Antibiotics (Basel). 2023 Jan 9;12(1):125. doi: 10.3390/antibiotics12010125.

ABSTRACT

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the 'real life' clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32-57]. At VAP diagnosis, the median PaO2/FiO2 was 120 [100-164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75-14] vs. 7 [4-13] days, OR (95% CI): 1.069 (1.003-1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies.

PMID:36671325 | DOI:10.3390/antibiotics12010125

BMJ Open. 2023 Jan 20;13(1):e068127. doi: 10.1136/bmjopen-2022-068127.

ABSTRACT

OBJECTIVE: Cardiac therapy drugs are widely used in the treatment of heart disease. However, the concern regarding adverse events (AEs) of cardiac therapy drugs have been rising. This study aimed to analyse cardiac therapy drug-related AEs using the Jinan adverse event reporting system (JAERS) database mining and conduct a comprehensive evaluation to provide safe medication information for patients.

DESIGN: Retrospective observational study.

SETTING: In this study, cardiac therapy drug-related AEs were detected using the JAERS database from January 2000 to March 2022.

METHODS: Reports of cardiac therapy drug-related AEs were extracted from JAERS database, and the basic information of patients, reports and common AEs were analysed. Four disproportionality analysis methods, proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA), were used to detect cardiac therapy drug-related signals. We further checked whether the detected signals exist on drug labels in China and two developed countries, the USA and Japan.

RESULTS: In total, 168 314 AEs were reported, of which 4788 were associated with cardiac therapy drugs. Using the PRR, ROR, MHRA and BCPNN method, we detected 52 signals, 52 signals, 33 signals and 43 signals, respectively. Among the 52 signals, 14 were not included on the drug labels of China. One (isosorbide mononitrate-head bilges) was not included on the drug labels of the three countries.

CONCLUSION: We identified 14 new cardiac therapy drug signals that did not appear on drug labels in China and 1 new signal that did not appear on drug labels in 3 counties. A causal link between cardiac therapy drugs and AEs should be evaluated in further studies.

PMID:36669842 | DOI:10.1136/bmjopen-2022-068127

J Clin Oncol. 2023 Jan 20:JCO2201285. doi: 10.1200/JCO.22.01285. Online ahead of print.

ABSTRACT

PURPOSE: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

PATIENTS AND METHODS: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and efficacy analyses included all patients who received milademetan.

RESULTS: Between July 2013 and August 2018, 107 patients were enrolled and received milademetan. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, ie, 3/14 days) were 15.0%, 5.0%, and 0%. Across all cohorts (N = 107), the disease control rate was 45.8% (95% CI, 36.1 to 55.7) and median progression-free survival was 4.0 months (95% CI, 3.4 to 5.7). In the subgroup with dedifferentiated liposarcomas, the disease control rate and median progression-free survival were 58.5% (95% CI, 44.1 to 71.9) and 7.2 months overall (n = 53), and 62.0% (95% CI, 35.4 to 84.8) and 7.4 months with the recommended intermittent schedule (n = 16), respectively.

CONCLUSION: An intermittent dosing schedule of 3/14 days of milademetan mitigates dose-limiting hematologic abnormalities while maintaining efficacy. Notable single-agent activity with milademetan in dedifferentiated liposarcomas has prompted a randomized phase III trial (MANTRA).

PMID:36669146 | DOI:10.1200/JCO.22.01285

Prog Mater Sci. 2022 Oct;130:100997. doi: 10.1016/j.pmatsci.2022.100997. Epub 2022 Jun 17.

ABSTRACT

When blood first encounters the artificial surface of a medical device, a complex series of biochemical reactions is triggered, potentially resulting in clinical complications such as embolism/occlusion, inflammation, or device failure. Preventing thrombus formation on the surface of blood-contacting devices is crucial for maintaining device functionality and patient safety. As the number of patients reliant on blood-contacting devices continues to grow, minimizing the risk associated with these devices is vital towards lowering healthcare-associated morbidity and mortality. The current standard clinical practice primarily requires the systemic administration of anticoagulants such as heparin, which can result in serious complications such as post-operative bleeding and heparin-induced thrombocytopenia (HIT). Due to these complications, the administration of antithrombotic agents remains one of the leading causes of clinical drug-related deaths. To reduce the side effects spurred by systemic anticoagulation, researchers have been inspired by the hemocompatibility exhibited by natural phenomena, and thus have begun developing medical-grade surfaces which aim to exhibit total hemocompatibility via biomimicry. This review paper aims to address different bio-inspired surface modifications that increase hemocompatibility, discuss the limitations of each method, and explore the future direction for hemocompatible surface research.

PMID:36660552 | PMC:PMC9844968 | DOI:10.1016/j.pmatsci.2022.100997

Mediterr J Hematol Infect Dis. 2023 Jan 1;15(1):e2023003. doi: 10.4084/MJHID.2023.003. eCollection 2023.

ABSTRACT

BACKGROUND AND OBJECTIVE: Patients with latent tuberculosis infection (LTBI) receiving chemotherapy for hematological malignancy (HM) are at high risk of developing active tuberculosis (TB) infection. The aim of this study is to show real-life data and results of the T-SPOT test and preventive isoniazid (INH) therapy in pre-chemotherapy LTBI screening in the HM patient group.

METHODS: This retrospective study includes 209 HM patients who had T-SPOT test between 2016 and 2021 in Sultan 2. Abdulhamid Han Training and Research Hospital in Istanbul, Turkey.

RESULTS: The prevalence of LTBI was 26.8% in 209 patients (n=56). Preventive INH therapy was initiated in 82.1% (n=46) of 56 patients with LTBI. 23.9% (n=11) of the 46 patients who received preventive INH therapy were unable to complete the treatment. Nine patients died due to malignancy; one was lost to follow-up, and only one had to stop INH treatment due to elevated liver enzymes. Elevated liver enzymes occurred in 4 (8.7%) patients using INH, while gastrointestinal symptoms occurred in 3 (6.5%) patients. Active TB infection emerged in none of the T-SPOT positive or indeterminate individuals but in one HIV(+) patient in the T-SPOT negative group. The active TB infection incidence rate was 217 cases/100.000hab/year (95% CI, 29-748).

CONCLUSIONS: INH treatment was generally well tolerated, and very few serious drug-related side effects were observed. Although LTBI cannot be demonstrated in patients with HIV(+) HM who are scheduled for chemotherapy, these patients should be closely monitored for the development of active TB infection.

PMID:36660361 | PMC:PMC9833312 | DOI:10.4084/MJHID.2023.003

Int J Burns Trauma. 2022 Dec 15;12(6):251-260. eCollection 2022.

ABSTRACT

INTRODUCTION: Atrial fibrillation is associated with increased morbidity and mortality in critically ill patients. Few studies have specifically examined this arrhythmia in burn patients. Given the significant clinical implications of atrial fibrillation, understanding the optimal management strategy of this arrhythmia in burn patients is important. Consequently, the purpose of this study was to examine rate- and rhythm-control strategies in the management of new onset atrial fibrillation (NOAF) and assess their short term outcomes in critically ill burn patients.

METHODS: We identified all patients admitted to our institution's burn intensive care unit between January 2007 and May 2018 who developed NOAF. Demographic information and burn injury characteristics were captured. Patients were grouped into two cohorts based on the initial pharmacologic treatment strategy: rate-(metoprolol or diltiazem) or rhythm-control (amiodarone). The primary outcome was conversion to sinus rhythm. Secondary outcomes included relapse or recurrence of atrial fibrillation, drug-related adverse events, and complications and mortality within 30 days of the NOAF episode.

RESULTS: There were 68 patients that experienced NOAF, and the episodes occurred on median days 8 and 9 in the rate- and rhythm-control groups, respectively. The length of the episodes was not significantly different between the groups. Conversion to sinus rhythm occurred more often in the rhythm-control group (P = 0.04). There were no differences in the incidences of relapse and recurrence of atrial fibrillation, and the complications and mortality between the groups. Hypotension was the most common drug-related adverse event and occurred more frequently in the rate-control group, though this difference was not significant.

CONCLUSIONS: Conversion to sinus rhythm occurred more often in the rhythm-control group. Outcomes were otherwise similar in terms of mortality, complications, and adverse events. Hypotension occurred less frequently in the rhythm-control group, and although this difference was not significant, episodes of hypotension can have important clinical implications. Given these factors, along with burn patients having unique injury characteristics and a hypermetabolic state that may contribute to the development of NOAF, when choosing between rate- and rhythm control strategies, rhythm-control with amiodarone may be a better choice for managing NOAF in burn patients.

PMID:36660265 | PMC:PMC9845808

Bioinformatics. 2023 Jan 1;39(1):btad006. doi: 10.1093/bioinformatics/btad006.

ABSTRACT

MOTIVATION: Side effects of drugs could cause severe health problems and the failure of drug development. Drug-target interactions are the basis for side effect production and are important for side effect prediction. However, the information on the known targets of drugs is incomplete. Furthermore, there could be also some missing data in the existing side effect profile of drugs. As a result, new methods are needed to deal with the missing features and missing labels in the problem of side effect prediction.

RESULTS: We propose a novel computational method based on transductive matrix co-completion and leverage the low-rank structure in the side effects and drug-target data. Positive-unlabelled learning is incorporated into the model to handle the impact of unobserved data. We also introduce graph regularization to integrate the drug chemical information for side effect prediction. We collect the data on side effects, drug targets, drug-associated proteins and drug chemical structures to train our model and test its performance for side effect prediction. The experiment results show that our method outperforms several other state-of-the-art methods under different scenarios. The case study and additional analysis illustrate that the proposed method could not only predict the side effects of drugs but also could infer the missing targets of drugs.

AVAILABILITY AND IMPLEMENTATION: The data and the code for the proposed method are available at https://github.com/LiangXujun/GTMCC.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36655793 | PMC:PMC9869719 | DOI:10.1093/bioinformatics/btad006

Sci Rep. 2023 Jan 19;13(1):1082. doi: 10.1038/s41598-023-28309-5.

ABSTRACT

Chemotherapy, although beneficial for improving outcomes in both localized and metastatic cancers, may be associated with significant adverse effects, especially for patients with decreased functional reserves. Prediction of patients who will not tolerate well chemotherapy treatment may help in modifying treatment plans and in reallocating resources to vulnerable patients. One hundred seventeen consecutive cancer patients over the age of 70 scheduled for chemotherapy treatment in a single cancer center were included in the study. Prediction of adverse chemotherapy outcomes were calculated using a prediction tool proposed and validated from the Cancer and Aging Research Group (CARG) and a prediction tool proposed by us, called Index4. The 2 tools were compared for their ability to predict grade 3 and 4 toxicities, Emergency Department (ED) and hospital admissions and chemotherapy discontinuation. The accuracy of both predictive tools was suboptimal. A high CARG score had a sensitivity of 46.3% and a specificity of 82% and an Index4 of 1 or above had a sensitivity of 53.7% and a specificity of 60% in predicting grade 3-4 adverse effects. The performance of the 2 tools in predicting ED and hospital admissions and chemotherapy discontinuation was comparable. An Index4 score of 0 was superior in predicting absence of grade 3-4 toxicities than a low CARG score (p = 0.002, McNemar's test). The CARG tool for chemotherapy adverse effect prediction in geriatric cancer patients and the Index4 were able to predict adverse outcomes with moderate accuracy. Given its ease of calculation Index4 may be an alternative to CARG tool, suitable for a busy oncology practice.

PMID:36658198 | PMC:PMC9852555 | DOI:10.1038/s41598-023-28309-5

Asia Pac J Clin Oncol. 2023 Jan 19. doi: 10.1111/ajco.13916. Online ahead of print.

ABSTRACT

AIM: To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases.

METHODS: We retrospectively studied patients with advanced OSS and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12 mg for adults and 10 mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3-week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR).

RESULTS: The median PFS was 9.8 ± .9 months, and the 6- and 10-month PFS rates were 73% and 33%, respectively. The median OS was 11.4 ± .6 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13%, respectively. No drug-related deaths or Grade 4 adverse events occurred in the patients. Five patients (33%) had Grade 3 adverse events. The most common drug-related adverse events were hand-food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax.

CONCLUSIONS: Anlotinib had a modest therapeutic effect in patients with advanced OSS after the failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment.

PMID:36658675 | DOI:10.1111/ajco.13916

J Immunother Cancer. 2023 Jan;11(1):e006222. doi: 10.1136/jitc-2022-006222.

ABSTRACT

BACKGROUND: Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.

METHODS: A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.

RESULTS: sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9-3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7-1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.

CONCLUSION: Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

PMID:36657813 | DOI:10.1136/jitc-2022-006222

Cureus. 2023 Jan 16;15(1):e33831. doi: 10.7759/cureus.33831. eCollection 2023 Jan.

ABSTRACT

Paxlovid (nirmatrelvir/ritonavir) is a game changer in the fight against COVID-19 due to its ease of administration and significant benefits of reducing progression to severe COVID-19, hospitalization, and death. Cardiac adverse events such as bradycardia and syncope are not known with this medication. We report a case of a 71-year-old patient who developed symptomatic bradycardia, syncopal episodes, and sinus pause after taking Paxlovid. Discontinuing medication and intravenous atropine helped to reverse the bradycardia and symptoms promptly. She did not require a pacemaker. We would like to report this possible association between Paxlovid and bradycardia. Until further information or studies are available, it is advised to promptly discontinue Paxlovid after any evidence of bradycardia and closely monitor for at least 40 hours in a hospital setting. The reported half-life (t 1/2) of the medication is 6.05 ± 1.79 hours and using 8 hours as a reference for the upper limit of t 1/2, around 97 % of the medication should be cleared off in about 40 hours (five half-lives).

PMID:36655157 | PMC:PMC9842109 | DOI:10.7759/cureus.33831

Innov Pharm. 2022 Dec 12;13(2). doi: 10.24926/iip.v13i2.4541. eCollection 2022.

ABSTRACT

Drug-induced Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) are rare but life-threatening immune-mediated drug reactions known as Severe Cutaneous Adverse Reactions (SCARs). These severe drug reactions have been associated with many commonly prescribed medications, including sulfonamides, allopurinol, carbamazepine, and several antiepileptic drugs including lamotrigine.1 Although the risk of these adverse events is recognized by many medical providers, the risk may be overlooked when prescribing lamotrigine for mood disorders. Review of the literature and the experience of these cases suggest that the risk of lamotrigine-associated SCARs is increased when starting lamotrigine at high initial doses. Here we present and discuss two cases of SCARs attributed to high-dose lamotrigine prescribed for mood disorders. A third patient also presented with a SCAR related to high-dose lamotrigine prescribed for a mood disorder during this time but was lost to follow-up and was not reachable. All three patients presented to our hospital system from 2019-2020. Due to this clinical experience, we recommend that pharmacists and prescribers alike be alerted of the risk of severe cutaneous drug reactions when lamotrigine is prescribed, particularly at initial doses greater than 25 mg.

PMID:36654707 | PMC:PMC9836753 | DOI:10.24926/iip.v13i2.4541

J Dermatol. 2023 Jan 17. doi: 10.1111/1346-8138.16715. Online ahead of print.

ABSTRACT

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous drug adverse reaction characterized by various cutaneous and systemic manifestations. However, reports on the various patterns of alopecia after DRESS are lacking. Thus, we aimed to describe cases of alopecia after DRESS and review the literature. This multicentric retrospective study reviewed the records of 182 patients diagnosed with DRESS from 2009 to 2021; of these, 10 who had alopecia after DRESS were included. Patients were diagnosed with permanent alopecia (n = 4), telogen effluvium (n = 5), and alopecia areata (n = 1), and were treated with topical minoxidil or alfatradiol (6; 60%), topical corticosteroids (3; 30%), dietary supplements (6; 60%), systemic corticosteroids (1; 10%), and intralesional corticosteroid injection (2; 20%). Although patients with permanent alopecia did not show hair regrowth after 6 months, those with telogen effluvium and alopecia areata experienced marked clinical improvement within 6 months. Various types of alopecia can persist over an extended period, even after the resolution of an acute episode of DRESS.

PMID:36651019 | DOI:10.1111/1346-8138.16715

Sci Rep. 2023 Jan 17;13(1):934. doi: 10.1038/s41598-022-27238-z.

ABSTRACT

Although numerous studies have reported the association between sarcopenia and the prognosis of hepatocellular carcinoma (HCC) patients, there is lack of a newer and more comprehensive meta-analysis. Herein, a comprehensive literature search was performed on PubMed, Web of Science, the Cochrane Library, and Embase databases to identify relevant studies published up to February 2022. The outcomes were overall survival (OS), recurrence, progression-free survival, tumor response, severe postoperative complications, and toxicity of drugs. A total of 57 studies involving 9790 HCC patients were included in the meta-analysis. The pooled prevalence of sarcopenia in HCC patients was 41.7% (95% CI 36.2-47.2%). Results demonstrated that sarcopenia was significantly associated with impaired OS (HR: 1.93, 95% CI 1.73-2.17, P < 0.001), higher risk of tumor recurrence (HR: 1.75, 95% CI 1.56-1.96, P < 0.001), lower objective response rate (OR: 0.37 95% CI 0.17-0.81, P = 0.012), and more drug-related adverse events (OR: 2.23, 95% CI 1.17-4.28, P = 0.015) in HCC patients. The subgroup analyses revealed that the OS of patients at the early stage of tumor was more severely affected by sarcopenia than for patients at other stages. Moreover, the presence of cirrhosis and Child Pugh class B increased the hazard of mortality from sarcopenia. This study has shown that sarcopenia is highly associated with poor prognosis in HCC patients. In addition, cirrhosis and poor liver functional reserve increase the danger of sarcopenia. OS was more impaired in HCC patients with sarcopenia at early stage of tumor than at other tumor stages.

PMID:36650190 | DOI:10.1038/s41598-022-27238-z

J Oral Rehabil. 2023 Jan 17. doi: 10.1111/joor.13414. Online ahead of print.

ABSTRACT

BACKGROUND: The nocebo response refers to the phenomenon where nonspecific factors, including negative verbal suggestion and treatment expectations, cause adverse events (AE) following a placebo treatment. Nonspecific factors are also likely to influence AE occurrence following administration of active pharmacological treatments.

OBJECTIVE: This meta-analysis aimed to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery.

METHODS: A systematic search was performed in PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials. Eligible studies had to report the number of patients experiencing at least one drug-related AE (patients with AE ≥ 1) separately for the active and placebo arms. The proportion of patients with AE ≥ 1 and drug-related dropouts were pooled, and risk differences (RDs) between patients in the placebo- and active arm were calculated.

RESULTS: In 50 independent RCTs of 47 identified articles, the pooled rates of patients with AE ≥ 1 were 22.8% in the placebo arm and 20.6% in the active arm. The pooled rates of drug-related dropout were 0.24% in the placebo arm and 0.08% in the active arm. There were no significant RDs in patients with AE ≥ 1 and drug-related dropouts.

CONCLUSION: These results show that patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.

PMID:36648379 | DOI:10.1111/joor.13414

Eur J Anaesthesiol. 2023 Jan 18. doi: 10.1097/EJA.0000000000001799. Online ahead of print.

ABSTRACT

BACKGROUND: HSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABAA) receptor.

OBJECTIVE: To investigate the efficacy and safety of HSK3486 for general anaesthesia induction and maintenance.

DESIGN: A single-blinded, randomised, parallel-group, phase 3 trial.

SETTING: Involving 10 study centres, from November 24, 2020 to January 25, 2021.

PATIENTS: A total of 129 patients undergoing nonemergency, noncardiothoracic, and nonbrain elective surgery.

INTERVENTION: Patients were randomly assigned at a 2:1 ratio into HSK3486 or propofol groups, to receive HSK3486 (0.4 mg kg-1) or propofol (2.0 mg kg-1) for induction before a maintenance infusion at initial rates of 0.8 and 5.0 mg kg-1 h-1, and were adjusted to maintain a bispectral index (BIS) of 40-60 until the end of surgery.

MAIN OUTCOME MEASURES: Noninferiority between the drugs was evaluated as the lower limit of the 95% confidence interval (CI) for the between-group difference in the success rate of anesthetic maintenance (primary outcome) >-8%. Secondary outcomes included successful anaesthetic induction, full alertness and spontaneous breathing recovery, time until leaving the postanaesthesia care unit and changes in BIS. Safety profiles were also measured.

RESULTS: Of 129 enrolled patients, 128 completed the trial, with 86 in the HSK3486 group and 42 in the propofol group. The success rate for the maintenance of general anaesthesia was 100% for both groups, and noninferiority of HSK3486 was confirmed (95% CI -4.28% to 8.38%). No significant differences were found between the two groups of patients with regard to secondary outcomes (all P > 0.05). There appeared to be a comparable incidence of treatment for emergency adverse events (TEAEs) (80.2% vs. 81.0%, P = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P = 0.451) in the HSK3486 and propofol groups.

CONCLUSION: HSK3486 had a noninferior efficacy profile compared to propofol, exhibiting excellent tolerance.

TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT04511728.

PMID:36647565 | DOI:10.1097/EJA.0000000000001799

JMIR Public Health Surveill. 2023 Jan 16;9:e40080. doi: 10.2196/40080.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) are unintended consequences of medication use and may result in hospitalizations or deaths. Timely reporting of ADRs to regulators is essential for drug monitoring, research, and maintaining patient safety, but it has not been standardized in Australia.

OBJECTIVE: We sought to explore the ways that ADRs are monitored or reported in Australia. We reviewed how consumers and health care professionals participate in ADR monitoring and reporting.

METHODS: The Arksey and O'Malley framework provided a methodology to sort the data according to key themes and issues. Web of Science, Scopus, Embase, PubMed, CINAHL, and Computer & Applied Sciences Complete databases were used to extract articles published from 2010 to 2021. Two reviewers screened the papers for eligibility, extracted key data, and provided descriptive analysis of the data.

RESULTS: Seven articles met the inclusion criteria. The Adverse Medicine Events Line (telephone reporting service) was introduced in 2003 to support consumer reporting of ADRs; however, only 10.4% of consumers were aware of ADR reporting schemes. Consumers who experience side effects were more likely to report ADRs to their doctors or pharmacists than to the drug manufacturer. The documentation of ADR reports in hospital electronic health records showed that nurses and pharmacists were significantly less likely than doctors to omit the description of the drug reaction, and pharmacists were significantly more likely to enter the correct classification of the drug reaction than doctors. Review and analysis of all ADR reports submitted to the Therapeutic Goods Administration highlighted a decline in physician contribution from 28% of ADR reporting in 2003 to 4% in 2016; however, within this same time period, hospital and community pharmacists were a major source of ADR reporting (ie, 16%). In 2014, there was an increase in ADR reporting by community pharmacists following the introduction of the GuildLink ADR web-based reporting system; however, a year later, the reporting levels dropped. In 2018, the Therapeutic Goods Administration introduced a black triangle scheme on the packaging of newly approved medicines, to remind and encourage ADR reporting on new medicines, but this was only marginally successful at increasing the quantity of ADR reports.

CONCLUSIONS: Despite the existence of national and international guidelines for ADR reporting and management, there is substantial interinstitutional variability in the standards of ADR reporting among individual health care facilities. There is room for increased ADR reporting rates among consumers and health care professionals. A thorough assessment of the barriers and enablers to ADR reporting at the primary health care institutional levels is essential. Interventions to increase ADR reporting, for example, the black triangle scheme (alert or awareness) or GuildLink (digital health), have only had marginal effects and may benefit from further improvement revisions and awareness programs.

PMID:36645706 | DOI:10.2196/40080

Lakartidningen. 2023 Jan 12;120:22097.

NO ABSTRACT

PMID:36644956

F1000Res. 2022 Apr 19;11:434. doi: 10.12688/f1000research.110268.2. eCollection 2022.

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines efficacy and safety have been tested in phase 3 studies in which cancer patients were not included or were underrepresented. Methods: The objective of this study is to evaluate the safety profile of the mRNA-1273 vaccine across cancer patients and its relationship to patients' demographics. We selected from our records all 18-years or older solid cancer patients under active treatment vaccinated with the complete three-dose schedule mRNA-1273 vaccine whose adverse drug reactions (ADRs) after each dose were recorded. Medical records were reviewed retrospectively to collect data between April 19, 2021, and December 31, 2021. Patients with documented previous infection by SARS-Cov-2 were excluded. Results: A total of 93 patients met the inclusion criteria. Local ADRs were reported more frequently after the first and second dose than after the third (41.9%, 43% and 31.1% of the patients respectively), while systemic ADRs followed the opposite pattern (16.1%, 34.4% and 52.6% of the patients respectively). We found a statistically significant association between sex and systemic adverse reactions after the third dose, p < 0.001 and between systemic adverse reactions after the second dose and systemic adverse reactions after the third dose, p = 0.001 A significant linear trend, p = 0.012, with a higher Eastern Cooperative Oncology Group (ECOG) score associated with a lower proportion of patients suffering from systemic side effects was found. Women had 5.79 times higher odds to exhibit systemic ADRs after the third dose (p=0.01) compared to males. Increasing age was associated with a decreased likelihood of exhibiting ADRs (p=0.016). Conclusion: The mRNA-1273 vaccine shows a tolerable safety profile. The likelihood of ADRs appears to be associated with gender and age. Its association with ECOG scores is less evident. Further studies are needed to elucidate this data in cancer patients.

PMID:36636471 | PMC:PMC9816496 | DOI:10.12688/f1000research.110268.2

Naunyn Schmiedebergs Arch Pharmacol. 2023 Jan 16. doi: 10.1007/s00210-023-02382-z. Online ahead of print.

ABSTRACT

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

PMID:36645429 | DOI:10.1007/s00210-023-02382-z