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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.)

Illicit drug mixtures containing opioids and stimulants have been responsible for the majority of fatal drug overdoses among occasional users, and those with either opioid use disorder (OUD) or substance use disorder (SUD). As a complementary strategy to current pharmacotherapies, active immunization with conjugate vaccines has been proposed as a viable intervention to treat OUD as well as other SUD for which there are either limited or no treatment options. Vaccination against opioids and stimulants could help address the limitations of current medications (e.g., patient access, compliance, misuse liability, and safety) by providing an additional tool to prevent drug misuse and/or overdoses. However, more research is needed to fully understand the potential benefits and limitations of using vaccines to treat SUD and overdose and to inform us on how to deploy this strategy in the field. Previous reports have shown promise by combining two vaccines into bivalent vaccine formulations to concurrently target multiple drugs. Here, multiple individual candidate monovalent vaccines were incrementally combined in multivalent vaccine formulations to simultaneously target fentanyl, carfentanil, oxycodone, heroin, methamphetamine, and their analogs or metabolites. Bi-, tri-, and quadrivalent vaccine formulations induced the formation of independent serum antibody responses against their respective opioid targets and selectively attenuated the distribution of each individual drug to the brain in mice and rats. Results indicate that a single injection of an admixed multivalent vaccine formulation may be more effective than coinjecting multiple monovalent vaccines at multiple sites. Finally, adding a methamphetamine conjugate vaccine to an quadrivalent opioid vaccine in a pentavalent formulation did not interfere with the production of effective antiopioid IgG antibodies. Multivalent vaccines could provide multifaceted, yet selective, protection against polydrug use and exposure., Competing Interests: The authors declare the following competing financial interest(s): M.P. is the co-inventor of patents disclosing haptens, conjugates, and multivalent formulations. M.P. is the co-inventor of patents disclosing fentanyl hapten-conjugates and methods for making and using same. M.P. and S.A. are co-inventors of patents disclosing fentanyl haptens, fentanyl hapten conjugates, and methods for making and using the same. D.S., M.R., and M.P. are co-inventors of patents disclosing the multivalent formulation and the methamphetamine vaccine. All other authors declare no conflict of interest., (© 2023 American Chemical Society.)

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.

Background: Our previous work has shown substantial national variation in the frequency of nephrology visits after kidney transplant. The low frequency of nephrology visits was associated with increased risk of transplant failure., Methods: We performed a qualitative study that included interviews and 5 focus groups of transplant recipients. The study took place at a transplant center in the Upper Midwest. Participants (N = 39) were selected if they had at least one of the previously described risk factors for decreased nephrology visits: ethnic minority, lower median household income, and residence less than 10 miles from the transplant center. The goal was to assess patients' perceptions and beliefs and perceived barriers to regular nephrology outpatient visits. All transcripts were coded using software for qualitative data analysis., Results: Transplant recipients understood the importance of keeping nephrology appointments and reflected positively on them. Regardless, they perceived barriers to adhering to the visit schedule, such as a value on self-reliance, which they described as increasing over time since transplant; a growing sense that they could interpret their bodies independently without needing to see the physician as regularly; and finally, the multitude of physical and mental health challenges inherent to posttransplant life. Other factors motivated patients to keep their regular nephrology visits, such as peer-support relationships and talking to other patients on dialysis therapy. Patients reported that talking to patients who had received a transplant before them helped them anticipate and cope with the mental and physical challenges associated with life posttransplant. A study limitation was that all participants were from a single transplant center., Conclusions: Although kidney transplant recipients understood the importance of keeping nephrology appointments, there were significant perceived barriers to these visits. Future interventions should address perceived barriers and motivate patients to keep regular nephrology visits posttransplant as a way to improve transplant outcomes., (Copyright © 2010 National Kidney Foundation, Inc. All rights reserved.)