Development of an antibacterial nanocomposite hydrogel for human dental pulp engineering.

Hydrogel-based regenerative endodontic procedures (REPs) are considered to be very promising therapeutic strategies to reconstruct the dental pulp (DP) tissue in devitalized human teeth. However, the success of the regeneration process is limited by residual bacteria that may persist in the endodontic space after the disinfection step and contaminate the biomaterial. The aim of this work was to develop an innovative fibrin hydrogel incorporating clindamycin (CLIN)-loaded Poly (d,l) Lactic Acid (PLA) nanoparticles (NPs) to provide the hydrogel with antibacterial properties. CLIN-PLA-NPs were synthesized by a surfactant-free nanoprecipitation method and their microphysical properties were assessed by dynamic light scattering, electrophoretic mobility and scanning electron microscopy. Their antimicrobial efficacy was evaluated on Enteroccocus fæcalis by the determination of the minimal inhibitory concentration (MIC) and the minimal biofilm inhibition and eradication concentrations (MBIC and MBEC). Antibacterial properties of the nanocomposite hydrogel were verified by agar diffusion assays. NP distribution into the hydrogel and release from it were evaluated using fluorescent PLA-NPs. NP cytotoxicity was assessed on DP mesenchymal stem cells (DP-MSCs) incorporated into the hydrogel. Type I collagen synthesis was investigated after 7 days of culture by immunohistochemistry. We found that CLIN-PLA-NPs displayed a drug loading of 10 ± 2 µg per mg of PLA polymer and an entrapment efficiency of 43 ± 7%. Antibiotic loading did not affect NP size, polydispersity index and zeta potential. The MIC for Enterococcus fæcalis was 32 µg mL-1. MBIC50 and MBEC50 were 4 and 16 µg mL-1, respectively. CLIN-PLA-NPs appeared homogenously distributed throughout the hydrogel. CLIN-PLA-NP-loaded hydrogels clearly inhibited E. faecalis growth. DP-MSC viability and type I collagen synthesis within the fibrin hydrogel were not affected by CLIN-PLA-NPs. In conclusion, CLIN-PLA-NP incorporation into the fibrin hydrogel gave the latter antibacterial and antibiofilm properties without affecting cell viability and function. This formulation could help establish an aseptic environment supporting DP reconstruction and, accordingly, might be a valuable tool for REPs.

On the use of Arion ater to biomonitor environmental pollution by Cd, Cu, Fe, Mn and Zn, with a special insight into the population variability.

The suitability of Arion ater as a biomonitor of Cd, Cu, Fe, Mn and Zn was assessed. Individual specimens were collected from 22 sampling sites. Slugs from 3 of the sites were analysed individually, whereas the slugs from the other sites were pooled to make a composite sample for each site. The tissue burdens did not differ between individuals from contaminated and uncontaminated sites, and there was no gradient of bioaccumulation of any of the elements in the surroundings of the smelter. Analysis of the individual specimens from the 3 sites revealed very high coefficients of variation for the metal concentrations. As a result of the high level of variation, large numbers of slugs are required to produce a low error in characterizing the mean concentration at each site. Furthermore, as a consequence of the similar mean concentrations and high variability, large numbers of samples are needed to detect significant differences between pairs of sites.

Evaluation of the estimation of midazolam concentrations and pharmacokinetic parameters in intensive care patients using a bayesian pharmacokinetic software (PKS) according to sparse sampling approach.

The aim of the study was to assess the performance of a bayesian program (PKS System, Abbott) for predicting midazolam concentrations and pharmacokinetic parameters in intensive care patients by comparing the pharmacokinetic parameters estimated by PKS to those calculated according to rich data. The study involved 42 patients receiving midazolam infusion for two hours or for several days. The program was used to predict plasma midazolam concentrations after feedback of 1, 2 or 3 concentrations. High correlation between observed and estimated concentrations was shown (r(2) > 0.992). Mean prediction error, mean absolute prediction error and root mean squared error were low for the patients of the reference and validation groups. From two or three feedback concentrations, midazolam pharmacokinetic parameters estimated by PKS were statistically comparable with those obtained using a rich pharmacokinetic analysis (P > 0.05 paired Wilcoxon test). Thus, PKS is useful for predicting midazolam concentrations and pharmacokinetic parameters when at least two feedback concentrations are known. This software seems to be appropriate for providing significant help to the clinician for midazolam dosage adjustment, according to midazolam concentrations and clinical sedation.

Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury.

BACKGROUND: Ketamine is used as an anaesthetic agent for short surgical procedures, and as a sedative and analgesic in intensive care patients. Intensive care patients with brain or spinal cord injury may have physiological changes that could alter the pharmacokinetics of ketamine. The pharmacokinetics of ketamine have been studied in healthy volunteers and in patients undergoing different types of surgery, but no data are available in intensive care patients. METHODS: We determined the pharmacokinetics of ketamine and its active metabolites, norketamine and dehydronorketamine, in 12 intensive care patients with brain or spinal cord injury. The effect of ketamine on haemodynamic variables was also investigated. RESULTS: The total clearance of ketamine, mean (SD), was 36.0 (13.3) ml min(-1) kg(-1), the volume of distribution (Vbeta) was 16.0 (8.6) litre kg(-1), and the elimination half-life was 4.9 (1.6) h. Ketamine did not alter any haemodynamic variables in the patients studied. CONCLUSIONS: Pharmacokinetic variables of ketamine in intensive care patients are greater than in healthy volunteers and in surgical patients. The increase in the volume of distribution is greater than the increase in clearance, resulting in a longer estimated half-life of ketamine in this patient group.

[Use of midazolam in postoperative sedation of patients with multiple organ failure treated with hemodiafiltration. Clinical study and pharmacokinetics]. / Utilisation du midazolam en sédation postopératoire chez des patients en défaillance polyviscérale, traités par hémodiafiltration. Etude clinique et pharmacocinétique.

OBJECTIVES: Evaluate the risk of accumulation of midazolam and conjugated 1-hydroxy-midazolam in high-risk ICU patients treated by continuous veno-venous haemofiltration. STUDY DESIGN: A prospective pharmocokinetic and clinical evaluation in 11 patients, with hepatic and renal failure. METHODS: Midazolam and metabolites were dosed in plasma and ultratiltration liquid by chromatography. Sedation was assessed by a simplified Ramsay score (EDS) with 4 levels. RESULTS: The mean duration of continuous infusion was 11 +/- 6 days. Peak plasma levels were over 150 ng ml-1 during the first 3 days, but normalized after that, only by drug adjustment based on scoring and clinical observation. There was no progressive accumulation of OH-midazolam, in spite of high levels (> 1000 ng ml-1). The Sieving coefficient (S) was 0.11 +/- 0.10 and 0.44 +/- 0.15 for midazolam and conjugated OH-midazolam respectively. A significant clearance (9.6 +/- 1.9 ml min-1) was observed for the conjugated products. T 1/2 beta was 11 h and was correlated with the mean time of recovery. A significant correlation was found between sedation score and both midazolam (r = 0.47) and OH-midazolam (r = 0.32). CONCLUSION: OH-midazolam risk of accumulation and significant clearance by haemodiafiltration should be taken into account in the drug adjustment in patients treated by continuous veno-venous haemofiltration.

[Sedation induced by midazolam in intensive care: pharmacologic and pharmacokinetic aspects]. / Sédation par le midazolam en réanimation: aspects pharmacologiques et pharmacocinétiques.

OBJECTIVE: Review on midazolam in order to optimize drug utilisation and therapeutic monitoring. DATA SOURCES: Research of English or French articles published until August 2001, using Medline database. The key words were: midazolam, pharmacokinetics, pharmacodynamic, sedation, drug interaction. STUDY SELECTION: Original articles, clinical cases and letters to the Editor were selected. Animal studies were excluded. DATA EXTRACTION: The articles were analysed according to their interest in midazolam clinical practice. DATA SYNTHESIS: Midazolam is a benzodiazepine widely used in intensive care unit, as a sedative, anxiety-relieving, and amnesic drug. Midazolam could be used in patients with cardiac, or respiratory failure, and in neurosurgery. A great interindividual variability on pharmacokinetic and pharmacodynamic response was observed. In intensive care patients, elimination half-life is known to be widely increased. Midazolam is metabolised by hepatic microsomes. The major metabolite is the 1-hydroxymidazolam, which is pharmacologically active. A prolonged sedation due to an accumulation of conjugated metabolite was observed in renal failure patients. Enzymatic inductors or inhibitors could influence pharmacokinetics and pharmacodynamic effects of midazolam. CONCLUSION: According to midazolam pharmacokinetic and pharmacodynamic variability, an individual dosage adjustment is essential for long-term sedation. Target controlled sedation could be a mean to limit the variability and to reach quickly the pharmacodynamic effect.

Midazolam disposition in patients undergoing continuous venovenous hemodialysis.

The aim of the study was to investigate the pharmacokinetics and removal of midazolam and unconjugated and glucuronidated 1-hydroxy-midazolam in 4 intensive care patients on continuous venovenous hemodialysis. Plasma midazolam and its metabolites were assessed by HPLC from blood samples collected during continuous infusion and after the end of infusion. Additional samples from the arterial and venous bloodlines and ultrafiltrate were drawn to calculate sieving coefficient and clearance of ultrafiltration. The elimination half-life of midazolam ranged from 7.6 to 22.8 hours. The clearance of ultrafiltration was between 0.13 and 4.7 ml/min and reached approximately 11% of the total clearance. The range of sieving coefficient was from 0.006 to 0.26, with an average fraction removal of 0.2%. 1-Hydroxy-midazolam glucuronide was removed by continuous hemodialysis (sieving 0.36 to 0.63), with a clearance of ultrafiltration ranging from 7.8 to 12.0 ml/min. These preliminary results showed that midazolam is not removed efficiently, and approximately half of the 1-hydroxy-midazolam glucuronide was removed by dialysis.