Rejected

Reversible cerebral vasoconstriction syndrome (RCVS) after heart transplantation is a rare, but serious complication, because of a high risk for permanent neurological deficits or allograft rejection. A 48-year-old female who underwent orthotropic heart transplantation presented with a sudden severe headache 10 days after transplantation. Although magnetic resonance angiography (MRA) findings at initial symptom onset were normal, MRA finding at the next day revealed multifocal vasoconstriction of cerebral arteries. Tacrolimus-induced RCVS was strongly suspected, and tacrolimus was immediately discontinued and basiliximab was added as an alternative immunosuppressant. Notably, neurological symptoms occurred at the time of sharp increase in serum tacrolimus levels and resolved when it decreased to low levels. Follow-up MRA showed complete remission and she recovered without any neurological symptom or allograft rejection. Our case suggests that prompt diagnosis with repeated MRA and immediate discontinuation of tacrolimus are essential to avoid severe neurological sequelae of RCVS.

This study sought to evaluate the long-term effect of transcatheter patent foramen ovale (PFO) closure on migraineurs with and without aura and examine the effect of residual right-to-left shunt.

Nacubactam is a novel, β-lactamase inhibitor with dual mechanism of action as an inhibitor of serine β-lactamases (classes A, C, and some class D) and an inhibitor of penicillin binding protein 2 in The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single and multiple ascending dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam 50 to 8,000 mg, multiple ascending doses of nacubactam 1,000 to 4,000 mg every 8 hours (q8h) for up to 7 days, or nacubactam 2,000 mg plus meropenem 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild-to-moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Co-administration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential β-lactam partner for nacubactam.ClinicalTrials.gov NCT02134834 (single ascending dose study); ClinicalTrials.gov NCT02972255 (multiple ascending dose study).

Endothelial glycocalyx degradation, critical for increased pulmonary vascular permeability, is thought to facilitate the development of sepsis into the multiple organ failure. Maresin conjugates in tissue regeneration 1 (MCTR1), a macrophage-derived lipid mediator, which exhibits potentially beneficial effects via the regulation of bacterial phagocytosis, promotion of inflammation resolution, and regeneration of tissue. In this study, we show that MCTR1 (100 ng/mouse) enhances the survival of mice with lipopolysaccharide (LPS)-induced (15 mg/kg) sepsis. MCTR1 alleviates LPS (10 mg/kg)-induced lung dysfunction and lung tissue inflammatory response by decreasing inflammatory cytokines (tumor necrosis factor-α, interleukin-1β [IL-1β], and IL-6) expression in serum and reducing the serum levels of heparan sulfate (HS) and syndecan-1. In human umbilical vein endothelial cells (HUVECs) experiments, MCTR1 (100 nM) was added to the culture medium with LPS for 6 hr. MCTR1 treatment markedly inhibited HS degradation by downregulating heparanase (HPA) protein expression in vivo and in vitro. Further analyses indicated that MCTR1 upregulates sirtuin 1 (SIRT1) expression and decreases NF-κB p65 phosphorylation. In the presence of BOC-2 or EX527, the above effects of MCTR1 were abolished. These results suggest that MCTR1 protects against LPS-induced sepsis in mice by attenuating pulmonary endothelial glycocalyx injury via the ALX/SIRT1/NF-κB/HPA pathway.

Effective analgesic alternatives to interscalene brachial plexus block are sought for shoulder surgery. Peri-articular infiltration analgesia is a novel, less invasive technique, but evidence surrounding its use is unclear. This systematic review and meta-analysis aims to evaluate the utility of peri-articular infiltration analgesia in shoulder surgery. We searched literature for trials comparing peri-articular infiltration analgesia with control or with interscalene brachial plexus block. Control groups received no intervention, placebo or systemic opioids. The primary outcome was cumulative oral morphine equivalent consumption during the first 24 h postoperatively. Secondary outcomes included: rest pain scores up to 48 h; risk of side-effects; and durations of post-anaesthetic care unit and hospital stay. Data were pooled with random-effects modelling. Seven trials (383 patients) were included. Compared with control, peri-articular infiltration analgesia reduced 24-h oral morphine consumption by a mean difference (95%CI) of -38.0 mg (-65.5 to -10.5; p = 0.007). It also improved pain scores up to 6 h, 36 h and 48 h, with the greatest improvement observed at 0 h (-2.4 (-2.7 to -1.6); p < 0.001). Peri-articular infiltration analgesia decreased postoperative nausea and vomiting by an odds ratio (95%CI) of 0.3 (0.1-0.7; p = 0.006). In contrast, peri-articular infiltration analgesia was not different from interscalene brachial plexus block for analgesic consumption, pain scores or side-effects. This review provides moderate evidence supporting peri-articular infiltration for postoperative analgesia following shoulder surgery. The absence of difference between peri-articular infiltration analgesia and interscalene brachial plexus block for analgesic outcomes suggests that these interventions are comparable, but further trials are needed to support this conclusion and identify the optimal peri-articular infiltration technique.

In humans, gabapentin an analgesic, undergoes non-proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses.

Levobupivacaine is a long-acting amide local anaesthetic used in analgesia and anaesthesia. Like other local anaesthetic drugs, levobupivacaine exhibits effects on motor and sensory nerves by inhibiting the opening of voltage-gated sodium channels, and hence propagation of neuronal action potentials. Levobupivacaine is the S(-) stereoisomer of dextrobupivacaine, although both are used commercially in the racemic form bupivacaine. A favourable safety and drug effect profile for levobupivacaine has led to widespread use. Levobupivacaine is generally well tolerated but dose adjustment is important in populations such as paediatrics and the elderly. The pharmacokinetic properties of levobupivacaine are similar to that of bupivacaine; both extensively metabolised in the liver, and excreted in the urine and faeces. In vitro, animal model and human studies confirm a lower risk of cardiac and central nervous system toxicity with levobupivacaine compared with bupivacaine. Clinical trials of relative potency are impaired by the variability in chosen endpoints for sensory and motor function blockade, but clinically significant differences in potency are minor, with most clinical trials showing similar duration and quality of anaesthesia between levo- and racemic bupivacaine. In practice, levobupivacaine is most commonly used in regional anaesthesia, neuraxial anaesthesia and local infiltration analgesia. This review includes an appraisal of evidence from clinical trials of the pharmacokinetic and pharmacodynamic properties of levobupivacaine.

To conduct a systematic literature review of brain neurostimulation for pain.