Plasma and soft tissue pharmacokinetics of ceftolozane/tazobactam in healthy volunteers after single and multiple intravenous infusion: a microdialysis study.

OBJECTIVES: To investigate ceftolozane/tazobactam pharmacokinetics (PK) in plasma and interstitial space fluid (ISF) of muscle and subcutaneous tissue and establish a population PK model. METHODS: Eight healthy volunteers received four IV doses of 1000/500 mg ceftolozane/tazobactam q8h in a prospective, open-labelled PK study. ISF concentration-time profiles were determined via in vivo microdialysis up to 8 h post-dose and efficacy of unbound ceftolozane and tazobactam was estimated using the time above MIC (%ƒT>MIC) and time above threshold concentration (%T>CT), respectively. A population PK model was established by merging derived plasma and soft tissue PK data. RESULTS: Ceftolozane reached %ƒT>MIC values of 100% in plasma, muscle and subcutaneous ISF for Enterobacteriaceae and 87%, 89% and 87%, respectively, for Pseudomonas aeruginosa. Tazobactam %T>CT was 21%, 22% and 21% in plasma, muscle and subcutaneous ISF, respectively. Plasma protein binding was 6.3% for ceftolozane and 8.0% for tazobactam. Multiple-dose ceftolozane AUC0-8 ISF/plasma ratios were 0.92 ±â€Š0.17 in muscle and 0.88 ±â€Š0.18 in subcutis, and tazobactam ratios were 0.89 ±â€Š0.25 in muscle and 0.87 ±â€Š0.21 in subcutis, suggesting substantial soft tissue penetration. CONCLUSIONS: Tazobactam %T>CT values were distinctly below proposed target values, indicating that tazobactam might be underdosed in the investigated drug combination. However, ISF/unbound plasma ratios of ceftolozane and tazobactam support their use in soft tissue infections. A plasma and soft tissue PK model adds important information on the PK profile of ceftolozane/tazobactam. Further investigations in patients suffering from wound infections are needed to confirm these findings.

Enzyme autoinduction by mitotane supported by population pharmacokinetic modelling in a large cohort of adrenocortical carcinoma patients.

OBJECTIVE: Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1- 6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life, and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring. METHODS: Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from therapeutic drug monitoring (TDM) of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules. RESULTS: A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. Body mass index was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity. CONCLUSION: The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

Using executive control training to suppress amygdala reactivity to aversive information.

The ability to regulate emotions is essential for adaptive behavior. This ability is suggested to be mediated by the connectivity between prefrontal brain regions and the amygdala. Yet, it is still unknown whether the ability to regulate emotions can be trained by using a non-emotional procedure, such as the recruitment of executive control (EC). Participants who were trained using a high-frequent executive control (EC) task (80% incongruent trials) showed reduced amygdala reactivity and behavioral interference of aversive pictures. These effects were observed only following multiple-session training and not following one training session. In addition, they were not observed for participants exposed to low-frequent EC training (20% incongruent trials). Resting-state functional connectivity analysis revealed a marginally significant interaction between training group and change in the connectivity between the amygdala and the right inferior frontal gyrus (IFG). Amygdala-IFG connectivity was significantly increased following the training only in the high-frequent EC training group. These findings are the first to show that non-emotional training can induce changes in amygdala reactivity to aversive information and alter amygdala-prefrontal connectivity.

Pharmacokinetics and clinical toxicity of prilocaine and ropivacaine following combined drug administration in brachial plexus anesthesia.

OBJECTIVE: Local anesthetics (LA) are often administered in combination for regional anesthesia in order to obtain the specific advantages (onset and duration of effect) of each drug. However, few data on the safety of such combinations are available and consequently plasma concentrations possibly associated with toxicity and interactions between the specific anesthetics are not sufficiently established. We measured pharmacokinetics and toxicity parameters of prilocaine and ropivacaine after combined use as single doses in brachial plexus blockade. METHODS: In an open clinical study using a combined dose regime (300 mg prilocaine followed immediately by 75 mg ropivacaine) total plasma concentrations of prilocaine and ropivacaine were measured serially in 60 patients using a gas-chromatographic method. The data were analyzed regarding a relationship with central nervous and cardiovascular toxicity. RESULTS: Following the administration in combination prilocaine and ropivacaine were rapidly absorbed. Mean prilocaine peak plasma concentrations (mean Cmax = 1.51 microg/ml) were measured between 15 and 30 min after injection. Highest ropivacaine plasma concentrations (mean Cmax = 1.12 microg/ml) were seen between 30 min and 1 hour after injection (calculated mean tmax = 44 min). One of 59 patients showed signs of myoclonus which were suspected of being due to intravascular injection. There was no relevant cardiovascular toxicity observed in terms of changes in the QRS complex, PQ interval prolongation, AV dissociation, occurrence of extrasystoles or sinus arrest. The pharmacokinetics of combined administration did not differ from those of prilocaine and ropivacaine given alone. CONCLUSION: The use of a combined prilocaine/ ropivacaine (300 mg/75 mg) dose regimen in patients given single dose for brachial plexus blockade can generally be regarded as safe with regard to peak plasma concentrations and cardiovascular toxicity and this holds true for patients with a higher perioperative risk profile (ASA III grading, American Society of Anesthesiologists). The considerable inter-individual variation in LA peak plasma concentrations observed in our patients and the one case of suspected accidental intravascular injection, highlight the necessity of adequate monitoring of the patients undergoing LA injections.

Surgery for full-thickness macular holes with short-duration prone posturing: results of a pilot study.

PURPOSE: To see whether surgical success and complication rates in surgery for full-thickness macular holes (FTMH) followed by 5 days prone posturing are comparable to those obtained with longer posturing regimes recorded in the literature. METHODS: A pilot study was carried out of pars plana vitrectomy, autologous platelet adjunct and 16% C2F6 tamponade followed by 5 days prone posturing in 38 eyes of 34 patients with idiopathic FTMH. A follow-up postal questionnaire was used to assess patients' perception of posturing and outcome. RESULTS: Fifty-three per cent of eyes gained 2 or more lines of Snellen acuity. Twenty-four per cent of patients with symptom duration of 12 months or less (29 patients) achieved a visual acuity of 6/12. Fifty-eight per cent of patients achieved N8 or better near vision. The only significant predictor of post-operative Snellen acuity was the stage of the hole (p = 0.02). Eighty-six per cent of questionnaire respondents felt that surgery had improved their quality of life. Eighty-seven per cent of all patients reported a reduction in, or elimination of, metamorphopsia. Fifty-four per cent of patients described posturing for 5 days as difficult or very difficult. Five patients admitted to posturing for less than 12 h a day, but all stated that they had postured for the full 5 days. Cataract was the commonest complication observed in this series (42% of patients have had or been listed for cataract surgery). CONCLUSIONS: Five days of prone posturing following vitrectomy for FTMH with autologous plaletet concentrate and C2F6 tamponade afforded success and complication rates comparable to those in published studies with longer posturing times.

[Circulating immune complexes and age]. / Zirkulierende Immunkomplexe und Alter.

The circulating immune complexes were quantitatively determined by PEG-precipitation in the serum samples of 413 from the clinical point of view healthy persons subdivided into several age groups. In comparison with the other age groups the age group of 0-15 years showed the lowest immune complex values (mean = 3.14 +/- 0.96 mg protein/ml) with a significant higher distribution (p = 5%). Significant differences between the persons of the age of 16-30, 31-45 and 46-60 years were not traceable. The average values of the circulating immune complexes amounted to 3.82 +/- 0.75, 3.9 +/- 0.67 respectively 3.91 +/- 0.38 mg protein/ml. In comparison with these three age groups the circulating immune complexes showed with an average value of 3.62 +/- 0.75 mg protein/ml a falling tendency for the persons more than 60 years old. There existed a statistical significant difference (p = 5%) for the persons of the age of 31-45 years. A sexual dependence of the immune complexes could not be found within the age groups. Autoantibodies (ANF, anti-dsDNA antibodies) were traceable in the serum of 23 (24.7%) of the persons more than 60 years old. The comparison of the sera with and without autoantibodies didn't show any significant difference with regard to the immune complexes.

[Early diagnosis of motorial and mental disturbances during a dispensary consulting-hour for children at risk (author's transl)]. / Früherfassung von motorischen und geistigen Störungen innerhalb einer Dispensairesprechstunde für Risikokinder.

During a dispensary consultating-hour for children at risk and prematureley born children a pediatrist, an orthopaedist, an ophthalmologist, a psychologist and a special educationalist judged the motorial and mental disturbances of 600 children at risk. 21 children with manifested cerebral motorial disturbances are confronted to 89 children with mental peculiarities. Concepts pertaining to a necessary special pedagogical as well as a psycho-therapeutical assistance are discussed.