Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Kinetics of use-dependent ventricular conduction slowing by antiarrhythmic drugs in humans

BACKGROUND. Rate-dependent conduction slowing by class I antiarrhythmic agents has clinically important consequences. Class I drugs are known to produce use-dependent sodium channel blockade. If rate-dependent conduction slowing by class I agents is due to sodium channel blocking actions, the kinetics of conduction slowing should be similar to those of depression of sodium current indexes in vitro. The purpose of the present investigation was to study the onset time course of ventricular conduction slowing caused by a variety of class I agents in humans. METHODS AND RESULTS. Twenty-seven patients undergoing electrophysiological evaluation for antiarrhythmic therapy were studied. Changes in QRS duration at initiation of ventricular pacing at cycle lengths of 400 and 500 msec were used to evaluate the kinetics of drug action. Mean time constants for each drug were similar to values for Vmax depression reported in vitro studies: flecainide, 24.9 +/- 11.6 beats in eight patients (versus 34.5 beats reported for Vmax block); propafenone, 17.8 +/- 6.9 beats in five patients (versus 8.4-20.8 beats); quinidine, 7.0 +/- 2.4 beats in six patients (versus 5.6-6.2 beats); and amiodarone, 3.6 +/- 2.0 beats for eight patients (versus 3.0 beats). Time constants were significantly different among the various drugs tested (p = 0.0002 at a cycle length of 400 msec; p = 0.002 at 500 msec), and there was a strong correlation (r = 0.89, p less than 0.0001) between values obtained at a cycle length of 400 msec and those at a cycle length of 500 msec. No rate-dependent changes in QRS duration were seen at onset of ventricular pacing among eight age- and disease-matched control patients not taking class I antiarrhythmic drugs, including three patients subsequently showing such changes during type I antiarrhythmic drug therapy. CONCLUSIONS. We conclude that class I agents produce use-dependent QRS prolongation in humans with characteristic kinetics for each agent that are similar to the kinetics of Vmax depression in vitro. These results suggest that rate-dependent ventricular conduction slowing by antiarrhythmic drugs in humans is due to use-dependent sodium channel blockade.     

Reduction in length of stay for patients undergoing oesophageal and gastric resections with implementation of enhanced recovery packages

Introduction

The high mortality and morbidity associated with resection for oesophagogastric malignancy has resulted in a conservative approach to the postoperative management of this patient group. In August 2009 we introduced an enhanced recovery after surgery (ERAS) pathway tailored to patients undergoing resection for oesophagogastric malignancy. We aimed to assess the impact of this change in practice on standard clinical outcomes.

Methods

Two cohorts were studied of patients undergoing resection for oesophagogastric malignancy before (August 2008 – July 2009) and after (August 2009 – July 2010) the implementation of the ERAS pathway. Data were collected on demographics, interventions, length of stay, morbidity and in-hospital mortality.

Results

There were 53 and 55 oesophagogastric resections undertaken respectively for malignant disease in each of the study periods. The median length of stay for both gastric and oesophageal resection decreased from 15 to 11 days (Mann– Whitney U, p<0.001) following implementation of the ERAS pathway. There was no significant increase in morbidity (gastric resection 23.1% vs 5.3% and oesophageal resection 25.9% vs 16.7%) or mortality (gastric resection no deaths and oesophageal resection 1.8% vs 3.6%) associated with the changes. There was a significant decrease in the number of oral contrast studies used following oesophageal resection, with a reduction from 21 (77.8%) in 2008–2009 to 6 (16.7%) in 2009–2010 (chi-squared test, p<0.0001).

Conclusions

The introduction of an enhanced recovery programme following oesophagogastric surgery resulted in a significant decrease in length of median patient stay in hospital without a significant increase in associated morbidity and mortality.     

Influence of SARS-CoV-2 Variant B.1.1.7, Vaccination,and Public Health Measures on the Spread of SARS-CoV-2

The spread of SARS-CoV-2 and the resulting disease COVID-19 has killed over 2.6 million people as of 18 March 2021. We have used a modified susceptible, infected, recovered (SIR) epidemiological model to predict how the spread of the virus in regions of France will vary depending on the proportions of variants and on the public health strategies adopted, including anti-COVID-19 vaccination. The proportion of SARS-CoV-2 variant B.1.1.7, which was not detected in early January, increased to become 60% of the forms of SARS-CoV-2 circulating in the Toulouse urban area at the beginning of February 2021, but there was no increase in positive nucleic acid tests. Our prediction model indicates that maintaining public health measures and accelerating vaccination are efficient strategies for the sustained control of SARS-CoV-2.     

Current controversies regarding pain assessment in neonates

Although over 40 methods of pain assessment in infants are available for use in clinical practice, unrecognized and under-treated pain remains one of the most commonly reported problems within the Neonatal Intensive Care Units. A number of factors have been found to account for differences in the robustness of the pain response in neonates of varying gestational ages. Discrepancies between behavioral and physiological pain indicators have also been reported. With newer technologies, there is an opportunity not only to verify infant pain perception, but these tools may allow an identification of which of the observed indicators are most sensitive in particular clinical situations. The current controversies regarding pain assessment in preterm and term infants are reviewed to define the most important issues and to develop a dialogue for future directions.     

High frequency oscillation in newborn infants with respiratory failure

Objective: To report ventilation strategies, survival and complications in 39 outborn infants treated with high frequency oscillatory ventilation (HFOV).
Methodology Data were collected prospectively between 1 May 1992 and 31 December 1993 on all infants treated with HFOV who had severe respiratory failure despite optimal conventional ventilation.
Results Twenty-eight out of 39 (72%) survived. Of the 15 infants with birthweights <1500g, eight survived. Best survival rates were for infants with pulmonary interstitial emphysema with air leak (4/5) and for infants of birthweight >1500g with hyaline membrane disease (8/8), and meconium aspiration syndrome (7/7). Three infants deteriorated while on HFOV and required extracorporeal membrane oxygenation. Complications were: (i) development of pulmonary interstitial emphysema (1); (ii) recurrence of pneumothorax (3); (iii) hypotension (2); and (iv) bronchopulmonary dysplasia (9). One of the eight infants weighing <1500g who received HFOV in the first week of life developed periventricular haemorrhage.
Conclusion The initial results of HFOV for severe respiratory failure were encouraging although a learning curve was encountered with its introduction.