Explore the vast range of titles available.

Background and Objective Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. Methods The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. Results Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. Conclusions Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. Clinical Trial Registration NCT02014558, NCT02456883, NCT02571816.

Endothelial cell dysfunction is a complex process involving various causes, early and late events, and subsequent consequences. This review provides an overview of each aspect and outlines therapeutic interventions targeting these stages. Causes of endothelial dysfunction encompass a spectrum of risk factors including hypertension, diabetes, smoking, obesity, inflammation, oxidative stress, and genetic predispositions. Early events such as endothelial activation, inflammatory response, and dysregulated vasomotor tone precede late events like oxidative stress, endothelial apoptosis, and microvascular rarefaction. The consequences include endothelial remodelling, neovascularization, organ dysfunction, and clinical manifestations, highlighting the diverse impacts across multiple systems. While depicted linearly, the progression of endothelial dysfunction is dynamic, influenced by various factors such as the underlying cause and affected vascular bed. Understanding these dynamics is crucial for tailoring therapeutic interventions, ranging from lifestyle modifications to targeted therapies, to address the underlying causes and effects effectively. Here we provide comprehensive understanding of endothelial cell dysfunction that is essential for developing strategies to mitigate the impact of this dysregulation on health and cardiovascular diseases progression.

Patient management is not based on a single decision. Rather, it is dynamic: based on a sequence of decisions, with therapeutic adjustments made over time. Adjustments are personalized: tailored to individual patients as new information becomes available. However, strategies allowing for such adjustments are infrequently studied. Traditional antibiotic trials are often nonpragmatic, comparing drugs for definitive therapy when drug susceptibilities are known. COMparing Personalized Antibiotic StrategieS (COMPASS) is a trial design that compares strategies consistent with clinical practice. Strategies are decision rules that guide empiric and definitive therapy decisions. Sequential, multiple-assignment, randomized (SMART) COMPASS allows evaluation when there are multiple, definitive therapy options. SMART COMPASS is pragmatic, mirroring clinical, antibiotic-treatment decision-making and addressing the most relevant issue for treating patients: identification of the patient-management strategy that optimizes the ultimate patient outcomes. SMART COMPASS is valuable in the setting of antibiotic resistance, when therapeutic adjustments may be necessary due to resistance.

Artificial intelligence (AI) is increasingly being integrated into diagnostic and therapeutic interventions, offering potential advantages in accuracy, efficiency, and clinical decision-making compared to conventional methods. This systematic review aimed to identify and characterise AI applications assessed in randomised controlled trials (RCTs), and to synthesise the reported clinical outcomes in comparison with standard approaches. A comprehensive search was conducted in PubMed, Scopus, and Web of Science for articles published between 2015 and June 2024. Eligible studies included randomised controlled trials involving patients with various medical conditions who received diagnostic or therapeutic interventions supported by AI technologies. Comparators included conventional diagnostic or treatment methods, placebo, or standard care. Two reviewers independently screened the studies, extracted data, and assessed risk of bias using the Cochrane RoB 1 tool. A total of 13 trials involving 10,566 participants met the inclusion criteria, spanning a range of medical specialties including gastroenterology, dermatology, radiology, oncology, neurology, and ophthalmology. While several trials reported improvements in diagnostic accuracy, treatment planning, or procedural efficiency, other studies showed inconsistent or limited benefits, highlighting the variability in outcomes depending on the clinical context and type of AI application. This review offers an updated synthesis of AI-based clinical interventions evaluated through randomised controlled trials and emphasises the need for further research to validate these tools, standardise their implementation, and assess their broader impact as health technology in modern healthcare systems.

Backgrounds and Aims We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury. Methods Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. l -Alanine ( l -Ala) and inosine 5′-monophosphate (IMP) were co-administered ig after the treatment. Results Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or l -Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and l -Ala + IMP further accelerated intestinal ulcer healing. Conclusion DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

Introduction Statins, widely prescribed drugs for treatment of cardiovascular disease, inhibit the biosynthesis of low density lipoprotein cholesterol (LDL-C). Despite providing major benefits, sub populations of patients experience adverse effects, including muscle myopathy and development of type II diabetes mellitus (T2DM) that may result in premature discontinuation of treatment. There are no reliable biomarkers for predicting clinical side effects in vulnerable individuals. Pharmacometabolomics provides powerful tools for identifying global biochemical changes induced by statin treatment, providing insights about drug mechanism of action, development of side effects and basis of variation of response. Objective To determine whether statin-induced changes in intermediary metabolism correlated with statin-induced hyperglycemia and insulin resistance; to identify pre-drug treatment metabolites predictive of post-drug treatment increased diabetic risk. Methods Drug-naïve patients were treated with 40 mg/day simvastatin for 6 weeks in the Cholesterol and Pharmacogenetics (CAP) study; metabolomics by gas chromatography-time-of-flight mass-spectrometry (GC–TOF–MS) was performed on plasma pre and post treatment on 148 of the 944 participants. Results Six weeks of simvastatin treatment resulted in 6.9% of patients developing hyperglycemia and 25% developing changes consistent with development of pre-diabetes. Altered beta cell function was observed in 53% of patients following simvastatin therapy and insulin resistance was observed in 54% of patients. We identified initial signature of simvastatin-induced insulin resistance, including ethanolamine, hydroxylamine, hydroxycarbamate and isoleucine which, upon further replication and expansion, could be predictive biomarkers of individual susceptibility to simvastatin-induced new onset pre-type II diabetes mellitus. No patients were clinically diagnosed with T2DM. Conclusion Within this short 6 weeks study, some patients became hyperglycemic and/or insulin resistant. Diabetic markers were associated with decarboxylated small aminated metabolites as well as a branched chain amino acid directly linked to glucose metabolism and fatty acid biosynthesis. Pharmacometabolomics provides powerful tools for precision medicine by predicting development of drug adverse effects in sub populations of patients. Metabolic profiling prior to start of drug therapy may empower physicians with critical information when prescribing medication and determining prognosis.

A study ancillary to a large trial showed that supplemental vitamin D 3 did not lower the risk of fractures among generally healthy midlife and older adults not selected for vitamin D deficiency, low bone mass, or osteoporosis.

Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the ’gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

In this study, the androgen-receptor inhibitor enzalutamide improved progression-free and overall survival in men with castration-resistant metastatic prostate cancer who had not received chemotherapy. Prostate cancer is the most commonly diagnosed cancer and the sixth leading cause of cancer-related death among men worldwide. 1 Strategies to block androgen-receptor signaling have formed the backbone of prostate-cancer therapy since the first description of the hormonal dependence of this cancer in 1941. 2 Advances in endocrine therapies have improved survival in men with high-risk locoregional prostate cancer. 3 , 4 However, new hormonal agents have been shown to extend survival in men with metastatic castration-resistant disease. 5 – 9 In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy (comprising a luteinizing hormone–releasing hormone [LHRH] analogue or orchiectomy with . . .

In this single-group, phase 2 study, the use of trastuzumab deruxtecan resulted in a response in 60% of women with HER2-positive advanced breast cancer who had received a median of six previous lines of therapy. The drug was associated with myelosuppression and gastrointestinal toxicity; interstitial lung disease was reported in 13.6% of the patients.