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This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs), combining the cytotoxicity of the drug payload with the specificity of monoclonal antibodies, are one of the rapidly evolving classes of anti-cancer agents. These agents have been successfully incorporated into the treatment paradigm of many malignancies, including non-small cell lung cancer (NSCLC). The NSCLC is the most prevalent subtype of lung cancer, having a considerable burden on the cancer-related mortality and morbidity rates globally. Several ADC molecules are currently approved by the Food and Drug Administration (FDA) to be used in patients with NSCLC. However, the successful management of NSCLC patients using these agents was met with several challenges, including the development of resistance and toxicities. These shortcomings resulted in the exploration of novel therapeutic targets that can be targeted by the ADCs. This review aims to explore the recently identified ADC targets along with their oncologic mechanisms. The ADC molecules targeting these biomarkers are further discussed along with the evidence from clinical trials. [ABSTRACT FROM AUTHOR]

Background: Rising resistance to antimicrobials, particularly in the case of methicillin-resistant Staphylococcus aureus (MRSA), represents a formidable global health challenge. Consequently, it is imperative to develop new antimicrobial solutions. This study evaluated 68 Chinese medicinal plants renowned for their historical applications in treating infectious diseases. Methods: The antimicrobial efficacy of medicinal plants were evaluated by determining their minimum inhibitory concentration (MIC) against MRSA. Safety profiles were assessed on human colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (HepG2) cells. Mechanistic insights were obtained through fluorescence and transmission electron microscopy (FM and TEM). Synergistic effects with vancomycin were investigated using the Fractional Inhibitory Concentration Index (FICI). Results: Rheum palmatum L., Arctium lappa L. and Paeonia suffructicosaas Andr. have emerged as potential candidates with potent anti-MRSA properties, with an impressive low MIC of 7.8 µg/mL, comparable to the 2 µg/mL MIC of vancomycin served as the antibiotic control. Crucially, these candidates demonstrated significant safety profiles when evaluated on Caco-2 and HepG2 cells. Even at 16 times the MIC, the cell viability ranged from 83.3% to 95.7%, highlighting their potential safety. FM and TEM revealed a diverse array of actions against MRSA, such as disrupting the cell wall and membrane, interference with nucleoids, and inducing morphological alterations resembling pseudo-multicellular structures in MRSA. Additionally, the synergy between vancomycin and these three plant extracts was evident against MRSA (FICI < 0.5). Notably, aqueous extract of R. palmatum at 1/4 MIC significantly reduced the vancomycin MIC from 2 µg/mL to 0.03 µg/mL, making a remarkable 67-fold decrease. Conclusions: This study unveil new insights into the mechanistic actions and pleiotropic antibacterial effectiveness of these medicinal plants against resistant bacteria, providing robust evidence for their potential use as standalone or in conjunction with antibiotics, to effectively combat antimicrobial resistance, particularly against MRSA. [ABSTRACT FROM AUTHOR]

Background: Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. β-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of β-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. Methods: The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of β-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of β-elemene regulating M1/M2-like polarization in vitro. Results: In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, β-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. β-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, β-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. Conclusions: These results indicated that β-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that β-elemene might serve as a promising drug for alleviating ischemic stroke injury. [ABSTRACT FROM AUTHOR]

Drug-drug interaction (DDI) is the combined effects of multiple drugs taken together, which can either enhance or reduce each other's efficacy. Thus, drug interaction analysis plays an important role in improving treatment effectiveness and patient safety. It has become a new challenge to use computational methods to accelerate drug interaction time and reduce its cost-effectiveness. The existing methods often do not fully explore the relationship between the structural information and the functional information of drug molecules, resulting in low prediction accuracy for drug interactions, poor generalization, and other issues. In this paper, we propose a novel method, which is a deep graph contrastive learning model for drug-drug interaction prediction (DeepGCL for brevity). DeepGCL incorporates a contrastive learning component to enhance the consistency of information between different views (molecular structure and interaction network), which means that the DeepGCL model predicts drug interactions by integrating molecular structure features and interaction network topology features. Experimental results show that DeepGCL achieves better performance than other methods in all datasets. Moreover, we conducted many experiments to analyze the necessity of each component of the model and the robustness of the model, which also showed promising results. The source code of DeepGCL is freely available at https://github.com/jzysj/DeepGCL. [ABSTRACT FROM AUTHOR]

AbstractObjectives: To achieve the AUC-guided dosing, we proposed three methods to estimate polymyxin B AUC across 24 h at steady state (AUCSS,24h) using limited concentrations after its first dose.Method: Monte Carlo simulation based on a well-established population PK model was performed to generate the PK profiles of 1000 patients with normal or abnormal renal function. Polymyxin B AUCSS,24h was estimated for each subject using three methods (two-point PK approach, three-point PK approach, and four-point PK approach) based on limited concentration data in its first dose and compared with the actual AUC at steady state calculated using the linear-trapezoidal formula. Sensitivity analysis was performed to examine the influence of each sampling time drifting on the estimated AUCSS,24h.Results: In patients with normal renal function, the mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -8.73%, 1.37%, and -0.48%, respectively. The corresponding value was -11.15%, 1.99%, and -0.28% in patients with renal impairment, respectively. The largest mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -12.63%, -6.47%, and -0.54% when the sampling time shifted. Three user-friendly and easy-to-use excel calculators were built based on these methods.Conclusions: Two-point PK approach may be sufficient to guide polymyxin B dosing in patients with normal renal function. For patients with renal insufficiency, three-point PK approach or four-point PK may be a better choice. The Excel calculators designed based on the three methods can be potentially used to optimize the dosing regimen of polymyxin B in the clinic. [ABSTRACT FROM AUTHOR]

Background The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. Methods We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. Results Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. Conclusions Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation. [ABSTRACT FROM AUTHOR]

Background Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. Methods The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. Results With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI],.22–.71]; P =.002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI,.68–.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI,.60–.99; P =.04). Conclusions The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials. [ABSTRACT FROM AUTHOR]

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On 25 September 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia.The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121.In rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed.BI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121.ClinicalTrials.gov number (NCT04672954). [ABSTRACT FROM AUTHOR]

We consider a dose-optimization design for a first-in-human oncology trial that aims to identify a suitable dose for late-phase drug development. The proposed approach, called the Pharmacometrics-Enabled DOse OPtimization (PEDOOP) design, incorporates observed patient-level pharmacokinetics (PK) measurements and latent pharmacodynamics (PD) information for trial decision-making and dose optimization. PEDOOP consists of two seamless phases. In phase I, patient-level time-course drug concentrations, derived PD effects, and the toxicity outcomes from patients are integrated into a statistical model to estimate the dose-toxicity response. A simple dose-finding design guides dose escalation in phase I. At the end of the phase I dose finding, a graduation rule is used to assess the safety and efficacy of all the doses and select those with promising efficacy and acceptable safety for a randomized comparison against a control arm in phase II. In phase II, patients are randomized to the selected doses based on a fixed or adaptive randomization ratio. At the end of phase II, an optimal biological dose (OBD) is selected for late-phase development. We conduct simulation studies to assess the PEDOOP design in comparison to an existing seamless design that also combines phases I and II in a single trial. [ABSTRACT FROM AUTHOR]

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimization studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants' exclusion from early‐phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria‐preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under‐ or overdosing. Population pharmacokinetic‐pharmacodynamic (PK‐PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimized antimalarial dosing in this complex and at‐risk yet understudied subpopulation. In this review, we reflect on what PK‐PD modelling can do in programmatic settings of most malaria‐endemic areas and how it can be used to inform antimalarial dose optimization for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimization studies in infants, and examples of how PK‐PD modelling has previously informed antimalarial dose optimization in this subgroup. Additionally, we discuss the limitations and gaps of PK‐PD modelling when used for dose optimization in infants. To utilize modelling well, there is a need to generate useful, sparse, PK and PD data in this subpopulation to inform antimalarial optimal dosing in infancy. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades. Aims: To investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats. Methods: Topical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined. Results: The PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application. Conclusions: ISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose. [ABSTRACT FROM AUTHOR]

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep. [ABSTRACT FROM AUTHOR]

Background: Remimazolam is a recently developed, ultrashort-acting benzodiazepine that is used as a general anesthetic. Some cases of remimazolam anaphylaxis have been reported, but its characteristics are not fully understood. We present an interesting case report and review of the literature to better understand remimazolam anaphylaxis. Case presentation: A 75-year-old man scheduled for robot-assisted gastrectomy was administered remimazolam for the induction of general anesthesia. After intubation, low end-expiratory CO2, high airway pressure and concurrent circulatory collapse were observed. Bronchoscopy revealed marked tracheal and bronchial edema, which we diagnosed as anaphylaxis. The patient suffered cardiac arrest after bronchoscopy but recovered immediately with intravenous adrenaline administration and chest compressions. We performed skin prick tests for the drugs used during induction except for remimazolam, considering the high risk of systemic adverse reactions to remimazolam. We diagnosed remimazolam anaphylaxis because the skin prick test results for the other drugs used during anesthesia were negative, and these drugs could have been used without allergic reactions during the subsequent surgery. Furthermore, this patient had experienced severe anaphylactic-like reactions when he underwent cardiac surgery a year earlier, in which midazolam had been used, but it was not thought to be the allergen at that time. Based on these findings, cross-reactivity to remimazolam and midazolam was suspected. However, the patient had previously received another benzodiazepine, brotizolam, to which he was not allergic, suggesting that cross-reactivity of remimazolam may vary among benzodiazepines. In this article, we reviewed the 11 cases of remimazolam anaphylaxis that have been described in the literature. Conclusions: Remimazolam is an ultrashort-acting sedative; however, it can cause life-threatening anaphylaxis. In addition, its cross-reactivity with other benzodiazepines is not fully understood. To increase the safety of this drug, further research and more experience in its use are needed. [ABSTRACT FROM AUTHOR]

Nausea and vomiting are common experiences and are often dreaded more than pain. This review discusses blonanserin, mirtazapine, and isopropyl alcohol as antiemetics. Blonanserin, an atypical antipsychotic with a high affinity for dopamine D2 and D3 receptors and serotonin receptor 5-HT2A, has less of a risk of extrapyramidal adverse effects. Transdermal blonanserin, available in Korea, Japan, and China in a small number of trials, has improved nausea in patients not responding to standard antiemetics. Mirtazapine is a noradrenergic and specific serotonergic antidepressant that has been used for multiple symptoms besides depression. There is little evidence that mirtazapine improves anorexia or nausea in advanced cancer but is as effective as olanzapine in reducing chemotherapy-induced nausea and vomiting. Isopropyl alcohol aromatherapy has been successfully used in the emergency department for nausea and vomiting with an onset to benefit more rapidly than standard antiemetics. Isopropyl alcohol prep pads can be used for home-going antiemetic therapy and as a bridge to treating acute nausea until standard antiemetics take effect. [ABSTRACT FROM AUTHOR]

Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated. Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity. Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response. Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition. Trial registration: jRCT2080222728 (January 29, 2015). [ABSTRACT FROM AUTHOR]

Introduction: Cancers in general, and specifically lung cancer, continue to have low patient survival rates when the patient is at an advanced stage when diagnosed. It appears that the local environment, especially fibroblasts and their signaling molecules, tends to induce metastasis, increase cancer cell resistance to treatment, and aid in tumor growth rates. Since 3-D models quickly become too complex and/or expensive and therefore rarely leave the lab they are developed in, it is interesting to develop a 2-D model that more closely mimics clustered tumor formation and bulk interaction with a surrounding fibroblast environment. Methods: In the present study, we utilize an off-the-shelf stereolithography 3-D printer, standard use well plates, magnets, and metallic tubes to create a customizable 2-D co-culture system capable of being analyzed quantitatively with staining and qualitatively with standard fluorescent/brightfield microscopy to determine cancer-fibroblast interactions while also being able to test chemotherapeutic drugs in a high-throughput manner with standard 96-well plates. Results: Comparisons from monoculture and co-culture growth rates show that the presence of fibroblasts allows for significantly increased growth rates for H460 cancer. Additionally, the viability of cancer cells can be quantified with simple cell staining methods, and morphology and cell-cell interactions can be observed and studied. Discussion: The high throughput model demonstrates that boundary condition changes can be observed between cancer cells and fibroblasts based upon the different chemotherapeutics that have been administered. [ABSTRACT FROM AUTHOR]

Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation. [ABSTRACT FROM AUTHOR]

Specialized pro‐resolving lipid mediators (SPMs) are known for their anti‐inflammatory and pro‐resolving actions. The aim of the present study was to find new functions of the SPM resolvin D1n‐3 DPA (RvD1n‐3 DPA) on oral epithelial cells. As a starting point, we used a dataset obtained by RNA high‐throughput sequencing of oral epithelial cells exposed to TNF‐α and RvD1n‐3 DPA versus TNF‐α alone. GOrilla enrichment analysis showed that the actin cytoskeleton was significantly overrepresented after adjustment for multiple hypothesis testing. As actin, amongst others, is closely related to cell migration, we then explored whether RvD1n‐3 DPA can modulate oral epithelial cell migration. To this end, we used an in vitro cell migration model, including TNF‐α treatment, to mimic an inflammatory cell state. The analysis revealed that RvD1n‐3 DPA increased oral epithelial cell migration in the presence but not in the absence of TNF‐α. Addition of RvD1n‐3 DPA also induced F actin accumulation around the cell nucleus, indicating that RvD1n‐3 DPA potentially can mediate processes of intracellular transport. This indicates that this lipid mediator may be a promising therapeutic candidate in oral mucosal wound healing. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics, including risperidone (RIS), are frequently indicated for various autism spectrum disorder (ASD) manifestations; however, "actionable" PGx testing in psychiatry regarding antipsychotic dosing and selection has limited applications in routine clinical practice because of the lack of standard guidelines, mostly due to the inconsistency and scarcity of genetic variant data. The current study is aimed at examining the association of RIS effectiveness, according to ABC-CV and CGI indexes, with relevant pharmacokinetics (PK) and pharmacodynamics (PD) genes. Methods: Eighty-nine ASD children who received a consistent RIS-based regimen for at least 8 weeks were included. The Axiom PharmacoFocus Array technique was employed to generate accurate star allele-predicted phenotypes of 3 PK genes (CYP3A4, CYP3A5, and CYP2D6). Genotype calls for 5 candidate PD receptor genes (DRD1, DRD2, DRD3, HTR2C, and HTR2A) were obtained and reported as wild type, heterozygous, or homozygous for 11 variants. Results: Based on the ABC total score, 42 (47.2%) children were classified as responders, while 47 (52.8%) were classified as nonresponders. Multivariate logistic regression analyses, adjusted for nongenetic factors, suggested nonsignificant impacts of the star allele-predicted phenotypes of all 3 PK genes on improvement in ASD symptoms or CGI scores. However, significant positive or negative associations of certain PD variants involved in dopaminergic and serotonergic pathways were observed with specific ASD core and noncore symptom subdomains. Our significant polymorphism findings, mainly those in DRD2 (rs1800497, rs1799978, and rs2734841), HTR2C (rs3813929), and HTR2A (rs6311), were largely consistent with earlier findings (predictors of RIS effectiveness in adult schizophrenia patients), confirming their validity for identifying ASD children with a greater likelihood of core symptom improvement compared to noncarriers/wild types. Other novel findings of this study, such as significant improvements in DRD3 rs167771 carriers, particularly in ABC total and lethargy/social withdrawal scores, and DRD1 rs1875964 homozygotes and DRD2 rs1079598 wild types in stereotypic behavior, warrant further verification in biochemical and clinical studies to confirm their feasibility for inclusion in a PGx panel. Conclusion: In conclusion, we provide evidence of potential genetic markers involved in clinical response variability to RIS therapy in ASD children. However, replication in prospective samples with greater ethnic diversity and sample sizes is necessary. [ABSTRACT FROM AUTHOR]

Purpose: The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. Methods: We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child–Turcotte–Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety. Results: Fifty four studies were included. All DOACs were classified as 'no additional risks known' for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as 'no additional risks known'. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as 'unsafe' in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as 'unknown' for CTP C. Conclusion: DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis. [ABSTRACT FROM AUTHOR]

Objective A lack of representation in pivotal trials currently limits guidance for the use of biologic DMARDs (bDMARDs) in PsA patients with a low number of actively inflamed joints. The aim of this study was to compare the effectiveness of a first bDMARD in PsA patients with a low vs high number of affected joints. Methods PsA patients with available 66/68 joint count assessments were divided into low joint count (LJC) patients when presenting with <3 tender or <3 swollen joints or high joint count (HJC) patients with ≥3 joints in both categories. We studied drug retention as a joint count independent effectiveness variable in LJC and HJC patients in univariate and multivariable adjusted Cox regression models. Results A total of 197 LJC patients differed not only in joint counts, but also had lower enthesitis scores, less often dactylitis, less disability and a better health-related quality of life at first bDMARD initiation than 190 HJC patients. However, LJC patients were less often on conventional synthetic DMARDs (csDMARDs). Despite these differences at baseline, bDMARD retention was not significantly different between LJC and HJC patients in both crude and adjusted analyses [hazard ratio (HR) 1.09 (95% CI 0.76, 1.58), P  = 0.52]. Furthermore, bDMARD retention was significantly better [HR 0.63 (95% CI 0.47, 0.85), P  < 0.002] when administered with csDMARD co-therapy. Conclusions bDMARDs were similarly effective in terms of drug retention in patients with low and high joint counts. In the setting of absent remission and a significant disease burden, bDMARDs should not be withheld from patients because they exhibit only a low joint count. [ABSTRACT FROM AUTHOR]

Ensitrelvir fumaric acid (Xocova®) is an oral SARS-CoV-2 main protease inhibitor developed by Shionogi for the treatment of SARS-CoV-2 infection. It is the first single-entity, nonpeptidic, noncovalent, small molecule antiviral of its kind. Following emergency regulatory approval in Japan in November 2022, ensitrelvir received standard approval in Japan on 5 March 2024 for the treatment of SARS-CoV-2 infection. This article summarizes the milestones in the development of ensitrelvir leading to this first standard approval for SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Tegileridine (艾苏特) is a small molecule μ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the β-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery. [ABSTRACT FROM AUTHOR]

Crovalimab (派圣凯®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH. [ABSTRACT FROM AUTHOR]

Context Although several epidemiological studies have examined the association between coffee or tea intake and the risk of cognitive disorders, the results to date are inconsistent. Objective An updated systematic review and dose–response meta-analysis was conducted to confirm the association between coffee, tea, and caffeine consumption and the risk of cognitive disorders. Data Sources PubMed, Embase, and Web of Science were searched from inception to January 2022 for relevant studies, including dementia, Alzheimer disease (AD), and cognitive impairment or decline. Data Extraction Two reviewers independently performed data extraction and assessed the study quality. Data Analysis Restricted cubic splines were used to conduct the dose–response meta-analysis for coffee and tea intake. Results Twenty-two prospective studies and 11 case-control studies involving 389 505 participants were eligible for this meta-analysis. Coffee and tea consumption was linked to a lower risk of cognitive disorders, with an overall relative risk (RR) of 0.73 (95% CI: 0.60–0.86) and 0.68 (95% CI: 0.56–0.80), respectively. The subgroup analysis revealed that ethnicity, sex, and outcomes had significant effects on this association. Protection was stronger for men than that for women in both coffee and tea consumption. A nonlinear relationship was found between coffee consumption and AD risk, and the strength of protection peaked at approximately 2.5 cups/day (RR: 0.74; 95% CI: 0.59–0.93). A linear relationship was found between tea consumption and cognitive disorders, and the risk decreased by 11% for every 1-cup/day increment. Conclusion This meta-analysis demonstrated that the consumption of 2.5 cups coffee/day minimizes the risk of AD, and 1 cup/day of tea intake leads to an 11% reduction in cognitive deficits. Effective interventions involving coffee and tea intake might prevent the occurrence of dementia. [ABSTRACT FROM AUTHOR]

Aims: Health food products (HFPs) are foods and products related to maintaining and promoting health. HFPs may sometimes cause unforeseen adverse health effects by interacting with drugs. Considering the importance of information on the interactions between HFPs and drugs, this study aimed to establish a workflow to extract information on Drug‐HFP Interactions (DHIs) from open resources. Methods: First, Information on drugs, enzymes, their interactions, and known DHIs was collected from multiple public databases and literature sources. Next, a network consisted of enzymes, HFP, and drugs was constructed, assuming enzymes as candidates for hubs in Drug‐HFP interactions (Method 1). Furthermore, we developed methods to analyze the biomedical context of each drug and HFP to predict potential DHIs out of the DHIs obtained in Method 1 by applying BioWordVec, a widely used biomedical terminology quantifier (Method 2‐1 and 2‐2). Results: 44,965 DHIs (30% known) were identified in Method 1, including 38 metabolic enzymes, 157 HFPs, and 1256 drugs. Method 2‐1 selected 7401 DHIs (17% known) from the DHIs of Method 1, while Method 2‐2 chose 2819 DHIs (30% known). Based on the different assumptions in these methods where Method 2‐1 specifically selects HFPs interacting with specific enzymes and Method 2‐2 specifically selects HFPs with similar function with drugs, the propsed methods resulted in extracting a wide variety of DHIs. Conclusions: By integrating the results of language processing techniques with those of the network analysis, a workflow to efficiently extract unknown and known DHIs was constructed. [ABSTRACT FROM AUTHOR]

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells, a subset of Vα7.2+ T cells, are a crucial link between innate and adaptive immunity, responding to various stimuli through TCR-dependent and independent pathways. We investigated the responses of MAIT cells and Vα7.2+/CD161− T cells to different stimuli and evaluated the effects of Cyclosporin A (CsA) and Vitamin D3 (VitD). Peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with various agents (PMA/Ionomycin, 5-OP-RU, 5-OP-RU/IL-12/IL-33) with or without CsA and VitD. Flow cytometric analysis assessed surface markers and intracellular cytokine production. Under steady-state conditions, MAIT cells displayed elevated expression of CCR6 and IL-13. They showed upregulated activation and exhaustion markers after activation, producing IFNγ, TNFα, and TNFα/GzB. CsA significantly inhibited MAIT cell activation and cytokine production. Conversely, Vα7.2+/CD161− T cells exhibited distinct responses, showing negligible responses to 5-OP-RU ligand but increased cytokine production upon PMA stimulation. Our study underscores the distinct nature of MAIT cells compared to Vα7.2+/CD161− T cells, which resemble conventional T cells. CsA emerges as a potent immunosuppressive agent, inhibiting proinflammatory cytokine production in MAIT cells. At the same time, VitD supports MAIT cell activation and IL-13 production, shedding light on potential therapeutic avenues for immune modulation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN. [ABSTRACT FROM AUTHOR]

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1–6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4–8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified. • Pharmacokinetics were evaluated in conscious, unrestrained adult male minipigs. • Doctrinal nerve agent countermeasures were studied across a large range of doses. • Physiological measures were also recorded for general safety assessment. • Orderly pharmacokinetic data and expected/minor physiological changes were observed. • The Göttingen minipig may provide a suitable large animal model for pharmacology. [ABSTRACT FROM AUTHOR]

Background: Anticonvulsant prophylaxis (ACP) for early post-traumatic seizures (PTS) is recommended in patients with traumatic brain injury (TBI). Phenobarbital (PB) may be used to prevent alcohol withdrawal syndrome (AWS) in at-risk patients. The dual-purpose use of PB in the TBI population would allow for consolidation of pharmacotherapy. Objective: The primary objective of this study was to determine the frequency of early PTS in TBI patients at risk of AWS treated with PB as ACP. Secondary objectives included determining rates of over sedation and endotracheal intubation. Methods: Patients received an intravenous (IV) loading dose of PB at 15-20 mg/kg followed by 1 mg/kg every 12 hours for 7 days with a goal level of 15-20 mcg/mL. Medication data, seizure frequency, and episodes of over sedation and endotracheal intubation were collected. Results: Eighty patients were treated with PB over a 1-year period. Thirty-nine patients were analyzed. Median loading dose was 19.9 (Interquartile Range 19.1-20.0) mg/kg with a median post load level of 21.7 mcg/mL (IQR 18.3-25.8) mcg/mL. One patient (2.6%) had electrographic evidence for early PTS. PB was discontinued in 4 (10.3%) patients out of concern for over sedation. One patient required endotracheal intubation after rapid PB loading. Conclusion: The frequency of early PTS was low when PB was used as primary ACP in patients with TBI at risk for AWS. Over sedation is a potential adverse effect that should be considered in the choice of ACP. No conclusions can be drawn as to the effectiveness of PB in preventing AWS. [ABSTRACT FROM AUTHOR]

Abnormal activation of the Wnt/β-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated β-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced β-catenin. The inhibitory effects of atovaquone on β-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer. [ABSTRACT FROM AUTHOR]

The quest for eco-friendly antifungal compounds from natural sources has surged, seeking alternatives to synthetic fungicides. In this study, we explored Cupressus sempervirens organic extracts antifungal potential against Botrytis cinerea, a destructive fungus causing grey mold disease in crops. Extracts from various phenological stages were evaluated for their antifungal activities. The dichloromethanolic extract from the flowering stage exhibited the highest efficacy, completely inhibiting B. cinerea mycelial growth, at 250 μg/mL and preventing conidia germination at 500 μg/mL. Bioguided fractionation and chromatography, led to the identification of isoquercetin as the active compound responsible for the antifungal effects. These findings present promising possibilities for the development of sustainable biofungicides to combat grey mould disease in agriculture. Further investigations into isoquercetin's potential as a biofungicide are warranted. [ABSTRACT FROM AUTHOR]

Tamarix gallica L. is a halophytic medicinal shrub traditionally used in the treatment of liver disorders. Leaf and flower infusions are widely used for anti-diarrheic and anti-inflammatory preparations. In this work, we have explored the combined effect of method (Maceration and Decoction) and solvent extraction (70% Methanol, 70% Ethanol, 70% Acetone, and Water) on phenolic composition and biological activities (antioxidant and anti-inflammatory) of different T. gallica organ extracts (Leaves, Flowers, Stems, and Fruits). Obtained results showed that Tamarix leaves reveal more potent antioxidant activity. Methanol (70%) was the best maceration solvent for the extraction of leaves and flowers with high total antioxidant and anti-radical capacities. HPLC analysis showed that catechin, isorhamnetin-3-O-glucoside, isoquercetin were the major phenolics in 70% methanolic extract. Furthermore, this extract showed considerable anti-inflammatory activity. This prospect could be of great importance in the valuation of this halophyte as a source of natural antioxidants and anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer (OVCA) stands as one of the most fatal gynecological malignancies. Honokiol (HNK) has been substantiated by numerous studies for its anti‐tumor activity against malignancies including OVCA. Consequently, this work was designed to elucidate the impact of HNK‐mediated modulation of the YAP/TAZ pathway on the biological functions of OVCA cells. Methods: OVCA cells were subjected to treatment with varying concentrations (0, 25, 50, 75, and 100 μM) of HNK, concomitant with the administration of YAP agonist (XMU). Assessment of cellular viability was executed employing the CCK‐8 assay, while quantification of cellular proliferation transpired via colony formation assays. Apoptosis was ascertained using flow cytometry, and expression of apoptosis‐related proteins (caspase‐3, Bcl‐2, Bax), EMT‐related proteins (E‐cadherin, N‐cadherin), migration‐associated proteins (MMP‐2, MMP‐9), and YAP/TAZ pathway‐related proteins was evaluated by western blot. Transwell experiments were conducted to assess cellular migratory and invasive propensities. Xenograft tumor models were built to observe tumor growth (volume and weight), apoptosis was assessed by TUNEL staining, and Ki67 expression was evaluated through IHC. Results: HNK exerted inhibitory effects on the viability and proliferative capacity of OVCA cells, elicited apoptotic responses, curtailed the migratory and invasive tendencies of cells, and downregulated the YAP/TAZ pathway. Stimulation with YAP agonist (XMU‐MP‐1) partially attenuated the impacts of HNK on OVCA cell biology. Experiments in vivo confirmed that HNK inhibited OVCA tumor growth. Conclusion: The outcomes of this investigation conclusively established that HNK orchestrated the modulation of the YAP/TAZ pathway, thereby exerting control over the malignant phenotypic manifestations of OVCA cells. The ascertained function of HNK in restraining cellular proliferation and tumor progression provided novel evidence of its anti‐proliferative activity within OVCA cells. [ABSTRACT FROM AUTHOR]

Background and Objective: Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers. Methods: AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms. Results: Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [tmax] 2.5–4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3–200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events. Conclusion: AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases. Clinical Trial Registry: Clinical Trial Registry no. CTR20221202 (http://www.chinadrugtrials.org.cn) registered on 6 June 2022 and ChiCTR2200061431 (http://www.chictr.org.cn) registered on 24 June 2022. [ABSTRACT FROM AUTHOR]

Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. We conducted a systematic review that included all pharmacological studies published after 2000. Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed. [ABSTRACT FROM AUTHOR]

Patients aged ≥65 years not only account for the majority of patients with atrial fibrillation (AF) and venous thromboembolism (VTE), they are also at a higher risk of morbidity, mortality, and undertreatment than younger patients. Several age-related physiological changes with effects on drug pharmacokinetics/−dynamics and blood vessel fragility as well as the higher prevalence of geriatric conditions such as frailty, multimorbidity, polypharmacy, fall risk, dementia, and malnutrition make older persons more vulnerable to disease- and anticoagulation-related complications. Moreover, because older patients with AF/VTE are underrepresented in oral anticoagulation (OAC) trials, evidence on OAC in older adults with AF/VTE is mainly based on subgroup analyses from clinical trials and observational studies. A growing body of such limited evidence suggests that direct oral anticoagulants (DOACs) may be superior in terms of efficacy and safety compared to vitamin K antagonists in older persons with AF/VTE and that specific DOACs may have a differing risk-benefit profile. In this narrative review, we summarize the evidence on epidemiology of AF/VTE, impact of age-related physiological changes, efficacy/safety of OAC, specifically considering individuals with common geriatric conditions, and review OAC guideline recommendations for older adults with AF/VTE. We also propose a research agenda to improve the evidence basis on OAC older individuals with AF/VTE, including the conduct of advanced age-specific and pragmatic studies using less restrictive eligibility criteria and patient-reported health outcomes, in order to compare the effectiveness and safety of different DOACs, and investigate lower-dose regimens and optimal OAC durations in older patients. • Older adults are underrepresented in anticoagulation trials and guidelines for AF and VTE • Advanced age and several geriatric conditions increase the risk of thromboembolic events and bleeding • Limited evidence suggests that DOACs may be more effective and safer than vitamin K antagonists in older adults • Apixaban and edoxaban might have the most favorable risk-benefit profile in older individuals [ABSTRACT FROM AUTHOR]

Objective: To review the pharmacokinetic (PK)–pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use. Data Sources: Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine–cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy. Data Summary: Differences in the PK–PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20 mg/m2 and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK–PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030. Conclusions: Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and safety of ketamine alone with those of ketamine‐dexmedetomidine combination for sedation during brain CT in paediatric patients with head injuries. Methods: We retrospectively analysed the data of paediatric patients who underwent sedation for brain CT at the ED. We included patients aged 6 months to 6 years with American Society of Anesthesiologists physical status I or II. The sedative protocol involved the administration of intramuscular (IM) ketamine 3 mg/kg (K), ketamine 2 mg/kg with dexmedetomidine 1.5 μg/kg (KD) or ketamine 1.5 mg/kg with dexmedetomidine 1.5 μg/kg (low‐KD). The primary and secondary outcomes were sedation failure and adverse events, respectively. Results: We included 77 patients; among them, 28, 23 and 26 were in the K, KD and low‐KD groups, respectively. In multivariable analysis, the combination groups (KD and low‐KD groups) were significantly associated with a lower possibility of sedation failure compared to the K group (adjusted odds ratio, 0.12; 95% confidence interval, 0.02–0.56). Moreover, there were no significant differences in adverse events between the groups, and the sedation‐related time variables also did not significantly differ among the three groups. Conclusions: Our findings indicated that a combination of IM ketamine‐dexmedetomidine provides effective sedation for paediatric patients undergoing brain CT without significant adverse events. Further research is needed to investigate the potential benefits of using lower doses of ketamine in combination. [ABSTRACT FROM AUTHOR]

Introduction: Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). Methods: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. Results: The study enrolled 49 HVs, with a median age of 39 (range 18–73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration–time curve from time 0 to infinity (AUC0–inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. Conclusion: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. Trial Registration: ISRCTN13175485. [ABSTRACT FROM AUTHOR]

Background: Optimizing care during labor protraction is a key strategy for reducing cesareans, especially among people with obesity. The pathophysiology of labor dystocia remains poorly understood, limiting precise interventions targeting the cause of protraction. Methods: In this secondary analysis of nulliparas (n = 92) with obesity (BMI ≥ 30 kg/m2) and spontaneous labor onset, we classified labor into four phenotypes based on duration of protraction and birth route: (1) no protraction, (2) short protraction and vaginal birth, (3) extended protraction meeting criteria for labor arrest, but with eventual progression and vaginal birth, and (4) extended protraction meeting criteria for labor arrest and cesarean birth. Across these phenotypes, we compared MVU, oxytocin dose, and novel measures of uterine responsiveness to oxytocin augmentation (MVU to oxytocin dose ratios). Results: In our sample, phenotype group 1 comprised 14.1% (n = 13); group 2 comprised 30.4% (n = 28); group 3 comprised 34.8% (n = 32); and group 4 comprised 20.7% (n = 19). Uterine responsiveness to oxytocin, but not MVU, decreased with each labor phenotype. Participants with cesarean birth had the lowest uterine responsiveness to oxytocin. Conclusion: Labor and birth outcomes were associated with measures of uterine responsiveness to oxytocin rather than MVU alone, and thus these may be more clinically appropriate measures for guiding clinical decision‐making. Current criteria for labor arrest are likely too stringent for nulliparas with obesity, many of whom appear to progress to safe vaginal birth after longer labor durations. Differences in uterine responsiveness to oxytocin augmentation across the groups suggests underlying physiologic differences in the labor phenotypes, which should drive future research targeting pathophysiology. [ABSTRACT FROM AUTHOR]

Rationale: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. Objectives: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. Conclusions: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure. [ABSTRACT FROM AUTHOR]

Rationale: Attentional bias to drug-related stimuli is hypothesised to contribute towards addiction. However, the acute effects of Δ9-tetrahydrocannabinol (THC) on attentional bias to cannabis cues, the differential response in adults and adolescents, and the moderating effect of cannabidiol (CBD) are unknown. Objectives: Our study investigated (1) the acute effects of vaporised cannabis on attentional bias to cannabis-related images in adults and adolescents and (2) the moderating influences of age and CBD. Methods: We conducted a randomised, double-blind, placebo-controlled, cross-over study where three weight-adjusted vaporised cannabis preparations: 'THC' (8 mg THC for a 75-kg person), 'THC + CBD' (8 mg THC and 24 mg CBD for a 75-kg person) and PLA (matched placebo). Cannabis was administered on 3 separate days to 48 participants, who used cannabis 0.5–3 days/week: 24 adolescents (12 females, aged 16–17) and 24 adults (12 females, aged 26–29). Participants completed a visual probe task with cannabis cues. Our primary outcome was attentional bias to cannabis stimuli, measured using the differential reaction time to a cannabis vs. neutral probe, on 200-ms trials. Results: In contrast to hypotheses, attention was directed away from cannabis cues on placebo, and there was a main effect of the drug (F(2,92) = 3.865, p = 0.024, η2p = 0.077), indicating THC administration eliminated this bias. There was no significant impact of CBD nor an age-by-drug interaction. Conclusions: Acute THC intoxication eliminated attentional bias away from cannabis cues. There was no evidence of differential response in adolescents compared to adults and no evidence that a moderate vaporised dose of CBD altered the impact of cannabis on attentional bias. Trial registration: This study was listed with the US National Library of Medicine and registered on ClinicalTrials.gov, URL: Do Adolescents and Adults Differ in Their Acute Response to Cannabis?—Full Text View—ClinicalTrials.gov, registration number: NCT04851392. [ABSTRACT FROM AUTHOR]

Serum angiotensin-converting enzyme (ACE) is the only biomarker routinely used in the laboratory diagnostics of sarcoidosis, and ACE inhibitor (ACEi) drugs are among the most prescribed drugs worldwide. Taking ACEi can mislead medical teams by lowering ACE activity, delaying diagnosis and giving a false impression of disease activity of sarcoidosis. We aimed to develop a simple method to detect the presence of ACEi drugs in samples, to investigate the ACEi medication-caused interference and consequences in a retrospective study. ACE activity and the level of ACE inhibition were determined for 1823 patients with suspected sarcoidosis. These values were compared with the therapeutic information at the first and follow-up visits. A total of 302 patients had biochemical evidence of an ACEi drug effect during diagnostic ACE activity testing. In their case, ACE activity was significantly lower (median(IQR): 4.41 U/L(2.93–6.72)) than in patients not taking ACEi (11.32 U/L(8.79–13.92), p<0.01). In 62 sarcoidosis patients, the ACEi reduced ACE activity to the reference range or below. Only in 40 % of the cases was the medication list recorded in the outpatient chart and only in 3 cases was low ACE activity associated with ACEi use. 67 % of the repeated ACE activity measurements were also performed during ACEi therapy. Our study revealed that the use of ACEi is common in patients with suspected sarcoidosis. The ACE activity lowering effect of ACEi drugs may escape the attention of medical teams which can lead to diagnostic errors and unnecessary tests. Nevertheless, these pitfalls can be avoided by using a method suggested by our team. [ABSTRACT FROM AUTHOR]

The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12‐32 weeks gestation admitted with PTL. Ninety‐four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2‐compartment structural model with first‐order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%‐60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose‐finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin. [ABSTRACT FROM AUTHOR]

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium‐glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK‐UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration‐time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5‐2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%‐82% and 89%‐93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK‐UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP. [ABSTRACT FROM AUTHOR]

Objective: To determine the tolerability and safety of concurrent peripheral nerve blocks and onabotulinumtoxinA treatment during a single outpatient clinic procedure visit. Background: Procedural interventions are available for the treatment of headache disorders. OnabotulinumtoxinA and peripheral nerve blocks are used as alternatives or in addition to oral therapies to reduce the frequency and intensity of migraine attacks. There is currently a lack of safety data focusing on the sequential administration of local anesthetic via peripheral nerve blocks and onabotulinumtoxinA during a single clinical encounter for the treatment of headache. The primary aim of the study was to determine the safety and tolerability of concurrent peripheral nerve blockade and onabotulinumtoxinA injections during a single outpatient clinic procedure visit. We hypothesized that the dual intervention would be safe and well tolerated by patients with chronic migraine and other headache disorders. Methods: A retrospective chart review was performed using clinical data from patients seen by multiple providers over a 16‐month timeframe at one outpatient headache clinic. Patients were identified by procedure codes and those receiving peripheral nerve block(s) and onabotulinumtoxinA injections during a single encounter within the study period were eligible for inclusion. Inclusion criteria were (1) patients 18 years and older who were (2) receiving both peripheral nerve blocks and onabotulinumtoxinA injections for the treatment of chronic migraine. Patients were excluded if they were under age 18, received their procedure outside of the clinic (emergency room, inpatient ward), or were receiving sphenopalatine ganglion blocks. Age‐ and sex‐matched patients who received one procedure, either peripheral nerve blocks or onabotulinumtoxinA, were used for control. The primary outcome of this safety study was the number of adverse events that occurred in the dual intervention group compared to the single intervention control arms. Information regarding adverse events was gathered via retrospective chart review. If an adverse event was recorded, it was then graded by the reviewer utilizing the Common Terminology Criteria for Adverse Events ranging from Grade 1 Mild Event to Grade 5 Death. Additionally, it was noted whether the adverse event led to treatment discontinuation. Results: In total, 375 patients were considered eligible for inclusion in the study. After age and sex matching of controls, 131 patients receiving dual intervention were able to be compared to 131 patients receiving onabotulinumtoxinA alone and 104 patients receiving dual intervention were able to be compared to 104 patients receiving peripheral nerve block(s) alone. The primary endpoint analysis showed no significant difference in total adverse events between dual intervention compared to nerve blocks alone or onabotulinumtoxinA alone. The number of adverse events that led to treatment discontinuation approached but did not reach statistical significance for those receiving dual intervention versus onabotulinumtoxinA alone in the number of adverse events that led to treatment termination (4.6%, 6/131 vs. 0.8%, 1/131, p = 0.065); however, the number of patients who discontinued therapy was not significantly different between those groups (2.3%, 3/131 vs. 0.8%, 1/131; p = 0.314; odds ratio 0.3 [0–3.2]; p = 0.338). Conclusions: In this retrospective chart review, there was no significant difference in adverse events or therapy discontinuation between patients receiving sequential peripheral nerve block(s) and onabotulinumtoxinA injections versus those receiving either peripheral nerve block(s) or onabotulinumtoxinA injections alone. As a result, we concluded that the combination procedure is likely safe and well tolerated in routine clinical practice. Plain Language Summary: At our headache center, we reviewed 366 patient charts for those receiving onabotulinumtoxinA, nerve blocks with local anesthetic, or both in the same visit for chronic migraine. Our goal was to compare the safety of performing both procedures at once versus each individual procedure. We found that the combination treatment with both injections of onabotulinumtoxinA and nerve blocks with local anesthetic for chronic migraine in the same appointment is well tolerated by patients. [ABSTRACT FROM AUTHOR]