Cells. 2023 Oct 11;12(20):2440. doi: 10.3390/cells12202440.

ABSTRACT

Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney's filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug-drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.

PMID:37887284 | PMC:PMC10605893 | DOI:10.3390/cells12202440

Hepatol Commun. 2023 Oct 27;7(11):e0276. doi: 10.1097/HC9.0000000000000276. eCollection 2023 Nov 1.

ABSTRACT

BACKGROUND: Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child-Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs).

METHODS: In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo.

RESULTS: In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal-systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (-11.2 ± 11.9%) and 3 mg BID (-14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%).

CONCLUSION: BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal-systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.

PMID:37889522 | DOI:10.1097/HC9.0000000000000276

Toxics. 2023 Oct 18;11(10):867. doi: 10.3390/toxics11100867.

ABSTRACT

Hepatotoxicity is one of the significant side effects of chronic diabetes mellitus (DM) besides nephrotoxicity and pancreatitis. The management of this disease is much dependent on the restoration of the liver to its maximum functionality, as it is the central metabolic organ that gets severely affected during chronic diabetes. The present study investigates if the silver nanoparticles decorated with curcumin (AgNP-Cur) can enhance the efficacy of metformin (a conventional antidiabetic drug) by countering the drug-induced hepatoxicity. Swiss albino rats were categorized into six treatment groups (n = 6): control (group I without any treatment), the remaining five groups (group II, IV, V, VI) were DM-induced by streptozocin. Group II was untreated diabetic positive control, whereas groups III was administered with AgNP-cur (5 mg/kg). Diabetic group IV treated with metformin while V and VI were treated with metformin in a combination of the two doses of NPs (5 and 10 mg/kg) according to the treatment schedule. Biochemical and histological analysis of blood and liver samples were conducted after the treatment. The groups V and VI treated with the combination exhibited remarkable improvement in fasting glucose, lipid profile (HDL and cholesterol), liver function tests (AST, ALT), toxicity markers (GGT, GST and LDH), and redox markers (GSH, MDA and CAT) in comparison to group II in most of the parameters. Histological evaluation and comet assay further consolidate these biochemical results, pleading the restoration of the cellular structure of the target tissues and their nuclear DNA. Therefore, the present study shows that the NPs can enhance the anti-diabetic action by suppression of the drug-mediated hepatoxicity via relieving from oxidative stress, toxic burden and inflammation.

PMID:37888717 | DOI:10.3390/toxics11100867

Pharmacy (Basel). 2023 Oct 7;11(5):160. doi: 10.3390/pharmacy11050160.

ABSTRACT

Pharmacotherapy plays a crucial role in symptom management in palliative care and is associated with risks potentially leading to drug-related problems (DRP). Pharmacists can identify DRPs and advise prescribers on optimizing drug therapy. The aim of this study was to identify DRP in a palliative care unit (PCU) and evaluate corresponding pharmaceutical interventions. A non-randomized before-and-after study in a PCU starts with a control phase, an interphase, and an intervention phase. Primary endpoint: DRP, including pharmaceutical interventions and their acceptance. The medication of all inpatients was recorded at set time points, assessed for potential and manifest DRP, and categorized. In the control phase, the ward pharmacist did not interfere with the clinical team. In the intervention phase, the pharmacist could intervene when a DRP was identified and give recommendations. During the 12-month period, 284 patients were included (control phase n = 138; intervention phase n = 146) and 1079 DRPs were identified (control phase n = 634; intervention phase n = 445). The number of DRPs/patient was significantly reduced by the pharmacist's interventions between the control and intervention phases (4 vs. 3 DRPs, p = 0.001). Overall acceptance of pharmaceutical interventions by prescribers was very high (227/256; 88%). DRPs are hardly preventable. With a clinical pharmacist as a member of the palliative care team, it is possible to reduce the number of DRPs and identify potential problems earlier.

PMID:37888505 | DOI:10.3390/pharmacy11050160

Case Rep Infect Dis. 2023 Oct 18;2023:8865265. doi: 10.1155/2023/8865265. eCollection 2023.

ABSTRACT

We report a hemodialysis MDR HIV-infected patient switched to fostemsavir with lenacapavir plus lamivudine for more than a year. She maintained a suppressed viral replication and did not present any clinical or biological drug-related side effects. The combination of lenacapavir plus fostemsavir looks promising in terms of safety and efficacy even in patients with end-stage renal disease awaiting renal transplant. Both drugs are first in class ARVs so that there is no cross resistance with previous drugs, maintaining their efficacy against MDR HIV.

PMID:37886135 | PMC:PMC10599868 | DOI:10.1155/2023/8865265

Endocr Metab Immune Disord Drug Targets. 2023 Oct 25. doi: 10.2174/0118715303180615231011053011. Online ahead of print.

ABSTRACT

BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus (T2DM). So far, few severe side effects have been reported for it.

CASE PRESENTATION: A 41-year-old woman was admitted to the Emergency Room with diffuse abdominal pain. The patient had a known case of T2DM, fatty liver disease, and hypertension and was treated with Metformin, Liraglutide, and Losartan. Her liver functional test (LFT) was consistent with hepatocellular injury; however, laboratory tests and abdominal ultrasound were used to rule out autoimmune hepatitis. Due to concerns for drug-induced liver injury (DILL), liraglutide was discontinued and N-acetyl cysteine was prescribed. On the fifth day of hospitalization, the patient's symptoms resolved and his LFT started to decrease on the sixth day after 2 months, the patient's liver enzyme levels returned to normal.

CONCLUSION: Liraglutide is one of the most important drugs in the treatment of T2DM.The most common side effects of this drug are constipation, nausea, vomiting, diarrhea, indigestion, and loss of appetite. In rare cases, symptoms of thyroid cancer, pancreatitis, and hypoglycemia have been reported, however, DILL is one of the extremely rare side effect of Liraglutide. It is important to increase the awareness of physicians about the liver injury of Liraglutide.

PMID:37885115 | DOI:10.2174/0118715303180615231011053011

BMC Pediatr. 2023 Oct 26;23(1):531. doi: 10.1186/s12887-023-04336-z.

ABSTRACT

BACKGROUND: A error in intravenous injection in pediatric wards can cause irreparable injuries. This study aimed to determine the level of knowledge and performance of nurses in terms of preparation and injection of intravenous drugs in pediatric wards of hospitals affiliated to Isfahan University of Medical Sciences.

METHODS: This cross-sectional study was conducted in 2022 on 156 nurses working in pediatric wards. The data was collected with demographic information questionnaire and the knowledge and performance of the participants were determined using a researcher-made questionnaire, including the five rights of medication administration (preparation and injection, medication error, drug side effects, family empowerment, and documentation) using self-reporting and observation methods. Formal and content validity was calculated using the opinions of 10 experts and Cronbach's alpha with 40 samples.

RESULTS: The mean and standard deviation of total nurses' knowledge and performance scores were 58.31 + 10.1 and 66.1 + 14.4, respectively. Moreover, the mean and standard deviation of nurses' knowledge scores were 63.55 + 14.3 for documentation, 46.1 + 7.9 for preparation and injection, 73.9 + 12.3 for drug side effects, 58.4 + 10.2 for medication error, and 69.4 + 9.4 for family empowerment. Besides, the mean performance was 69.1 + 17.6 for documentation, 61.3 ± 9.9 for preparation and injection, 78.21 + 12 for drug side effects, 58.6 + 15 for medication error, and 65.4 + 17.7 for family empowerment.

CONCLUSION: The results showed that the mean knowledge and pharmacological performance of nurses working in pediatric wards in different areas of the principles of medicine were not at the desired level, and this can affect children adversely.

PMID:37884932 | PMC:PMC10601159 | DOI:10.1186/s12887-023-04336-z

S Afr Med J. 2023 Aug 3;113(8):63-68. doi: 10.7196/SAMJ.2023.v113i8.428.

ABSTRACT

BACKGROUND: Phentermine is an internationally recognised amphetamine derivative with significant appetite-suppressing properties. The drug is indicated for the short-term management of obesity, as the long-term (LT) use of phentermine may potentially be associated with severe cardiovascular side-effects, abuse and dependence. The LT use hereinafter describes periods exceeding 12 consecutive weeks. This use may also be associated with potential drug-drug interactions (PDDIs), which may result in adverse drug reactions (ADRs). The literature reports that phentermine is often prescribed LT and for several other off-label indications, increasing the risk for individuals to experience adverse drug events (ADEs) and drug-drug interactions (DDIs). There are, to our knowledge, no South African (SA) studies investigating the prevalence of co-prescribing LT phentermine with drugs that may potentially cause DDIs.

OBJECTIVE: To determine the prevalence of mild, moderate and severe DDIs with phentermine use when the duration of therapy in private healthcare exceeded 12 consecutive weeks.

METHODS: A cross-sectional drug utilisation review (DUR) was done by using data obtained from a SA pharmacy benefit management (PBM) company's database. Retrospective data of medicine claims for phentermine, from 1 January 2015 to 31 December 2019, were extracted for analysis. The number of days phentermine was supplied was used to identify the study population, in other words, those patients who received the drug LT. A drug interaction checker (Drugs.com) was used to identify potential mild, moderate and severe DDIs when using phentermine and co-prescribed drugs concurrently.

RESULTS: A total of 889 patients received phentermine LT. The top 20 drugs identified as being frequently co-prescribed in this study population demonstrated no mild PDDI, 15 (75%) moderate PDDIs and 5 (25%) severe PDDIs. The most common co-prescribed drug in the moderate group was dextromethorphan (n=282, 31.72%) and the least co-prescribed was formoterol (n=52, 5.85%). Among the drug group 'severe PDDIs', tramadol (n=416, 46.79%) was most frequently prescribed, whereas phenylpropanolamine (n=69, 7.76%) was the least prescribed to patients in this group.

CONCLUSION: There are patients who receive LT phentermine therapy despite the potential severe consequences that may result. These patients may receive concomitant therapy with phentermine and other pharmaceutical constituents, which may potentially cause DDIs, more specifically, moderate and severe DDIs. As such, these patients are not only confronted with the consequences of DDIs but are also at risk to experience ADRs as the residual effect of PDDIs.

PMID:37882119 | DOI:10.7196/SAMJ.2023.v113i8.428

Rev Med Suisse. 2023 Oct 25;19(847):2002-2006. doi: 10.53738/REVMED.2023.19.847.2002.

ABSTRACT

Acute heart failure is a leading cause of hospitalisations with an increasing economic and public health burden. Management of acute heart failure involves the use of diuretics to treat congestion and improve morbimortality. Despite current guidelines, numerous patients maintain congestion and often leave the hospital setting with incomplete volume depletion, leading to an increased risk of rehospitalisation. A recent multicentric randomised controlled trial studied the administration of acetazolamide in addition to standard care with loop diuretics in the acute setting. There was a significantly faster decongestion, based on a pragmatic clinical score, with very few side effects.

PMID:37878100 | DOI:10.53738/REVMED.2023.19.847.2002

Support Care Cancer. 2023 Oct 25;31(12):652. doi: 10.1007/s00520-023-08128-0.

ABSTRACT

PURPOSE: Oral anti-cancer agents (OAAs) represent a new frontier in cancer treatment, but we do not know how well patients incorporate the strategies that they are taught for managing the side effects of OAAs into their daily lives. The purpose of this study was to understand how OAA side effects influenced patients' lives and what strategies patients used to manage them.

METHODS: The study used an interpretive descriptive design utilizing photo elicitation interviews (PEI). Two pharmacists employed at the study ambulatory oncology clinic assisted with recruitment. Participants took photos and subsequent interviews focused on talking to participants about each photo, eliciting participant perspectives describing side effects of OAAs and management strategies. A directed content analysis approach was used to analyze the transcribed interviews.

RESULTS: A total of nine participants were included in the study. Three themes and associated sub-themes emerged: making changes to nutritional habits due to OAA side effects (hydration and food), strategies to alleviate OAA side effects (medication and non-medication related), and methods of coping with OAA effects (intra- and interpersonal). Changing nutritional habits was an important strategy to manage OAA side effects. Medication-related strategies to alleviate OAA side effects could be nuanced and, additionally, there was wide variability in coping methods used.

CONCLUSION: Patient education on OAAs and side effects is not always tailored to each unique patient and their circumstances. This study uncovered how participants devised their own distinct strategies to prevent or manage OAA side effects in an effort to help improve patients' experiences when taking OAAs.

PMID:37878093 | DOI:10.1007/s00520-023-08128-0

Drug Ther Bull. 2023 Oct 25:dtb-2023-000057. doi: 10.1136/dtb.2023.000057. Online ahead of print.

NO ABSTRACT

PMID:37879879 | DOI:10.1136/dtb.2023.000057

Drug Ther Bull. 2023 Oct 25:dtb-2023-000007. doi: 10.1136/dtb.2023.000007. Online ahead of print.

ABSTRACT

Semaglutide (▼Ozempic solution for injection, ▼Rybelsus tablets-Novo Nordisk) was initially granted market authorisation for the treatment of type 2 diabetes as an adjunct to diet and exercise. In 2021 and 2022, regulatory agencies in the USA and Europe licensed semaglutide (▼Wegovy solution for injection-Novo Nordisk) for the treatment of individuals who are obese, or overweight and who have at least one weight-related comorbidity. Manufacturer-sponsored randomised controlled trials have shown a loss of almost 12% of body weight over a 68-week period, however, once the medication is stopped people regain most of their pretreatment weight. Gastrointestinal adverse events occur commonly with semaglutide, and pancreatitis, diabetic retinopathy and severe allergic reactions have also been reported. Extensive hype in social and general media has resulted in increased demand for semaglutide leading to supply problems across the various licensed products including those used for treatment of diabetes. In the UK, the National Institute for Health and Care Excellence has recommended semaglutide as an option for weight management for a maximum treatment duration of 2 years. Further studies are underway to assess the effect of semaglutide on longer-term health benefits.

PMID:37879878 | DOI:10.1136/dtb.2023.000007

Drug Ther Bull. 2023 Nov;61(11):162. doi: 10.1136/dtb.2023.000055.

NO ABSTRACT

PMID:37875311 | DOI:10.1136/dtb.2023.000055

Zhonghua Zhong Liu Za Zhi. 2023 Oct 23;45(10):898-903. doi: 10.3760/cma.j.cn112152-20220530-00373.

ABSTRACT

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

PMID:37875426 | DOI:10.3760/cma.j.cn112152-20220530-00373

Expert Opin Drug Saf. 2023 Oct 24. doi: 10.1080/14740338.2023.2274946. Online ahead of print.

ABSTRACT

BACKGROUND: The triglyceride-lowering drug, icosapent ethyl (IPE), was granted a new indication for the reduction of atherosclerotic cardiovascular disease risk in 2019.This study aimed to investigate the safety profile of IPE by mining the FDA Adverse Event Reporting System (FAERS) database.

METHODS: The reporting odds ratio was used to analyze IPE's adverse events (AEs) based on the FAERS data from July 2012 to December 2022. We described the characteristics of AE reports and evaluated the clinical prioritization of AEs. Then we defined and analyzed nine interested adverse drug reactions (ADRs) in both overall and subgroups, and investigated the times to onset.

RESULTS: The findings of our study strengthen the evidence for an increased risk of atrial fibrillation using IPE. IPE alone may not increase the risk of bleeding unless combined with antithrombotic drugs. Similar to statins, IPE alone can increase the risk of musculoskeletal pain, drug-related hepatic disorders, and hyperglycemia, but the risk could not double when IPE was combined with statins. Most ADRs occur in the early stage of treatment.

CONCLUSIONS: This study provides a comprehensive real-world safety profile of IPE, which indicates that IPE is well-tolerated.

PMID:37873598 | DOI:10.1080/14740338.2023.2274946

Rheumatology (Oxford). 2023 Oct 23;62(SI3):SI237-SI241. doi: 10.1093/rheumatology/kead307.

ABSTRACT

Polypharmacy is increasingly common in rheumatology due to the complex nature of managing chronic autoimmune diseases. To date there has been limited research into the impact of polypharmacy on rheumatology patients. In this article we reviewed the literature to characterize the prevalence of polypharmacy and its effect on patients. In addition, we have highlighted some key drug-drug interactions to consider involving DMARDs as well as complementary and alternative medicines. There is emerging evidence demonstrating that polypharmacy contributes to adverse outcomes and alters treatment response. This association is best described in RA and is less clear in other patient cohorts. It is also unclear whether polypharmacy is directly harmful or just a surrogate marker for other factors affecting outcomes. Rheumatologists should be aware of the risk of polypharmacy as well as specific drug-drug interactions that can occur in managing chronic autoimmune disease.

PMID:37871915 | DOI:10.1093/rheumatology/kead307

JAMA Netw Open. 2023 Oct 2;6(10):e2339446. doi: 10.1001/jamanetworkopen.2023.39446.

NO ABSTRACT

PMID:37870837 | DOI:10.1001/jamanetworkopen.2023.39446

J Clin Oncol. 2023 Oct 23:101200JCO2302005. doi: 10.1200/JCO.23.02005. Online ahead of print.

ABSTRACT

PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.

PATIENTS AND METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS).

RESULTS: primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3-43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6-17.8); median PFS, 6.9 months (95% CI, 5.6-8.0); median OS, 13.4 months (95% CI, 11.9-15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4-72.4); median DOR, 22.1 months (95% CI, 9.6-not reached); median PFS, 11.9 months (95% CI, 8.2-13.0); median OS, 21.1 months (95% CI, 15.3-29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.

CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

PMID:37870536 | DOI:10.1200/JCO.23.02005

Cureus. 2023 Sep 21;15(9):e45675. doi: 10.7759/cureus.45675. eCollection 2023 Sep.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have been discovered to be associated with autoimmune toxicities that may present as dermatologic, gastrointestinal, hepatic, pulmonary, endocrine, and rarely hematologic reactions. Recent studies have also discovered hematological adverse effects as a result of ICI use of which isolated neutropenia is the gravest and the rarest manifestation. Asymptomatic neutropenia cannot be ignored, and close monitoring is, at least, warranted. Severe neutropenia with neutropenic fever needs hospital admission and prompt treatment to avoid further morbidity and/or mortality. In this report, we present a rare case of Grade 4 neutropenia resulting from nivolumab, anti-PD-1 antibody, in a patient diagnosed with invasive bladder cancer. The patient was successfully treated with steroids and supportive measures.

PMID:37868579 | PMC:PMC10590144 | DOI:10.7759/cureus.45675

Drug Alcohol Depend. 2023 Oct 5;253:110987. doi: 10.1016/j.drugalcdep.2023.110987. Online ahead of print.

ABSTRACT

Despite the thousands of lives lost during the ongoing opioid crisis, a scarcity of new and effective clinical treatments for opioid use disorder (OUD) remains. To address this unmet need, some researchers have turned to dissociative and psychedelic drugs to treat multiple psychiatric conditions. In particular, low doses of ketamine have been shown to attenuate opioid withdrawal and drug use in clinical and preclinical studies. However, ketamine has misuse liability and dissociative side effects that may limit its widespread application as a treatment for OUD. More recently, (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite that lacks misuse potential, has gained attention for its effectiveness in depression and stress models. To uncover its role in OUD, we tested the time-dependent effects of (2R,6R)-HNK on oxycodone withdrawal and reinstatement of oxycodone conditioned place preference (CPP). In male and female oxycodone-dependent mice, we found that 24h pretreatment with (2R,6R)-HNK (10 or 30mg/kg, s.c.) reduced the frequency of withdrawal-like behaviors and global withdrawal scores during naloxone-precipitated withdrawal, whereas 1h pretreatment with (2R,6R)-HNK only reduced paw tremors and the sum of global withdrawal scores but not GWS Z-scores. In other experiments, both 1h and 24h pretreatment with (2R,6R)-HNK (30mg/kg, s.c.) blocked drug-induced reinstatement of oxycodone CPP. Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.

PMID:37864957 | DOI:10.1016/j.drugalcdep.2023.110987