Pharmaceutical Research最新文献

The purpose of this review is to provide a concise overview of phytochemicals and their possible effects on gastrointestinal (GI) malignancies via modification of the mitogen-activated protein kinase (MAPK) signaling cascade. Abnormal activation of the MAPK pathway significantly contributes to GI cancer progression and is associated with various facets of cancer, including cellular proliferation, apoptosis, invasion, angiogenesis, and metastasis. Although standard medications are essential for managing GI cancers, their side effects frequently present considerable obstacles to the patient's quality of life. Thus, there is increasing emphasis on phytochemicals that are safe, non-toxic, and multitargeted properties. In recent years, phytochemicals have garnered significant interest in antitumor therapy, leveraging their multifaceted signaling regulatory actions to activate several biological mechanisms, thereby offering substantial benefits in tumor inhibition. These phytochemicals have the ability to reduce tumor development and induce cancer cell death by selectively inhibiting several components of the MAPK pathway in in vitro and in vivo GI cancer models. Thus, this review highlights the current knowledge on phytochemicals that modulate MAPK pathway in GI cancers, their mode of action along with their limitations. In conclusion, phytochemicals offer a promising strategy for addressing dysregulation of the MAPK pathway in gastrointestinal cancer, necessitating further investigation.

Purpose: Mechanical, interfacial, and shear stresses encountered during development, manufacturing and transportation of biologics can compromise monoclonal antibody (mAb) stability. However, most scale-down shaking models often depend solely on orbital agitation and overlook the effect of the solid-liquid interface. To study this gap, stress conditions were applied to simulate early-stage product development and real-world transportation in this work.

Methodology: Accordingly, the aggregation profiles of Cetuximab and Tocilizumab formulations, with and without polysorbate 80 (PS80), were systematically compared after applying horizontal and orbital shaking. Protein aggregation was assessed using orthogonal techniques such as size-exclusion chromatography, dynamic light scattering, flow imaging microscopy, ultraviolet-visible spectroscopy, and visual inspection.

Results: Horizontal shaking more effectively revealed Cetuximab's susceptibility to aggregation under mechanical and interfacial stress whereas orbital shaking conditions were not as discriminative. Furthermore, to explore the effect of vial surface chemistry on subsequent protein aggregation, Cetuximab was subjected to horizontal shaking stress using both untreated and silanized glass vials. Interestingly, hydrophobic silanized vials without surfactant resulted in increased Cetuximab aggregation compared to untreated vials. In contrast, Cetuximab with PS80 showed fewer aggregates in silanized vials than in glass vials.

Conclusion: These results underscore the value of selecting right-for-purpose agitation models and highlight the need to explore the triple interface for improving stress screening in drug product development.

Objective: Conventional low-dose levetiracetam (LEV) for post-neurosurgical seizure prophylaxis often yields subtherapeutic serum levels. This study characterized the population pharmacokinetics (PPK) of intravenous LEV to optimize dosing in neurosurgical patients.

Methods: We conducted a retrospective PPK analysis in 87 neurosurgical patients (131 concentrations). Nonlinear mixed-effects modeling was used. Monte Carlo simulations identified regimens achieving ≥ 90% probability of target attainment (PTA) for trough concentrations (C_min) of 12-46 μg/mL.

Results: LEV median daily dose was 15.4 (7.7-43.5) mg/kg. A median of 1.5 (1-6) concentration samples were collected per patient. The LEV concentrations was 9.11 (1.39-33.79) μg/mL. Importantly, 78 random concentrations and C_min of 10 patients were all subtherapeutic. Seizures occurred in 13 patients (14.9%); all responded to dose escalation/valproate. A one-compartment model described PK. Estimated clearance (CL) and volume of distribution were 3.73 L/h and 28.10 L, respectively. Covariate analysis identified CrCl and mannitol coadministration as significant CL determinants. Monte Carlo simulations indicated that without mannitol, 1 g q8h (0.5h infusion for CrCl at 20-89 mL/min; 4h infusion for CrCl at 90-129 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 130-180 mL/min) achieved > 90% PTA. With mannitol, higher doses were required: 1 g q8h (4h infusion, CrCl at 20-49 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 50-89 mL/min; 4h infusion for CrCl at 90-180 mL/min).

Conclusion: Standard LEV prophylaxis dosing often yields inadequate exposure in neurosurgical patients. LEV clearance is influenced by CrCl and mannitol use, higher doses is required for patients with concurrent mannitol therapy.

Objective: Bicyclol, a hepatoprotective agent, is often used in combination with other drugs for liver diseases, including drug-induced liver injury (DILI), raising concerns about potential drug-drug interactions (DDIs). This study investigates the interaction between bicyclol and key transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, BCRP, BSEP) to predict transporter-related DDI risks.

Methods: Transporter interaction studies were conducted using cell lines or membrane vesicles overexpressing human uptake and efflux transporters. The substrate and inhibitory potential of bicyclol were systematically evaluated through transport and inhibition assays. The static model and criteria were applied to assess the risk of transporter-related DDIs in vivo.

Results: Bicyclol was not a substrate of above-mentioned transporters. Regarding inhibition, it was not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, or BSEP (IC₅₀s > 100 μM). However, it was a marginal inhibitor of OCT2 (IC₅₀ = 76.2 μM), a weak inhibitor of P-gp (IC₅₀ = 123 μM), and a strong inhibitor of BCRP (IC₅₀ = 8.5 μM). The static model predicted that only BCRP would be inhibited in vivo by bicyclol, suggesting dose optimization might be required for BCRP substrates.

Conclusions: Here, we systematically elucidated the substrate and inhibition potential of bicyclol on major human drug transporters for the first time, which may provide the basis for rational co-administration of bicyclol, potentially broadening its clinical application.

Objective: The development of protein formulations is grappled by the complexity of maintaining protein integrity during the arduous formulation process. While several excipients have been employed for the stabilization of proteins, including the recombinant human growth hormone (rhGH), a precise process control is still paramount. This study aims to investigate the effect of mannitol polymorphism on the structural stability of rhGH in its spray-dried formulations.

Methods: rhGH was co-spray dried with mannitol at protein:mannitol ratios (1:0.5 to 1:6, w/w). Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) characterized mannitol crystallinity. Furthermore, circular dichroism (CD) spectroscopy measured secondary structure pre- and post-accelerated storage (40°C/75% RH, 4 weeks), and SDS-PAGE was leveraged to evaluate protein aggregation.

Results: Spray-dried powders exhibited spherical particles (1-5 µm) with surface indentations. PXRD reported high levels of mannitol crystallization with ratios of 1:0.5, 1:1.5, and 1:6, which was corroborated by the change in crystallization index using DSC. Parallelly, it corresponded to reductions in α-helix content ranging from 21.8 to 25%, after storage. In contrast, the 1:4 ratio predominantly demonstrated an 8.4% increase in α-helix content, indicating enhanced stability. SDS-PAGE confirmed greater aggregation in samples with higher mannitol crystallization, whereas the 1:4 formulation minimized aggregation.

Conclusion: Mannitol crystallization strongly influences rhGH stability in spray-dried powders. An optimal protein:mannitol ratio of 1:4 helped maintain mannitol in the amorphous state, preserved secondary structure, and reduced aggregation during storage. These findings underscore excipient crystallization as a key determinant of protein stability and identify a stabilizing composition for spray-dried rhGH.

Purpose: This review aims to examine the impact of three-dimensional (3D) printing technologies on enhancing psychiatric pharmacotherapy through facilitating personalized and patient-centered drug delivery. This research specifically addresses problems such as poor medication compliance, polypharmacy, and palatability issues, especially in pediatric and elderly populations.

Methods: A thorough review of the literature was conducted, focusing on novel advances in 3D printing techniques, including fused deposition modeling (FDM), semisolid extrusion (SSE), stereolithography, inkjet printing, binder jetting, and selective laser sintering (SLS). Selected research highlighted the application of such technologies in developing customized oral drug dosage forms. Emphasis was placed on the exploitation of polymers like Eudragit® E PO, flavor-masking excipients, and their combination with biosensor and artificial intelligence (AI) systems. Case studies were assessed to ascertain their relevance and innovation in the development of psychiatric medications.

Results: 3D printing allows the manufacture of tailored psychiatric drugs with greater dosing versatility, taste masking, and the ability to merge several active drug ingredients into a single pharmaceutical form. Patient-friendly dosage forms such as chew gummies and chocolate tablets demonstrated enhanced acceptability. Also, forthcoming technologies such as 4D printing and AI-driven biosensors yield intelligent, interactive drug release systems that are specific to individual physiological or behavioral inputs.

Conclusions: 3D printing represents a paradigm-shifting advance in psychiatric care, offering solutions to long-standing treatment compliance and fixed-dose challenges. Although regulatory and scalability challenges persist, the intersection of pharmaceutical engineering, material science, and artificial intelligence creates an encouraging platform for the future of precision mental care therapies.

Exosomes (EXM), cell-secreted nanoscale vesicles, are now used as promising tools for therapeutic protein, nucleic acid, and small molecule delivery. However, various challenges, such as rapid immune system clearance, ineffective cargo loading, and reduced targeting specificity, hold them back from being clinically translated. Recent breakthroughs in EXM engineering have made them excellent biomolecule delivery tools. This review critically explores state-of-the-art strategies to maximize cargo incorporation, reengineer EXM surfaces, and create synthetic EXM mimetics. We present important engineering methods, such as genetic manipulation to increase cargo encapsulation, functionalization with targeting ligands, and designing synthetic vesicle structures. We further discuss the therapeutic uses of engineered EXM for different applications, such as cancer treatment, gene therapy, and regenerative medicine, highlighting their potential to evade biological barriers like the blood-brain barrier. Challenges in manufacturing, quality control, and regulatory concerns of translating engineered EXM into clinical therapies are also discussed. We emphasized the upcoming trends that would facilitate improving EXM-based delivery platforms, such as the creation of multifunctional engineered EXM and the incorporation of artificial intelligence for tailored drug delivery. This review stresses the revolutionary value of EXM engineering in establishing next-generation targeted therapeutics, unveiling new fronts for precision medicine and personalized health.

PURPOSE OR OBJECTIVE: Each Easyhaler^® Salbutamol 100 μg dry powder inhaler (DPI) uniquely requires pre-actuation shaking, unlike most commercial DPIs. This study aimed to investigate the aerodynamic and functional implications of pre-actuation shaking to determine its effect on drug delivery performance.

Methods: Device actuation was performed following 0 to 5 pre-actuation shakes. Performance was assessed using a multi-technique approach: cascade impaction, dose uniformity testing (DUSA), laser diffraction (SprayTec), optical microscopy, and scanning electron microscopy (SEM). Key parameters measured included emitted dose (ED), delivered dose (DD), fine particle dose (FPD), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and throat deposition.

Results: Delivered dose remained relatively constant regardless of shaking. However, FPD and FPF significantly improved with increased shaking, particularly at three to five shakes. Cascade impaction demonstrated reduced throat deposition and greater deposition in stages 3-4 (< 5 µm respirable fraction) under these conditions. An inverse correlation between throat deposition and FPF was identified. SEM and microscopy confirmed consistent particle morphology and blend uniformity, while laser diffraction showed a predominance of larger carrier particles under 0-shake conditions.

Conclusions: Pre-actuation shaking substantially influences the aerosolization performance of Easyhaler^® Salbutamol. At least three vertical shakes are required to achieve optimal fine particle delivery and reduce throat deposition. These findings highlight the importance of proper patient instruction on device handling. Further studies should assess whether similar effects occur with other Easyhaler^® formulations.

Objective: Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics by regulating gene expression, halting cell cycle progression, and inducing apoptosis. This study explores the structure-activity relationship of 2-mercaptoquinazolin-4(3H)-one derivatives as potential anticancer agents and HDAC inhibitors.

Methods: The library compounds were prepared via a three-step pathway by incorporating 2-mercaptoquinazoline and a hydroxamic acid moiety. The cytotoxicity of 27 synthesized hydroxamic acid derivatives was evaluated against SW620 (colon cancer), MDA-MB-231 (breast cancer), and MRC-5 (normal lung fibroblast) cell lines. Molecular docking studies on HDAC-isoforms for the 4a-i were also performed to identify the essential structural features that contribute to the biological activities.

Results: The results demonstrated that substituents at the N-3 position significantly influenced anticancer activity, with methyl-substituted derivatives (4a-i) exhibiting the highest cytotoxicity, followed by phenyl-substituted (7a-i) and benzyl-substituted (10a-i) compounds. Among the tested compounds, 4a (-H) and 4c (7-CH₃) showed as the most potent active compounds, with IC₅₀ values of 4.24 ± 1.16 µM and 3.61 ± 0.32 µM against SW620 cells, and 2.93 ± 0.68 µM and 3.34 ± 0.32 µM against MDA-MB-231 cells, respectively. HDAC inhibition assays revealed that 4a-d and 4 g exhibited superior inhibitory activity compared to SAHA. Further investigation of 4a and 4c in SW620 cells showed that both compounds induced G2/M phase cell cycle arrest and promoted apoptosis, supporting their potential as promising HDAC inhibitors with anticancer properties.

Conclusions: Among the most active compounds, 4a and 4c may serve as promising leads for the development of novel HDAC-targeted anticancer therapies.