Pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy

OBJECTIVE: The clinical effect of beta-lactam antibiotics depends on the time of drug concentration above the minimal inhibitory concentration (MIC) for a susceptible bacterium. Continuous infusion (CI) of beta-lactams such as meropenem may therefore be a more rational approach than intermittent bolus injections (IB). The aim of this study was to test whether CI of meropenem achieves effective drug concentrations comparable to IB in patients treated by continuous renal replacement therapy (CRRT). DESIGN: Prospective, randomised cross-over study. SETTING: Twelve-bed medical intensive care unit (ICU). PATIENTS AND INTERVENTIONS: Six ICU patients were randomised to receive either meropenem 1 g IB every 12 h or a 0.5 g i.v. loading dose followed by 2 g i.v. CI over 24 h. After 2 days, regimens were crossed over. Meropenem pharmacokinetics were determined on days 2 and 4. MEASUREMENTS AND RESULTS: Peak serum concentration [median (25% and 75% quartiles)] after short infusion of 1 g meropenem were 62.8 (51.4; 85.0) mg/l, trough levels at 12 h were 8.1 (4.5; 18.7) mg/l, and serum half-life was 5.3 (5.1; 7.0) h. Steady-state concentrations during CI were 18.6 (13.3; 24.5) mg/l. The AUCs during either treatment were comparable and determined as 233 (202; 254) mg/l*h (IB) and 227 (182; 283) mg/l*h (CI), respectively. Four hours after IB, drug concentrations dropped below CI steady-state concentrations. CONCLUSION: Appropriate antibacterial concentrations of meropenem in patients with CRRT are easily achievable with CI. CI may be an effective alternative dosing regimen to IB. A prospective comparison of the clinical efficacy of the two dosage regimens is warranted.     

Propiverine compared to oxybutynin in neurogenic detrusor overactivity--results of a randomized, double-blind, multicenter clinical study

OBJECTIVES: To compare the efficacy and tolerability of propiverine and oxybutynin in patients with neurogenic detrusor overactivity. METHODS: Patients were eligible, if at least 18 years of age and suffering from neurogenic detrusor overactivity. Eligibility also required a maximum cystometric capacity less than 300 ml. After a one-week run-in period, propiverine 15 mg t.i.d. or oxybutynin 5mg t.i.d. were administered for 21 days. As primary efficacy outcomes urodynamic parameters were assessed. As tolerability outcome the percentage of patients with newly manifesting anticholinergic adverse events was taken. RESULTS: 131 patients were recruited at 20 study centers. The maximum cystometric capacity (ml) was increased significantly in the propiverine group from 198 (+/-110) to 309 (+/-166), and in the oxybutynin group from 164 (+/-64) to 298 (+/-125). Similarly, maximum detrusor pressure during the filling phase (cm H(2)O) was lowered significantly in the propiverine group from 56.8 (+/-36.2) to 37.8 (+/-31.6), and in the oxybutynin group from 68.6 (+/-34.5) to 43.1 (+/-29.2). No significant differences resulted between treatment groups. Anticholinergic adverse events were reported less frequently in the propiverine compared to the oxybutynin group (63.0% versus 77.8%). Dryness of the mouth, the most frequent adverse event, was reported significantly less (47.1% versus 67.2%; p=0.02) in the propiverine compared to the oxybutynin group. CONCLUSION: Propiverine and oxybutynin are equally effective in increasing bladder capacity and lowering bladder pressure in patients with neurogenic detrusor overactivity. The trend for better tolerability of propiverine compared to oxybutynin achieved significance for dryness of the mouth.     

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.     

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.     

The effects of exposure to diazepam during various stages of gestation or during lactation on the development and behavior of rat pups

In the present study we have investigated the effects of diazepam (DZP) (10 mg/kg) treatment of rat dams during different periods of gestation or during lactation on the development and behavior of their offspring. The results show that DZP exposure during different phases of early development has differing effects on later behavior. Exposure during mid-gestation resulted in early and transient hyperactivity, but no learning or memory deficits at 2 months of age were observed. However, both late prenatal and early postnatal exposure to DZP resulted in significant behavioral changes. Late prenatal treatment caused no hyperactivity but resulted in poor performance on the learning and retention of a choice discrimination task, while early postnatal exposure resulted in consistent and lasting hyperactivity and in substantial discrimination learning and retention deficits at 2 months of age.     

Pseudomonas aeruginosa cytotoxin: the Asp197-Gly-Asp-Tyr-His-Tyr-His-Tyr202 containing loop is critical for plasma membrane binding

The cytotoxin from Pseudomonas aeruginosa is a pore-forming toxin that binds specifically to water channel-related molecules of the erythrocyte membrane. Here, we have defined a domain, Asp¹⁹⁷-Gly-Asp-Tyr-His-Tyr²⁰² of the cytotoxin, to be essential for receptor binding. Cytotoxin point mutants from the recombinant gene carrying substitutions in the domain were characterized in terms of inhibiting the binding of radioiodinated natural cytotoxin to rat erythrocyte and producing cytotoxic effects in human granulocytes. A synthetic peptide representing residues 191–211 of the cytotoxin acted as a competitive inhibitor at a concentration of 10^–5 M. In contrast, two other cytotoxin-specific peptides were inactive. Structure prediction of the binding sequence shows a loop structure with similarities to the sequence around His³³² in Aeromonas aerolysin essential to receptor binding.     

Monitoring of physical activity and heart rate variability in patients with chronic heart failure using cardiac resynchronization devices

Cardiac resynchronization therapy (CRT) devices not only deliver effective treatment but may also serve as valuable diagnostic tools in heart failure management. In the present study, the minutes of daily physical activity and heart rate variability, measured by sensors incorporated into such a device, reflected the effects of CRT and were related to New York Heart Association functional class.