AcelRx Pharmaceuticals (United States)

Abstract To combat antibiotic-resistant priority pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, novel antibiotics are urgently needed1-3. DNA polymerases, essential for DNA replication but structurally distinct between bacteria and eukaryotes, represent promising yet underexplored targets4,5. The replicative polymerase in Gram-positive bacteria, PolC, is specifically inhibited by ibezapolstat, a guanine nucleobase analogue with an aromatic modification at the N2-position6,7. Following the success of ibezapolstat against Clostridioides difficile infections (CDI) in Phase 2 studies8,9, next-generation compounds with distinct pharmacokinetic properties are being designed to target other Gram-positive pathogens10. However, mechanistic insight into the mode of action of PolC inhibitors is lacking. Here, using cryo-electron microscopy, we show that ibezapolstat and next-generation inhibitor ACX-801 use the nucleobase analogue to pair with DNA within the active site of E. faecium PolC, similar to dGTP. The N2-linked aromatic group is positioned perpendicularly to the nucleobase and inserted into an induced binding pocket. Our results explain reduced susceptibility due to mutation of F1276, that plays a pivotal role in the creation of this pocket and engages in interactions with both the aromatic and nucleobase moieties. This work lays the foundation for rational development of an innovative class of antimicrobials against Gram-positive priority pathogens.

Background:Opioids are effective for treating acute pain but have safety, tolerability, and addiction concerns while nonopioid analgesics have limited efficacy. Suzetrigine, an oral, nonopioid small molecule, selectively inhibits the voltage-gated sodium channel 1.8 (NaV1.8) and has potential to provide efficacious and safe relief for acute pain without addiction concerns.Methods:To evaluate suzetrigine for treatment of acute pain, two phase 3, randomized, double-blind, placebo- and active-controlled trials were conducted in adults with moderate-to-severe acute pain on the verbal categorical rating scale and 4 or greater on the numeric pain rating scale after abdominoplasty (n = 1,118) or bunionectomy (n = 1,073). After surgery, participants were randomized to suzetrigine (100 mg, then 50 mg every 12 h), hydrocodone bitartrate/acetaminophen (5/325 mg every 6 h), or placebo for 48 h. The primary endpoint was time-weighted sum of the pain intensity difference in numeric pain rating scale from 0 to 48 h (SPID48) versus placebo. Key secondary endpoints were SPID48 versus hydrocodone bitartrate/acetaminophen and time to 2-point or greater reduction in numeric pain rating scale from baseline versus placebo.Results:The primary endpoint was achieved in both trials with suzetrigine demonstrating statistically significant and clinically meaningful reduction in pain versus placebo. The least squares mean difference in SPID48 between suzetrigine and placebo was 48.4 (95% CI, 33.6 to 63.1; P < 0.0001) after abdominoplasty and 29.3 (95% CI, 14.0 to 44.6; P = 0.0002) after bunionectomy. Neither trial achieved the first key secondary endpoint of superiority of suzetrigine versus hydrocodone bitartrate/acetaminophen on SPID48. For the second key secondary endpoint of time to 2-point or greater reduction in numeric pain rating scale, suzetrigine had a more rapid onset of clinically meaningful pain relief versus placebo after abdominoplasty (119 min vs. 480 min; nominal P < 0.0001) and bunionectomy (240 min vs. 480 min; nominal P = 0.0016). Adverse events were similar to those seen in postsurgical settings.Conclusions:As compared with placebo, suzetrigine reduced moderate-to-severe acute pain over 48 h after abdominoplasty or bunionectomy. Pain reduction with suzetrigine was similar to that with hydrocodone bitartrate/acetaminophen. Suzetrigine was associated with adverse events that were mild to moderate in severity.

Herein, we describe a novel device configuration for a double-plate electrowetting-on-dielectric system with a floating top-electrode. As a conventional double-plate EWOD device requires a grounded electrode on the top-plate, it will cause additional fabrication complicity and cost during the encapsulation process. In this work, we found that by carefully designing the electrode arrangement and configuring the driving electronic circuit, the droplet driving force can be maintained with a floating electrode on the top-plate. This can provide the possibilities to integrate additional electrical or electrochemical sensing functions on the top-plate. We use both finite element analysis and the fabricated system to validate the theory, and the results indicate that floating top-electrode EWOD systems are highly reliable and reproducible once the design considerations are fully met.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

BackgroundIntravenous patient-controlled analgesia (PCA) equipment and opioid cost analyses on specific procedures are lacking. This study estimates the intravenous PCA hospital cost for the first 48 postoperative hours for three inpatient surgeries.MethodsDescriptive analyses using the Premier database (2010–2012) of more than 500 US hospitals were conducted on cost (direct acquisition and indirect cost for the hospital, such as overhead, labor, pharmacy services) of intravenous PCA after total knee/hip arthroplasty (TKA/THA) or open abdominal surgery. Weighted average cost of equipment and opioid drug and the literature-based cost of adverse events and complications were aggregated for total costs.ResultsOf 11,805,513 patients, 272,443 (2.3%), 139,275 (1.2%), and 195,062 (1.7%) had TKA, THA, and abdominal surgery, respectively, with approximately 20% of orthopedic and 29% of abdominal patients having specific intravenous PCA database cost entries. Morphine (57%) and hydromorphone (44%) were the most frequently used PCA drugs, with a mean cost per 30 cc syringe of $16 (30 mg) and $21 (6 mg), respectively. The mean number of syringes used for morphine and hydromorphone in the first 48 hours were 1.9 and 3.2 (TKA), 2.0 and 4.2 (THA), and 2.5 and 3.9 (abdominal surgery), respectively. Average costs of PCA pump, intravenous tubing set, and drug ranged from $46 to $48, from $20 to $22, and from $33 to $46, respectively. Pump, tubing, and saline required to maintain patency of the intravenous PCA catheter over 48 hours ranged from $9 to $13, from $8 to $9, and from $20 to $22, respectively. Supplemental non-PCA opioid use ranged from $56 for THA to $87 for abdominal surgery. Aggregated mean intravenous PCA equipment and opioid cost per patient were $196 (THA), $204 (TKA), and $243 (abdominal surgery). Total costs, including for adverse events, complications, and intravenous PCA errors, ranged from $647 to $694.ConclusionAlthough there is variation between different types of surgery, the hospital cost of intravenous PCA after major surgery is substantial. Novel technology should demonstrate cost-effectiveness in addition to clinical superiority.