Exploring the safety profile of tremelimumab: an analysis of the FDA adverse event reporting system.

BACKGROUND: Despite the approval of tremelimumab in 2022, there is a lack of pharmacovigilance studies investigating its safety profile in real-world settings using the FDA Adverse Event Reporting System (FAERS) database. AIM: This pharmacovigilance study aimed to comprehensively explore the adverse events (AEs) associated with tremelimumab using data mining techniques on the FAERS database. METHOD: The study utilized data from the FAERS database, covering the period from the first quarter of 2004 to the third quarter of 2022. Disproportionality analysis, the Benjamini Hochberg adjustment method and volcano plots were used to identify and evaluate AE signals associated with tremelimumab. RESULTS: The study uncovered 233 AE cases associated with tremelimumab. Among these cases, pyrexia (n = 39), biliary tract infection (n = 23), and sepsis (n = 21) were the three main AEs associated with tremelimumab use. The study also investigated the system organ classes associated with tremelimumab-related AEs. The top three classes were gastrointestinal disorders (17.9%), infections and infestations (16.6%), and general disorders and administration site infections (11.2%). Several AEs were identified that were not listed on the drug label of tremelimumab. These AEs included pyrexia, biliary tract infection, sepsis, dyspnea, infusion site infection, hiccup, appendicitis, hypotension, dehydration, localised oedema, presyncope, superficial thrombophlebitis and thrombotic microangiopathy. CONCLUSION: This pharmacovigilance study identified several potential adverse events signals related to tremelimumab including some adverse events not listed on the drug label. However, further basic and clinical research studies are needed to validate these results.

Estimated Costs of Drug-Related Problems Prevented by Pharmacist Prescription Reviews Among Hospitalized Internal Medicine Patients.

BACKGROUND AND OBJECTIVES: Data are lacking on the estimated costs of pharmacist prescription reviews (PPRs) for hospitalized internal medicine patients. This study investigates the estimated costs of drug-related problems (DRPs) prevented by PPRs among hospitalized internal medicine patients. METHODS: We reviewed all medication orders for patients at an academic teaching hospital in China for 2 years. DRPs were categorized using the Pharmaceutical Care Network Europe classification. The severity of the potential harm of DRPs was assessed by the Harm Associated with Medication Error Classification (HAMEC) tool. The estimated cost of PPRs was calculated. RESULTS: A total of 162426 medication orders for 4314 patients were reviewed, and 1338 DRPs were identified by pharmacists who spent 2230 hours performing PPRs. Among the 1080 DRPs that were prospectively intervened upon, 703 were resolved. The HAMEC tool showed that 47.1% of DRPs were assessed as level 2, 30.4% as level 3, 20.6% as level 1, and 0.6% carried a life-threatening risk. Pharmacist interventions contributed to the prevention of DRP errors and a reduction of $339 139.44. This resulted in a mean cost saving of $482.42 per patient at an input cost of $21 495.06 over the 2 years. The benefit-cost ratio was 15.8. CONCLUSION: PPRs are beneficial for detecting potential DRPs and creating potential cost savings among hospitalized internal medicine patients.

RAGE signaling pathway is involved in CUS-induced depression-like behaviors by regulating the expression of NR2A and NR2B in rat hippocampus DG.

NMDA receptors play pivotal roles in the neurobiology of chronic stress-induced mood disorders. But the mechanism for chronic stress to disturb the expression of NMDA receptor subunits is still unclear. Recent researches indicated the involvement RAGE signaling pathway in regulation of glutamate system functions. In this study, we hypothesized RAGE signaling pathway mediated chronic stress-induced alteration in the expression of NMDA receptor subunits, leading to depressive-like behaviors. CUS decreased the expression of RAGE, NR2A, and NR2B, inhibited the phosphorylation of transcript factor ERK and CREB in rat hippocampus DG. RAGE knockdown in hippocampus DG by RAGE shRNA lentiviral particles induced depressive-like behaviors, reduced the mRNA and protein expression of NR2A and NR2B, and inhibited the phosphorylation of ERK and CREB. RAGE over-expression in hippocampus DG by RAGE adenovirus particles reversed the effects of CUS on depressive-like behaviors, ERK and CREB phosphorylation, and NR2A and NR2B expression. Our findings suggests that RAGE signaling pathway at least partially participates in the regulation of NR2A and NR2B expression, which mediates the effects of chronic stress on the depressive-like behaviors. These data provide evidence for RAGE signaling as a possible new pathway through which chronic stress results in the maladaptation of NMDA receptors.

Delirium induced by tigecycline treatment for Acinetobacter baumannii infection: A case report.

RATIONALE: Tigecycline is a broad-spectrum antimicrobial agent structurally belong to tetracyclines and covers against many multidrug-resistant organisms. Arising clinical cases reporting its adverse drug reactions have emerged alongside with the increasing off label use globally. By literature review, delirium caused by tigecycline has not been reported yet. We present what we believe to be the first case of tigecycline-induced delirium. PATIENT CONCERNS: A 77-year-old male patient with end-stage renal disease was hospitalized due to acute exacerbation of chronic obstructive pulmonary disease. DIAGNOSIS: The patient developed delirium after infused with a loading dose of tigecycline for pulmonary infection. INTERVENTIONS: All potential causes inducing delirium were evaluated and the symptoms improved soon after discontinuation of tigecycline. He experienced delirium once again after reusing tigecycline for the exacerbation of the pulmonary infection even without a loading dose. Tigecycline was discontinued and the symptoms quickly relieved. OUTCOMES: According to the Naranjo adverse drug reaction probability scale, tigecycline was the probable cause of his delirium. LESSONS: Clinicians should be aware of this potential adverse effect of tigecycline. We recommend that clinicians monitor patients for signs and symptoms of delirium during treatment with tigecycline.

Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories.

Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.

A critical role for protein degradation in the nucleus accumbens core in cocaine reward memory.

The intense associative memories that develop between cocaine-paired contexts and rewarding stimuli contribute to cocaine seeking and relapse. Previous studies have shown impairment in cocaine reward memories by manipulating a labile state induced by memory retrieval, but the mechanisms that underlie the destabilization of cocaine reward memory are unknown. In this study, using a Pavlovian cocaine-induced conditioned place preference (CPP) procedure in rats, we tested the contribution of ubiquitin-proteasome system-dependent protein degradation in destabilization of cocaine reward memory. First, we found that polyubiquitinated protein expression levels and polyubiquitinated N-ethylmaleimide-sensitive fusion (NSF) markedly increased 15 min after retrieval while NSF protein levels decreased 1 h after retrieval in the synaptosomal membrane fraction in the nucleus accumbens (NAc) core. We then found that infusion of the proteasome inhibitor lactacystin into the NAc core prevented the impairment of memory reconsolidation induced by the protein synthesis inhibitor anisomycin and reversed the effects of anisomycin on NSF and glutamate receptor 2 (GluR2) protein levels in the synaptosomal membrane fraction in the NAc core. We also found that lactacystin infusion into the NAc core but not into the shell immediately after extinction training sessions inhibited CPP extinction and reversed the extinction training-induced decrease in NSF and GluR2 in the synaptosomal membrane fraction in the NAc core. Finally, infusions of lactacystin by itself into the NAc core immediately after each training session or before the CPP retrieval test had no effect on the consolidation and retrieval of cocaine reward memory. These findings suggest that ubiquitin-proteasome system-dependent protein degradation is critical for retrieval-induced memory destabilization.

Activation of NF-κB in basolateral amygdala is required for memory reconsolidation in auditory fear conditioning.

Posttraumatic stress disorder (PTSD) is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA), but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC). We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.

A memory retrieval-extinction procedure to prevent drug craving and relapse.

Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.

NMDA receptor glycine modulatory site in the ventral tegmental area regulates the acquisition, retrieval, and reconsolidation of cocaine reward memory.

RATIONALE AND OBJECTIVES: Accumulating clinical and preclinical studies have shown that the memories of the rewarding effects of drugs and their paired cues may contribute to relapse and persistent cocaine use. Glutaminergic actions in the ventral tegmental area (VTA) have been shown to regulate the rewarding effect of drugs and conditioned responses to drug-associated cues, but the role of the VTA in the acquisition, retrieval, and reconsolidation of cocaine cues is not yet known. METHODS: In the present study, we used 7-chlorothiokynurenic acid (7-CTKA), an N-methyl-D-aspartate (NMDA) receptor glycine modulatory site antagonist with no rewarding effects, to examine the role of the NMDA receptor glycine modulatory site in the acquisition, retrieval, and reconsolidation of cocaine-related reward memory using the conditioned place preference (CPP) paradigm. RESULTS: Separate groups of Sprague-Dawley rats were trained to acquire cocaine-induced CPP. Vehicle or 7-CTKA was microinjected into the VTA or substantia nigra (SN) (5 µg/µl) at different time points: 10 min before each CPP training session (acquisition), 10 min before the reactivation of CPP (retrieval), and immediately after the reactivation of CPP (reconsolidation). Cocaine-induced CPP was retested 24 h and 1 and 2 weeks after 7-CTKA administration. 7-CTKA microinjected into the VTA, but not SN, significantly impaired the acquisition, retrieval, and reconsolidation of cocaine-induced CPP without affecting cocaine-induced locomotion. CONCLUSIONS: Our findings suggest that the NMDA receptor glycine modulatory site in the VTA plays a major role in cocaine reward memory, and NMDA receptor glycine site antagonists may be potential pharmacotherapies for the management of relapse.

PKMζ maintains drug reward and aversion memory in the basolateral amygdala and extinction memory in the infralimbic cortex.

The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories, but how this mechanism is maintained is unknown. Protein kinase M ζ (PKMζ) was recently shown to be necessary and sufficient for long-term potentiation maintenance and memory storage. In the present study, we used conditioned place preference (CPP) and aversion (CPA) to examine whether PKMζ maintains both morphine-associated reward memory and morphine withdrawal-associated aversive memory in the basolateral amygdala (BLA). We also investigate the role of PKMζ in the infralimbic cortex in the extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. We found that intra-BLA but not central nucleus of the amygdala injection of the selective PKMζ inhibitor ZIP 1 day after CPP and CPA training impaired the expression of CPP and CPA 1 day later, and the effect of ZIP on memory lasted at least 2 weeks. Inhibiting PKMζ activity in the infralimbic cortex, but not prelimbic cortex, disrupted the expression of the extinction memory of CPP and CPA. These results indicate that PKMζ in the BLA is required for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory, and PKMζ in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues.

Glycogen synthase kinase 3ß in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory.

Exposure to cocaine-associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3ß (GSK-3ß) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK-3ß in the BLA in the reconsolidation of cocaine cue memories. GSK-3ß activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)-induced conditioned place preference increased after re-exposure to a previously cocaine-paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK-3ß inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue-induced GSK-3ß activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK-3ß, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue-induced increases in GSK-3ß activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK-3ß activity in the BLA mediates the reconsolidation of cocaine cue memories.

Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory.

During abstinence, memories of drug-associated cues persist for many months, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats. Morphine CPP training (10 mg/kg, 4 pairings) increased PKMζ levels in accumbens core but not shell. Injections of the PKMζ inhibitor ζ inhibitory peptide (ZIP) into accumbens core but not shell after CPP training blocked morphine CPP expression for up to 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibits PKMζ, but not by the conventional and novel PKC inhibitor staurosporine, which does not effectively inhibit PKMζ. ZIP injections into accumbens core after training also blocked the expression of cocaine (10 mg/kg) and high-fat food CPP but had no effect on CPA induced by naloxone-precipitated morphine withdrawal. Accumbens core injections of Tat-GluR2(3Y), which inhibits GluR2-dependent AMPA receptor endocytosis, prevented the impairment in morphine CPP induced by local ZIP injections, indicating that the persistent effect of PKMζ is on GluR2-containing AMPA receptors. Results indicate that PKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.

Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats.

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and survival by controlling translation in response to nutrients and growth factors, has been demonstrated to be involved in neuronal adaptations that underlie drug addiction and learning and memory. We investigated the potential role of the mTOR signaling pathway in relapse to cocaine seeking by using the cue-induced reinstatement model in self-administering rats. We found that exposure to a cocaine-related cue induced reinstatement to cocaine seeking and increased phosphorylation of p70s6 kinase (p70s6k) and ribosomal protein s6 (rps6), measures of mTOR activity, in the nucleus accumbens (NAc) core but not shell. Furthermore, inhibition of NAc core but not shell p70s6k and rps6 phosphorylation by rapamycin decreased cue-induced reinstatement of cocaine seeking. Finally, stimulation of NAc core p70s6k and rps6 phosphorylation by NMDA enhanced cue-induced reinstatement, an effect reversed by rapamycin pretreatment. Additionally, rapamycin infusion into the NAc core or shell did not alter ongoing cocaine self-administration or cue-induced reinstatement of sucrose seeking. These findings indicate that cue-induced reinstatement of cocaine seeking is mediated by activation of the mTOR signaling pathway in the NAc core.

Basolateral amygdala cdk5 activity mediates consolidation and reconsolidation of memories for cocaine cues.

Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor beta-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine-context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala beta-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral beta-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.