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Infection and Drug Resistance 2024Previous studies have indicated that the development of severe adverse events is associated with linezolid peak concentration (C), but the factors affecting linezolid C...
PURPOSE
Previous studies have indicated that the development of severe adverse events is associated with linezolid peak concentration (C), but the factors affecting linezolid C and evidences on therapeutic drug monitoring to anticipate toxicity in drug-resistant tuberculosis (DR-TB) patients have not been clarified clearly. This study aimed to explore the factors influencing linezolid C and investigate the association between linezolid concentration and hematological toxicity.
PATIENTS AND METHODS
This study included patients with drug-resistant tuberculosis treated with linezolid from January 2022 to September 2023. We analyzed the factors affecting linezolid C using chi-squared and binary logistic regression. The diagnostic utility of linezolid C in predicting hematological toxicity was evaluated using receiver operating characteristic (ROC) analysis.
RESULTS
A total of 76 patients were enrolled in the study. 63.20% met the standard rates for linezolid C. Age (P=0.036), weight (P=0.0016), and creatinine clearance (P=0.0223) significantly correlated with the C. Hematological toxicity was observed in 46.05% (35/76) of patients, characterized by thrombocytopenia (31.58%, 24/76), anemia (6.58%, 5/76), and leukopenia (21.05%, 16/76). ROC curve analysis confirmed the predictive value of linezolid C for thrombocytopenia with an area under curve of 0.728.
CONCLUSION
Suboptimal linezolid C was prevalent among patients with DR-TB, with age, weight, and renal function emerging as influential factors. Elevated linezolid C increases the risk of thrombocytopenia. Meticulous monitoring of linezolid C is imperative during anti-DR-TB therapy to tailor treatment and mitigate hematological toxicity.
PubMed: 38933777
DOI: 10.2147/IDR.S464429 -
Frontiers in Pharmacology 2024The association between the administration of sodium-glucose cotransporter 2 inhibitors (SGLT2is) during acute kidney injury (AKI) and the incidence of major adverse...
BACKGROUND
The association between the administration of sodium-glucose cotransporter 2 inhibitors (SGLT2is) during acute kidney injury (AKI) and the incidence of major adverse kidney events (MAKEs) is not known.
METHODS
This retrospective cohort study included patients with AKI and compared the outcomes for those who were treated with SGLT2is during hospitalization and those without SGLT2i treatment. The associations of SGLT2i use with MAKEs at 10 and 30-90 days, each individual MAKE component, and the pre-specified patient subgroups were analyzed.
RESULTS
From 2021 to 2023, 374 patients were included in the study-316 without SGLT2i use and 58 with SGLT2i use. Patients who were treated with SGLT2is were older; had a greater prevalence of diabetes, hypertension, chronic heart failure, and chronic kidney disease; required hemodialysis less often; and presented stage 3 AKI less frequently than those who were not treated with SGLT2is. Logistic regression analysis with nearest-neighbor matching revealed that SGLT2i use was not associated with the risk of MAKE10 (OR 1.08 [0.45-2.56]) or with MAKE30-90 (OR 0.76 [0.42-1.36]). For death, the stepwise approach demonstrated that SGLT2i use was associated with a reduced risk (OR 0.08; 0.01-0.64), and no effect was found for kidney replacement therapy (KRT). The subgroups of patients who experienced a reduction in the risk of MAKEs in patients with AKI treated with SGLT2is were those older than 61 years, those with an eGFR >81, and those without a history of hypertension or DM ( ≤ 0.05 for all).
CONCLUSION
The use of SGLT2is during AKI had no effect on short- or medium-term MAKEs, but some subgroups of patients may have experienced benefits from SGLT2i treatment.
PubMed: 38933678
DOI: 10.3389/fphar.2024.1356991 -
Frontiers in Pharmacology 2024Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and...
Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C) and the area under the concentration-time curve (AUC) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. http://www.chinadrugtrials.org.cn, identifier CTR20210064.
PubMed: 38933676
DOI: 10.3389/fphar.2024.1359939 -
Frontiers in Pharmacology 2024Functional dyspepsia is a highly prevalent digestive disorder. The limited effectiveness of current pharmaceutical interventions necessitates the exploration of...
BACKGROUND
Functional dyspepsia is a highly prevalent digestive disorder. The limited effectiveness of current pharmaceutical interventions necessitates the exploration of alternative therapeutic options for functional dyspepsia. Xiangsha liujunzi decoction, a well-known traditional Chinese medicine formulation, has been widely employed in the treatment of functional dyspepsia in China. Nevertheless, the effectiveness of Xiangsha liujunzi decoction in the treatment of functional dyspepsia remains uncertain.
OBJECTIVE
To examine the effectiveness and safety of Xiangsha liujunzi decoction for treating functional dyspepsia.
METHODS
We retrieved seven databases containing randomized controlled trials on functional dyspepsia published up until 31 July 2023. The quality of these studies was evaluated using the Cochrane Risk of Bias assessment tool. The analysis of data was performed using the software RevMan 5.4. The total clinical effectiveness rate was evaluated as the primary outcome. In addition, gastric emptying rate, symptom score and safety evaluation were evaluated as the secondary outcomes.
RESULTS
The meta-analysis included 23 studies, involving 2,101 individuals. Xiangsha liujunzi decoction demonstrated a significantly higher clinical effectiveness rate compared to the control group (RR 1.27; 95% CI 1.21, 1.33; < 0.00001). Moreover, it exhibited superior gastric emptying rate and symptom score improvement compared to the control group. Nevertheless, no remarkable differences were detected in safety between Xiangsha liujunzi decoction and the control group (RR 0.67; 95% CI 0.16, 2.76; = 0.58).
CONCLUSION
The findings of this study suggest that Xiangsha liujunzi decoction exhibits effectiveness and no significant adverse events observed. However, because of the low quality of the enrolled studies, more high-quality and strict design randomized controlled trials are required in the future.
PubMed: 38933675
DOI: 10.3389/fphar.2024.1356899 -
Frontiers in Pharmacology 2024Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent and critical side effects due to chemotherapeutics. In China, Xiao-Ban-Xia-Tang (XBXT) has...
BACKGROUND
Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent and critical side effects due to chemotherapeutics. In China, Xiao-Ban-Xia-Tang (XBXT) has already been applied extensively to prevent and treat CINV. However, there is limited testimony on the effectiveness and safety of this purpose, and there was no correlative systematic review. The aim of this review was to systematically evaluate the effectiveness and safety of XBXT in preventing and treating CINV.
METHODS
The systematic search was conducted in eight databases to acquire randomized controlled trials (RCTs) that appraised the effect of XBXT in treating CINV. The vomiting and nausea relief efficiency, eating efficiency, quality of life, and adverse reactions were explored for efficacy assessment. Bias risk was rated by manipulating the Cochrane risk of bias tool 2.0 (RoB 2). The retrieved investigations were analyzed by utilizing ReviewManager 5.4 and Stata 17.0. The quality of evidence was evaluated adopting the GRADE tool.
RESULTS
A total of 16 clinical RCTs of XBXT in the treatment of CINV were incorporated into the investigation, with a total of 1246 participants. The meta-analysis showed that compared with conventional antiemetic drugs, XBXT and antiemetics improved the vomiting relief efficiency (RR 1.35, 95% confidence interval: 1.25-1.46, < 0.00001), nausea relief efficiency (N = 367, RR 1.23, 95% CI: 1.09-1.38, < 0.00001), and quality of life (RR = 1.37, 95% CI: 1.14-1.65, = 0.0009) and reduced the adverse events (N = 370, RR 0.53, 95% CI: 0.29-0.96, = 0.04). XBXT and DARAs raised eating efficiency compared with DARAs (N = 208, RR 1.30, 95% CI: 1.07-1.57, = 0.007). The data existed as statistically significant, and the publication bias was identified as relatively low from the funnel plot and trim and fill analysis. In addition, sensitivity analysis demonstrated robust outcomes. The quality of evidence for each outcome ranged from moderate to high.
CONCLUSION
There is some encouraging evidence that XBXT and antiemetics had better therapeutic effects and safety in treating CINV than antiemetic drugs alone. The quality assessment and low publication bias indicated that the overall criterion was scientific. Better research is required to verify the evidence designed with large-scale RCTs and rigorous methods.
UNLABELLED
https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=281046.
PubMed: 38933673
DOI: 10.3389/fphar.2024.1393597 -
Frontiers in Pharmacology 2024We conducted an overview to assess immune adverse effects associated with the COVID-19 vaccine, guiding safer choices and providing evidence-based information to...
BACKGROUND
We conducted an overview to assess immune adverse effects associated with the COVID-19 vaccine, guiding safer choices and providing evidence-based information to clinicians.
METHODS
Forty-three studies on adverse effects of vaccines were reviewed from PubMed, Embase, and Web of Science. Single-arm meta-analyses estimated summary effects, incidence, presentation, etc. An overview using single-arm meta-analysis and reported the findings following the guidelines outlined in the 'Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) specifically focusing on myocarditis and thrombosis. After screening 2,591 articles, 42 studies met the inclusion criteria. Methodological quality was evaluated using AMSTAR 2. Disagreements were resolved via consensus. Data analysis utilized a random-effects model in R software to estimate incidence rates of selected adverse events.
RESULTS
After removing 1,198 duplicates and screening out irrelevant articles from a total of 2,591, we included 42 studies. Adverse reactions to vaccinations include myocarditis, thrombosis, skin reactions, GBS, etc. thrombosis and myocarditis are the most dangerous diseases associated with vaccination. Myocarditis occurred in 6% of Vector vaccine recipients, compared to 61% of mRNA vaccine recipients. Thrombosis was more common after Vector vaccination (91%) than after mRNA vaccination (9%). Furthermore, eight studies conducted anti-PF4 antibody tests and yielded a positivity rate of 67%. Meta-analysis showed that among all patients with Vaccine-induced Thrombotic Thrombocytopenia, cerebral venous sinus thrombosis occurred in 66%, and intracranial hemorrhage occurred in 43%. The rates of deep vein thrombosis and pulmonary thromboembolism in vaccinated patients were 13% and 23%, respectively, with a pooled case fatality rate of 30%.
CONCLUSION
The results of this overview indicate the majority of adverse reactions are self-limiting and require minimal intervention, while rare occurrences such as myocarditis and thrombosis pose a potentially fatal threat.
PubMed: 38933672
DOI: 10.3389/fphar.2024.1308768 -
Frontiers in Pharmacology 2024Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody-drug...
Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody-drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases. A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses. Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%). The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC. https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232.
PubMed: 38933670
DOI: 10.3389/fphar.2024.1377924 -
Frontiers in Pharmacology 2024Antibiotic resistance has emerged as a global concern. Xiyanping injection (XYP), a traditional Chinese medicine injection, has been extensively utilized for the...
Potential efficacy and safety of Xiyanping injection as adjuvant therapy in treatment of suppurative acute tonsillitis: a meta-analysis, trial sequential analysis, and certainty of evidence.
Antibiotic resistance has emerged as a global concern. Xiyanping injection (XYP), a traditional Chinese medicine injection, has been extensively utilized for the treatment of suppurative acute tonsillitis (SAT) in China, exhibiting clinical efficacy. Consequently, there is a need for further evaluation of the potential effectiveness and safety of this treatment. This meta-analysis consolidated data from multiple independent studies to assess the overall treatment efficacy of XYP as adjuvant therapy in patients with SAT. The search for randomized controlled trials (RCTs) encompassed databases from their inception to 1 April 2024, including the Cochrane Library, PubMed, Embase, SinoMed, CNKI, Wanfang, VIP, and CBM. Data extraction, methodological quality assessment, and meta-analysis were performed independently by two researchers. Review Manager 5.4 was used for data analysis. Various tools were employed for assessment, including forest plots to visualize results, funnel plots to detect publication bias, trial sequential analysis to estimate sample size, and GRADE to evaluate evidence quality. A comprehensive analysis of 32 RCTs involving 4,265 cases was conducted. When compared to conventional treatments (CTs; β-lactams/clindamycin hydrochloride injection/ribavirin) alone, the combination of XYP with CTs demonstrated significant reductions in symptom duration. This included sore throat (MD = -21.08, 95% CI: -24.86 to -17.29, < 0.00001), disappearance of tonsillar redness and swelling (mean difference [MD] = -20.28, 95% confidence interval [CI]: -30.05 to -10.52, < 0.0001), tonsil purulent discharge (MD = -22.40, 95% CI: -28.04 to -16.75, < 0.00001), and normalization of temperature (MD = -19.48, 95% CI: -22.49 to -16.47, < 0.00001). Furthermore, patients receiving CTs combined with XYP exhibited lower levels of interleukin-6 (MD = -7.64, 95% CI: 8.41 to -6.87, < 0.00001) and interleukin-8 (MD = -5.23, 95% CI: -5.60 to -4.86, < 0.00001) than those receiving CTs alone. Additionally, the combination therapy significantly improved the recovery rate (relative risk [RR] = 1.55, 95% CI: 1.37 to 1.77, < 0.00001), white blood cell count recovery rate (RR = 1.13, 95% CI: 1.04 to 1.23, = 0.004), and disappearance rate of tonsillar redness and swelling (RR = 0.51, 95% CI: 1.14 to 1.38, < 0.00001), with no significant increase in adverse events (RR = 0.47, 95% CI: 0.20 to 1.10, = 0.08). The current systematic review and meta-analysis tentatively suggest that the combination of XYP and CTs yields superior clinical outcomes for patients with SAT compared to CTs alone, with a favorable safety profile. Nonetheless, these findings warrant further confirmation through more rigorous RCTs, given the notable heterogeneity and publication bias observed in the included studies. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=296118, identifier CRD42022296118.
PubMed: 38933666
DOI: 10.3389/fphar.2024.1327856 -
Trauma Surgery & Acute Care Open 2024The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials...
BACKGROUND
The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness.
METHODS
We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes.
RESULTS
We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention.
CONCLUSIONS
AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials.
TRIAL REGISTRATION NUMBERS
NCT01818427, NCT02086500 and NCT03477006.
LEVEL OF EVIDENCE
II.
PubMed: 38933603
DOI: 10.1136/tsaco-2024-001465 -
Frontiers in Oncology 2024Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human...
INTRODUCTION
Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR).
PATIENTS AND METHODS
Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model.
RESULTS
Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925).
CONCLUSION
In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.
PubMed: 38933451
DOI: 10.3389/fonc.2024.1377842