DARU Journal of Pharmaceutical Sciences最新文献

Background: New psychoactive substances (NPS) pose a rapidly evolving public health challenge due to their diverse chemical structures and psychoactive effects, necessitating a comprehensive understanding of their classification, mechanisms of action, and detection.

Objectives: Recognizing critical gaps in the understanding and management of NPS, this review aimed to synthesize current liter-ature. Specifically, we sought to elucidate the evolving classifications of NPS, delineate their underlying molecular mechanisms of action to inform therapeutic strategies, and critically evaluate existing detection methodologies to ad-dress current analytical limitations, thereby providing an essential, integrated perspective on this rapidly changing landscape.

Methods: A narrative literature review was conducted to analyze NPS classification, molecular mechanisms, and detection techniques. Searches were performed across Web of Science, Scopus, PubMed, and Elsevier, using keywords such as "synthetic cathinones", "designer drugs", "new psychoactive substance(s)", "detection of new psychoactive sub-stances" and "toxicology." Inclusion criteria prioritized studies primarily focused on NPS with clearly defined com-pounds (e.g., UNODC, EMCDDA classifications) and published within the last four years. Eligible publications en-compassed in vivo and in vitro studies, original research, and various review types. Exclusion criteria involved liter-ature outside the specified timeframe and studies on established drugs of abuse or licit substances, unless a direct comparative analysis with NPS was presented.

Results: The review synthesized a classification framework for NPS, detailed the molecular mechanisms underlying their psychoactive effects, and summarized current detection methodologies. Furthermore, it underscored the significant health risks associated with NPS use, including addiction, psychological disturbances, organ toxicity, and fatal outcomes.

Conclusion: The continued emergence and proliferation of NPS necessitate ongoing research to fully characterize their specific effects and associated risks. This review provides a foundational synthesis of current knowledge, not only supporting the development of evi-dence-based interventions to mitigate their public health impact, but also serving as a catalyst for new research direc-tions aimed at a deeper understanding and more effective management of these evolving compounds.

Background: The co-delivery of two therapeutic agents within a single nanoparticle platform offers a potential strategy to improve treatment efficacy while minimizing adverse effects. Albumin as a biocompatible carrier could facilitate simultaneous delivery of cargos to the tumoral region based on passive targeting gained by enhanced permeability and retention (EPR).

Objectives: This study aimed to develop, characterize, and assess a dual-drug delivery system incorporating rapamycin and SN38, utilizing the nanoparticle albumin bound technique, for the treatment of breast cancer.

Methods: Albumin bound NPs of SN38 and rapamycin were prepared using probe sonication method. NPs were characterized using dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM) techniques to confirm their hydrodynamic diameter and structural properties. Drug loading (DL) and entrapment efficiency (EE) were measured using validated reverse phase high performance liquid chromatography (RP-HPLC) methods. Cellular cytotoxicity assay, cellular internalization, quantitatively cellular uptake, colony formation assay, and sphere formation assay were performed. To track NPs destiny as a 24 h follow up in the biodistribution part, NPs were intravenously injected to the BALB/c tumor bearing mice.

Results: Blank NPs showed hydrodynamic diameter of about 121 nm, drug incorporation resulted in sizes around 200 nm. No toxicity was observed by MTT assay for blank albumin NPs. MTT assay of drug loaded NPs showed higher toxicity for dual drug loaded NPs compared to single drug loaded NPs. Confocal images and flow cytometry showed high accumulation of NPs in cytoplasmic space of 4T1 cells. All of the experimental groups showed significant decrease in colony formation and sphere formation in comparison to the control group. NPs were also preferentially accumulated in the tumoral region in vivo due to their suitable size.

Conclusion: In conclusion, the designed drug delivery system proposes great potential for breast cancer treatment.

Introduction: Esophageal squamous cell carcinoma (ESCC) is a prevalent and lethal cancer, with traditional treatments often ineffective. This study investigates the anti-proliferative and anti-metastatic effects of natural compounds Urolithin A (UA) and Urolithin B (UB) on ESCC cell lines KYSE-30 and YM-1.

Methods: KYSE-30 and YM-1 ESCC cells were treated with UA and UB, and their viability assays, cell cycle arrest, apoptosis, expressions of mRNA linked to apoptosis and metastasis, generation of reactive oxygen species (ROS), activity of MMP-2 and MMP-9, along with mRNA expressions of MMP-2 and MMP-9, and migration were assessed.

Results: The results showed that UA (which had lower IC₅₀ than UB) and UB reduced the viability of both KYSE-30 and YM-1 cells. Furthermore, UA and UB exhibited lower toxicity towards normal HFF cells compared to ESCC cells. Both UB and the more effective UA induced apoptosis and caused G2/M cell cycle arrest in KYSE-30 and YM-1 cells. Additionally, UA and UB elevated ROS production and led to a decrease in Bcl-2 expression while increasing the expression of Bax and p21 genes. A decrease in the mRNA expression and enzymatic activity of MMP-2 and MMP-9 was observed following treatment with UA and UB.

Conclusion: UB and, more potently, UA show the potential to induce apoptosis while reducing metastatic properties and migration of ESCC cells, suggesting them as promising candidates for new anti-ESCC therapies; however, further preclinical and clinical research is needed to fully understand their anti-cancer effects and mechanisms.

Background: Sepsis, a major global health issue, often progresses to septic shock with high morbidity and mortality. Corticosteroids especially low-dose hydrocortisone have shown promise in septic shock management. However, the role of hydrocortisone as pre-emptive therapy in early septic shock remains unclear.

Objective: This study investigates the effects of pre-emptive administration of low-dose, short-course hydrocortisone on outcomes in patients with early septic shock.

Methods: A double-blind, randomized controlled trial was conducted, enrolling individuals with early septic shock. Patients were randomized to receive either low-dose, short-course hydrocortisone (50 mg every 6 h for 48 h) as pre-emptive therapy or usual care. The primary outcome was vasopressor requirement.

Results: Pre-emptive low-dose, short-course hydrocortisone significantly reduced the duration of vasopressor therapy (P = 0.03), cumulative vasopressor dose (38.52 mg vs. 99.11 mg, P = 0.02), and the necessity for mechanical ventilation (10% vs. 40%, P = 0.02). The hydrocortisone group exhibited a lower incidence of septic shock (20% vs. 40%), although this difference was not statistically significant (P = 0.17). No significant differences were observed in mortality rates (2 deaths per group), Sequential Organ Failure Assessment (SOFA) scores (P = 0.29), or ICU length of stay (P = 0.66). Serious adverse events were comparable between the two groups.

Conclusions: Although pre-emptive hydrocortisone did not change the progression from early septic shock to septic shock, it significantly reduced both the duration of vasopressor therapy and the cumulative vasopressor dose in patients who entered the shock phase, without any significant adverse events.

Cancer leads the list of causes of death worldwide, and the search for new and rapid treatment options for this disease has accelerated. New chemotherapeutic agents that inhibit tumor growth and proliferation are being introduced to the market; however, it presents various challenges, including the lengthy effectiveness of clinical trials, difficulty transitioning to phase 3 clinical stages, and high financial costs. A drug that had previously gained popularity in the market, has recently been repositioned for a different purpose, making it an excellent target for the treatment of several diseases. This review specifically focuses on the anti-cancer effects of repositioned antipsychotic medications that were studied for cancer treatment as well as their combination studies with other chemotherapeutic agents, using a literature search. A literature review covering the last 15 years was conducted using the PubMed (MEDLINE), Google Scholar, and Web of Science databases, with the keywords 'anticancer,' 'antipsychotic drugs,' and 'drug repurposing' used in combination. Studies that yielded productive results across broad historical ranges were included in the review. Initially, the correlation between schizophrenia patients and cancer was explored. Next, antipsychotic drugs with reported anticancer activities were identified, and their in vitro and in vivo anticancer mechanisms were revealed. Finally, the potential contributions and significance of these drugs in future therapeutic approaches were highlighted. In conclusion our literature search has revealed that antipsychotic medications can be useful in treating cancer.

Background: The effectiveness of PD-1 inhibitors for treating endometrial cancer (EC) remains a topic of debate. Guidelines lack consistency regarding the preferred treatments for advanced cases, as well as for patients experiencing metastasis or recurrence. Thus, our goal was to assess the efficacy of Dostarlimab, a PD-1 inhibitor, in EC by incorporating data from clinical trials to create a more comprehensive database.

Methods: We conducted a thorough and systematic search of the Scopus, Medline, Embase, and Web of Science databases, identifying all eligible studies on Dostarlimab's efficacy in endometrial cancer.

Results: Our data demonstrated that the hazard ratio of OS in the pooled proportion of participants was 43%. The hazard ratio of PFS in the pooled proportion of EC patients was 0.39 (95% CI: 0.31-0.49). The overall analysis generated a probability of remaining in response of 72.71% (95% CI: 60.94-84.49%). In addition, pooling the results from both subgroups of EC patients, including proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR), yielded an ORR of 33.93% (95% CI: 21.49-46.37%) and a DCR of 51.73% (95% CI: 37.0-66.42%). Overall, the deficient mismatch repair group compared to the proficient mismatch repair group showed better outcomes. Finally, the dMMR subgroup showed a median PFS of 7.86 months (95% CI: 4.46-11.26).

Conclusion: Dostarlimab demonstrated limited efficacy in patients with pMMR EC, but it represented better outcomes in those with dMMR EC.

Background: Glucocorticoids are associated with withdrawal syndrome, but specific glucocorticoid types that cause severe conditions remain unclear.

Objectives: This study identified glucocorticoids that exhibit significant pharmacovigilance signals for withdrawal, directly comparing the different types to determine those that exhibit a higher risk. We also aimed to investigate the routes of administration for glucocorticoids that are most likely to cause glucocorticoid withdrawal syndrome (GWS) and identify the age, sex, and regional groups among which GWS is more common.

Methods: We extracted the region, severity, age group, sex, and indications from VigiBase reports on GWS from January 2013 to December 2023.

Results: Among 343,296 adverse drug reactions, 1,713 were withdrawal syndrome, with a higher prevalence among females (60%). Prednisone accounted for 28% of the cases, followed by hydrocortisone (17%) and betamethasone (14%). Case numbers tended to peak in 2021, with the highest incidence between ages 18-44 (36%) and significant regional variations for different glucocorticoids. Most cases (77%) were serious, with 18% requiring prolonged hospitalization. Predominant administration routes were topical for betamethasone, triamcinolone, and hydrocortisone; oral for prednisone and prednisolone; and intravenous for methylprednisolone. Disproportionality signals indicated that hydrocortisone exhibited the highest association with GWS (reporting odds ratio [ROR]: 4.04, 95% confidence interval [CI]: 3.59-4.53), followed by betamethasone (ROR: 3.81, 95% CI: 3.35-4.32), triamcinolone (ROR: 2.15, 95% CI: 1.83-2.52), and cortisone (ROR: 1.57, 95% CI: 0.99-2.50).

Conclusion: Abrupt withdrawal of glucocorticoid therapy may cause GWS. Healthcare providers should inform patients about the potential risks of withdrawal, particularly when prescribing topical hydrocortisone and betamethasone, topical and nasal triamcinolone, and oral and topical cortisone, to promote safer practices.

Background: Cleaning activities are critical in pharmaceutical manufacturing to prevent cross-contamination of Active Pharmaceutical Ingredients (APIs). Traditionally, cleaning validation protocols have focused on production lines. However, there is a growing trend toward extending these protocols to Quality Control (QC) laboratories, encompassing both glassware and stainless-steel equipment.

Objectives: This paper presents a systematic approach for developing cleaning validation protocols specifically designed for QC laboratory equipment, aimed at improving cleaning effectiveness and ensuring regulatory compliance.

Methods: The proposed methodology includes: (i) identifying the worst-case API; (ii) performing recovery studies to optimize sampling methods and solvent selection; and (iii) employing statistical tools such as descriptive analysis and hypothesis testing to refine the protocol in line with current industry standards.

Results: A case study involving Oxcarbazepine demonstrates the application of the proposed protocol, evaluating surface contamination across various QC instruments and assessing detergent residues to validate cleaning effectiveness.

Conclusion: The proposed strategy provides a structured, statistically grounded framework for developing cleaning validation protocols in QC laboratories, promoting effective contamination control and adherence to regulatory standards.