Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Characterization of a novel 3-quinuclidinone reductase possessing remarkable thermostability.

The 3-quinuclidinone reductase plays an irreplaceable role in the biopreparation of (R)-3-quinuclidinol, an intermediate vital for synthesis of various pharmaceuticals. Thermal robustness is a critical factor for enzymatic synthesis in industrial applications. This study characterized a new 3-quinuclidinone reductase, named SaQR, with significant thermal stability. The SaQR was overexpressed in a GST-fused state, and substrate and cofactor screening were conducted. Additionally, three-dimensional structure prediction using AlphaFold and analysis were performed, along with relevant thermostability tests, and the evaluation of factors influencing enzyme activity. The findings highlight the remarkable thermostability of SaQR, retaining over 90% of its activity after 72 h at 50°C, with an optimal operational temperature of 85°C. SaQR showed typical structural traits of the SDR superfamily, with its cofactor-determining residue being aspartic acid, conferring nicotinamide adenine dinucleotide (NAD(H)) preference. Moreover, K+ and Na+, at a concentration of 400 mM, could significantly enhance the activity, while Mg2+ and Mn2+ only display inhibitory effects within the tested concentration range. The findings of molecular dynamics simulations suggest that high temperatures may disrupt the binding of enzyme to substrate by increasing the flexibility of residues 205-215. In conclusion, this study reports a novel 3-quinuclidinone reductase with remarkable thermostability.

Gastrointestinal adverse effects associated with the use of intravenous oliceridine compared with intravenous hydromorphone or fentanyl in acute pain management utilizing adjusted indirect treatment comparison methods.

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Penehyclidine for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Gynecological Laparoscopic Surgery Under Combined Intravenous and Inhalation Anesthesia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: We designed this study to investigate the effect of intravenous use of penehyclidine on postoperative nausea and vomiting (PONV) after gynecological laparoscopic surgery. Patients and Methods: Ninety-two Women Patients (Aged ≥ 18) Scheduled for Elective Gynecologic Laparoscopy Were Enrolled in the Current Study. Patients Were Equally Randomized Assigned Into Penehyclidine group (PHC group: received a bolus of penehyclidine 10 µg/kg during the induction of anesthesia, then followed by a continuous infusion of 10 µg/kg penehyclidine at a fixed rate of 2.0 mL/h in postoperative intravenous analgesia pump over 48h, 0.5 mg upper limit respectively) or Control group (received 0.9% saline in replace of penehyclidine at the same time points). The primary outcome measure was the incidence of postoperative nausea and vomiting in the postanesthesia care unit and ward area. Quality of Recovery-15 (QoR-15) scores and general comfort questionnaire (GCQ) scores were assessed on postoperative day (POD) 1, 2. Results: Patients between two groups had comparable baseline characteristics. Compared with the Control group, the incidence and severity of PONV, postoperative nausea (PON), and postoperative vomiting (POV) were significantly lower in the PHC group at 2h (PONV: P = 0.002, P = 0.004, respectively; PON: P = 0.018, P = 0.038, respectively; POV: P = 0.011, P = 0.072, respectively), 24h (PONV: P = 0.003, P = 0.001, respectively; PON: P = 0.010, P = 0.032, respectively; POV: P = 0.006, P = 0.044, respectively), and 48h (PONV: P = 0.003, P = 0.002, respectively; PON: P = 0.007, P = 0.019, respectively; POV: P = 0.002, P = 0.013, respectively) after surgery. The QoR-15 and GCQ scores of the PHC group were significantly higher than those of the Control group at POD 1, 2 (P < 0.001; P < 0.001, respectively). Conclusion: Our findings suggest that perioperative intravenous application of penehyclidine can effectively prevent postoperative nausea and vomiting in gynecological laparoscopic surgery patients and improve postoperative recovery.

Outcomes of Patients with COPD Treated with ICS/LABA Before and After Initiation of Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI).

INTRODUCTION: Triple therapy (fluticasone furoate/umeclidinium/vilanterol; FF/UMEC/VI) has been shown to improve symptoms and reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. This real-world study compared exacerbation rates and healthcare resource utilization (HCRU) before and after initiation of FF/UMEC/VI in patients with COPD previously treated with inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA). METHODS: This retrospective cohort study included commercial and Medicare Advantage with Part D administrative claims data from September 01, 2016, to March 31, 2020, of patients diagnosed with COPD. The index date was the date of the first FF/UMEC/VI claim (September 2017-March 2019). The 12 months prior to index (baseline) were used to assess patient characteristics and outcomes; the 12 months following index (follow-up) were used to assess study outcomes. All patients had ≥ 30 consecutive days' supply of any ICS/LABA dual therapy during the 12 months prior to FF/UMEC/VI initiation. Subgroup analyses included patients with ≥ 30 consecutive days' supply of budesonide/formoterol (BUD/FORM) during baseline. Analyses of patients with ≥ 1 COPD exacerbation during baseline were reported as well. RESULTS: The overall population included 1449 patients (mean age 70.75 years; 54.18% female), of whom 540 were patients in the BUD/FORM subgroup. Significantly fewer patients experienced any exacerbation during follow-up versus baseline (overall population 53.49% vs 62.59%; p < 0.001; BUD/FORM subgroup 55.00% vs 62.41%; p = 0.004). Effects on exacerbation reduction were more pronounced among patients with ≥ 1 exacerbation during baseline. Lower COPD-related HCRU was observed during the follow-up compared with baseline for both the overall population and the BUD/FORM subgroup. CONCLUSION: Patients with COPD treated with ICS/LABA during baseline, including patients specifically treated with BUD/FORM and those with a history of ≥ 1 exacerbation, had fewer COPD exacerbations and lower COPD-related HCRU after initiating FF/UMEC/VI.

Does maropitant provide more effective perioperative pain management than meloxicam in bitches undergoing ovariohysterectomy? The first report on the comparison of visceral algesia-analgesia for ovariohysterectomy.

Ovariohysterectomy (OVH) is a widely used surgical procedure in small animal practice. In developing countries, injectable anesthetics such as ketamine and xylazine are commonly used in veterinary medicine. Pharmacological agents with analgesic activity, such as ketamine and meloxicam, are not sufficiently effective in reducing visceral pain. Therefore, this study aimed to investigate the visceral analgesia and anti-inflammatory effectiveness of maropitant compared with those of meloxicam during and after OVH in bitches. In this study, thirty-six bitches were randomly divided into the maropitant, meloxicam, and control groups. The heart rate (HR), peripheral oxygen saturation, and respiratory rate were monitored during the procedure. Pain scores were assessed using the University of Melbourne pain scale (UMPS). Rescue analgesia was not necessary for any bitch at any time point. Blood samples were collected before anesthesia induction and 24 h after the operation to determine C-reactive protein (CRP) levels. No significant difference was observed in HR between the control and meloxicam groups when the right ovary was removed, and the HR of the maropitant group was significantly (p < 0.05) lower than that of the control group. The pain scores of the maropitant group were significantly (p < 0.05) lower than those of the other groups. However, no significant differences were observed in CRP levels between the groups. In conclusion, compared to meloxicam, maropitant provided more effective visceral analgesia in bitches undergoing OVH, although no significant difference was found in its anti-inflammatory effect.

Inpatient Admissions and Re-Admissions in Medicare Beneficiaries Initiating Umeclidinium/Vilanterol or Tiotropium Therapy.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) who are hospitalized are more likely to die from their illness and have increased likelihood of re-admission than those who are not. Subsequent re-admissions further increase the burden on healthcare systems. This study compared inpatient admission rates and time-to-first COPD-related inpatient admission among Medicare beneficiaries with COPD indexed on umeclidinium/vilanterol (UMEC/VI) versus tiotropium (TIO). Patients and Methods: This retrospective study used the All-Payer Claims Database to investigate hospital admission and re-admission outcomes in Medicare beneficiaries with COPD with an initial pharmacy claim for UMEC/VI or TIO from 1 January 2015 to 28 February 2020. Inpatient admissions, baseline, and follow-up variables were assessed in patients indexed on UMEC/VI and TIO after propensity score matching (PSM), with time-to-first on-treatment COPD-related inpatient admission as the primary endpoint. Re-admissions were assessed among patients with a COPD-related inpatient admission in the 30- and 90-days post-discharge. Results: Post-PSM, 7152 patients indexed on UMEC/VI and 7069 on TIO were eligible for admissions analysis. The mean (standard deviation [SD]) time-to-first COPD-related inpatient admission was 46.71 (87.99) days for patients indexed on UMEC/VI and 44.96 (85.90) days for those on TIO (p=0.06). The mean (SD) number of inpatient admissions per patient was 1.24 (2.92) for patients indexed on UMEC/VI and 1.26 (3.05) for those on TIO (p=0.49). Proportion of patients undergoing re-admissions was similar between treatments over both 30 and 90 days, excluding a significantly lower proportion of patients indexed on UMEC/VI than those indexed on TIO for COPD-related re-admissions for hospital stays of 4-7 days and 7-14 days, and all-cause re-admissions for stays of 4-7 days. Conclusion: Patients with COPD using Medicare in the US and receiving UMEC/VI or TIO reported similar time-to-first inpatient admission and similar proportion of re-admissions.

The alpha-7 nicotinic acetylcholine receptor agonist PHA-543613 reduces food intake in male rats.

Obesity is a prevalent disease, but effective treatment options remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that central administration of the α7nAChR agonist PHA-543613 (PHA) would decrease food intake and body weight in adult male Sprague Dawley rats. Intracerebroventricular (ICV) PHA administration in chow-fed rats produced a suppression of energy intake and weight gain over 24 h. Next, to evaluate effects of ICV PHA on palatable food intake, rats were maintained on a choice diet of rodent chow and 45 % high fat diet (HFD); under these conditions, ICV PHA produced no significant changes in energy intake from either food, or body weight gain, in the 24 h post-injection. However, when given a choice of chow or a higher-fat 60 % HFD, ICV PHA reduced intake of 60 % HFD, but not chow; body weight gain was also suppressed. Further experiments evaluating conditioned taste avoidance (CTA) and pica in response to ICV PHA suggested that the suppressive food intake and body weight effects after ICV injection of PHA were not due to nausea/malaise. Finally, an operant conditioning study showed that responding on a progressive ratio schedule of reinforcement for high-fat food pellets decreased after ICV PHA. Collectively, these studies show that PHA reduces energy intake under some but not all dietary conditions. Importantly, central PHA decreases both food intake as well as motivation for highly palatable, energy dense foods in rats without inducing nausea/malaise, suggesting that the α7nAChR could be a viable target for developing treatments for obesity.

Real-World Effectiveness of Fluticasone Furoate/Umeclidinium/Vilanterol Once-Daily Single-Inhaler Triple Therapy for Symptomatic COPD: The ELLITHE Non-Interventional Trial.

Purpose: Real-life effectiveness data on once-daily single-inhaler triple therapy (odSITT) with the inhaled corticosteroid fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting ß2-agonist vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) are important to complement evidence from well-controlled randomized clinical trials. Effectiveness of odSITT was quantified by assessing health status and symptoms in usual care. Patients and Methods: ELLITHE was a single-country (Germany), multicenter, open-label, non-interventional effectiveness study between 2020 and 2022, evaluating the effect of treatment initiation with FF/UMEC/VI 100/62.5/25 µg once-daily via the ELLIPTA inhaler on improvements in clinical outcomes versus baseline in COPD patients. The primary endpoint was the change in the total COPD Assessment Test (CAT) score between baseline and month 12. Key secondary endpoints included change in CAT score over time, occurrence of exacerbations until month 12, changes in forced expiratory volume in one second (FEV1), inhaler adherence, and safety. Results: Nine hundred and six patients were included (age 66.6 years, 55.6% male, mean FEV1 52.6% of predicted, mean CAT 21.5 units, 1.4 exacerbations/year pre-study). About 63.9% of patients were escalated from dual therapies, and 18% were switched from multiple-inhaler triple therapies. Reductions in CAT score at month 12 were statistically significant and above the threshold of clinical importance (-2.6 units; p < 0.0001). CAT score also improved at interim visits. CAT improvements were more pronounced in patients with high baseline scores and better inhaler adherence. Exacerbations during follow-up were rare (0.2 events/year) compared to pre-study (1.4 events/year). FEV1 was improved by 93 mL (p < 0.0001). No new safety effects were observed. Conclusion: In usual care, treatment with odSITT resulted in significant and clinically relevant improvements of CAT score and FEV1 in COPD patients, regardless of the occurrence of exacerbations. These findings challenge the current guideline recommendations for SITT only in patients experiencing exacerbations.

Outcomes Following Initiation of Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol versus Multiple-Inhaler Triple Therapy Among Medicare Advantage with Part D Beneficiaries and Those Commercially Enrolled for Health Care Insurance in the United States.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) have been shown to benefit from triple therapy commonly delivered by multiple-inhaler triple therapy (MITT); however, the complexity of MITT regimens may decrease patient adherence. Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), a once-daily single-inhaler triple therapy (SITT), became available in the United States (US) in 2017, but real-world data comparing outcomes for SITT versus MITT are currently limited. This study compared outcomes among patients with COPD initiating MITT versus SITT with FF/UMEC/VI who were either Medicare Advantage with Part D (MAPD) beneficiaries or commercial enrollees in the US. Methods: Retrospective study using administrative claims data from the Optum Research Database for patients with COPD who initiated FF/UMEC/VI or MITT between September 1, 2017, and March 31, 2019 (index date: first pharmacy claim for FF/UMEC/VI cohort; earliest day of ≥30 consecutive days-long period of overlap in the day's supply of all triple therapy components for MITT cohort). COPD exacerbations, adherence to triple therapy, and all-cause and COPD-related health care resource utilization (HCRU) and costs were compared between FF/UMEC/VI and MITT initiators. Results: In total, 4659 FF/UMEC/VI initiators and 9845 MITT initiators for the MAPD population, and 821 FF/UMEC/VI initiators and 1893 MITT initiators for the commercial population were included in the study. MAPD beneficiaries initiating FF/UMEC/VI had a significantly lower annual rate of severe exacerbations compared to MITT initiators (0.26 vs 0.29; p=0.014). They also had a significantly higher mean adherence (proportion of days covered) (0.51 vs 0.37; p<0.001) and significantly lower all-cause and COPD-related inpatient stays compared to MITT initiators ([32.02% vs 34.27%; p=0.017], [16.09% vs 17.72%; p=0.037]). Trends were similar among the commercial population, but the results were not statistically significant. Conclusion: FF/UMEC/VI initiators had significantly fewer severe exacerbations, higher triple therapy adherence, and lower HCRU costs compared to MITT initiators for MAPD beneficiaries.

Real-World Disease Burden and Healthcare Resource Utilization Among Patients with COPD and Asthma Using Triple Therapy (FF/UMEC/VI) in the United States.

Purpose: Chronic obstructive pulmonary disease (COPD) and asthma are associated with chronic inflammation of the respiratory tract; despite some overlap of symptoms, they are considered separate disorders. Triple therapy is recommended for patients with COPD and asthma whose symptoms remain uncontrolled despite dual therapy. There are limited real-world studies evaluating outcomes among patients with COPD and asthma who are receiving inhaled triple therapy. This United States (US)-based real-world study aimed to evaluate clinical and economic outcomes among patients with COPD and asthma receiving single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI]). Patients and Methods: Retrospective pre-post study using claims data from the Optum Clinformatics® database. Patients with COPD and asthma were indexed on the first date of FF/UMEC/VI prescription (1 October 2017-31 March 2019). Each patient acted as their own control. Patients were required to have continuous health plan enrollment for 12 months prior to (pre-treatment) and following (post-treatment) index. Exacerbations, all-cause and COPD-related healthcare resource utilization, and costs were compared before and after FF/UMEC/VI initiation. Results: Overall, 2743 patients were included (mean age: 71 years; 64% female). Cardiovascular disease was the most prevalent comorbidity during both the pre- and post-treatment periods (90% for both periods). There was a lower proportion of patients with ≥1 COPD exacerbation or ≥1 asthma exacerbation post-treatment versus pre-treatment (51% vs 57%, p<0.0001, and 22% vs 32%, p<0.0001, respectively). Fewer patients had ≥1 all-cause office visit post-treatment versus pre-treatment (99.3% vs 99.7%, p=0.0329); more patients had ≥1 COPD-related office visit post-treatment versus pre-treatment (89.6% vs 87.5%, p=0.0035). Total all-cause healthcare costs were significantly higher post-treatment versus pre-treatment ($72,809 vs $63,734, p<0.0001). The driver of increased costs appeared to be primarily non-COPD-related (COPD-related costs: post-treatment $27,779 vs pre-treatment $25,081, p=0.0062). Conclusion: FF/UMEC/VI reduced exacerbations among patients with COPD and asthma in a real-world setting in the US.

Impact of body weight-based dosing of palonosetron and ondansetron on postoperative nausea and vomiting following laparoscopic sleeve gastrectomy: a randomized, double-blind study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a frequent adverse effect following laparoscopic sleeve gastrectomy. Palonosetron with a standard dosing (75 µg) schedule has been questioned due to its low efficiency in obese patients. This study aimed to investigate the effectiveness and safety of the body weight-based dosing of palonosetron in managing PONV following laparoscopic sleeve gastrectomy. METHODS: A single-center, prospective, double-blinded randomized study was conducted between August 2021 and December 2021. Patients who underwent laparoscopic sleeve gastrectomy were prospectively recruited in the study. One hundred patients were randomly divided into palonosetron (Group P) and ondansetron (Group O). The demographic and clinical variables were recorded. The primary outcome of the study was the incidence of PONV between the two groups during the hospitalization. The secondary outcomes were the number of rescue anti-emetic and analgesic medications and the Functional Living Index-Emesis scores. RESULTS: There were 50 patients in each group (Group P and Group O). There were significant differences in the scores of POVN, nausea, and vomiting favoring Group P. In Group P, the rate of patients using rescue anti-emetics was significantly lower. The incidence of complete response and proportion of patients with higher Functional Living Index-Emesis scores were significantly higher in patients using palonosetron. CONCLUSIONS: The use of palonosetron significantly reduced the incidence of PONV following laparoscopic sleeve gastrectomy. There was a significant improvement in the scores of Functional Living Index-Emesis in patients using palonosetron.

Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Palonosetron for prevention of delayed chemotherapy-induced nausea and vomiting in pediatric patients: a meta-analysis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are common adverse events in patients undergoing emetogenic chemotherapy. Palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), has demonstrated non-inferiority to first-generation 5-HT3 RAs for CINV in pediatric patients. Although palonosetron has a long half-life and prolonged antiemetic action, its efficacy against delayed CINV in pediatric patients is not well understood. Therefore, this meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy of palonosetron for delayed CINV in pediatric patients. METHODS: A literature search of MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science databases was performed. A meta-analysis was performed using forest plots, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. A funnel plot was constructed to explore publication bias. RESULTS: The literature search retrieved 842 records, of which 23 full-text articles were assessed, including six RCTs. Meta-analysis of four RCTs that reported on the complete response (CR: defined as no emesis and no rescue medication) rate for delayed CINV revealed that palonosetron was statistically superior to first-generation 5-HT3 RAs (RR = 1.21 [95% CI 1.09-1.35]; p < 0.01). Although the number of studies included was small, no publication bias was observed in the funnel plots. In addition, the CR rate for overall and acute CINV was also significantly higher for palonosetron (RR = 1.25 [95% CI 1.01-1.54]; p = 0.04 and RR = 1.06 [95% CI 1.01-1.12]; p = 0.03, respectively). CONCLUSION: Palonosetron is effective in the prophylaxis of delayed CINV in pediatric patients.

Changes in Oral Corticosteroid Utilization in Patients with COPD Following Initiation of FF/UMEC/VI.

Purpose: Oral corticosteroids (OCS) play a role in the treatment of acute chronic obstructive pulmonary disease (COPD) exacerbations; however, chronic use is not recommended due to the high rate of systemic complications, development of comorbidities, and increased mortality. Data assessing the real-world impact of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) on OCS utilization rates are limited. This study assessed the impact of FF/UMEC/VI on OCS use among patients with COPD previously treated with OCS. Patients and Methods: A retrospective database study of patients with COPD aged ≥40 years who initiated FF/UMEC/VI from 1 November 2017 to 31 December 2018, identified through the MarketScan® Commercial and Medicare Supplemental databases. Patients were required to have ≥1 dispensing of an OCS prior to initiation of FF/UMEC/VI (index) and were followed up for 12 months post-index. OCS utilization patterns, potential OCS-related adverse events, healthcare resource utilization (HCRU), and costs were compared between the 12-month pre- and post-index periods. Results: A total of 2013 patients were identified (mean age 63.5 years, 55.7% female). The proportion of patients with ≥1 OCS claim decreased by 32.2% between the pre- and post-index period (67.8% vs 100%; p < 0.001). Comparing the post-index period to the pre-index period, mean number of OCS pharmacy claims per patient decreased from 3.3 to 2.5 (p < 0.001) and mean daily dose was reduced from 3.1 to 2.6 mg/day (p = 0.004); 30.0% of patients reduced their daily dose by 90-100%. Reductions were also seen in COPD-related HCRU. The proportion of patients with an inpatient admission for COPD decreased from 11.4% to 7.1% (p < 0.001), emergency room visits decreased from 23.1% to 17.4% (p < 0.001), and office visits from 97.5% to 90.1% (p < 0.001). Similar results were seen for all-cause HCRU. Conclusion: Among patients with COPD with prior OCS use, FF/UMEC/VI initiation resulted in significant reductions in OCS utilization, COPD-related HCRU (including hospitalization), and all-cause HCRU.

Pooled Analysis of Studies Evaluating Fosnetupitant and Risk Factors for Cisplatin-Induced Nausea and Vomiting During the Extended Overall Phase.

INTRODUCTION: Fosnetupitant is a novel neurokinin 1 receptor antagonist (NK1RA) with favorable antiemetic efficacy in patients receiving emetogenic chemotherapy. This study assessed the efficacy of fosnetupitant in combination with palonosetron and dexamethasone and identified risk factors for chemotherapy-induced nausea and vomiting (CINV) for up to 168 h after treatment using pooled data from Japanese studies. METHODS: A pooled analysis of randomized phase II and phase III studies was performed to compare the efficacy of fosnetupitant and fosaprepitant in patients receiving cisplatin-based chemotherapy. The complete response (CR; no vomiting and no rescue medication) rate, CINV risk factors in various phases (0-120, 0-168, and 120-168 h), and impact of the number of risk factors on the time to treatment failure (TTF) were examined in the overall and NK1RA evaluable populations. RESULTS: In the combined cohort of NK1RA evaluable patients (n = 980), the CR rate at 0-168 h was significantly better in the fosnetupitant 235 mg group than in the fosaprepitant group (rate difference = 6.8%, 95% confidence interval = 1.0-12.7, p = 0.022). In the overall (n = 1368) and NK1RA evaluable populations, the CINV risk factor at 120-168 h was treatment failure in the first 120 h. TTF deteriorated as the number of identified CINV risk factors increased. CONCLUSION: This analysis revealed that fosnetupitant could have long-acting antiemetic potency (> 120 h) and indicated the importance of antiemetic therapy at 0-120 h for CINV up to 168 h after chemotherapy.

A New Aspect of Penehyclidine Hydrochloride in Alleviating Myocardial Ischemia-Reperfusion Injury: Ferroptosis.

Penehyclidine hydrochloride (PHC) is an anticholinergic drug with cardioprotective effects. Ferroptosis is closely related to myocardial ischaemia-reperfusion injury (MIRI). In the present study, MIRI was induced in rats by left anterior descending coronary artery ligation. PHC pretreatment increased haemodynamic parameters and histopathological damage and reduced myocardial infarction size in the MIRI model. PHC pretreatment also inhibited ferroptosis, which was characterized by the decreased levels of Fe2+, 4-hydroxynonenal and ACSL4, and increased levels of GPX4, GSH-Px and GST. In response to 6 h of oxygen-glucose deprivation and 18 h of reoxygenation, PHC pretreatment had the same effects on these factors in H9c2 cells and reduced lipid ROS levels. Furthermore, ACSL4 overexpression reversed the protective effects of PHC on H9c2 cells. These results indicated that PHC inhibited MIRI through ACSL4-mediated ferroptosis. This study demonstrated that PHC could inhibit ferroptosis in MIRI and the relationship among PHC, ACSL4, ferroptosis and MIRI. This study demonstrated the inhibitory effect of PHC on ferroptosis and showed that PHC affects MIRI through ACSL4-mediated ferroptosis in vivo and in vitro.