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Introduction: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects., Methods: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO 2 ) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone., Results: While both NLX and NLMF rapidly reversed %SaO 2 to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO 2 levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute., Discussion: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans., Competing Interests: A patent application was filed by the Allegheny Health Network US-20220152017-A1 for the preparation of covalent naloxone nanoparticles and SA is an inventor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Averick, Kassick, Song, Zhang, Vigliaturo, Luengas, Silva-Ortiz, Pravetoni and Raleigh.)

Background: For the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy [TNT]) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario., Summary: We have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments with regard to surgery and long-term oncological results. Our aim was to describe the evidence that supports the use of a specific regime in everyday clinical practice., Key Points: There is solid evidence for the use of TNT in patients with LARC. There are no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence., (© 2023 S. Karger AG, Basel.)

Strychnine poisoning induces seizures that result in loss of control of airway muscles, leading to asphyxiation and subsequent death. Current treatment options are limited, requiring hands-on medical care and isolation to low-stimulus environments. Anticonvulsants and muscle relaxants have shown limited success in cases of severe toxicity. Furthermore, nonfatal strychnine poisoning is likely to result in long-term muscular and cognitive damage. Due to its potency, accessibility, and lack of effective antidotes, strychnine poses a unique threat for mass casualty incidents. As a first step toward developing an anti-strychnine immunotherapy to reduce or prevent strychnine-induced seizures, a strychnine vaccine was synthesized using subunit keyhole limpet hemocyanin. Mice were vaccinated with the strychnine immunoconjugate and then given a 0.75 mg/kg IP challenge of strychnine and observed for seizures for 30 min. Vaccination reduced strychnine-induced events, and serum strychnine levels were increased while brain strychnine levels were decreased in vaccinated animals compared to the control. These data demonstrate that strychnine-specific antibodies can block the seizure-inducing effects of strychnine and could be used to develop a therapeutic for strychnine poisoning.

Innovative therapies to complement current treatments are needed to curb the growing incidence of fatal overdoses related to synthetic opioids. Murine and chimeric monoclonal antibodies (mAb) specific for fentanyl and its analogs have demonstrated pre-clinical efficacy in preventing and reversing drug-induced toxicity in rodent models. However, mAb-based therapeutics require extensive engineering as well as in vitro and in vivo characterization to advance to first-in-human clinical trials. Here, novel murine anti-fentanyl mAbs were selected for development based on affinity for fentanyl, and efficacy in counteracting the pharmacological effects of fentanyl in mice. Humanization and evaluation of mutations designed to eliminate predicted post-translational modifications resulted in two humanized mAbs that were effective at preventing fentanyl-induced pharmacological effects in rats. These humanized mAbs showed favorable biophysical properties with respect to aggregation and hydrophobicity by chromatography-based assays, and thermostability by dynamic scanning fluorimetry. These results collectively support that the humanized anti-fentanyl mAbs developed herein warrant further clinical development for treatment of fentanyl toxicity.

The mu opioid receptor antagonist naloxone has been a vital, long-standing countermeasure in the ongoing battle against opioid use disorders (OUD) and toxicity. However, due to its distinctive short elimination half-life, naloxone has shown diminished efficacy in cases of synthetic opioid poisoning as larger or repeated doses of the antidote have been required to achieve adequate reversal of severe respiratory depression and prevent episodes of renarcotization. This report describes the synthesis, characterization, and in vivo evaluation of a novel, nanoparticle-based naloxone formulation that provides extended protection against the toxic effects of the powerful synthetic opioid fentanyl. The strategy was predicated on a modified two-step protocol involving the synthesis and subsequent nanoprecipitation of a poly(lactic- co -glycolic acid) polymer scaffold bearing a covalently linked naloxone chain end (drug loading ∼7% w/w). Pharmacokinetic evaluation of the resulting covalently loaded naloxone nanoparticles ( c NLX-NP) revealed an elimination half-life that was 34 times longer than high dose free naloxone (10 mg/kg) in male Sprague-Dawley rats. This enhancement was further demonstrated by c NLX-NP in subsequent in vivo studies affording protection against fentanyl-induced respiratory depression and antinociception for up to 48 h following a single intramuscular injection. These discoveries support further investigation of c NLX-NP as a potential therapeutic to reverse overdose and prevent renarcotization from fentanyl and its potent analogs., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Competing Interests: None

Purpose of the Study: The definitive treatment for liver failure is, currently, liver transplantation. Research into other possible treatments, focused on achieving regeneration of the liver parenchyma, have led to the development of methods to generate hepatocytes from stem cells. In our study, we transplant allogenic adipose-derived stem cells (ASCs), not previously differentiated to hepatocytes, to treat acute liver failure induced by intraperitoneal administration of carbon tetrachloride (CCl4) in a Sprague-Dawley rat model., Material and Methods: The ASCs were delivered via the tail vein, having previously been labeled with PKH26, a fluorescent membrane marker. Two control groups were established, Group 1(n = 15) consisting of olive oil (5 mL/kg) and Group 2(n = 15): 1 × 10(6) PKH26-labeled ASCs. Further, two study groups, Group 3(n = 30): CCl4 dissolved in olive oil and Group 4(n = 30): CCl4 dissolved in olive oil and 1 × 10(6) PKH26-labeled ASCs completed the experimental design., Results: Blood samples were analyzed, finding AST and ALT levels significantly higher in treatment over control groups at 24 and 48 hours. The mortality rates were statistically different between control groups and Group 3 (Group 1-3 p = .04, Group 2-3 p = .04) and between Groups 3 and 4 (p = .02). Examining the liver parenchyma, a significantly higher number of ASCs were observed in Group 4 than in Group 2 at all time points (p = .00)., Conclusions: The intravenous injection of allogenic ASCs in this model of CCl4-induced liver failure reduced the mortality in treated animals. ASCs injected in the rat tail vein were found in the liver in animals with induced acute liver failure.

Surgical resection remains the only option of cure for patients with colorectal liver metastases, and no patient should be precluded from surgery. There is much controversy not only regarding the most appropriate therapeutic approach in the neoadjuvant setting but also after surgery is performed. Many patients will experience early relapses but others will be long survivors. We need to establish reliable prognostic and predictive factors to offer a tailored treatment. Several prognostic factors after metastasectomy have been identified: high C-reactive protein levels, a high neutrophil-lymphocyte ratio, elevated neutrophil count and low serum albumin are related to a worst outcome. Elevated CEA and Ki 67 levels, intrahepatic and perihepatic lymph node invasion are also some of the markers related to a worst outcome. In contrast, the administration of preoperative chemotherapy has been associated with a better prognosis after hepatectomy. The administration of adjuvant chemotherapy should be done taking in consideration these factors. Regarding predictive factors, determination of ERCC1, TS, TP and DPD and UGT1 polymorphisms assessment could be considered prior to chemotherapy administration. This would avoid treatment related toxicities and increase this population quality of life.

Objective: to assess the effectiveness of ondansetron in preventing postoperative nausea and vomiting after elective laparoscopic cholecystectomy, and the effect of this anesthetic on hospital stay., Methods: this randomized, double-blind, placebo-controlled study was done in the General Surgery Service of the Getafe University Hospital. Patients who were scheduled for laparoscopic cholecystectomy to treat uncomplicated cholelithiasis, and who had an ASA status of I-II, were recruited. Before surgery the patients received either ondansetron 4 mg or placebo intravenously. This study was approved by the local ethics committee., Results: 56 patients were included, 29 in the ondansetron group and 27 in the placebo group. In the latter, 4 patients were later excluded because of conversion to open surgery. Postoperative nausea and emetic episodes were experienced by 7% of the patients in the ondansetron group and 47% in the placebo group (p = 0.0007). Oral intake started 7 h after surgery in the ondansetron group and 11 h after surgery in the placebo group (p = 0.04), with a mean difference of 4 h. Hospital stay was 30 h and 48 h respectively (p = 0.01), with a mean difference of 18 h., Conclusion: ondansetron given prior to surgery at a dose of 4 mg prevents postoperative nausea and vomiting after laparoscopic cholecystectomy, and reduces hospital stay.