Search Results (5,975)

(1) Background: Invasive fungal diseases (IFDs) represent significant challenges in clinical practice, particularly among immunocompromised individuals, leading to substantial morbidity and mortality. The present document aims to provide evidence-based consensus for the timely initiation of antifungal treatment, focusing on early empiric approaches among immunocompromised patients. (2) Methods: A multidisciplinary expert panel of nine healthcare professionals (HCPs) reviewed the literature, including guidelines and consensus reports (2013–2023; PubMed, Scopus). The panel defined appropriate empiric antifungal approaches for invasive candidiasis, aspergillosis, and mucormycosis among hematological and critically ill patients. Consensus was defined as ≥75% agreement. (3) Results: A total of 47 statements were included. The experts recommend that early targeted antifungal therapy is critical for high-risk patients with suspected IFDs. Empiric therapy may be initiated before definitive diagnosis, considering the local fungal prevalence and the patient’s risk category. Close monitoring is essential, and switching between antifungal classes may be necessary for patients who experience deterioration or side effects. The transition from intravenous to oral therapy depends on the specific infection, the availability of therapeutic drug monitoring, and the patient’s progress. (4) Conclusions: Implementing this targeted, early approach may improve the outcomes of vulnerable patients with IFDs. Full article

Background/Objectives: Cyclosporine A (CsA) is a key immunosuppressant in post-transplantation therapy protocol characterized by large interindividual and intraindividual pharmacokinetic (PK) variability and a narrow therapeutic range necessitating therapeutic drug monitoring (TDM) to prevent graft rejection and minimize side effects. TDM data can be used for developing PK models with the objective of identification and quantification of variability factors that contribute to the differences in CsA concentrations. Methods: Retrospectively collected data from medical records of 58 patients (children and young adults) regarding CsA blood concentrations, concomitant medications, and laboratory findings of significance were used for the population PK model development in NONMEM^® (version 7.5) with first-order conditional estimation method with interaction (FOCE-I). Simulation of the concentrations and area under the curve (AUC) was performed in the web application e-campsis^®. RStudio (version 4.5.0) was used for the purpose of descriptive statistics analysis and graphs plotting. Results: A one-compartment model with first-order absorption and elimination best described the data. Value of clearance (CL/F) was estimated to be 15 L/h, and volume of distribution (V/F) was 71.1 L for a typical patient weighing 40 kg. Interindividual variability (IIV) on CL/F and V/F was 34.91% and 43.05%, respectively. Interoccasional variability (IOV) was 12.25%. Body weight (WT) was introduced allometrically on CL/F and V/F, with the estimated exponent of 0.89 for CL/F and 1 (fixed) for V/F. According to the final model, CL/F decreases with increasing haemoglobin (HGB) value. A difference of almost 22.5% in CL/F was observed among patients’ HGB values reported in the study. Conclusions: Our findings indicate that HGB levels significantly influence CsA PK, particularly minimum concentration (C_min), highlighting the importance of regular HGB levels monitoring together with CsA levels. Full article

Neonatal seizures are common complications in neonatal intensive care units. They have been noticed to be more common in preterm infants, but they can also affect term infants. Levetiracetam is a broad-spectrum antiepileptic drug that has been studied to manage seizures, yet limited data are available on its use in neonatal seizures. Objectives: Study the effect of levetiracetam on neonatal seizures in terms of maintaining seizure freedom after the initiation of levetiracetam and investigating its safety profile in the neonate population. Method: Retrospective cohort study comparing two groups of patients identified through accessing their medical profiles after searching the following keywords: phenobarbital, levetiracetam, and neonatal seizures amongst all NICU admissions in King Abdulaziz Medical City, Ministry of National Guard Health Affairs, from the period between December 2016 and January 2020. Forty-eight patients were included based on the inclusion/exclusion criteria. The selected sample was further subclassified into 28 neonates who received phenobarbital and 20 who received levetiracetam. Results: Seizure control was significantly observed in neonates with onset <24 h and those born at <37 weeks GA. In the first arm, 22 out of 28 neonates achieved seizure freedom while using phenobarbital; in the second arm, 11 out of 20 neonates achieved seizure control on levetiracetam after failing with phenobarbital. While seizure control was better achieved by phenobarbital, it was found that almost 57% of the first arm developed side effects on phenobarbital; however, only 10% of the neonates on levetiracetam developed side effects. While PB remains effective for acute suppression, LEV demonstrated a superior safety profile with no serious adverse events and a high rate of successful seizure management as an add-on therapy (83% control in combined cohorts). Conclusions: The study concluded that using levetiracetam could result in improved outcomes. LEV is a safe and effective alternative or adjunct to PB. Its use may mitigate the neurotoxic risks associated with GABAergic drugs, though continuous EEG monitoring is essential to ensure electrical seizure cessation and avoid electroclinical dissociation. The number of patients who received levetiracetam initially is not considered a representative sample to reach a conclusion on the use of levetiracetam as an effective monotherapy. Full article

Introduction: Overweight and obesity are becoming increasingly prevalent. Incretin-based obesity treatments—glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonists (GIP/GLP-1 RAs or dual agonists)—are a major stride in the evolution of obesity management. However, like weight loss with other means, they are associated with an inadvertent significant loss of lean body mass, including muscle. This has led to a resurgence in research for the preservation of lean body mass, the loss of which occurs with weight loss. The purpose of this narrative review is to discuss the mechanisms involved with lean body loss and capture the research landscape of the different classes of pharmacological agents being developed to address this problem. Methodology: We queried PubMed, Medline, and Scopus for randomized controlled trials and phase II or phase III trials using key words to capture the breath of this topic—obesity, weight loss, muscle loss, lean mass, and muscle preservation. Animal studies were excluded. We analyzed the studies conducted to date. Results: Weight loss, regardless of the method used to achieve it, is inadvertently accompanied by lean body mass loss, to varying degrees. There are several mechanisms that govern the loss of lean body mass and, more specifically, the loss of muscle mass; as such, several classes of medications have been explored, targeting different pathways and receptors—including bimagrumab (activin receptor agonist), tesamorelin (growth hormone releasing hormone agonists), and enobosarm (selective androgen receptor modulator). Most of these drugs are in the early phases of research development, but some show great promise. Conclusion: This narrative review attempts to detail the physiology of muscle mass loss when accompanied by weight loss and identify pharmacological targets that can be utilized to minimize it with mechanisms, effects, side effects, and research developmental progress. Full article

Background/Objectives: Combination therapy for schizophrenia may exacerbate side effects mediated by multiple brain receptors. This study aimed to elucidate the pharmacodynamic and pharmacokinetic interactions between chlorpromazine and risperidone. We investigated dopamine 2 (D₂), serotonin 2A (5-HT_2A), histamine 1 (H₁), and muscarinic acetylcholine (mACh) receptor occupancy in the brain as well as pharmacokinetic interactions after oral administration of chlorpromazine and risperidone in rats. Methods: Rats were orally administered chlorpromazine, risperidone, or their combination. A tracer cocktail solution was injected intravenously to measure multiple receptor occupancies simultaneously. Tracer and drug concentrations in the brain tissue and plasma were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Receptor occupancy increased in a dose-dependent manner. The doses required for 70% D₂ receptor occupancy were 4.5 mg/kg for chlorpromazine and 1.5 mg/kg for risperidone. Co-administration of chlorpromazine (4.5 mg/kg) and risperidone (1.5 mg/kg) resulted in an increase in D₂ and 5-HT_2A receptor occupancy to approximately 90%. Risperidone alone caused a transient increase in H₁ receptor occupancy to 80%, while co-administration increased mACh receptor occupancy to 60%. Co-administration with chlorpromazine significantly increased the plasma concentrations of risperidone and its metabolite, paliperidone, and decreased the oral clearance of risperidone by 5.9-fold. Conclusions: Co-administration of chlorpromazine and risperidone increases the occupancy of D₂, 5-HT_2A, and mACh receptors in the rat brain and increases the plasma concentrations of risperidone and paliperidone, suggesting a potential risk of enhanced adverse effects due to both pharmacokinetic and pharmacodynamic interactions involving target and non-target brain receptors. Full article

Background: Bortezomib, a proteasome inhibitor used in multiple myeloma (MM), is associated with several adverse effects, most notably peripheral neuropathy. Ototoxicity, however, remains a rare and underrecognized complication. Case presentation: We report the case of a 74-year-old man with MM who developed sudden unilateral sensorineural hearing loss following subcutaneous bortezomib administration. Audiometry confirmed severe right-sided hearing loss. MRI of the internal auditory canal was normal. Given the absence of other ototoxic agents, bortezomib was identified as the likely causative drug. The patient was treated with intratympanic dexamethasone injections, achieving partial hearing recovery. Subsequent chemotherapy re-exposure triggered another hearing decline, which again improved after repeated intratympanic treatment. Conclusions: Bortezomib-related ototoxicity is a rare but potentially reversible adverse event. This case suggests that early intratympanic corticosteroid therapy may mitigate cochlear injury, allowing continuation of chemotherapy for patients responding well to bortezomib. Full article

Background/Objectives: Diabetes mellitus is a serious global disease characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. It represents a major health concern affecting millions of people worldwide. This condition can lead to severe complications significantly affecting patients’ quality of life. Due to the limitations and side effects of current therapies, the search for safer and more effective antidiabetic agents, particularly from natural sources, has gained considerable attention. This study investigates the antidiabetic potential of seaweed-derived compounds through structure-based virtual screening targeting α-glucosidase. Methods: A library of compounds derived from the Seaweed Metabolite Database was subjected to a hierarchical molecular docking protocol against α-glucosidase. Extra Precision (XP) docking was employed to identify the top-ranked ligands based on their binding affinities. Drug-likeness was assessed according to Lipinski’s Rule of Five, followed by pharmacokinetic and toxicity predictions to evaluate ADMET properties. Density Functional Theory (DFT) calculations were performed to analyze the electronic properties and chemical reactivity of the selected compounds. Furthermore, molecular dynamics simulations were carried out to examine the stability and dynamic behavior of the ligand–enzyme complexes. Results: Following XP docking and ADMET prediction, four promising compounds were selected: Colensolide A, Rhodomelol, Callophycin A, and 7-(2,3-dibromo-4,5-dihydroxybenzyl)-3,7-dihydro-1H-purine-2,6-dione. Molecular dynamics simulations further confirmed the structural stability and strong binding interactions of these compounds within the α-glucosidase active site. Conclusions: This investigation demonstrated the important role of seaweed-derived compounds in inhibiting α-glucosidase activity. Further experimental validation is warranted to confirm their biological activity and therapeutic potential. Full article

Background/Objectives: Leishmaniasis constitutes one of the most fatal parasitic diseases globally, adversely impacting the health of individuals residing in both intertropical and temperate zones. In these geographical areas, the administration of treatment is often inconsistent and largely ineffective with the available pharmaceuticals, as these exhibit more pronounced side effects than the therapeutic advantages they purport to provide. Methods: Consequently, the current investigation seeks to engage in molecular modeling of novel pharmacological candidates incorporating 1,2,3 disubstituted triazole moieties, coordinated with Cu^II metal centers, in pursuit of promising bioactive properties. Results: Two complexes were prepared and X-ray analysis revealed a comparable structural configuration surrounding the copper (II) atom. The planar square coordination geometry was elucidated through the assessment of the ${\tau }_4=0$ (tau four) parameters. The comprehensive characterization encompasses HRMS-ESI (+), NMR, elemental analyses, mid-infrared, and UV-vis spectroscopic techniques. Time-dependent density functional theory (TD-DFT) analyses will substantiate the findings obtained through UV-vis spectroscopy. Crucially, the biological assays against Leishmania (L.) amazonensis revealed that Complex 1 exhibited outstanding potency against the intracellular amastigote form, demonstrating a half-maximal inhibitory concentration (IC₅₀) of 0.4 µM. This activity was 6-fold higher than that of amphotericin B (IC₅₀ = 2.5 µM) and 33-fold higher than pentamidine (IC₅₀ = 13.3 µM). Furthermore, Complex 1 showed a promising selectivity index (SI = 9.7) against amastigotes, surpassing the reference drugs and meeting the criteria for a lead compound. While less active on promastigotes, both complexes demonstrated high stability in DMSO solution, a prerequisite for biological testing. Conclusions: These results unequivocally identify Complex 1 as a highly promising candidate for the development of new antileishmanial therapies, warranting further in vivo studies. Full article

Inflammation is the body’s natural immune response to invasion by foreign pathogens and is closely linked to many diseases. Chronic inflammation, if not properly controlled, can pose serious health risks and even threaten life. Currently, the main anti-inflammatory drugs are classified into steroidal and non-steroidal anti-inflammatory drugs, but both have significant side effects that limit their clinical applications. α-Hederin, a pentacyclic triterpenoid saponin, is derived from various plants, including Pulsatilla chinensis, Hedera helix, and Nigella sativa. It has been reported that α-hederin can be used to treat both acute and chronic inflammatory diseases. However, it has poor water solubility and low bioavailability. This study shows that α-hederin can directly self-assemble into a hydrogel through hydrogen bonds and van der Waals forces, called He-Gel. The mechanical properties of He-Gel were further characterized using rheological and microrheological methods. Its self-assembly mechanism was comprehensively elucidated through a combination of spectroscopic analyses and computational chemistry. Furthermore, in vitro experiments showed that He-Gel exhibits lower cytotoxicity and more excellent anti-inflammatory activity compared to free α-hederin. In conclusion, this research provides a solution for the further development of α-hederin. Unlike conventional approaches that rely on polymers as drug carriers, this preparation method is both green and economical. More importantly, it highlights that direct self-assembly of natural small molecules represents a promising strategy for anti-inflammatory therapy. Full article

Agomelatine (AG) is a novel antidepressant characterized by distinct mechanism of action and minimal side effects. However, extensive first-pass hepatic metabolism limits its clinical efficacy after oral administration, leading to low bioavailability (<5%). To get around these restrictions, the current study set out to create and assess a rectal thermosensitive in situ gel using biosynthesized AG-silver nanoparticles (AG-AgNPs). AG-AgNPs were successfully synthesized with gum acacia as a stabilizing agent, using silver nitrate as a precursor, and ascorbic acid as a reducing agent. The in situ gel formulation was optimized using a 3² factorial design, and then physicochemical, in vitro, and in vivo assessments were conducted. Nanoparticle formation was also evidenced by the appearance of a visible color change, UV-VIS, TEM, and XRD analysis techniques, which depicted spherical-shaped nanoparticles and a crystalline nature. The formulated optimized thermosensitive in situ gel showed good properties, which included drug content of 91.64%, gelation temperature of 26.63 °C, pH of 7.2, gel strength of 36.98 s, and sustained drug release of 80.24% in 6 h. The relative bioavailability in animal studies showed a remarkable increase in systemic availability with 277.5% relative bioavailability in comparison to an oral tablet formulation. In summary, results show that the AG-AgNP-loaded thermosensitive in situ gel could have potential use as a rectal delivery drug for bypassing first-pass effects and improving bioavailability for the drug Agomelatine. Full article

Background: Atherosclerosis (AS) serves as the primary pathological basis for cardiovascular disease-related deaths worldwide, posing a severe threat to public health security. Heat shock protein 90 (HSP90) plays a crucial regulatory role in the pathological progression of AS, emerging as a potential target for anti-atherosclerosis drug development in recent years. Calenduloside E (CE) is a pentacyclic triterpenoid saponin isolated from Aralia elata (Miq.) Seem. Previous studies have confirmed its anti-atherosclerotic activity, but its weak efficacy and narrow therapeutic index limit its clinical application. In this study, the CE scaffold was hybridized with a ticagrelor-derived fragment to enhance anti-atherosclerotic activity. In this study, the CE scaffold was hybridized with a ticagrelor fragment to achieve improved activity. Methods: Based on the principle of molecular hybridization, CE was linked to the active fragment of ticagrelor via a PEG chain. Ten CE derivatives were synthesized by modifying the sugar substituents. In vitro experiments were conducted to detect cytotoxicity and protective activity against ox-LDL-induced HUVECs injury. Molecular docking and Surface Plasmon Resonance (SPR) assays were used to evaluate the interaction between CE derivatives and the known target HSP90β. Combined with Microscale Thermophoresis (MST), SwissTargetPrediction, and molecular docking, other potential targets of CE derivatives were identified. Results: In the ox-LDL-induced HUVECs injury model, all compounds except C2 and C9 exhibited protective activity. Among these compounds, compound C5 exhibited the optimal protective effect, with an EC₅₀ value of 1.44 μM. Molecular docking results revealed that both C5 and CE could bind to HSP90β by forming hydrogen bonds with the key amino acid Asp93. Additionally, SPR results indicated that C5 and CE had similar binding affinities to HSP90β, with dissociation constants (K_D) of 1.73 μM and 1.72 μM, respectively. MST demonstrated that C5 binds to HSP90β with an affinity 111 times higher than that of ticagrelor. SwissTargetPrediction and molecular docking identified P2Y12 as another potential target of derivative C5. Conclusions: Compound C5 exerts protective effect against ox-LDL-induced HUVECs injury by targeting HSP90β. Its effective concentration is significantly improved compared with that of the parent CE, which provides a possibility for reducing clinical dosage and toxic side effects in subsequent studies. Furthermore, C5 may exert its effects by targeting another potential target, P2Y12, offering references for the rational design of novel anti-atherosclerotic drugs. Full article

Chagas disease remains a major public health challenge due to the limited effectiveness and considerable side effects of existing treatments, particularly during the chronic stage. Açaí (Euterpe oleracea) seeds have gained increasing attention as a source of bioactive compounds with potential therapeutic applications. In this study, hydroalcoholic extracts and solvent fractions obtained from açaí seeds were chemically characterized by ESI/MS and HPLC–MS/MS and evaluated for their cytotoxicity and antiparasitic activity against different developmental stages of Trypanosoma cruzi (Y strain). Chemical profiling revealed a predominance of phenolic compounds, particularly catechins and procyanidins, which were identified as major constituents of the hydroalcoholic extract and the ethyl acetate fraction. Cytotoxicity assays performed on murine peritoneal macrophages demonstrated low toxicity, with CC₅₀ values exceeding 500 µg/mL for most samples, indicating a favorable in vitro safety profile. Antiparasitic assays showed weak activity against epimastigote forms; however, significant inhibitory effects were observed against bloodstream trypomastigotes, cell culture-derived trypomastigotes, and intracellular amastigotes. Notably, the hydroalcoholic extract exhibited the highest selectivity against intracellular amastigotes, with a selectivity index greater than 10, fulfilling key criteria proposed by the Drugs for Neglected Diseases initiative (DNDi) for early-stage hit compounds. Flow cytometry analysis showed that both the hydroalcoholic extract and the ethyl acetate fraction induced parasite cell death through late apoptosis-like and necrosis. Together, these findings highlight the antiparasitic potential of E. oleracea seed extracts, particularly against clinically relevant stages of T. cruzi, and support further investigation of these bioproducts as promising candidates for the development of new therapeutic strategies for Chagas disease. Full article

Systemic anticancer therapy causes a number of side effects; therefore, local drug release devices may play an important role in this area. In this study, we developed polyurethane-dendrimer foams containing different amounts of third-generation poly (amidoamine) dendrimers (PAMAM G3) to evaluate their ability to encapsulate and release the model anticancer drug doxorubicin (DOX), as well as their biocompatibility and effectiveness against normal and cancer cells in vitro. PU–PAMAM foams containing 10–50 wt% PAMAM G3 were prepared using glycerin-based polyether polyol and castor oil as co-components. Structural and rheological analyses revealed that foams containing up to 20 wt% PAMAM G3 exhibited a well-developed porous structure, while higher dendrimer loadings (≥30 wt%) led to irregular cell shapes, pore coalescence, and thinning of cell walls, and indicated a gradual loss of structural integrity. Rheological creep–recovery measurements confirmed the structural findings: moderate PAMAM G3 incorporation (≤20 wt%) increased both the instantaneous and delayed elastic modulus (E₁ ≈ 130–140 kPa; E₂ ≈ 80 kPa) and enhanced elastic recovery, reflecting improved cross-link density and foam stability. Higher dendrimer contents (30–50 wt%) caused a decline in these parameters and higher viscoelastic compliance, indicating a softer, less stable structure. The DOX loading capacity and encapsulation efficiency increased with PAMAM G3 content, reaching maximum values of 35% and 51% for 30–40 wt% PAMAM G3, respectively. However, the most sustained DOX release profiles were observed for matrices containing 20 wt% PAMAM G3. Analysis of cumulative release and kinetic modeling revealed a transition from diffusion-controlled release at low PAMAM contents to burst-dominated release at higher dendrimer loadings. Importantly, matrices containing 10–20 wt% PAMAM G3 also indicated selective anticancer action against squamous cell carcinoma (SCC-15) compared to non-cancerous human keratinocytes (HaCaT). Moreover, the DOX they released effectively destroyed cancer cells. Overall, PU–PAMAM foams containing 10–20 wt% PAMAM G3 provide the most balanced combination of structural stability, controlled drug release, and cytocompatibility. These materials therefore represent a promising platform as passive carriers in drug delivery systems (DDSs), such as local implants, anticancer patches, or bioactive wound dressings. Full article

Gastrointestinal disorders negatively affect populations worldwide. Considering the side effects of synthetic drugs, natural products can be a safe and effective alternative to help treat gastric ulcers and diarrhea. In this context, the present study reviewed the antiulcerogenic and antidiarrheal activities of species of the genus Croton (Euphorbiaceae). The scientific documents were retrieved from different databases, covering publications from the first report on the topic in 1998 to October 2025. Although the genus Croton comprises approximately 1200 species, only 11 have been evaluated for their antiulcerogenic and antidiarrheal potential in in vivo and in vitro studies. Among the identified bioactive constituents, the diterpenes trans-dehydrocrotonin and trans-crotonin, isolated from Croton cajucara, demonstrated significant antiulcerogenic activity in several experimental models in vivo. Similarly, the compound crofelemer, isolated from the latex of the bark of Croton lechleri, has shown promising results in several clinical trials for the treatment of diarrhea. Furthermore, flavonoids including rutin and quercitrin have been detected in Croton campestris. Regarding gastroprotective mechanisms, evidence suggests that extracts and essential oils obtained from Croton species may act through the nitric oxide pathway, promoting an antiulcerogenic effect. Additional studies are needed to investigate the gastroprotective and antiulcerogenic potential of at least 17 Croton species used empirically in traditional medicine for the treatment of gastrointestinal disorders but still without scientific validation. Full article

Inflammatory bowel disease is a result of inappropriate continuous non-specific inflammation in the intestinal tract, which in turn is aggravated by defects in the activation of the mucosal immune system and in the barrier function of the intestinal epithelium. The most prominent manifestations of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterized by a continuous pattern that commonly starts with lesions in rectum mucosa and is contained in the colon. On the other hand, CD affects the ileum and colon in a discontinuous pattern, and the lesions are often transmural. Conventional therapies often face limitations such as systemic side effects, poor drug stability, and low site-specificity. In recent years, nanoparticle (NP) systems have emerged as a promising strategy to overcome these challenges, offering improved targeting, controlled release, and enhanced therapeutic efficacy. Several studies have shown that the preferential accumulation of NPs in the inflamed colon is influenced by the pathophysiological changes associated with IBD, including alterations in transit time, pH value, enzymatic activity, microbial composition, and mucus integrity. These disease-specific characteristics provide unique opportunities to design smart and responsive NPs that enhance drug delivery and therapeutic efficacy while minimizing systemic exposure. This work presents an overview of novel technologies based on nanosystems, with the ability to specifically target the affected areas of the GI tract in inflammatory bowel disease. Full article