Mechanism-based pharmacokinetic-pharmacodynamic modeling of the efficacy and safety of (semi-)synthetic opioids

The objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics of onset and offset of the pharmacological effects at the mu-opioid receptor, 2) selectivity of action (antinociception versus respiratory depression), 3) the interspecies extrapolation of the PK-PD correlation of the antinociceptive and respiratory depressant effect, 4) the role of active metabolites, 5) kinetics of antagonism of the respiratory depressant effect. Preclinical investigations were performed to develop and validate mechanism-based PK-PD models for the effects of opioids on antinociception and respiration. These PK-PD models were subsequently applied to characterize the effects of buprenorphine and fentanyl in humans. It was shown that the developed PK-PD model can be used to predict the efficacy and safety outcome of opioids in animals. Furthermore, the PK-PD model had excellent properties to enable animal-to-human extrapolation of the efficacy and safety outcome.LEI Universiteit LeidenLACD

Effect of different endodontic regeneration protocols on wettability, roughness and chemical composition of surface dentin

Introduction We investigated the changes in physiochemical properties of dentin surfaces after performing different endodontic regeneration protocols. Methods Human dentin slices were randomized into 4 treatment groups and 1 untreated control group (n = 10). One treatment group was irrigated with sodium hypochlorite (NaOCl) for 5 minutes followed by EDTA for 10 minutes. The other 3 treatment groups were irrigated with NaOCl; treated for 4 weeks with triple antibiotic paste (TAP), diluted triple antibiotic paste (DTAP), or calcium hydroxide (Ca[OH]2); and then irrigated with EDTA. After treatment, contact angles between a blood analog and dentin surfaces were evaluated. Surface roughness and chemical composition were characterized using optical profilometry and energy-dispersive X-ray spectroscopy, respectively. One-way analysis of variance followed by Fisher least significant difference tests were used for statistical analyses. Results All treatment groups showed a significant reduction in wettability and a significant increase in surface roughness when compared with untreated dentin. Dentin treated with Ca(OH)2 had significantly lower wettability compared with all other groups. No significant difference in wettability was found between dentin treated with DTAP and TAP protocols. Dentin treated with TAP had significantly higher surface roughness compared with all other groups. Untreated dentin and NaOCl + EDTA–treated dentin had significantly higher calcium and phosphorus as well as significantly lower carbon compared with dentin treated with Ca(OH)2, DTAP, and TAP. Conclusions Endodontic regeneration protocols had a significant effect on wettability, surface roughness, and chemical composition of surface dentin. The Ca(OH)2 protocol caused a significant reduction in dentin wettability compared with TAP or DTAP protocols

Attachment and proliferation of dental pulp stem cells on dentine treated with different regenerative endodontic protocols

Aim To investigate the attachment and proliferation of dental pulp stem cells (DPSC) on dentine treated with various endodontic regeneration protocols. Methodology Standardized dentine samples were irrigated with sodium hypochlorite (1.5% NaOCl) and ethylenediaminetetraacetic acid (17% EDTA) and randomized into four treatment groups and two control groups. The treatment groups were treated with a clinically used concentration of triple antibiotic paste (TAP), double antibiotic paste (DAP), calcium hydroxide (Ca(OH)2) or diluted TAP in a methylcellulose system (DTAP) for 1 week. Each sample in the treatment groups was then irrigated with EDTA. The two control groups were treated with EDTA or received no treatment. Dental pulp stem cells were seeded on each dentine specimen (10 000 cells). Lactate dehydrogenase activity assays were then performed to evaluate the attached DPSC after 1 day of incubation. Water-soluble tetrazolium assays were used to determine DPSC proliferation after three additional days of incubation. Friedman's test followed by least significant difference were used for statistical analyses (α = 0.05). Results Triple antibiotic paste and DTAP regeneration protocols, as well as EDTA-treated dentine, caused significant increases in DPSC attachment to dentine. Triple antibiotic paste, DAP and Ca(OH)2 regeneration protocols caused significant reductions in DPSC proliferation on dentine. However, the DTAP regeneration protocol did not have any significant negative effects on DPSC proliferation. Conclusions The clinically used endodontic regeneration protocols that include the use of TAP, DAP or Ca(OH)2 medicament negatively affected DPSC proliferation on dentine. However, the use of DTAP medicament during regenerative endodontic treatment may not adversely affect the proliferation of DPSC

Time-Dependent Behavior of Excavation in Cohesive Soils Using the Bounding Surface Model

The study was to investigate the behavior of excavation in cohesive soils using the bounding surface model. The model and the finite element formulation are described and verified. Then the ground movements were predicted around an excavation in several types of cohesive soils. The results of the analysis demonstrate the effects of the consolidation process and permeability on the stability of the excavation and that the displacements at excavation boundaries increase with increasing permeability and time but at a lower rate as the permeability value decreased. Also the study shows a significant influence of the critical state parameters on the behavior of excavation in normally consolidated clay comparing with the surface configuration and hardening parameters of the model. Thus the modified Cam-clay model which employs a lower number of parameters can be used for the problems of excavation in normally consolidated cla

Evaluation of selected properties of a new root repair cement containing surface pre-reacted glass ionomer fillers

Objective This study evaluated selected properties of a prototype root repair cement containing surface pre-reacted glass ionomer fillers (S-PRG) in comparison to mineral trioxide aggregate (MTA) and intermediate restorative material (IRM). Materials and methods The antibacterial effect of S-PRG, MTA, and IRM cements was tested against Porphyromonas gingivalis and Enterococcus faecalis after 1 and 3 days of aging of the cements. The set cements were immersed in distilled water for 4 h to 28 days, and ion-releasing ability was evaluated. Initial and final setting times of all cements were evaluated using Gilmore needles. The push-out bond strength between radicular dentin and all cements was tested at different levels of the roots. Results S-PRG and IRM cements, but not MTA cement, demonstrated significant antibacterial effect against P. gingivalis. All types of cements exhibited significant antibacterial effect against E. faecalis without being able to eliminate the bacterium. S-PRG cement provided continuous release of fluoride, strontium, boron, sodium, aluminum, and zinc throughout all tested time points. Both initial and final setting times were significantly shorter for S-PRG and IRM cements in comparison to MTA. The push-out bond strength was significantly lower for S-PRG cement in comparison to MTA and IRM at coronal and middle levels of the roots. Conclusions S-PRG cement demonstrated significant antibacterial effects against endodontic pathogens, multiple ion-releasing ability, relatively short setting time, and low bonding strength. Clinical relevance S-PRG cement can be used as a one-visit root repair material with promising antibacterial properties and ion-releasing capacity

Experimental evaluation of a solar water heater integrated with a corrugated absorber plate and insulated flat reflectors

When it comes to renewable energy, solar water heaters are among the fastest-growing technologies. Comparatively speaking, integrated collector-storage solar water heater systems cost less than other solar water heater designs. Therefore, both the construction and the operation of a combined collector-storage solar water heater are quite straightforward. The integrated storage solar collector coupled with reflectors has been experimentally investigated. The reflectors were insulated from the back side when working during the day hours and as insulated cover during the night hours. While comparing the combined collector-storage solar water heater with and without insulated reflectors, the results showed that the insulated reflectors increased the thermal efficiency by 23%. Furthermore, on the coldest day, the stored water reached a high of 82 degrees Celsius, though it was only 46 degrees Celsius that same morning

Short Term Outcomes of Percutaneous Pulmonary Balloon Valvuloplasty in Adult Patients with Pulmonary Stenosis

Background: Percutaneous Balloon Pulmonary Valvuloplasty (BPV) is now the treatment of choice for pulmonary valve stenosis (PS) Patients and Methods. It is a retrospective study involving 40 consecutive patients with moderate to severe PS underwent BPV in Ibn Albitar Hospital for Cardiac Surgery from Sept. 2003 to Sept. 2004 , were medical records , Electrocardiograms ( ECG ) , Echo Doppler studies , and Catheterization data were reviewed carefully. Results: Mean pressure gradient across pulmonary valve (PV) was reduced from 112 +/- 46 mmHg before intervention to 49 It/- 34.7 after intervention. Procedure failure occurred in one patient (2.5 %), four patients (10%) developed mild to moderate pulmonary regurgitation , no mortality was detected. Conclusion: BPV is effective and safe procedure for patients with valvular PS