Microbiological Stability of Allopurinol, Clindamycin Hydrochloride, Naltrexone Hydrochloride, Spironolactone and Ursodiol Oral Liquids Compounded in PCCA Base, SuspendIt®.

The individual physicochemical stabilities of Allopurinol, Clindamycin Hydrochloride, Naltrexone Hydrochloride, Spironolactone and Ursodiol in the proprietary suspending vehicle PCCA SuspendIt® have been previously studied and published by the author. Accordingly, Beyond-Use-Dates (BUDs) of 180 days were assigned to the five drugs based on the results of the respective studies. The data were donated to the United States Pharmacopeia (USP) for possible adoption as Official Compounded Drug Monographs. Following an extensive review process, all five studies were approved and published by the USP. However, due to a lack of microbiological stability information, the BUDs were limited to 90 days. The current study was undertaken as a follow-up project to determine the microbiological stability of these five drugs in PCCA SuspendIt® utilizing the same compounding procedures from the original studies. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The goal was to provide a viable, compounded alternative for Allopurinol, Clindamycin Hydrochloride, Naltrexone Hydrochloride, Spironolactone and Ursodiol in a thixotropic liquid dosage form, with an extended BUD of 6 months to meet patient needs. Given that the physical and chemical stabilities of all five drugs have been previously established and adopted by the USP as official compounded monographs, additional microbiological stability data would allow the official BUDs in the USP to be extended to 180 days to conform to the physicochemical stabilities. The current study showed that the preservative system in PCCA SuspendIt® successfully protected all the suspensions from growth of challenge microorganisms per the USP Chapter <51> AME Test. The results of the current study combined with the previous physicochemical studies demonstrate the following: Allopurinol is physically, chemically and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature over a bracketed allopurinol concentration range of 10 - 20 mg/mL. Clindamycin Hydrochloride is physically, chemically and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature at a concentration of 10-mg/mL of clindamycin. Naltrexone Hydrochloride is physically, chemically and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature, over a bracketed naltrexone hydrochloride concentration range of 0.5 - 5.0 mg/mL. Spironolactone is physically, chemically and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature at a concentration of 5 mg/mL of spironolactone. Ursodiol is physically, chemically and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature, over a bracketed ursodiol concentration range of 50 - 100 mg/mL. Taken collectively, the current study in conjunction with the earlier studies provide viable, compounded alternatives for Allopurinol, Clindamycin Hydrochloride, Naltrexone Hydrochloride, Spironolactone and Ursodiol in the suspending vehicle PCCA SuspendIt in liquid dosage forms, with an extended beyond-use-date to meet patient needs.

Medications for Obesity: A Review.

Importance: Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia. Observations: AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16 964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants). Conclusion and Relevance: Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.

The safety and effectiveness of naldemedine for opioid-induced constipation in patients with advanced cancer in real-world palliative care settings: a multicenter prospective observational study.

PURPOSE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects. METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events. RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed. CONCLUSION: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings. TRIAL REGISTRATION NUMBER: UMIN000031381, registered 20/02/2018.

Activation of µ receptors by SR-17018 through a distinctive mechanism.

Agonists at µ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve ß-arrestin2. Agonists biased against ß-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed µ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted µ receptor availability in PathHunter CHO cells using the irreversible antagonist, ß-funaltrexamine (ß-FNA), and compared efficacies and apparent potencies of twelve agonists, including several previously reported as biased, in ß-arrestin2 recruitment and cAMP assays. With full receptor availability all agonists had partial efficacy for stimulating ß-arrestin2 recruitment relative to DAMGO, while only TRV130 and buprenorphine were partial agonists as inhibitors of cAMP accumulation. Limiting receptor availability by prior exposure to ß-FNA (100 nM) revealed morphine, oxycodone, PZM21, herkinorin, U47700, tianeptine and U47931e are also partial agonists in the cAMP assay. The efficacies of all agonists, except SR-17018, correlated between ß-arrestin2 recruitment and cAMP assays, with depleted receptor availability in the latter. Furthermore, naloxone and cyprodime exhibited non-competitive antagonism of SR-17018 in the ß-arrestin2 recruitment assay. Limited antagonism by naloxone was also non-competitive in the cAMP assay, while cyprodime was competitive. Furthermore, SR-17018 only negligibly diminished ß-arrestin2 recruitment stimulated by DAMGO (1 µM), whereas fentanyl, morphine and TRV130 all exhibited the anticipated competitive inhibition. The data suggest that SR-17018 achieves bias against ß-arrestin2 recruitment through interactions with µ receptors outside the orthosteric agonist site. This article is part of the Special Issue on "Ligand Bias".

Naltrexone accelerated oral traumatic ulcer healing and downregulated TLR-4/NF-kB pathway in Wistar rats.

OBJECTIVE: To assess the effect of naltrexone on oral mucosal healing using a traumatic ulcer model DESIGN: Wistar rats (n = 112) received distilled water (control) or naltrexone (0.5, 10, or 50 mg/kg/day). Ulcers were induced on the buccal mucosa using a round skin biopsy punch (diameter 6 mm). Euthanasia was performed on days 1, 3, 7, and 14. Healing was assessed by ulcer area, histological scores, histomorphometric analysis (number of polymorphonuclears, mononuclears, and fibroblasts), and collagen percentage. Immunohistochemistry for TLR-2, TLR-4, NF-kB, and CD31 was evaluated. Nociceptive threshold was measured daily. RESULTS: The 50 mg/kg group showed reduced ulcer area on days 1 (p < 0.001), 3 (p < 0.05), and 14 (p < 0.01). In this group, there was, on day 14, an increase in the percentage of reepithelization (p = 0.043) and collagen (p < 0.05), an increase in connective tissue maturation (p = 0.016), and on day 7 an increase in fibroblasts (p < 0.001). The 10 mg/kg dose reduced the ulcer area on day 1 (p < 0.001). The 50 mg/kg group showed lower expression of TLR-4 (p < 0.001) on day 1, NF-kB on days 1 (p < 0.05) and 14 (p < 0.05), and CD31 on day 14 (p < 0.05). The 0.5 and 10 mg/kg doses reduced TLR-4 expression on day 1 (p < 0.05; p < 0.01, respectively). Nociceptive threshold increased in the 50 mg/kg group (p < 0.01). CONCLUSION: Naltrexone enhanced traumatic oral ulcer healing by reducing TLR-4/NF-kB signaling and promoting fibroblast proliferation and collagen deposition. Additionally, naltrexone reduced pain in rats.

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Effect of Preadministration of Nalmefene on Sufentanil-Induced Cough During Induction of General Anesthesia in Patients Undergoing Breast Surgery: A Double-Blind Randomized Controlled Trial.

Purpose: This study was designed to investigate the effects of preadministration of nalmefene before general anesthesia induction on sufentanil-induced cough (SIC) in patients undergoing breast surgery. Patients and Methods: A total of 105 patients scheduled for elective breast surgery under general anesthesia were selected and randomly assigned into three groups: normal saline (Group C), low-dose nalmefene 0.1 µg·kg-1 (Group LN), and high-dose nalmefene 0.25 µg·kg-1 (Group HN). Sufentanil 0.5 µg·kg-1 was injected intravenously within 2 s after 5 min of intervention. The count and severity of cough within 2 min after sufentanil injection, as well as the time to first cough, were recorded. In addition, we also collected intraoperative hemodynamic data, postoperative pain scores, the incidence of receiving rescue analgesics, and side effects up to 24 h after surgery. Results: Compared to Group C, the incidence of SIC was significantly lower in Group LN and HN (64.7% vs 30.3% and 14.7%, respectively; P < 0.001), but no significant difference was observed between the two groups (P=0.126). Compared to Group C, the risk factors decreased by 53.4% (95% confidence interval [CI] =0.181-0.735, P=0.008) in Group LN and by 75.9% (95% CI=0.432-0.898, P=0.001) in Group HN. Of the patients with SIC, less frequent SIC within 2 min after induction and a lower proportion of severe coughs were observed than Group C (P < 0.05), and no difference was detected between Group LN and HN. Additionally, the onset time to the first SIC did not differ significantly between the groups. Intraoperative hemodynamic data, postoperative pain scores, and side effects in the first 24 h did not differ among the groups. Conclusion: Preadministration of nalmefene prior to induction of general anesthesia effectively suppressed SIC in patients undergoing breast surgery, without affecting intraoperative hemodynamic fluctuation and postoperative pain intensity.

The identification and treatment of alcohol problems in primary care (iTAPP) study: protocol for a stepped wedge cluster randomized control trial testing the 15-method in a primary care setting.

BACKGROUND: The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as specialized treatment for mild to moderate alcohol dependence in Sweden. A feasibility study of the 15-method in Danish primary care found the method acceptable and feasible. AIMS: To evaluate the effectiveness of the 15-method in a Danish primary care setting in (1) lowering the proportion of patients exceeding the Danish low-risk alcohol consumption limit of ten standard units per week and a maximum of four standard units on a single day for men and women, and (2) increasing the likelihood of alcohol use being addressed during a consultation in general practice. Further, the rate of prescribed pharmacological treatment for alcohol problems (Disulfiram, Naltrexone, Acamprosate, and Nalmefene) will be measured along with the use of the biomarkers Alanine Transaminase and Gamma-Glutamyl Transferase. METHODS: Stepped wedge cluster randomized controlled trial in sixteen general practices in the Region of Southern Denmark. Following a three-month baseline, the practices are randomly assigned to launch dates in one of four clusters. General practitioners and nurses receive three hours of training in the 15-method before launch. Patient questionnaires will collect data on alcohol consumption levels among patients affiliated with the practices. The healthcare professionals will register consultations in which alcohol is addressed in their patient filing system. Pharmacological treatment rates and the use of biomarkers will be collected through Danish national registries. The study follows the Medical Research Council's guidelines for developing and evaluating complex interventions. DISCUSSION: From the patient's perspective, the 15-method may help identify alcohol-related problems at an earlier stage with flexible treatment offers in a familiar setting. For healthcare professionals, it addresses a traditionally challenging topic by equipping them with concrete tools, communication training, and clear treatment directives. From a societal perspective, primary care holds a unique position to identify hazardous and harmful alcohol use across different age groups, with potential public health and economic benefits through early identification and intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT05916027. Retrospectively registered 22 June 2023.

A case of naltrexone-induced acute eosinophilic pneumonia.

Acute eosinophilic pneumonia (AEP) is a rare cause of acute respiratory failure. Clinical presentations can range from dyspnoea, fever and cough, to rapidly progressive and potentially fulminant respiratory failure. While its exact cause is often unknown, associations with inhalational injuries and exposures to new medications have been described.We report a case of a middle-aged, non-smoking man with a history of alcohol use disorder. He presented with 4 days of shortness of breath that started hours after taking injectable naltrexone (Vivitrol). The patient had rapidly worsening hypoxaemia, necessitating emergent bronchoscopy with transbronchial biopsies and bronchoalveolar lavage which showed 66% eosinophils. The patient was intubated for the procedure and unable to get extubated due to worsening hypoxaemic respiratory failure with high fractional inspired oxygen requirements. Chest radiograph showed worsening lung infiltrates and with a high index of suspicion for AEP, he was started empirically on methylprednisolone. He had rapid improvement in his respiratory status and was extubated on day 5 of admission then discharged on day 8. Histopathological examination confirmed acute/subacute eosinophilic pneumonia. A 3-week post-discharge follow-up chest radiograph confirmed the full resolution of pulmonary infiltrates.Naltrexone-induced AEP is rare, with only six other cases reported in the literature. Careful history taking and prompt evaluation for AEP are important given the potential for rapid progression to acute hypoxic respiratory failure and the excellent response to steroid treatment.

Total and H-specific growth/differentiation factor 15 levels are unaffected by liraglutide or naltrexone/bupropion administration.

AIM: To investigate growth/differentiation factor 15 (GDF-15) levels in response to antiobesity medications, namely, liraglutide (Lira) and naltrexone/bupropion (N/B), in individuals with overweight or obesity. MATERIALS AND METHODS: This was a prospective, non-randomized clinical trial with a two-arm, parallel design. A total of 42 individuals with overweight or obesity without type 1 or type 2 diabetes mellitus were enrolled. The participants received either Lira 3 mg or N/B 32/360 mg, along with diet and exercise, according to comorbidities, cost and method of administration. Participants underwent clinical and laboratory measurements at baseline, as well as at the 3- and 6-month time points. Anthropometric measurements and body composition analysis via bioelectrical impendence analysis were performed. Total blood samples for GDF-15 and H-specific GDF-15 were collected in the fasting state and every 30 min for 3 h after the consumption of a standardized mixed meal. RESULTS: Overall, participants' weight was reduced by 9.29 ± 5.34 kg at Month 3 and 11.52 ± 7.52 kg at Month 6. Total and H-specific GDF-15 levels did not show significant changes during the mixed meal compared to values before the meal when all participants were examined at baseline, and at 3 and 6 month follow-ups. No statistical significance was found when participants were examined by subgroup (Lira vs. N/B). No significant differences between treatment groups in postprandial area under the curve (AUC) or incremental AUC values were found at baseline or in the follow-up months with regard to total and H-specific GDF-15 levels. CONCLUSION: Neither total nor H-specific GDF-15 levels are affected by Lira or N/B treatment in patients with overweight or obesity.

Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia.

INTRODUCTION: A significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue syndromes. There remains no clear pharmacological therapy for patients with this subtype of PCC, which can be referred to as post-COVID fatigue syndrome (PCFS). A low dose of the opioid antagonist naltrexone (ie, low-dose naltrexone (LDN)) has emerged as an off-label treatment for treating fatigue and other symptoms in PCC. However, only small, non-controlled studies have assessed LDN in PCC, so randomised trials are urgently required. METHODS AND ANALYSIS: A prospective, randomised, double-blind, parallel arm, placebo-controlled phase II trial will be performed to assess the efficacy of LDN for improving fatigue in PCFS. The trial will be decentralised and open to eligible individuals throughout the Canadian province of British Columbia (BC). Participants will be recruited through the province-wide Post-COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN) and research volunteer platform (REACH BC). Eligible participants will be 19-69 years old, have had a confirmed or physician-suspected SARS-CoV-2 infection at least 3 months prior and meet clinical criteria for PCFS adapted from the Institute of Medicine ME/CFS criteria. Individuals who are taking opioid medications, have a history of ME/CFS prior to COVID-19 or history of significant liver disease will be excluded. Participants will be randomised to an LDN intervention arm (n=80) or placebo arm (n=80). Participants in each arm will be prescribed identical capsules starting at 1 mg daily and follow a prespecified schedule for up-titration to 4.5 mg daily or the maximum tolerated dose. The trial will be conducted over 16 weeks, with assessments at baseline, 6, 12 and 16 weeks. The primary outcome will be fatigue severity at 16 weeks evaluated by the Fatigue Severity Scale. Secondary outcomes will include pain Visual Analogue Scale score, overall symptom severity as measured by the Patient Phenotyping Questionnaire Short Form, 7-day step count and health-related quality of life measured by the EuroQol 5-Dimension questionnaire. ETHICS AND DISSEMINATION: The trial has been authorised by Health Canada and approved by The University of British Columbia/Children's and Women's Health Centre of British Columbia Research Ethics Board. On completion, findings will be disseminated to patients, caregivers and clinicians through engagement activities within existing PCC and ME/CFS networks. Results will be published in academic journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05430152.

Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target.

Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients. Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years). NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol. Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX. Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX. The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca2+) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.

Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study.

OBJECTIVE: Little is known about the effect of a multi-drug weight loss strategy in obesity treatment, particularly combining bupropion/naltrexone and glucagon-like peptide 1 (GLP-1) analogue. The purpose of this study was to evaluate if there are any additive effects of prescribing bupropion/naltrexone on top of GLP-1 analogue as weight loss therapy. METHODS: This was a retrospective cohort study of adult patients with a body mass index (BMI) ≥ 30 kg/m2 prescribed GLP-1 analogue therapy at an obesity specialist clinic in Vancouver, Canada. We compared a 6 and 12-month change in total body weight loss (TBWL) for those receiving monotherapy from the initiation of GLP-1 analogue therapy with those receiving combination therapy from the initiation of bupropion/naltrexone added-on therapy. Patients prescribed combination therapy were stratified into responder (loss of ≥ 5% TBWL) and non-responder (TBWL < 5%) subgroups based on initial response to the GLP-1 analogue alone for any amount of time. RESULTS: The mean weight loss among patients prescribed GLP-1 analogue monotherapy at 12 months was 11.42 kg, SD 9.95 (9.6% TBWL). There was no significant difference between these two treatment strategies overall (HR 0.88, 95% CI 0.68 to 1.14, p = 0.35). However, when stratified by response to initial GLP analogue therapy, the addition of bupropion/naltrexone was associated with a statistically significant reduction in weight in both the responder (4.3% TBWL (p < 0.01)) and non-responder groups (4.0% TBWL (p < 0.01)). CONCLUSIONS: GLP-1 analogues are an effective treatment for weight loss, and the addition of bupropion/naltrexone is associated with greater weight loss including in patients who are initially non-responsive to GLP-1 analogues.

Comparison of the Efficacy of Anti-Obesity Medications in Real-World Practice.

Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.

Repurposing drugs for treatment of alcohol use disorder.

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

Efficacy and safety of naldemedine for opioid-induced constipation in older patients with cancer: a retrospective study.

BACKGROUND: Opioids are pain relievers that are often associated with opioid-induced constipation (OIC) that worsens with age. We performed a multicenter, retrospective analysis on the efficacy and safety of naldemedine, an opioid receptor antagonist, in treating OIC in patients with cancer (age >75 years). METHODS: The electronic medical records of cancer patients who received naldemedine at 10 Japanese institutions between 7 June 2017 and August 31, 2019, were retrieved. Patients aged ≥75 years who were treated with naldemedine for the first time and hospitalized for at least 7 days before and after initiating naldemedine therapy were included in this analysis. RESULTS: Sixty patients were observed for at least 7 days before and after starting naldemedine. The response rate was 68.3%, and the frequency of bowel movements increased significantly after naldemedine administration in the overall population ( P  < 0.0001) and among those who defecated <3 times/week before naldemedine administration ( P  < 0.0001). Diarrhea was the most frequent adverse event in all grades, observed in 45% of patients, of which 92.6% were Grade 1 or 2. Grade 4 or higher adverse events, including death, were not observed. CONCLUSION: Naldemedine exhibits significant efficacy and safety in OIC treatment in older patients with cancer.

Activation of epidermal growth factor receptors in triple-negative breast cancer cells by morphine; analysis through Raman spectroscopy and machine learning.

Triple negative breast cancer (TNBC) is a very aggressive form of breast cancer, and the analgesic drug morphine has been shown to promote the proliferation of TNBC cells. This article investigates whether morphine causes activation of epidermal growth factor receptors (EGFR), the roles of µ-opioid and EGFR receptors on TNBC cell proliferation and migration. While examining the changes with molecular techniques, we also aimed to investigate the analysis ability of Raman spectroscopy and machine learning-based approach. Effects of morphine on the proliferation and migration of MDA.MB.231 cells were evaluated by MTT and scratch wound-healing tests, respectively. Morphine-induced phosphorylation of the EGFR was analyzed by western blotting in the presence and absence of µ-receptor antagonist naltrexone and the EGFR-tyrosine kinase inhibitor gefitinib. Morphine-induced EGFR phosphorylation and cell migration were significantly inhibited by pretreatments with both naltrexone and gefitinib; however, morphine-increased cell proliferation was inhibited only by naltrexone. While morphine-induced changes were observed in the Raman scatterings of the cells, the inhibitory effect of naltrexone was analyzed with similarity to the control group. Principal component analysis (PCA) of the Raman confirmed the epidermal growth factor (EGF)-like effect of morphine and was inhibited by naltrexone and partly by gefitinib pretreatments. Our in vitro results suggest that combining morphine with an EGFR inhibitor or a peripherally acting opioidergic receptor antagonist may be a good strategy for pain relief without triggering cancer proliferation and migration in TNBC patients. In addition, our results demonstrated the feasibility of the Raman spectroscopy and machine learning-based approach as an effective method to investigate the effects of agents in cancer cells without the need for complex and time-consuming sample preparation. The support vector machine (SVM) with linear kernel automatically classified the effects of drugs on cancer cells with ∼95% accuracy.

Duration of the preemptive analgesic effects of low- and high-frequency transcutaneous electrical nerve stimulation in rats with acute inflammatory pain.

Transcutaneous electrical nerve stimulation (TENS) activates various pathways to induce antinociceptive effects, based on the frequencies used. This study evaluates the preemptive analgesic effects and their duration of low- (LT: 4 Hz) and high-frequency TENS (HT: 100 Hz) using a rat model of acute inflammatory pain. Acute inflammation was induced by injecting 1% formalin into the hind paws of rats. LT or HT was applied for 30 min before formalin injection. Pain-related behaviors, such as licking, flinching, and lifting, were recorded for 60 min postinjection. Immunohistochemistry was used to assess the number of phosphorylated extracellular signal-regulated kinase (pERK)- and c-fos-positive cells in the spinal cord. Naloxone, a µ-opioid receptors (MORs) antagonist, and naltrindole, a δ-opioid receptors (DORs) antagonist, were administered before TENS application. Pain behavior duration and pERK- and c-fos-positive cell expression were then measured. LT and HT pretreatment significantly reduced both pain behaviors and the number of pERK- and c-fos-positive cells postformalin injection. Naloxone and naltrindole partially reversed the effects of LT and HT, respectively. Notably, HT's analgesic effect lasted up to 120 min whereas that of LT persisted for 90 min. LT and HT effectively exerted their preemptive analgesic effects on acute inflammatory pain by inhibiting pERK and c-fos expression in the spinal cord. HT presented a longer-lasting effect compared to LT. MOR and DOR activation may contribute to LT and HT's analgesic mechanisms, respectively.

Utilization of Anti-obesity Medications After Bariatric Surgery: Analysis of a Large National Database.

PURPOSE: A significant proportion of patients experience insufficient weight loss or weight regain after bariatric surgery. There is a paucity of literature describing anti-obesity medication (AOM) use following bariatric surgery. We sought to identify prevalence and trends of AOM use following bariatric surgery. MATERIALS AND METHODS: We utilized the IBM Explorys® database to identify all adults with prior bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy). Those prescribed AOMs (semaglutide, liraglutide, topiramate, phentermine/topiramate, naltrexone/bupropion, orlistat) within 5 years of surgery were further identified. Data was analyzed to characterize AOM utilization among different age, demographic, and comorbid populations. RESULTS: A total of 59,160 adults with prior bariatric surgery were included. Among AOMs studies, prevalence of use was highest for topiramate (8%), followed by liraglutide (2.9%), phentermine/topiramate (1.03%), naltrexone/bupropion (0.95%) semaglutide (0.52%), and orlistat (0.17%). Age distribution varied, with the highest utilization among those age 35-39 years for topiramate, 40-44 years for phentermine/topiramate and naltrexone/bupropion, 45-49 years for semaglutide, and 65-69 years for liraglutide and orlistat. African American race was associated with higher utilization across all AOMs. Among comorbidities, hypertension, hyperlipidemia, and diabetes mellitus were most associated with AOM use. CONCLUSION: Despite a relatively high incidence of weight regain, AOMs are underutilized following bariatric surgery. It is imperative that barriers to their use be addressed and that AOMs be considered earlier and more frequently in patients with insufficient weight loss or weight regain after bariatric surgery.