Objective: To evaluate the efficacy and safety of a preservative-free tafluprost/timolol maleate fixed-dose combination compared with preservative-free tafluprost monotherapy in Chinese patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: This was a multicenter, randomized, double-blind, parallel-controlled clinical trial conducted across 25 centers, including the Eye & ENT Hospital of Fudan University, from January 2019 to November 2022. Patients diagnosed with OAG or OHT who required enhanced intraocular pressure (IOP) reduction after a 4-week washout period were enrolled. Participants were randomized 1∶1 to receive either tafluprost/timolol or tafluprost once daily for 3 months. The primary endpoint was the change from baseline in mean diurnal IOP (the average of measurements at 8:00, 10:00, and 16:00) at Month 3. Secondary endpoints included IOP changes at individual time points and the proportion of responders achieving predefined IOP reduction thresholds. Safety was assessed via the incidence of adverse events (AEs). Analysis of covariance (ANCOVA) using the Markov Chain Monte Carlo (MCMC) method was employed for the primary endpoint; superiority was established if the upper limit of the 95% confidence interval (CI) was<0 mmHg (1 mmHg=0.133 kPa). Continuous variables in secondary endpoints were compared using ANCOVA, and responder rates were analyzed using Fisher's exact test. Results: A total of 219 patients were enrolled (tafluprost/timolol group: n=110; tafluprost group: n=109). The primary efficacy analysis set included 215 patients (tafluprost/timolol: n=107; tafluprost: n=108). Baseline characteristics were well-balanced between the two groups. The majority of patients were male [127 (59.1%)] with a mean age of (44.80±15.71) years at screening. At Month 3, the mean diurnal IOP reduction from baseline was (6.56±3.44) mmHg in the tafluprost/timolol group and (5.36±2.94) mmHg in the tafluprost group. After adjusting for baseline IOP, the between-group difference was -1.312 mmHg (95%CI: -2.010 to -0.696); as the upper limit was<0 mmHg, tafluprost/timolol demonstrated superior IOP-lowering efficacy to tafluprost. Responder rates for IOP reductions of≥15%,≥25%, and≥30% were significantly higher in the tafluprost/timolol group (P=0.016, 0.028, and 0.032, respectively). The incidence of ocular AEs was 20.0% (22/110) in the tafluprost/timolol group and 26.6% (29/109) in the tafluprost group. The most common AE was conjunctival hyperemia, occurring in 2.7% (3/110) and 8.3% (9/109) of the groups, respectively. Conclusion: Compared with preservative-free tafluprost monotherapy, the tafluprost/timolol combination provides significantly greater IOP reduction in patients with OAG and OHT, while maintaining a favorable safety profile.

The increasing demand for oral liquid formulations (OLFs), highlights the need to optimize pharmacotherapy in pediatric and geriatric populations, where swallowing difficulties and dose individualization are critical. One such drug is bisoprolol, a highly selective β1-adrenergic receptor blocker widely used in the management of cardiovascular diseases, for which individualized dose titration is frequently required, particularly in pediatric and geriatric patients. Conventional solid dosage forms often lack the flexibility required, potentially compromising adherence and increasing the risk of medication errors. This study aimed to develop safe, stable, and palatable OLFs of bisoprolol fumarate suitable for individualized dosing. A Quality by Design (QbD)-oriented approach was employed to define the Quality Target Product Profile (QTPP) and identify Critical Quality Attributes (CQAs), including drug content, pH, and organoleptic properties. Two sets of formulations were prepared: sugar-free drops and syrups, each at two strengths (2.5 and 5.0 mg mL[-1]). Physical, chemical, and microbiological stability were assessed over 12 months under long-term (4 °C and 25 °C) and 6 months under accelerated conditions (40 °C), using a validated methodology. All formulations remained within predefined specifications, showing no significant degradation or physicochemical changes. Microbiological quality and palatability were maintained throughout the study. These findings demonstrate that the strategy based on QbD principles enables the development of robust, patient-centric OLFs, representing a reliable alternative to extemporaneous preparations and supporting safer, more flexible cardiovascular therapy.

Echinocandin antifungal drugs, such as caspofungin, inhibit β-1,3-glucan synthesis to impair cell wall formation. Caspofungin is effective in the clinic against Aspergillus and Candida species but ineffective against Cryptococcus neoformans, the fungus responsible for life-threatening meningoencephalitis in immunocompromised individuals. The mechanisms of caspofungin resistance in C. neoformans are associated with calcineurin signaling and functions that influence membrane and cell wall composition. The synergistic effects of caspofungin have been studied in combination with various inhibitors, but it is not known whether resistance can be overcome by agents that target the endoplasmic reticulum to influence protein glycosylation, as well as cell wall and membrane composition. Additionally, the role of the polysaccharide capsule of C. neoformans in blocking the access of caspofungin to the target Fks1 glucan synthase is not clear. Here, we identified a potential synergistic effect between caspofungin and the glycosylation inhibitor tunicamycin, with a significant reduction in proliferation, capsule attachment, and chitin and β-1,3-glucan levels when the drugs were used in combination. A targeted screen also identified other agents that influence ER function and that potentially display synergy with caspofungin. Overall, our analysis provides evidence that targeting the ER to impair cell wall and membrane integrity and capsule formation is an effective strategy to overcome caspofungin resistance in C. neoformans.IMPORTANCECryptococcus neoformans is the major cause of life-threatening meningoencephalitis in immunocompromised people. Unfortunately, the number of antifungal drugs available to treat cryptococcal disease is quite limited, and unlike other pathogenic fungi, C. neoformans is intrinsically resistant to the echinocandin group of drugs. These drugs target cell wall biosynthesis, and the mechanisms of cryptococcal resistance are not entirely clear. In this study, we demonstrate synergy between the echinocandin drug caspofungin and tunicamycin, an inhibitor of protein glycosylation in the endoplasmic reticulum. Combined treatment impacts cell wall and plasma membrane composition, thus providing insights into approaches to overcome resistance.

Infantile hemangioma (IH) is a benign tumor that appears in the first year of life and typically involutes within 3 to 4 years. Ulcerative IH, the most common complication, poses a significant burden to patients. Early referral of high-risk cases reduces morbidity. Current literature on risk factors and prognosis is limited. Segmental and mixed IH in urogenital, head, neck, and lip areas show higher ulceration risk. Diagnosis is typically clinical; histopathology is rarely performed. Atypical cases require positive glucose transporter-1 immunohistochemistry. Larger lesions, delayed intervention, and bacterial infection worsen prognosis, prolong healing, and increase recurrence. Condition-dependent treatments, including oral propranolol (starting at 1 mg/kg or less daily, maintenance at 2 to 3 mg/kg daily), timolol prophylaxis, and wound management care combined with laser therapy, shorten therapy duration and minimize recurrence. Empiric antibiotics are indicated for infected ulcerative IH. Surgery is indicated for life-threatening cases (eg, chest wall hemangiomas requiring transfusion or airway obstruction) and high-morbidity cases (eg, lip lesions affecting speech or periorbital lesions impairing vision). The Infantile Hemangioma Referral Score helps clinicians identify high-risk patients who require prompt referral, thereby preventing delayed treatment.

Infantile hemangioma (IH) is the most common benign soft tissue tumor of infancy with its pathogenesis yet to be elucidated. IHs are defined as vascular tumors of infancy and the diagnosis of IH is largely based on clinical findings, most commonly the characteristic strawberry appearance. IHs follow a stereotyped life cycle of rapid growth, a plateau, and eventual involution, and most do not require treatment. If complicated, first-line medical treatment of IH is oral propranolol, currently the most commonly used and efficacious drug. Surgery remains an option but is reserved for IHs primarily not responsive to medical treatment.

Numerous pharmacogenomic (PGx) associations of pharmacokinetics and pharmacodynamics of commonly prescribed medications have been reported. Yet, the evidence supporting their association on survival remains underexamined. We sought to investigate the CYP2D6-metoprolol association and determine whether the established variability in drug exposure and hemodynamic response would translate into differences in mortality across metabolizer status in the Montreal Heart Institute Hospital Cohort. Single random plasma samples were collected from 996 patients receiving metoprolol tartrate. Bioanalytical quantification was performed via liquid chromatography-tandem mass spectrometry, while CYP2D6 metabolizer status was based on standardized classifications. Cox regression models adjusted for age, sex, cardiovascular history, concomitant medications, and CYP2D6 inhibitors were used to assess the time to death since enrolment. Overall, 24.3% (n = 242) of patients were deceased at follow-up (median 101.4 months). Higher metabolizer status at CYP2D6 was associated with lower risk of death (HR = 0.82, 95% CI: 0.67-0.99; p = 0.04). Metoprolol concentrations were no longer associated with mortality after adjusting for possible confounders. Our study suggests that CYP2D6-inferred metabolizer status can inform on mortality risk in patients treated with metoprolol. Larger initiatives are required to confirm the association of CYP2D6 metabolizer status with clinical events beyond pharmacokinetic and hemodynamic considerations.

Malaria-causing Plasmodium parasites must pass through several host cell types to complete their life cycle. This cell traversal is facilitated by perforin-like proteins (PLPs), among which PLP2 is essential for erythrocyte rupture by gametocytes. However, the mechanism by which PLP2 forms pores is not yet understood. Here, we combine cryo-electron microscopy and tomography to reveal the structural basis of Plasmodium vivax PLP2-mediated membrane attack. PvPLP2 assembles on lipid bilayers into heterogeneous arc- and ring-shaped pores with variable stoichiometries. Among them, we determine the structure of a 17-subunit pore complex in which the pore-forming MACPF domains form the central β-barrel, while the peripheral Apicomplexan PLP C-terminal β-pleated sheet (APCβ) domains anchor the complex to the membrane surface. A disulfide-stabilized mutant captures an intermediate pre-pore complex prior to membrane insertion, delineating the structural transitions that underpin β-barrel deployment. Functionally, PvPLP2 acts preferentially on the inner leaflet of the erythrocyte membrane, a specificity driven by its affinity for negatively charged lipids. Together, these findings establish the pore-formation pathway for a key Plasmodium virulence factor and provide a structural framework for rational design of transmission-blocking agents that prevent gametocyte egress.

Intranasal delivery offers a direct route to the brain, circumventing the blood-brain barrier (BBB) and minimizing systemic toxicity. However, its efficiency is mainly limited by the nasal mucosal barrier (NMB). Here, low-intensity pulsed ultrasound (LIPUS) without depending on the microbubbles (MBs) to amplify energy, is directly used to reversibly open the NMB by disrupting tight junction proteins. A bionic nanovesicle (iRGD-anti-programmed cell death ligand 1 (aPD-L1) & carvedilol (β-blocker) @ macrophage-derived extracellular vesicles, iMPC) is designed to co-deliver carvedilol for β-receptor blockade to reduce T-cell exhaustion, and aPD-L1 to enhance T-cell anti-tumor activity in orthotopic glioblastoma (GBM) mice during the two-hour window for NMB opening. Consequently, compared to free aPD-L1, up to a 33.38-fold increase of aPD-L1 in the GBM region is obtained with LIPUS-mediated intranasal delivery of iMPC. Reactivating T cells significantly enhances immunotherapy, leading to a 40% tumor reduction, extended survival, and long-term immune memory in orthotopic GBM mice. Overall, the LIPUS-mediated NMB opening strategy notably enhances nose-to-brain drug delivery efficiency, offering a promising platform for treating brain diseases.

Antiarrhythmic drug therapy in cardiomyopathies remains challenging because arrhythmic risk, drug efficacy, and pro-arrhythmic vulnerability vary substantially across phenotypes. This review summarizes contemporary guideline and consensus recommendations on antiarrhythmic drug use in hypertrophic, dilated, non-dilated left ventricular, and arrhythmogenic cardiomyopathies.

Epileptogenesis is increasingly recognized as a multifactorial process driven by persistent neuroinflammation, oxidative stress, and dysregulated intracellular signaling, highlighting the need for therapeutic strategies that extend beyond symptomatic seizure control. The present study investigated the potential effects of prophylactic carvedilol administration on behavioral seizure progression and associated pathological alterations during the PTZ-induced kindling model, with particular emphasis on inflammatory and signaling pathways implicated in epileptogenesis. Repeated PTZ administration resulted in progressive behavioral seizure development, impaired open-field performance, hippocampal neuronal damage, reduced GABA levels, increased oxidative stress and inflammatory mediators, and altered hippocampal NLRP3 expression, along with changes in PI3K-, AKT-, and mTOR-related protein expression. Carvedilol treatment was associated with lower behavioral seizure scores, improved open-field performance, preservation of hippocampal architecture, restoration of GABA content, and attenuation of oxidative and inflammatory alterations. Carvedilol treatment was also accompanied by reduced NLRP3 levels and changes in PI3K/AKT/mTOR-related measurements. These findings demonstrate associations between carvedilol treatment and multiple pathological processes during PTZ-induced kindling, but do not establish direct pathway-specific causality.