Edith Lackner

Minimal local anaesthetic volumes for sciatic nerve block: evaluation of ED99 in volunteers

BACKGROUND This randomized, double-blinded volunteer study was designed to evaluate the ED(99) volume of local anaesthetic for sciatic nerve blocks using a step-up/step-down methodology. METHODS A maximum of 20 volunteers were included to receive an ultrasound-guided sciatic nerve block with mepivacaine 1.5% and a starting volume of 0.2 ml mm(-2) cross-sectional nerve area. In cases of a complete sensory block, the volume was reduced by 0.02 ml mm(-2) cross-sectional nerve area until the first block failed. Thereafter, the volume of local anaesthetic was increased by 0.02 ml mm(-2) cross-sectional nerve area. After three cycles of successful/failed blocks, the ED(99) volume of local anaesthetic could be calculated by a probability function. The influence of the volumes of local anaesthetics on sensory onset times and duration of sensory block was evaluated by linear regression. RESULTS The ED(99) volume of local anaesthetic for sciatic nerve block was calculated with 0.10 ml mm(-2) cross-sectional nerve area. The correlation between the volume of local anaesthetic and the sensory onset time was weak (r=0.14), whereas the correlation between the volume of local anaesthetic and the duration of sensory block was moderate (r=0.65). CONCLUSIONS This is the first study where an ED(99) volume of local anaesthetic for sciatic nerve block has been evaluated. The resulting local anaesthetic volume of 0.10 ml mm(-2) cross-sectional nerve area seems to have no impact on sensory onset time, whereas the duration of sensory block is shorter.

Magnetic Resonance Imaging Analysis of the Spread of Local Anesthetic Solution after Ultrasound-guided Lateral Thoracic Paravertebral Blockade: A Volunteer Study

Background:This study was designed to examine the spread of local anesthetic (LA) via magnetic resonance imaging after a standardized ultrasound-guided thoracic paravertebral blockade. Methods:Ten volunteers were enrolled in the study. We performed ultrasound-guided single-shot paravertebral blocks with 20 ml mepivacaine 1% at the thoracic six level at both sides on two consecutive days. After each paravertebral blockade, a magnetic resonance imaging investigation was performed to investigate the three-dimensional spread of the LA. In addition, sensory spread of blockade was evaluated via pinprick testing. Results:The median (interquartile range) cranial and caudal distribution of the LA relative to the thoracic six puncture level was 1.0 (2.5) and 3.0 (0.75) [=4.0 vertebral levels] for the left and 0.5 (1.0) and 3.0 (0.75) [=3.5 vertebral levels] for the right side. Accordingly, the LA distributed more caudally than cranially. The median (interquartile range) number of sensory dermatomes which were affected by the thoracic paravertebral blockade was 9.8 (6.5) for the left and 10.7 (8.8) for the right side. The sensory distribution of thoracic paravertebral blockade was significantly larger compared with the spread of LA. Conclusions:Although the spread of LA was reproducible, the anesthetic effect was unpredictable, even with a standardized ultrasound-guided technique in volunteers. While it can be assumed that approximately 4 vertebral levels are covered by 20 ml LA, the somatic distribution of the thoracic paravertebral blockade remains unpredictable. In a significant percentage, the LA distributes into the epidural space, prevertebral, or to the contralateral side.

Blood, tissue and intracellular concentrations of Azithromycin during and after end of therapy

ABSTRACT Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC0–24)/MIC90 ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycins clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Therapy with topical non-steroidal anti-inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. WHAT THIS STUDY ADDS • This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. AIMS To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C). METHODS This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren Emulgel gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. RESULTS All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren Emulgel and were approximately 30-40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren Emulgel (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation. CONCLUSION DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.

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.

Feasibility of microdialysis for determination of protein binding and target site pharmacokinetics of colistin in vivo

Tissue pharmacokinetics and plasma protein binding of colistin have not been described in humans in vivo. Colistin concentrations in plasma, muscle, and subcutis of healthy volunteers were measured by microdialysis after a single dose of 2.5 million IU of colistin methanesulfonate. In vitro microdialysis experiments and an in vivo pilot study were performed prior to the in vivo main study. Concentration‐time profiles of total colistin in plasma were comparable with previously described values. The unbound fraction of colistin in plasma (fu) ranged from 2.8% to 14.1%. Low plasma fu correlated with low unbound colistin concentrations in muscle and subcutis. In vitro, mean relative recovery of microdialysis probes was higher in the reverse dialysis setting compared to the forward dialysis mode (71 ± 9% vs. 45 ± 14%, respectively); mean overall recovery in the main study in vivo was 49 ± 5%. Present data suggest that colistin is extensively protein bound in plasma and poorly distributed into soft tissue. However, differences in relative recovery between forward and reverse dialysis in vitro indicate that results might have been influenced by adhesion of colistin to microdialysis equipment. Microdialysis should be considered as a semiquantitative method for the estimation of unbound colistin levels in soft tissue.

Blood, Tissue, and Intracellular Concentrations of Erythromycin and Its Metabolite Anhydroerythromycin during and after Therapy

ABSTRACT For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ± 3.45) and lowest in WBCs (0.27 ± 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin.

Lack of dermal penetration of topically applied gentamicin as pharmacokinetic evidence indicating insufficient efficacy

Background Treatment of skin and superficial soft tissue infections with topically applied antibiotics is a controversial topic, because only few clinical studies exist and target site concentrations after topical treatment are widely unknown. Objectives This study aimed to investigate the target site concentration of topically applied gentamicin as a potential cause of therapeutic failure and to explore if microporation by laser might be used to improve penetration of gentamicin through the skin barrier. Methods Six healthy volunteers were included in this cross-over Phase 1 study. On two study days, separated by a washout period, microdialysate and plasma sampling was performed for 6 h after administration of 500 mg of gentamicin cream on a predefined area. On one of the study days the skin was microporated before drug application using the P.L.E.A.S.E. Professional laser system. Results In intact skin, Cmax and AUC values were 3.3 ± 5.64 ng/mL and 5.4 ± 10.4 ng·h/mL, respectively; thereby far under the threshold needed to treat common pathogens. With a Cmax of 474.2 ± 555.3 ng/mL laser application showed a significant increase in tissue penetration and decrease in pharmacokinetic variability; however, even after microporation no therapeutically active concentrations were achieved as indicated by Cmax/epidemiological cut-off ratios of 0.237 and 0.059 for Staphylococcus aureus and Pseudomonas aeruginosa, respectively. Solely after administration on microporated skin, plasma concentrations of gentamicin were quantifiable (lower limit of quantification 10 pg/mL). Conclusions This study confirmed that after topical administration gentamicin penetration through the dermal barrier is insufficient, providing pharmacokinetic evidence that topical gentamicin in its current form might be inappropriate to treat skin infections.

Dose-response assessment of tariquidar for inhibition of P-glycoprotein at the human blood-brain barrier using (R)-[11C]verapamil PET

Background Positron emission tomography (PET) with the radiolabelled substrate of the multidrug efflux transporter Pglycoprotein (P-gp) (R)-[C]verapamil (VPM) can be used to assess P-gp function at the blood-brain barrier (BBB). We have shown in rats that performing VPM PET scans after half-maximum inhibition of P-gp with the third-generation P-gp inhibitor tariquidar (TQD) is more sensitive for detecting regional differences in cerebral P-gp function than VPM baseline scans [1]. In order to translate this concept to humans a detailed understanding of the dose-response relationship of TQD for inhibition of P-gp at the human BBB is required.