Pharmacokinetics of oxycodone/naloxone and its metabolites in patients with end-stage renal disease during and between haemodialysis sessions

The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions.; Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system.; Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low.; Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis

Noninvasive cardiac output and blood pressure monitoring cannot replace an invasive monitoring system in critically ill patients

Background: Monitoring of cardiac output and blood pressure are standard procedures in critical care medicine. Traditionally, invasive techniques like pulmonary artery catheter (PAC) and arterial catheters are widely used. Invasiveness bears many risks of deleterious complications. Therefore, a noninvasive reliable cardiac output (CO) and blood pressure monitoring system could improve the safety of cardiac monitoring. The aim of the present study was to compare a noninvasive versus a standard invasive cardiovascular monitoring system. Methods: Nexfin HD is a continuous noninvasive blood pressure and cardiac output monitor system and is based on the development of the pulsatile unloading of the finger arterial walls using an inflatable finger cuff. During continuous BP measurement CO is calculated. We included 10 patients with standard invasive cardiac monitoring system (pulmonary artery catheter and arterial catheter) comparing invasively obtained data to the data collected noninvasively using the Nexfin HD. Results: Correlation between mean arterial pressure measured with the standard arterial monitoring system and the Nexfin HD was r2 = 0.67 with a bias of -2 mmHg and two standard deviations of ± 16 mmHg. Correlation between CO derived from PAC and the Nexfin HD was r2 = 0.83 with a bias of 0.23 l/min and two standard deviations of ± 2.1 l/min; the percentage error was 29%. Conclusion: Although the noninvasive CO measurement appears promising, the noninvasive blood pressure assessment is clearly less reliable than the invasively measured blood pressure. Therefore, according to the present data application of the Nexfin HD monitoring system in the ICU cannot be recommended generally. Whether such a tool might be reliable in certain critically ill patients remains to be determined

Regenerative endodontics: a true paradigm shift or a bandwagon about to be derailed?

Aims: Regenerative endodontic techniques (RETs) have been hailed as a paradigm shift for the management of traumatised non-vital immature permanent anterior teeth. In this article the aim was to critically appraise the literature with regards to the outcome of regenerative endodontics on root development. Methods: Critical review of the literature where regenerative endodontic techniques have been used in the management of immature non-vital teeth with continuation of root development as the main outcome reported. Results: Most studies published were in the form of case reports and series with very few randomised controlled trials with a high risk of bias. Continuation of root development following the use of RET has been shown to be unpredictable at best with lower success in those teeth losing vitality as a result of dental trauma. Conclusions: Despite the high success of regenerative endodontics in terms of periodontal healing including resolution of clinical and radiographic signs and symptoms of infection, continuation of root development remains an unpredictable outcome. The use of a blood clot as a scaffold in regenerative endodontics should be reviewed carefully as that might offer an environment for repair rather than regeneration. In addition, preservation of structures, such as Hertwig’s epithelial root sheath, may have an important bearing on the success of this approach and should be further investigated

Antimicrobial activity of ProRoot MTA in contact with blood

Dental materials based on Portland cement, which is used in the construction industry have gained popularity for clinical use due to their hydraulic properties, the interaction with tooth tissue and their antimicrobial properties. The antimicrobial properties are optimal in vitro. However in clinical use contact with blood may affect the antimicrobial properties. This study aims to assess whether antimicrobial properties of the Portland cement-based dental cements such as mineral trioxide aggregate (MTA) are also affected by contact with blood present in clinical situations. ProRoot MTA, a Portland cement-based dental cement was characterized following contact with water, or heparinized blood after 1 day and 7 days aging. The antimicrobial activity under the mentioned conditions was assessed using 3 antimicrobial tests: agar diffusion test, direct contact test and intratubular infection test. MTA in contact with blood was severely discoloured, exhibited an additional phosphorus peak in elemental analysis, no calcium hydroxide peaks and no areas of bacterial inhibition growth in the agar diffusion test were demonstrated. ProRoot MTA showed limited antimicrobial activity, in both the direct contact test and intratubular infection test. When aged in water ProRoot MTA showed higher antimicrobial activity than when aged in blood. Antimicrobial activity reduced significantly after 7 days. Further assessment is required to investigate behaviour in clinical situations.ERDF (Malta) for the financing of the testing equipment through the project: “Developing an Interdisciplinary Material Testing and Rapid Prototyping R&D Facility” (Ref. no. 012)

Systemically administered amoxicillin/ metronidazole versus azithromycin as adjuncts to subgingival instrumentation during non-surgical periodontal therapy. A systematic review

The aim of this systematic review was to compare the combination of amoxicillin and metronidazole or azithromycin when used as adjunct systemic antibiotics during the non-surgical periodontal therapy of chronic periodontitis. The databases Medline, Embase, Cochrane and Biosis were electronically searched. Additionally, a hand search was conducted up to24 October 2019. From 76 papers, only two papers could be included in the analysis. The calculated mean probability of having probing depth (PD) ≤ 3 mm after non-surgical periodontal therapy in moderate (4-6 mm) and deep (> 6 mm) pockets accounted for 7% and 6% for the combination of amoxicillin and metronidazole. For azithromycin it was 3% and 1%, respectively. The mean probability of persisting pockets ≥ 5 mm was 0 for moderate pockets with both antibiotic therapies whereas for deep pockets therapy with amoxicillin and metronidazole seems slightly lower. On the basis of two studies included in this systematic review, azithromycin as an adjunct to scaling and root planing in the non-surgical adjunctive treatment of chronic periodontitis seems to provide clinical results similar to the combination of amoxicillin and metronidazole. On behalf of patients' compliance and well-being, the use of azithromycin as an adjunct to non-surgical periodontal therapy of chronic periodontitis may be a substitute to amoxicillin and metronidazole. However, interpretation should be taken with caution, since the results are based on two studies only; thus, further clinical trials are necessary to underline or refute this trend

Conventional finite element models estimate the strength of metastatic human vertebrae despite alterations of the bone's tissue and structure.

INTRODUCTION Pathologic vertebral fractures are a major clinical concern in the management of cancer patients with metastatic spine disease. These fractures are a direct consequence of the effect of bone metastases on the anatomy and structure of the vertebral bone. The goals of this study were twofold. First, we evaluated the effect of lytic, blastic and mixed (both lytic and blastic) metastases on the bone structure, on its material properties, and on the overall vertebral strength. Second, we tested the ability of bone mineral content (BMC) measurements and standard FE methodologies to predict the strength of real metastatic vertebral bodies. METHODS Fifty-seven vertebral bodies from eleven cadaver spines containing lytic, blastic, and mixed metastatic lesions from donors with breast, esophageal, kidney, lung, or prostate cancer were scanned using micro-computed tomography (μCT). Based on radiographic review, twelve vertebrae were selected for nanoindentation testing, while the remaining forty-five vertebrae were used for assessing their compressive strength. The μCT reconstruction was exploited to measure the vertebral BMC and to establish two finite element models. 1) a micro finite element (μFE) model derived at an image resolution of 24.5 μm and 2) homogenized FE (hFE) model derived at a resolution of 0.98 mm. Statistical analyses were conducted to measure the effect of the bone metastases on BV/TV, indentation modulus (Eit), ratio of plastic/total work (WPl/Wtot), and in vitro vertebral strength (Fexp). The predictive value of BMC, μFE stiffness, and hFE strength were evaluated against the in vitro measurements. RESULTS Blastic vertebral bodies exhibit significantly higher BV/TV compared to the mixed (p = 0.0205) and lytic (p = 0.0216) vertebral bodies. No significant differences were found between lytic and mixed vertebrae (p = 0.7584). Blastic bone tissue exhibited a 5.8% lower median Eit (p< 0.001) and a 3.3% lower median Wpl/Wtot (p<0.001) compared to non-involved bone tissue. No significant differences were measured between lytic and non-involved bone tissues. Fexp ranged from 1.9 to 13.8 kN, was strongly associated with hFE strength (R2=0.78, p< 0.001) and moderately associated with BMC (R2=0.66, p< 0.001) and μFE stiffness (R2=0.66, p< 0.001), independently of the lesion type. DISCUSSION Our findings show that tumour-induced osteoblastic metastases lead to slightly, but significantly lower bone tissue properties compared to controls, while osteolytic lesions appear to have a negligible impact. These effects may be attributed to the lower mineralization and woven nature of bone forming in blastic lesions whilst the material properties of bone in osteolytic vertebrae appeared little changed. The moderate association between BMC- and FE-based predictions to fracture strength suggest that vertebral strength is affected by the changes of bone mass induced by the metastatic lesions, rather than altered tissue properties. In a broader context, standard hFE approaches generated from CTs at clinical resolution are robust to the lesion type when predicting vertebral strength. These findings open the door for the development of FE-based prediction tools that overcomes the limitations of BMC in accounting for shape and size of the metastatic lesions. Such tools may help clinicians to decide whether a patient needs the prophylactic fixation of an impending fracture

Human caspases in vitro: expression, purification and kinetic characterization

A number of strategies and protocols for the expression, purification and kinetic characterization of human caspases are described in the literature. We have systematically revised these protocols and present comprehensive optimized expression and purification protocols for caspase-1 to -9 as well as improved assay conditions for their reproducible kinetic characterization. Our studies on active site titration revealed that the reproducibility is strongly affected by the presence of DTT in the assay buffer. Furthermore, we observed that not all caspases show a linear relationship between enzymatic activity and protein concentration, which explains the discrepancy between published values of specific activities from different laboratories. Our broad kinetic analysis allows the conclusion that the dependency of caspase activities on protein concentration is an effect of concentration-dependent dimerization, which can also be influenced by kosmotropic salts. The protocol recommendations as an outcome of this work will yield higher reproducibility regarding expression and purification of human caspases and contribute to standardization of enzyme kinetic data