Common Adverse Reactions Research Articles

Surveillance for adverse events following immunization in Hebei Province, China, 2018-2020

ABSTRACT The aim of this study was to analyze the incidence and characteristics of adverse events following immunization (AEFI) with post-licensure vaccines used in Hebei province from 2018 to 2020 and to evaluate the safety of vaccines. All information of AEFI was gained from national adverse event following immunization surveillance system (NAEFISS) in Hebei Province from 2018 to 2020. Descriptive epidemiology method was used to analyze the data about AEFI in Hebei province. Reporting rates of AEFI were calculated by sex, age, city, categories of AEFI, severity of AEFI, reaction categories, etc. A total of 35,999 AEFI were reported through NAEFISS, and the average annual rate was 47.64/100,000 doses. The reporting rates of common adverse reactions and rare adverse reactions were 46.37/100,000 doses and 1.05/100,000 doses. The male-to-female ratio was 1.26:1. Most of the AEFI were concentrated in the ≤1 year age group and were reported in the second quarter and third quarter. The majority of AEFI were reported to be recovered or improved, and about 62% of the AEFI occurred within 24 hours after vaccination. Vaccines associated with the highest reporting rate of AEFI were diphtheria, tetanus and acellular pertussis combined vaccine (DTaP, 170.45/100,000 doses). The reporting rate of allergic rash was found to be the highest in the adverse reactions (0.29/100,000 doses). The majority of AEFI cases were common adverse reactions, while serious rare adverse reactions caused by vaccines were extremely uncommon, and all vaccines used in Hebei Province were safe.

Modulation of p300 acetylation to protect against doxorubicin-induced cardiotoxicity

Abstract Background Doxorubicin (DOX) is a widely-used anti-neoplastic agent, but the most common adverse reaction to its use is cardiotoxicity(1). DOX acts by producing reactive oxygen species (ROSs) that cause DNA damage(1,2), which activates various proteins, including the tumour suppressor p53 and the acetyltransferase p300. When activated, p300 acetylates and increases the activity of p53 which leads to increased apoptotic activity(3). Cardiotoxicity results because the heart has limited mechanisms to dispose of ROSs(4), and because cardiomyocytes have a low turnover rate(5). Purpose We examined the p300 inhibitor Theracurmin (THR)(6,7) as a candidate to prevent DOX cardiotoxicity using an in-vivo mouse model, and sought to elucidate the underlying molecular mechanisms using in-vitro studies. Methods C57BL/6 mice were pre-treated with THR or vehicle (as control), then administered DOX or vehicle. Cardiac function was evaluated by echocardiography and cardiac catheterization. In vitro studies used cardiac fibroblasts (FBs) and cardiac endothelial cells (ECs) pre-treated with THR, then with DOX, as in the animal studies. Western blotting and rt-qPCR was used to quantify protein and mRNA levels of genes in the p53-p300 pathway or related to apoptosis, oxidative stress, and cell cycle control. Results DOX-treated mice showed significant decreases in left ventricular (LV) ejection fraction (LVEF, p=0.0004), fractional shortening (FS, p=0.0012), and a significant increase in end-systolic volume (ESV, p=0.0004). We also showed a significant decrease in anterior (LVAW;d, p=0.005) and posterior (LVPW;d, p=0.005) wall thickness of the LV in these mice. However, when mice were pre-treated with THR prior to DOX administration, we saw significant increases in LVEF (p=0.045) and LVPW;d (p=0.015), and a significant decrease in ESV (p=0.0047) compared to those that were not pre-treated. In-vitro analyses demonstrated a significant increase in cleaved caspase 3 protein expression in DOX-treated ECs (p=0.007), that was not prevented by THR pre-treatment. In DOX-treated FBs, we saw a reduction in AKT mRNA (p=0.017) and increases in BAX 9p=0.008), P21 (p=0.0001), and GADD45 (0.037) mRNA expression. In DOX-treated ECs, we also saw significant increases in BAX (p=0.015) and P21 (p=0.011) mRNA expression. These changes in mRNA expression were not reversed with THR pre-treatment in either cell type. Conclusion THR pre-treatment successfully mitigated functional deficits and structural deficits associated with DOX cardiotoxicity. In-vitro studies show that THR pre-treatment was not sufficient to significantly prevent changes in key molecular targets associated with apoptosis. Further studies are required to elucidate the mechanism behind the observed functional changes.Abstract OverviewAbstract Results

Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.

To investigate the short-term and long-term efficacy and safety of thalidomide in the treatment of intermediate and severe β-thalassemia. We analyzed patients with intermediate and severe β-thalassemia treated at our hospital from February 2019 to February 2024. Patients who received treatment for more than 3 months were included. The efficacy of thalidomide was assessed by comparing changes in hemoglobin (Hb), ferritin, bilirubin, and Hb electrophoresis before and after treatment. Adverse drug reactions during treatment were also recorded. A total of 42 β-thalassemia patients were included, with thalidomide dosages ranging from 75 to 150 mg/d. The response rates at 1, 3, and 6 months of treatment were 73.8% (31/42), 75.0% (24/32), and 94.7% (18/19), respectively. The increase in Hb levels was primarily attributed to fetal hemoglobin (HbF). After 1 month of treatment, the HbF percentage increased from a baseline of 34.04 ± 27.58% to 56.25 ± 28.40% (P < .001). At 3 and 6 months, HbF further increased to 67.21 ± 27.12% (P < .001) and 73.93 ± 22.96% (P < .001), respectively. The average duration of thalidomide treatment was 25.3 ± 9.2 months (range: 4-60 months), with 6 patients treated for over 60 months and 18 patients for over 48 months. Two homozygous patients who failed thalidomide treatment achieved Hb levels above 100 g/L and discontinued transfusion therapy after 3 months of hydroxyurea treatment. The most common adverse reaction was somnolence, which was mild and tolerable. Thalidomide demonstrates significant and sustained therapeutic effects in β-thalassemia patients. The adverse reactions are mild and tolerable, allowing patients to continue treatment.

Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice（2024 edition）

Neuroendocrine neoplasms are a group of heterogeneous tumors originating from the neuroendocrine system, which can occur in any part of the body. Pulmonary and gastroenteropancreatic neuroendocrine tumors are the most common. In recent years, the global incidence of neuroendocrine tumors has increased more significantly than other types of tumors, especially in the past 40 years. The drug treatment of neuroendocrine tumors includes somatostatin analogues, anti-angiogenesis targeting drugs, nuclide therapy and chemotherapy. Surufatinib is an oral tyrosine kinase receptor inhibitors that targets for vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R), has received approval in 2020 and 2021 for the treatment of locally advanced or metastatic, progressive nonfunctional, well-differentiated (G1, G2) neuroendocrine tumors (NETs) of both pancreatic and extrapancreatic origin that are unresectable. Ongoing exploratory studies are investigating its potential application in other tumor types. Common adverse reactions observed during surufatinib treatment include hypertension, proteinuria, bleeding events, and hepatic lab test abnormal and diarrhea. Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice (2024 edition) aims to provide standardized guidance for its rational use and enhance patient compliance to maximize therapeutic benefits.

Efficacy and safety of rituximab in the treatment of pediatric myasthenia gravis

Objective: To evaluate the efficacy and safety of rituximab in pediatric myasthenia gravis (MG). Methods: Case series study. The clinical manifestations, laboratory tests, treatment plans and prognosis of 27 pediatric MG patients treated with rituximab from June 2013 to June 2023 at Children's Medical Center of Peking University First Hospital were retrospectively collected. Results: There were 5 males and 22 females in 27 MG children. The onset age was 2.1 (1.6, 4.8) years, ranging from 8 months to 11 years. The clinical classification included 20 children (74%) of ocular MG and 7 children (26%) of generalized MG. Seventeen children (63%) had positive MG-related pathogenic antibodies, including 17 children of anti-AchR antibody and 1 of them also had anti-MuSK antibody. Rituximab was used as first-line immunosuppressant in 13 children, second-line immunosuppressant in 13 children and third-line immunosuppressant in 1 child. Immunosuppressants used before rituximab including 8 children of cyclosporine, 3 children of tacrolimus, 1 child of azathioprine, 1 child of mycophenolate mofetil and 1 child of cyclosporine combined with azathioprine. Rituximab was used for at least half a year with a follow-up period of more than 12 months. At the last follow-up after rituximab treatment, all children achieved improved or above, 14 children (52%) achieved complete stable remission, 7 children (26%) achieved pharmacologic remission, 1 child (4%) achieved minimal manifestations, and 5 children (18%) improved. After rituximab treatment, 27 children all could reduce the immunomodulation therapy and shorten the course of glucocorticoid therapy, and 22 children (81%) had stopped the glucocorticoid therapy. Among the 14 children with poor efficacy of other immunosuppressants, rituximab had complete stable remission of 7 children. The most common adverse reaction was respiratory infection (4 children (15%)). Only 2 children had allergic reaction to rituximab and got better after symptomatic treatment. Conclusions: Rituximab has good efficacy and tolerance in pediatric MG. Early application of rituximab can improve the prognosis and shorten the course of glucocorticoid treatment.

Chinese Expert Consensus on the Combination of Targeted Therapy and Immunotherapy with Locoregional Therapy for Intermediate/Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, it ranks as the second most common cause of cancer deaths in China. Most HCC patients are first diagnosed at an advanced stage. In recent years, targeted therapy combined with immunotherapy has become the preferred regimen for systemic treatment of intermediate-advanced HCC, while targeted therapy combined with immunotherapy plus local treatment could further improve the efficacy in many clinical studies. To better guide the clinical treatment for effective and safe combination therapy, our interdisciplinary panel on the treatment of intermediate-advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists, radiologists, interventional radiologists and traditional Chinese medicine physicians have formulated this consensus based on current clinical studies and clinical medication experience for reference. The consensus contained 15 recommendations, including the applicable population and management, local treatment selection, conversion strategy, treatment strategy after tumor progression and management of common adverse reactions.

AST-001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial.

This study examined the efficacy of AST-001 for the core symptoms of autism spectrum disorder (ASD) in children. This phase 2 clinical trial consisted of a 12-week placebo-controlled main study, a 12-week extension, and a 12-week follow-up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high-dose, low-dose, or placebo-to-high-dose control group during the main study. The placebo-to-high-dose control group received placebo during the main study and high-dose AST-001 during the extension. The a priori primary outcome was the mean change in the Adaptive Behavior Composite (ABC) score of the Korean Vineland Adaptive Behavior Scales II (K-VABS-II) from baseline to week 12. Among 151 enrolled participants, 144 completed the main study, 140 completed the extension, and 135 completed the follow-up. The mean K-VABS-II ABC score at the 12th week compared with baseline was significantly increased in the high-dose group (P = 0.042) compared with the placebo-to-high-dose control group. The mean CGI-S scores were significantly decreased at the 12th week in the high-dose (P = 0.046) and low-dose (P = 0.017) groups compared with the placebo-to-high-dose control group. During the extension, the K-VABS-II ABC and CGI-S scores of the placebo-to-high-dose control group changed rapidly after administration of high-dose AST-001 and caught up with those of the high-dose group at the 24th week. AST-001 was well tolerated with no safety concern. The most common adverse drug reaction was diarrhea. Our results provide preliminary evidence for the efficacy of AST-001 for the core symptoms of ASD.

Metabolic Side Effects from Antipsychotic Treatment with Clozapine Linked to Aryl Hydrocarbon Receptor (AhR) Activation.

Metabolic syndrome (MetS) is the most common adverse drug reaction from psychiatric pharmacotherapy. Neuroreceptor blockade by the antipsychotic drug clozapine induces MetS in about 30% of patients. Similar to insulin resistance, clozapine impedes Akt kinase activation, leading to intracellular glucose and glutathione depletion. Additional cystine shortage triggers tryptophan degradation to kynurenine, which is a well-known AhR ligand. Ligand-bound AhR downregulates the intracellular iron pool, thereby increasing the risk of mitochondrial dysfunction. Scavenging iron stabilizes the transcription factor HIF-1, which shifts the metabolism toward transient glycolysis. Furthermore, the AhR inhibits AMPK activation, leading to obesity and liver steatosis. Increasing glucose uptake by AMPK activation prevents dyslipidemia and liver damage and, therefore, reduces the risk of MetS. In line with the in vitro results, feeding experiments with rats revealed a disturbed glucose-/lipid-/iron-metabolism from clozapine treatment with hyperglycemia and hepatic iron deposits in female rats and steatosis and anemia in male animals. Decreased energy expenditure from clozapine treatment seems to be the cause of the fast weight gain in the first weeks of treatment. In patients, this weight gain due to neuroleptic treatment correlates with an improvement in psychotic syndromes and can even be used to anticipate the therapeutic effect of the treatment.

Ozanimod: A Review in Relapsing Forms of Multiple Sclerosis.

Ozanimod (Zeposia®), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P1 and S1P5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.

DNA methylation inhibitors adverse reaction characteristic analysis: a descriptive analysis from WHO-VigiAccess.

DNA methylation inhibitors (azacitidine, decitabine) have revolutionized the treatment dilemma of myelodysplastic syndromes (MDS), a group of malignant hematopoietic disorders. This study evaluates the adverse drug reactions (ADRs) following the use of DNA methylation inhibitors in the World Health Organization (WHO) VigiAccess database and compares the characteristics of ADRs between the two drugs to select the drug with the minimum individualized risk for patients. This study employed a retrospective descriptive analysis method. We compiled ADR reports for two marketed DNA methylation inhibitors for the treatment of MDS from WHO-VigiAccess. Data collected included demographic data such as age groups, gender, and regions of global patients covered by ADR reports, as well as data on the disease systems and symptoms caused by ADRs recorded in the annual reports and reports received by WHO. By calculating the proportion of ADRs reported for each drug, we compared the similarities and differences in ADRs between the two drugs. Overall, 23,763 adverse events (AEs) related to the two DNA methylation inhibitors were reported in VigiAccess. The results showed that the top 10 most common AEs were febrile neutropenia, bone marrow suppression, neutropenia, anemia, pancytopenia, leukopenia, thrombocytopenia, bone marrow failure, agranulocytosis, and hematotoxicity. The top five common types of DNA methylation inhibitor AEs were blood and lymphatic system disorders (11,178 cases, 47.0%), cardiac organ diseases (1,488 cases, 6.3%), various congenital familial genetic diseases (49 cases, 0.2%), ear and labyrinth diseases (100, 4.2%), and endocrine system diseases (57, 2.4%). There is no Strong correlation between DNA methylation inhibitors and ADRs. Current comparative observational studies of these inhibitors show that there are common and specific adverse reactions in the ADR reports received by WHO for these drugs. Clinicians should improve the rational use of these drugs based on the characteristics of ADRs.

Most Common Symptomatic Adverse Reactions of Cancer Treatments From US Drug Labels (2015-2021) to Inform Selection of Patient-Reported Outcomes

ObjectivesIncorporating patient-reported outcomes (PROs) to assess symptomatic adverse events (AEs) in cancer clinical trials (CTs) is important to characterize treatment tolerability. Cancer therapies approved over the past decade have expanded the types of expected toxicities. To inform future symptomatic AE PRO item selection, we identified the most common symptomatic adverse reactions from recently approved products. MethodsWe reviewed approvals from 2015 to 2021 for lung, breast, and hematologic cancer indications. Using United States Prescribing Information safety data, we recorded symptomatic adverse reactions reported in ≥20% of patients in the experimental arm of CTs supporting approvals. We calculated the proportion of arms reporting each symptomatic adverse reaction. ResultsIn total, 130 experimental arms were included (lung = 30, breast = 10, hematologic = 90). For all cancer types, fatigue and diarrhea were reported in >50% of the arms. Nausea was reported in ≥50% of the arms for all except lung. Vomiting, decreased appetite, and alopecia, were reported in ≥50% of breast cancer arms. Rash, musculoskeletal pain, and cough were reported in >50% of leukemia/lymphoma arms. Cough was common (50%) in multiple myeloma arms. ConclusionsHeterogeneity in symptomatic adverse reactions across CTs supports the use of item libraries when building a PRO strategy to assess tolerability. Fatigue, diarrhea, and nausea were the most frequent symptomatic adverse reactions reported in contemporary cancer CTs and could provide a starting point when selecting PRO symptomatic AE items. Additional symptomatic AE PRO items should be selected based on the mechanism of action, early clinical data, published literature, and patient and clinician input.

The Effectiveness and Safety of Remdesivir Use in COVID-19 Patients with Neutropenia: A Retrospective Cohort Study

Background: The COVID-19 pandemic poses severe risks for immunocompromised patients, especially those with neutropenia due to chemotherapy. This study evaluates the safety and effectiveness of remdesivir use in COVID-19 patients with neutropenia. Methods: This retrospective study used the Chang Gung Research Database (CGRD) and extracted data from 98,763 patients with COVID-19 diagnosed between April 2021 and September 2022. The patients were divided into groups based on their remdesivir use and the presence of neutropenia. The adverse effects of remdesivir and their outcomes were analyzed after propensity score matching. Results: We compared common adverse effects of remdesivir in neutropenic patients before and after a 5-day regimen. A slight decrease in heart rate was observed but lacked clinical significance. There were no significant differences observed in hemoglobin, liver function tests, and blood glucose levels. After propensity score matching of COVID-19 patients with neutropenia according to gender, age, dexamethasone use, oxygen use, MASCC score, and WHO ordinal scale, no significant differences were found in length of stay, intubation rate, or ICU admission rate between the matched patients. Conclusions: Our study found remdesivir to be safe for COVID-19 patients with neutropenia, with no common adverse reactions observed. However, its effectiveness for these patients remains uncertain.

Augmentation with prazosin for patients with depression and a history of trauma: A randomised, double-blind, placebo-controlled study.

Depression with a history of trauma often responds poorly to conventional antidepressants and has a poor prognosis. Prazosin, an α1-adrenoceptor blocker, has shown promise in treating post-traumatic stress disorder symptoms, particularly nightmares. Its potential in treating depression with trauma history warrants investigation. This randomised, double-blind, placebo-controlled study aimed to investigate the efficacy and tolerability of low-dose prazosin (0.5-1 mg/day) as an augmentation strategy in patients with depression and a history of trauma. We sought to determine if prazosin could provide rapid symptom improvement and enhance overall treatment response compared to placebo in this difficult-to-treat patient population. This randomised, double-blind, placebo-controlled clinical study included 59 patients with first-episode or recurrent unipolar or bipolar depression. After basic antidepressant treatment, they were randomly assigned to a prazosin (0.5-1 mg/day) or placebo group for a 6-week double-blind controlled study. The Montgomery-Åsberg Depression Rating Scale, 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) were used to evaluate efficacy. There were no significant differences in the results of the demographic and clinical symptom assessment between the two groups (p > 0.05). The difference between the HAMD-17 and HAMA scores was statistically significant after 3 days of treatment (p < 0.05). The difference in response rate between the two groups was statistically significant after week 4 of treatment (end of week 4, 56.7% vs. 24.1%, p = 0.011; end of week 6, 80.0% vs. 48.3%, p = 0.011). The incidence of adverse reactions in the prazosin and placebo groups was 20.0% and 24.1%, respectively, with no statistically significant differences (p > 0.05); however, the prazosin group had a lower incidence of sleeplessness or nightmares (3.3% vs. 20.7%, p = 0.039) but a higher incidence of orthostatic hypotension (16.7% vs. 0%, p = 0.007). The severity of orthostatic hypotension was mild to moderate. Low-dose prazosin can effectively improve the emotional symptoms of patients with depression and a history of trauma, and the common adverse reaction is mild-to-moderate orthostatic hypotension. ChiCTR2200063642.

Oral Mucositis in Adult Cancer Patients Undergoing Chemotherapy: Six-Month On-Treatment Follow-Up.

Objectives. Oral mucositis (OM) is a common adverse reaction associated with chemotherapy. We conducted a six-month longitudinal study to estimate the cumulative incidence of OM during the first six months of chemotherapy in adult patients with cancer other than head and neck cancer. Secondary objectives were as follows: (a) to scrutinize the oral health status of these patients and its evolution during chemotherapy, as assessed by oral health indices; (b) to estimate adherence to prescribed oral hygiene protocol during chemotherapy; and (c) to analyze ulceration-free survival in these patients. Methods. Sixty-four patients participated. Dental health and oral hygiene were assessed at baseline and at the end. Every month, blood tests were performed and oral lesions were recorded. This study was observational, with the only intervention being instruction in the hygiene protocol. The cumulative incidence of OM was estimated with the patient as the unit of analysis. A repeated measures ANOVA was applied to analyze the monthly blood test results. Ulceration-free survival analysis was conducted with adherence to the oral hygiene protocol as a grouping factor, followed by Cox proportional-hazards regression. Results. The six-month cumulative incidence rate was 43.75%, 95%CI (31.58-56.67%) for OM grade 2 or higher. The hazard ratio of ulceration associated with adherence to the hygiene protocol was 0.154, 95%CI (0.049-0.483), adjusted for age, sex, baseline hygiene index, and class of treatment. Conclusions. Compliance with hygiene recommendations would decrease the OM risk by more than six times, compared to non-compliance.

Platelet-Rich Plasma Injection Combined With Q-Switched Ruby Laser in the Treatment of Periorbital Hyperpigmentation.

Periorbital hyperpigmentation is a prevalent skin condition that represents a large quantity of cases seen in cosmetic dermatology. Patients tend to be left with pigmentation after Q-switched ruby laser treatment, especially the perioribital area. The study is conducted to compare the effect of PRP injection combined with laser therapy versus laser alone for periorbital hyperpigmentation treatment. In this single-center, case-control study, 30 patients with periorbital hyperpigmentation were allocated to receive PRP injection injection after Q-switched ruby laser or Q-switched ruby laser only, followed by a 12-week and 24-week follow-up visit. Visual analogue scale, Sadick tear trough rating scale, and patients' self-evaluation were used to evaluate the therapeutic effect. The combined group achieved a better improvement in long-term effect and had effect on facial rejuvenation. Patient satisfaction was higher in the combined group. Erythema and mild pain were the most common adverse reactions of both groups. Combining with PRP injection can improve the therapeutic effect of Q-switched ruby laser in treating periorbital hyperpigmentation and lessen the risk of post-inflammatory hyperpigmentation, indicating a new option for POH treatment.

The effect of gene polymorphism on ticagrelor metabolism: an in vitro study of 22 CYP3A4 variants in Chinese Han population.

Ticagrelor is a novel oral antiplatelet agent which can selectively inhibit P2Y12 receptor. Bleeding and dyspnea are common adverse reactions of ticagrelor in clinic. The side effects of ticagrelor are correlated with the plasma concentration of ticagrelor. This study aimed to evaluate the catalytic characteristics of 22 CYP3A4 alleles identified in the Chinese Han population on the metabolism of ticagrelor in vitro, focusing on the effect of CYP3A4 polymorphism on ticagrelor metabolism. In this study, insect cells were used to express 22 CYP3A4 variants, which were then incubated with 1-50 µM ticagrelor at 37 °C for 30 minutes to obtain the metabolite (AR-C124910XX). AR-C124910XX was detected by UHPLC-MS/MS to calculate the kinetic parameters, including Km, Vmax and CLint. Compared to the wild-type, most CYP3A4 alleles exhibited significant differences in intrinsic clearance. The intrinsic clearance of CYP3A4*11, *18 and *33 was much higher than that of wild-type; four variants exhibited similar intrinsic clearance values as the wild-type enzyme; The remaining 14 variants showed significantly reduced intrinsic clearance values, ranging from 1.48% to 75.11% of the wild-type; CYP3A4*30 displayed weak or no activity. This study conducted a comprehensive assessment of the effect of CYP3A4 variants on ticagrelor's metabolism. The results suggested that there is allele-specific activity towards ticagrelor in vitro. These findings can provide some insights and predictions for treatment strategies and risk assessments associated with ticagrelor in clinical practice.

Rethinking about Metformin: Promising Potentials.

Metformin is widely used drugs in the treatment of type 2 diabetes mellitus. However, the mechanisms of action are complex and are still not fully understood yet. Metformin has a dose-dependent blood sugar-lowering effect. The most common adverse reactions of metformin are gastrointestinal symptoms, and women tend to be more experienced than men. A positive correlation between the administration of duration and the daily dose of metformin and the risk of vitamin B12 deficiency is confirmed. Novel glucose-lowering mechanism through the activation of AMP-activated protein kinase and alteration of gut microbiota composition is identified. In addition, metformin has immunomodulatory properties in various mechanisms, including anti-inflammatory actions, and so forth. Metformin improves insulin sensitivity, which may reduce the risk of tumor growth in certain cancers. The antiviral effects of metformin may occur through several mechanisms, including blocking angiotensin converting enzyme 2 receptor, and so forth. These potential mechanisms of metformin are promising in various clinical settings, such as inflammatory diseases, autoimmune diseases, cancer, and coronavirus disease 2019.

Simultaneous Confidence Intervals for Signal Detection and Ascertaining Precision of Adverse Event Rates in Clinical Trials

The marketing authorization of a medicinal product is contingent upon demonstration of safety and efficacy in support of the product’s labeled conditions of use. To demonstrate safety, one group of adverse events that requires detailed consideration is common adverse reactions (ARs). ARs and their frequency are reported in prescription drug labeling in the US and EU. The determination of these adverse reactions generally takes a simple approach—usually, inclusion is through the frequency of reporting and whether the adverse event (AE) rate for the drug exceeds the placebo rate. This standard method does not account for confounders or multiplicity. To overcome these limitations, we propose a Monte Carlo approach to detect drug safety signals in clinical trials. We fit regression models incorporating covariates to assess the drug effect on the rate of AEs. Adjustment for multiplicity is carried out through the construction of simultaneous confidence intervals accounting for arbitrary correlations. A computationally efficient multiplier bootstrap approach using the Rademacher sequences is developed to generate random samples from the joint distribution of the estimators for all the AE rates. Compared to Bonferroni-based methods, the proposed method leads to narrower simultaneous confidence intervals and is more powerful in detecting potential safety signals.

Clinical guidance for cannabidiol-associated hepatotoxicity: A narrative review.

There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug-induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non-medical use necessitates clear direction in the diagnosis and management of CBD-associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD-related hepatotoxicity.

Mechanisms Underlying the Protective Effects of Obeticholic Acid-Activated FXR in Valproic Acid-Induced Hepatotoxicity via Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulations.

Valproic acid (VPA)-induced hepatotoxicity is among the most common and severe adverse drug reactions, limiting its clinical application. Recent studies have suggested that activating the farnesoid X receptor (FXR) could be a promising therapeutic approach to alleviate VPA-induced hepatotoxicity; however, related research remains limited. This study aims to comprehensively investigate the mechanisms underlying FXR activation by obeticholic acid (OCA) for the treatment of VPA-induced hepatotoxicity. Network pharmacology was performed to identify potential targets and pathways underlying the amelioration of VPA-induced hepatotoxicity by OCA. The identified pathways were validated through GEO data analysis, and the affinities between OCA and potential key targets were predicted using molecular docking as well as molecular dynamics simulations. A total of 462 targets associated with VPA-induced hepatotoxicity and 288 targets of OCA were identified, with 81 shared targets. KEGG pathway and GO enrichment analysis indicated that the effect of OCA on VPA-induced hepatotoxicity primarily involved lipid metabolism, as well as oxidative stress and inflammation. The results from GEO data analysis, molecular docking, and molecular dynamics simulations revealed a close association between bile secretion, the PPAR signaling pathway, and the treatment of VPA-induced hepatotoxicity by OCA. Our findings suggest that OCA exhibits potential therapeutic efficacy against VPAinduced hepatotoxicity through multiple targets and pathways, thereby highlighting the therapeutic potential of FXR as a target for treating VPA-induced hepatotoxicity.