In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation

The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here we report the development and characterization of a first-in-class novel azole analog [1-(4-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone (FLB-12)] that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., liver X receptor, farnesoid X receptor, estrogen receptor α, peroxisome proliferator-activated receptor γ, and mouse constitutive androstane receptor). We investigated the toxicity and PXR antagonist effect of FLB-12 in vivo. Compared with ketoconazole, a prototypical PXR antagonist, FLB-12 is significantly less toxic to hepatocytes. FLB-12 significantly inhibits the PXR-activated loss of righting reflex to 2,2,2-tribromoethanol (Avertin) in vivo, abrogates PXR-mediated resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in colon cancer cells in vitro, and attenuates PXR-mediated acetaminophen hepatotoxicity in vivo. Thus, relatively selective targeting of PXR by antagonists is feasible and warrants further investigation. This class of agents is suitable for development as chemical probes of PXR function as well as potential PXR-directed therapeutics.     

Donor-specific antibodies accelerate arteriosclerosis after kidney transplantation

In biopsies of renal allografts, arteriosclerosis is often more severe than expected based on the age of the donor, even without a history of rejection vasculitis. To determine whether preformed donor-specific antibodies (DSAs) may contribute to the severity of arteriosclerosis, we examined protocol biopsies from patients with (n=40) or without (n=59) DSA after excluding those with any evidence of vasculitis. Among DSA-positive patients, arteriosclerosis significantly progressed between month 3 and month 12 after transplant (mean Banff cv score 0.65 ± 0.11 to 1.12 ± 0.10, P=0.014); in contrast, among DSA-negative patients, we did not detect a statistically significant progression during the same timeframe (mean Banff cv score 0.65 ± 0.11 to 0.81 ± 0.10, P=not significant). Available biopsies at later time points supported a rate of progression of arteriosclerosis in DSA-negative patients that was approximately one third that in DSA-positive patients. Accelerated arteriosclerosis was significantly associated with peritubular capillary leukocytic infiltration, glomerulitis, subclinical antibody-mediated rejection, and interstitial inflammation. In conclusion, these data support the hypothesis that donor-specific antibodies dramatically accelerate post-transplant progression of arteriosclerosis.     

Perioperative intravenous lidocaine infusion for postoperative pain control: a meta-analysis of randomized controlled trials

Introduction

Various strategies have been proposed for postoperative pain control. Among those, intravenous lidocaine infusion (IVLI) has gained in interest. However, its clinical benefit remains unclear. This systematic review is an evaluation of the analgesic efficacy and safety of IVLI during general anesthesia.

Methods

A systematic search was performed using MEDLINE, EMBASE, Cochrane, and SCOPUS databases, likewise, grey literature. The review included all randomized controlled trials that used a placebo or any comparator and evaluated IVLI during general anesthesia for any type of surgery. Primary outcomes were pain control and opioid requirement. Secondary outcomes were mortality, length of stay, ileus recovery time, nausea/vomiting, and adverse events. Random effects models were used and heterogeneity was assessed using the I² index.

Results

From 5,472 citations retrieved, 29 studies involving a total of 1,754 patients met eligibility. At six hours postoperatively, intravenous lidocaine infusion reduced pain at rest (weighted mean difference [WMD] ?8.70, 95% confidence intervals [CI] ?16.19 to ?1.21), during cough (WMD ?11.19, 95% CI ?17.73 to ?4.65), and during movement (WMD ?9.56, 95% CI ?17.31 to ?1.80). Intravenous lidocaine infusion also reduced opioid requirement (morphine) (WMD ?8.44 mg, 95% CI ?11.32 to ?5.56), time to first flatus (WMD ?7.62 hr, 95% CI ?10.78 to ?4.45), time to first feces (WMD ?10.71 hr, 95% CI ?16.14 to ?5.28), nausea/vomiting (risk ratios = 0.71, 95% CI 0.57-0.90), and hospital length of stay (WMD ?0.17 days, 95% CI ?0.41 to 0.07). Abdominal surgery was strongly associated with benefit. For the 12 studies that systematically screened adverse events, the incidence of cardiac and neurologic adverse events was comparable. Eight studies observed toxic plasma levels.

Discussion

Perioperative IVLI reduced postoperative pain and opioid requirement, as well as ileus recovery time, hospital length of stay, and nausea/vomiting. Intravenous lidocaine infusion was effective mainly in abdominal surgery populations. Considering that toxic levels were detected and that adverse events were not systematically screened for in most studies, dose and safety of IVLI should be established before recommending its use.     

Coronary vein angioplasty with noncompliant balloon for resistant coronary vein stenosis during left ventricular lead implantation

This report describes a patient who underwent cardiac resynchronization therapy (CRT) in the setting of a severe stenosis in the lateral coronary vein that prevented passage of a left ventricular lead. The stenosis was unresponsive to standard compliant balloon dilatation but was successfully treated with a noncompliant balloon. Venoplasty with noncompliant balloon should be considered for resistant coronary vein stenosis encountered during CRT device implantation.     

Human pre-elafin inhibits a Pseudomonas aeruginosa-secreted peptidase and prevents its proliferation in complex media

Pseudomonas aeruginosa is a life-threatening opportunist human pathogen frequently associated with lung inflammatory diseases, namely, cystic fibrosis. Like other species, this gram-negative bacteria is increasingly drug resistant. During the past decade, intensive research efforts have been focused on the identification of natural innate defense molecules with broad antimicrobial activities, collectively known as antimicrobial peptides. Human pre-elafin, best characterized as a potent inhibitor of neutrophil elastase with anti-inflammatory properties, was also shown to possess antimicrobial activity against both gram-positive and gram-negative bacteria, including P. aeruginosa. Its mode of action was, however, not known. Using full-length pre-elafin, each domain separately, and mutated variants of pre-elafin with attenuated antipeptidase activity toward neutrophil elastase, we report here that both pre-elafin domains contribute, through distinct mechanisms, to its antibacterial activity against Pseudomonas aeruginosa. Most importantly, we demonstrate that the whey acidic protein (WAP) domain specifically inhibits a secreted peptidase with the characteristics of arginyl peptidase (protease IV). This is the first demonstration that a human WAP-motif protein inhibits a secreted peptidase to prevent bacterial growth in vitro. Since several WAP-motif proteins from various species demonstrate antimicrobial function with variable activities toward bacterial species, we suggest that this mechanism may be more common than initially anticipated.     

Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: a possible 'anti-proarrhythmic' role for amlodipine

Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 μM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD₉₀). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I_Kr-blocking (dofetilide) and I_Ks-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.     

Influence of gender on the outcome of severe sepsis: a reappraisal

BACKGROUND: The influence of gender on survival of patients with severe sepsis is unclear. Earlier studies suggested better survival in women, possibly related to the sex-steroid profile. METHODS: To investigate whether mortality from severe sepsis was higher in men than in women and whether the difference varied with menopausal status, we studied 1,692 patients with severe sepsis included in the OutcomeRea database over an 8-year period. We conducted a nested case-control study, accurately matching men and women on three criteria: a death propensity score, age, and center. Subgroup analyses were performed on individuals 50 years old (men vs postmenopausal women). RESULTS: We matched 1,000 men to 608 women with severe sepsis before and after adjustment for confounding factors (ie, chronic respiratory failure; metastatic cancer; immunocompromised status; emergency surgery, acute respiratory failure, and shock at admission; urinary tract infection; and type of microorganism). Overall hospital mortality was significantly lower in women (adjusted odds ratio [OR], 0.75; 95% confidence interval [CI], 0.57 to 0.97; p = 0.02). In the group > 50 years old (481 women, 778 men), hospital mortality was significantly lower in women (OR, 0.69; 95% CI, 0.52 to 0.93; p = 0.014). Hospital mortality was not significantly different between men and women in the younger group (127 women, 222 men) [OR, 1.01; 95% CI, 0.52 to 1.97; p = 0.98]. Level of care, as assessed using the nine equivalents of nursing manpower use score, was identical in men and women. CONCLUSIONS: Among individuals > 50 years old with severe sepsis, women have a lower risk of hospital mortality than men.