Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Improved bioavailability of levodopa using floatable spray-coated microcapsules for the management of Parkinson’s disease

Oral administration of levodopa (LD) is the gold standard in managing Parkinson’s disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.MOE (Min. of Education, S’pore)Accepted versio

Exposure to Titanium Dioxide Nanoparticles Induces Autophagy in Primary Human Keratinocytes

10.1002/smll.201201363SMALL93387-392SMALBGERMANYComplete

POMEGRANATE ACTIVATES TFEB TO PROMOTE AUTOPHAGY-LYSOSOMAL FITNESS AND MITOPHAGY

10.1038/s41598-018-37400-19

Expression and characterization of soluble amino-terminal domain of NR2B subunit of N-methyl-d-aspartate receptor

N-methyl-d-aspartate (NMDA) receptors are involved in mediating excitatory synaptic transmissions in the brain and have been implicated in numerous neurologic disorders. The proximal amino-terminal domains (ATDs) of NMDA receptors constitute many modulatory binding sites that may serve as potential drug targets. There are few biochemical and structural data on the ATDs of NMDA receptors, as it is difficult to produce the functional proteins. Here an optimized method was established to reconstitute the insoluble recombinant ATD of NMDA receptor NR2B subunit (ATD2B) through productive refolding of 6xHis-ATD2B protein from inclusion bodies. Circular dichroism and dynamic light scattering characterizations revealed that the solubilized and refolded 6xHis-ATD2B adopted well-defined secondary structures and monodispersity.More significantly, the soluble 6xHis-ATD2B specifically bound ifenprodil to saturation. Ifenprodil bound to 6xHis-ATD2B with a dissociation constant (KD) of 127.5±45 nM, which was within the range of the IC50 determined electrophysiologically. This is the first report on a functional recombinant ATD2B with a characterized KD

Exclusion of alternative exon 33 of Ca(V)1.2 calcium channels in heart is proarrhythmogenic

Alternative splicing changes the Ca(V)1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca(V)1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the Ca(V)1.2 calcium channel in heart function. Exclusion of exon 33 in Ca(V)1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca(V)1.2.33 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca(V)1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33(-/-)-null mice. These mice contained Ca(V)1.2.33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/-mice from beta-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing Ca(V)1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in Ca(V)1.2 channels may play in the pathogenesis of human heart failure remains unclear

Transcript scanning reveals novel and extensive splice variations in human L-type voltage-gated calcium channel, Cav1.2 α1subunit

10.1074/jbc.M407023200Journal of Biological Chemistry2794344335-44343JBCH