DARU Journal of Pharmaceutical Sciences最新文献

Background: Metoprolol, a widely used β-blocker, is administered as a racemic mixture, with (S)-metoprolol being more pharmacologically active. Its metabolism by CYP2D6 exhibits significant inter-individual variability due to genetic polymorphisms. While enantioselective pharmacokinetics have been studied in single-dose trials, data on long-term therapy in hypertensive patients is limited. This study examines urinary enantiomer profiles to assess variability in metabolism and excretion.

Objectives: This study investigates the enantiomeric profile of metoprolol in urine samples collected from hypertensive patients receiving long-term racemic metoprolol therapy. The research aims to improve the analytical performance of the method to explore the enantioselective metabolism and excretion of the drug, focusing on the variation in enantiomer ratios among patients and the potential implications for clinical practice.

Methods: Urine samples were collected from 30 hypertensive patients treated with racemic metoprolol. The samples were analyzed using capillary electrophoresis (CE) with clarithromycin as a chiral selector. Prior to CE analysis, liquid-liquid extraction was performed to isolate metoprolol from urine. The CE method employed an online preconcentration method and had a detection limit of 0.015 µg mL^-1 for each enantiomer, a linear range of 0.05 to 2.0 µg mL^-1, and demonstrated intra-day and inter-day precision below 6.3%, with accuracy within 5.6%.

Results: Metoprolol enantiomers were quantified in patients' urine samples, with enantiomer ratios varying among individuals. The enantiomer ratio (S/R) exceeded 1 in most patients, reflecting higher (S)-metoprolol concentrations. However, in approximately 40% of patients, the ratio was less than 1, suggesting possible enantioselective renal excretion.

Conclusion: The study confirms that there is substantial inter-individual variability in the enantioselective metabolism and excretion of metoprolol among hypertensive patients. The findings emphasize the need to consider enantioselective pharmacokinetics in clinical practice, especially for chiral drugs like metoprolol. The results also suggest that the duration of treatment may affect the metabolism and excretion of enantiomers, warranting further investigation into the effects of long-term drug administration on enantiomeric ratios.

Background: Fluoxetine, an antidepressant, has shown potential anticancer effects. However, its therapeutic efficacy is limited by its poor bioavailability and rapid metabolism. Nanotechnology is advancing medicine, particularly in developing suitable drug delivery systems to improve therapeutic effects and reduce drug side effects.

Objectives: This study aims to synthesize chemically conjugated fluoxetine-dextran nanoparticles (FLX-DEX NPs) to improve the pharmacokinetic profile in plasma and brain to improve antidepressant and anticancer activity against glioma and breast cancer. Besides this, it also targets to reduce the side effects of the drug via delivering the payload to pathological cells.

Methods: Fluoxetine was conjugated to aldehyde-functionalized dextran to give pH stimulus release from its nanoparticles. The spectral and morphological characterization was performed using dynamic light scattering (DLS), atomic force microscopy (AFM), UV, FTIR and ¹HNMR. The stability was determined using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) to evaluate thermal stability and phase transitions of the fluoxetine-dextran nanoparticles. Non-compartmental model was employed to compare the pharmacokinetics of FLX and its nanoparticles in the plasma and various parts of Sprague-Dawley rats. Furthermore, the in vitro safety profile, cytotoxic activity on MCF-7 breast cancer and U87 glioma cell lines and antidepressant effects were measured using various animal models. The levels of dopamine and serotonin in brain were monitored after a fortnight treatment of FLX and its NPs.

Results: The nanoparticles were found to be round to slightly elliptical, having size less than 50 nm and charge -15-20 mV. These nanoparticles were more stable to the drug as depicted by thermoanalysis. The particles showed a controlled and pH stimuli released. The C_max, T_max, t_1/2, volume of distribution and plasma elimination values were 5.23, 2, 15 h, 1.94 and 0.045, respectively, on oral administration of 30 mg/ kg/day. They passed 20% and 18% viability against MCF-7 and glioma cancer at 10 mg/kg/day dose without retarding its anti-depressant effect.

Conclusion: FLX-DEX NPs offer dual therapeutic benefits, enhancing anticancer activity and antidepressant effects. The extended half-life and controlled fluoxetine release improved the pharmacokinetics and therapeutic outcomes, suggesting a promising nanotechnology-based approach for cancer and depression treatment.

Background: Mebendazole (MBZ) is an anthelmintic drug that was repurposed as an anti-cancer agent.

Objectives: This study aimed at formulating MBZ into stearylamine tailored spanlastics dispersed in nanogel for enhancing MBZ anti-tumor efficacy against skin cancer.

Methods: MBZ spanlastics were prepared by thin film hydration using 2¹ × 3¹ factorial design. The formulation variables were the total amount (mg) of Span 60 and Tween 80 in the formulations and the ratio between Span 60 and Tween 80.

Results: Optimal spanlastics formulation was composed of 400 mg of Span 60 and Tween 80 in a ratio of 2:1 and showed EE% of 78 ± 2.9% and PS of 284.00 ± 35.36 nm. Stearylamine (20 mg) was added to the optimized formulation and showed acceptable positive charge (zeta potential = 47.53 ± 1.50 mV). It was dispersed in 30% Tetronic^®1107 solution to form a nanogel. MBZ nanogel was assessed for their cytotoxic effect on cell proliferation against human malignant melanoma and epidermoid carcinoma cell lines and showed 38.70 ± 1.70% and 48.60 ± 0.50% (respectively) cell proliferation compared to the control group (100%). Finally, its permeation through Wistar rat skin was tested.

Conclusion: SA-spanlastics nanogel holds potential as an effective nanocarrier for boosting MBZ anti-cancer efficacy.

Objectives: Rosa damascena Mill. has been studied in clinical trials for the treatment of diverse gastrointestinal diseases. The aim of this study is to conduct a systematic review and meta-analysis of clinical trials using R. damascena in the management of gastrointestinal disorders.

Evidence acquisition: PubMed, Web of Science, Embase, Scopus, and Google Scholar were searched up to Jun 30, 2024. Clinical trials utilizing R. damascena for gastrointestinal disorders were included in the study. The study protocol was registered in PROSPERO (CRD42024519644). The main keywords for the search were R. damascena, gastrointestinal, digestive system, and clinical trials. The Cochrane RoB 2.0 tool was employed for quality assessment of randomized controlled trials. A summary of intervention effects for each study was provided by calculating standardized mean differences and accompanying 95% confidence intervals using a random-effects model. Weighted mean differences and heterogeneity between studies were assessed using Hedges's method and Cochran's Q test, respectively. Additionally, the risk ratio (RR) index was utilized to investigate the effect of R. damascena.

Results: Thirteen studies were included for systematic review. The results showed that the use of R. damascena significantly improves the Quality of life (SMD: 0.84, CI95%: 0.03 to 1.65, P = 0.041) and mean defecation frequency per week (SMD: 0.86, CI95%:0.14 to 1.58, P = 0.018) in patients with constipation. However, no improvement was observed in the Bristol stool form scale in patients with constipation, and this relationship was not statistically significant either (SMD: -1.34, CI95%: -4.39 to 1.71, P = 0.388). Also, the rate of incomplete evacuation significantly improved in patients with constipation (RR: 0.78, CI95%: 0.63 to 0.94, P = 0.035).

Conclusion: Based on the results of this study, R. damascena could have promising effects on symptoms of patients with functional constipation and their quality of life. Future studies should focus on standardizing methodologies, exploring different dosage levels, and investigating its effects on a wider range of gastrointestinal conditions.

Background: Rituximab (RTX) is one of the treatment options for refractory myasthenia gravis (MG), yet the optimal dosing schedule remains undetermined. Our study aims to explore this issue and offer a valuable reference for clinical dosing.

Methods: This is a single-arm meta-analysis. Studies in adults with myasthenia gravis published before 31 December 2023 were searched in PubMed, Web of Science, and other databases. Two primary effectiveness outcomes were analyzed: (1) Proportion of patients achieving minimal manifestation status (MMS) or better, (2) Change in Quantitative MG Score (QMGs) after RTX treatment. Safety outcomes included the incidence and description of serious adverse events (SAEs) and adverse events (AEs). Forest plots were generated to provide an overview and detailed combined effects. Publication bias was evaluated using funnel plots and the Egger test. Conventional dose refers to an RTX regimen similar to that used for the treatment of B-cell lymphoma: 375 mg/m² per week for 4 weeks or 1000 mg for Weeks 1 and 3. Dosing regimens below the conventional dose in a treatment cycle are defined as low dose.

Results: A total of 1037 MG patients received RTX treatment. Overall, 59.0% (95% CI: 48.2-69.8%, n = 599) of patients achieved MMS or better, with a mean decrease in QMGs of 6.81 (95% CI, -9.27 to -4.35, n = 222). The low-dose group showed a higher proportion of patients achieving MMS or better (76.6% vs 51.6%) and a more significant decrease in QMGs from baseline (-9.04 vs -3.62) compared to the conventional dose group (P < 0.01). Differences in the incidence of SAEs and AEs between the two groups were not significant (P > 0.05). Univariate meta-regression analyses showed that the dose administered was significantly associated with the proportion of MMS or better and the change in QMGs, whereas the proportion of Musk patients was not significantly associated with any of the outcomes. Stepwise logistic regression analyses showed that non-refractory MG, mild disease severity (MGFA classification), and low-dose were significant predictors for achieving an MMS or better prognosis, whereas for achieving improvement or better, only low dose was an independent predictor.

Conclusion: RTX can improve clinical symptoms, reduce QMGs in MG patients and the use of oral glucocorticoids and other immunosuppressants. The efficacy of low-dose RTX in treating MG patients is more effective than conventional-dose RTX and demonstrates a better safety profile. Mild disease severity, non-refractory MG, low dose, and MuSK-MG over AChR-MG predict better efficacy. Large randomized controlled trials are necessary to evaluate the efficacy and safety of RTX in MG patients and its various subtypes.

Introduction: Leukocytoclastic vasculitis (LCV) is a small-vessel inflammatory condition that can rarely occur as an adverse drug reaction (ADR). Vancomycin-induced LCV is an uncommon but potentially serious complication, particularly in patients with pre-existing renal impairment.

Reason for the report: This case report describes a patient with end-stage renal disease (ESRD) who developed LCV following vancomycin therapy for a catheter-related infection. The report emphasizes the diagnostic challenges and the importance of prompt and appropriate management of this ADR. A 53-year-old male with ESRD developed skin lesions and systemic symptoms after receiving vancomycin for catheter-related infection. The diagnosis of LCV was confirmed through a skin biopsy. Discontinuation of vancomycin with initiation of mycophenolate mofetil and prednisolone resulted in significant improvement in the patient's condition.

Outcome: The presented case underlines the recognition of vancomycin-induced LCV, especially in the vulnerable population of patients with ESRD. It emphasizes the need for a high degree of suspicion of drug-related adverse events and early diagnosis and management to achieve good outcomes.

Clinical trial number: Not applicable.

Background: The inappropriate use of antibiotics increases the costs of treatment, antibiotic resistance, increased disease length and duration of hospital stay.

Objectives: The aim of this study was investigating the pattern of use and effectiveness of the Linezolid in COVID-19 hospitalized patients.

Methods: In this retrospective cross-sectional analytical study was carried out from February 2020 (from the beginning of the pandemic in Iran) to the end of September 2020, 32 COVID-19 patients that used Linezolid were included. The data retrieved from medical document's unit and analysis was performed by SPSS statistical software version 20.

Results: According to the three elements of the 1- culture of resistant bacteria 2-the correct daily dose and 3-adequate duration of the drug, consumption pattern of Linezolid was irrational in 24 (75%) COVID-19 patients and it was rational only in 8 (25%) patients. Twenty-three (71.9%) patients received sufficient doses of the drug and 9 (28.1%) patients did not receive the required minimum dose. Four (50%) patients who rationally received Linezolid improved and the remaining 4 died. Leukopenia occurred in 1 patient (3.1%), anemia appeared in 24 individuals (75%), and 15 patients (46.9%) developed thrombocytopenia.

Conclusion: We suggest that the prescription of Linezolid is in accordance with the standard instructions and the stewardship antibiotic program to reduce the medication costs, drug side effects, and the prevalence of antibiotic resistance.

Objective(s): Some forms of breast cancer such as triple-negative phenotype, are serious challenge because of high metastatic cases, high mortality and resistance to conventional therapy motivated the search for alternative treatment approaches. Nanomaterials are promising candidates and suitable alternatives for improving tumor and cancer cell treatments.

Materials and methods: Biosynthesis of ZnO NPs by help of Berberis integerrima fruit extract, has been done. Analysis of Zinc Oxide NPs using DLS, FTIR, SEM, and EDS techniques have been performed. Moreover, biological activities of ZnO NPs evaluated through MTT method, Flow cytometry, and real time PCR methods. Biocatalytic and apoptotic activity of ZnO NPs on healthy HFF (human fibroblast cell line), MDA-MB 231, and MDA-MB 468 (triple negative breast cancer cell lines, (TNBC)) evaluated. Furthermore, Bax, Bcl-2 and caspase-3 apoptotic genes expression changes in cancer cells assessed in compare to GAPDH as a house keeping gene.

Results: Physico-chemical investigation demonstrated ZnO NPs were confirmed by Berberis integerrima fruit extract for the first time. The MTT assay and Flow cytometry results indicated biocompatibility of the ZnO NPs in normal cell line and high anticancer potential against TNBC MDA-MB-231 and MDA-MB-468 cell lines. The IC50 of ZnO NPs were 104.4 and 44.86, 20.96 after 24 hours for HFF, MDA-MB-231 and MDA-MB-468 cells, respectively.

Conclusion: The current research showed a fast, cost effective and ecofriendly method for ZnO NPs nanoparticle synthesis. Furthermore, In vitro data analysis demonstrated biocompatibility and highly anticancer effects of biosynthesized ZnO NPs against TNBC cancerous cells.