Objective:
To review the literature and our institutional experience regarding the risk of meningitis in patients with spontaneous lateral skull base cerebrospinal fluid (sCSF) leaks awaiting ...surgical repair, and the roles of antibiotic prophylaxis and pneumococcal vaccination, if known.
Methods:
A retrospective chart review and systematic review of the literature was undertaken to identify the incidence of meningitis in patients with sCSF leaks awaiting surgical repair. Adults managed surgically for sCSF leaks at an academic tertiary care center over a 10-year period were included. Data was collected on receipt of prophylactic antibiotics and/or pneumococcal vaccines during the timeframe between diagnosis and surgical repair.
Results:
Institutional review identified 87 patients who underwent surgical repair of spontaneous leaks, with a 0% incidence of meningitis over a median duration of 2 months while awaiting surgery (mean 5.5 months, range 0.5-118 months). Eighty-eight percent of patients did not receive prophylactic antibiotics. No studies in the published literature demonstrated the impact of prophylactic antibiotics or pneumococcal vaccine on meningitis risk.
Conclusions:
There appears to be a low risk of meningitis among patients with lateral skull base sCSF leaks awaiting surgery for short durations (≤2 months), even in the absence of prophylactic antibiotics. There is a substantial gap in the published literature assessing the risk of meningitis and roles of antibiotics and vaccination in this patient population, indicating the need for large-scale study to conclusively elucidate the nature of this risk.
Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in ...modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (tmax: 1–2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED50 = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.
•Noncanonical pharmacokinetic properties have hampered kappa antagonist development.•Chemistry improvements identified novel compounds with kappa antagonist activity.•LY2456302 exhibits canonical pharmacokinetic properties and kappa selectivity in vivo.•LY2456302 has antidepressant-like properties and reduces ethanol self-administration.•LY2456302 is a novel research tool with favorable properties for clinical development.
To report the audiometric and surgical outcomes of a series of patients having undergone implantation of a novel transcutaneous bone conduction implant (t-BCI).
Retrospective case series.
Single ...academic tertiary referral center.
Adults (≥18 yr) implanted between December 1, 2019, and August 1, 2021, with audiometric data available before and after device implantation and a minimum of 4 weeks follow-up.
Surgical t-BCI.
Change in aided pure tone average (PTA) after implantation. Secondary outcomes include average operative time, and adverse events.
Twenty-three patients underwent implantation of the t-BCI via either a conventional or minimally invasive surgical approach. The most common indication for implantation was unilateral conductive hearing loss with a history of chronic otitis media. The mean operative time was 59 minutes. The mean preimplantation unaided air conduction PTA was 65 dB, and mean postimplantation was 27.2 dB. The mean change in PTA was 37.8 dB, which was significant ( p < 0.0001). There were 30.4% of the patients that suffered from adverse events, the most common of which were pain (8.7%) and device-related complications (13%). One major adverse event occurred, involving magnet displacement that impaired device activation and required reoperation for replacement.
Forming the largest series of patients implanted with this t-BCI in the published literature, our data demonstrate that implantation of the device is feasible via either a traditional or minimally invasive surgical approach, with good audiometric benefit and a favorable safety profile.
Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells ...expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K i = 0.565 nM for κ opioid receptor binding while having a K i = 35.8 nM for μ opioid receptors and a K i = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a 35S-guanosine 5′O-3-thiotriphosphate (35SGTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.
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Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis ...in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30μM, and failed to inhibit human mPGES-2 at 62.5μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.
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We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led ...initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of (cyclopentyl)ethylbenzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the ...(1S,2R,5R,6R)-2-amino-bicyclo3.1.0hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-(3,4-difluorophenyl)sulfanylmethyl-4-hydroxy-bicyclo3.1.0hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
Historically, stapedectomy complication rates are quoted as 1% profound postoperative sensorineural hearing loss (SNHL), 5%-10% nonprofound SNHL, and 5%-10% revision surgery.
We sought to reassess ...rates of post-stapedotomy complications based on our experience using contemporary surgical technique.
A retrospective case series was carried out at an academic tertiary referral center. Adult patients undergoing stapedotomy from 2013 to 2020 were included. Primary outcomes were rates of hearing loss and revision surgery. Rates of dizziness, tinnitus, dysgeusia, and proportions of patients who achieved air-bone gap (ABG) closure at 8-12 weeks postoperatively were also assessed.
Four hundred sixty-eight stapedotomies in 399 patients with a median follow-up duration of 99 days (range, 11-5134) were reviewed. One patient (0.21%) suffered profound SHNL and 15 (3.20%) patients suffered nonprofound SNHL. The revision rate for stapedotomies from our institution was 4.49% (21 total revision surgeries). In 277 operations (59.19%), the patient had closure of the ABG within 10 dB. A further 132 (28.21%) had closure of the ABG between 10 and 20 dB. Air pure-tone audiometry scores improved by an average of 25.03 dB. Eighty-three (17.74%) patients complained of postoperative dizziness, which resolved by the time of the first follow-up appointment in all but 26 (5.56%). Seventeen patients (3.63%) complained of tinnitus, and 22 (4.70%) complained of dysgeusia.
SNHL, complications, and revision rates for stapedotomy in the modern era may be substantially lower than those currently presented to patients based on classic techniques and historical data.
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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
The objective of this study is to assess diagnostic yield of imaging modalities used to evaluate patients presenting with pulsatile tinnitus (PT).
PubMed, Embase, and Scopus were queried using the ...search terms "pulsatile tinnitus," "pulse-synchronous tinnitus," and "pulse synchronous tinnitus" with no date limitations.
Studies that reported diagnostic imaging for patients presenting with PT were included. Data were reviewed for sample size, gender, age, imaging study, indications, and diagnoses. The primary outcome measure from aggregated data was the yield of positive diagnoses made with each imaging modality. The quality of evidence was assessed for risk of bias.
From an initial search of 1145 articles, 17 manuscripts met inclusion criteria, of which 12 studies evaluated individual imaging modalities. The number of unique patients included was 1232. The diagnostic yield varied between modalities: carotid ultrasound (21%, 95% confidence interval CI: 12%-35%), CT temporal bone (65%, CI: 20%-93%), computed tomographic angiography (86%, CI: 80%-90%), and MRI/magnetic resonance angiography (58%, CI: 43%-72%).
Studies on the diagnostic approach to PT are limited by heterogeneity in both inclusion criteria and reporting standards. A wide range of imaging modalities are used in practice during the initial evaluation of PT, and the diagnostic yield for imaging can be improved by utilizing more specific clinical indications.
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