xa0nmol l-1 ) group.nnnCONCLUSIONSnOur results provide the first direct evidence of an increased risk for ABCB1-mediated DDIs at the BBB in elderly persons, which may have important consequences for pharmacotherapy of the elderly.

The non-invasive serum biomarker soluble Axl accurately detects advanced liver fibrosis and cirrhosis

Soluble Axl (sAxl) was recently shown to be strongly released into the blood during liver fibrogenesis and hepatocellular carcinoma suggesting sAxl as a biomarker of liver diseases. In this study we are the first to evaluate sAxl in human serum in comparison to Enhanced Liver Fibrosis (ELF) test and transient elastography (TE; Fibroscan) for its value to detect significant (F≥2), advanced fibrosis (F≥3), and cirrhosis (F4) in different liver disease etiologies and healthy controls. To properly determine the diagnostic accuracy of sAxl, a test cohort as well as a validation cohort was employed using liver biopsy as a reference method. Most notably, sAxl was confirmed to be an accurate biomarker of liver fibrosis and cirrhosis. Its accuracy was increased, if total serum albumin was added to build a sAxl/albumin ratio. Thereby an AUC of 0.763, 0.776, 0.826, and 0.832 was achieved corresponding to histological fibrosis stages F≥2, F≥3, F4 with liver biopsy as a reference method, and cirrhosis according to imaging techniques, respectively. With a cut-off of 1.29, a sensitivity, specificity, PPV, and NPV of 78.5%, 80.1%, 44%, 94.9% for the detection of cirrhosis was achieved. In comparison, ELF test and TE showed an AUC of 0.910, and 0.934, respectively, for the detection of cirrhosis. However, performance of TE was not possible in 14.4% of patients and both, ELF™ test and TE bear the disadvantage of high costs. In conclusion, the sAxl/albumin ratio is suggested as an accurate biomarker of liver fibrosis and cirrhosis. Due to its easy applicability and low costs it is suitable as screening parameter for significant to advanced liver fibrosis and cirrhosis, especially if TE is not available or not applicable.