Advances in Pharmacological and Pharmaceutical Sciences最新文献

Malaria continues to be a significant global health challenge, particularly in tropical and subtropical regions, due to its high morbidity and mortality rates. The development of resistance to conventional antimalarial drugs underscores the urgent need for novel therapeutic approaches. Artemisinin-based combination therapies (ACTs) are effective but face emerging resistance issues. This study explores the antimalarial efficacy of Annona muricata leaf extract (AME) when combined with artesunate (ART), chloroquine (CQ), and pyrimethamine (PYR) in Plasmodium berghei-infected ICR mice. Fresh A. muricata leaves were processed to produce a crude ethanolic extract. ART, CQ, and PYR were prepared and administered to ICR mice infected with P. berghei ANKA. The study evaluated the parasitemia levels and survival rates, comparing combination treatments to monotherapies. The combination treatments were analyzed for synergistic interactions. Results indicated that AME alone exhibited significant antimalarial activity, especially at higher doses. The combination of AME with ART and PYR demonstrated significant synergistic effects, achieving over 90% inhibition of parasitemia and significantly prolonging mean survival times up to 30 days. However, the combination of AME with CQ did not show synergistic effects. These findings suggest that AME, particularly in combination with ART or PYR, could enhance antimalarial efficacy and offer a promising alternative to current treatments, potentially mitigating drug resistance issues. Further research is warranted to validate these combinations and explore their mechanisms of action.

Urinary tract infections (UTIs) are one of the most important causes of morbidity and healthcare spending. Combination therapy is the treatment of choice for biofilm-associated infections due to the simultaneous action of two drugs on two separate cellular targets and their safety. This study aimed to evaluate the effect of the combination of some bioactive natural products with conventional antibiotics against the biofilm of uropathogenic Staphylococcus spp. Antibacterial and antibiofilm activities were determined by the broth microdilution test. The checkerboard method was used for combination studies. The cytotoxicity of the best synergistic combinations was evaluated on Raw 264.7 macrophage cells and urinary epithelial cells (UROtsa) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Plumbagin also showed the best biofilm-inhibiting and eradicating activities compared to curcumin, berberine, thymol, quercetin, and gallic acid. The best synergistic combinations against biofilm inhibition and eradication were C1: cefixime (5.33 µg/mL) + thymol (32 µg/mL); C2: cefazolin (1.16 µg/mL) + thymol (21.33 µg/mL); C3: amikacin (0.18 µg/mL) + curcumin (37.33 µg/mL); C4: kanamycin (0.25 µg/mL) + curcumin (14 µg/mL); and C5: amoxicillin (1.16 µg/mL) + curcumin (21.33 µg/mL). Time-kill studies revealed that the highest antibiofilm activities of the best combinations were observed at 24 h. Eradication activities were more significant than inhibitory activities. Compared to C3, C4, and C5 combinations, C1 and C2 combinations showed less cytotoxicity against the two tested cell lines UROtsa and Raw 264.7. This study shows that the best antibiofilm synergistic effect was obtained with the combination of thymol with cefixime and cefazolin, associated with low cytotoxicity. These associations could be considered potential candidates for the development of combination therapies against Staphylococcus spp. biofilm-associated infections. While this study demonstrates promising in vitro results, further in vivo validation is necessary to confirm the efficacy and safety. Additionally, mechanistic studies are needed to understand the synergistic pathways, and future research should address scalability and formulation for clinical use.

Background: Drug-drug interactions (DDIs) pose a significant challenge in drug therapy, particularly due to concerns about the safety and effectiveness of combined medications. Rifampicin is a strong inducer of the enzyme CYP2C9, which likely reduces warfarin's effectiveness. This study aims to investigate the prevalence and severity of clinically significant interactions by analyzing changes in international normalized ratio (INR) levels. Method: The study was a retrospective observational analysis conducted from 2014 to 2024, using data on INR measurements from patients treated concurrently with warfarin and rifampicin. INR values were recorded at multiple time points, including baseline, during concomitant treatment, and after discontinuation. Results: A significant proportion (86.3%) of the 102 patients using warfarin concurrently with rifampicin experienced a DDI, resulting in a notable reduction in INR (p < 0.0001), with a median decrease to 1.3 (IQR 1.1-1.6). Among the patients who achieved the target INR (55.9%), warfarin dose was increased by a median of 5.5 mg, and the median time to INR stabilization was 18 days. However, approximately 31% of patients did not reach the target INR despite dose adjustments. Conclusion: The warfarin-rifampicin interaction is clinically significant, as it can diminish warfarin's anticoagulant effect, potentially compromising patient health outcomes. Close monitoring and individualized treatment plans are crucial for patients receiving both medications concurrently.

NorUrsodeoxycholic acid (norUDCA) is a side-chain-shortened derivative of ursodeoxycholic acid (UDCA) with specific pharmacological properties, including cholehepatic shunting, making it a promising candidate for a range of cholestatic and metabolic liver diseases. This phase I study evaluates the safety, tolerability, and pharmacokinetics of single ascending doses of norUDCA in healthy adults under fasting conditions. In this open-label, dose-escalation study, healthy adults (aged 18-45 years) were enrolled into 3 successive dose escalation cohorts, receiving norUDCA oral tablets of 500 mg (n = 14), 1000 mg (n = 14), and 1500 mg (n = 14) once daily. The primary endpoints were the incidence rate of dose-limiting toxicities (DLTs), assessment of maximum tolerated dose (MTD) after single dose administration, and an establishment of the recommended phase II dose. Secondary endpoints included pharmacokinetic assessments and evaluation of dose proportionality. Following single-dose administration of 500 mg, 1000 mg, and 1500 mg, no DLTs were observed, and the MTD was determined to be 1500 mg/day. Maximum plasma concentration (C _max) and plasma exposure [area under the curve (AUC)] to norUDCA increased dose proportionally from 500 to 1500 mg/day. Median time to achieve maximum plasma concentration (T _max) for norUDCA at 1500 mg/day cohort (3 h) was comparable to 1000 mg/day cohort (3 h) but lower than 500 mg/day cohort (4 h). The half-life was longer in 1500 mg/day (16 h) cohort compared to 500 mg/day (15 h) and 1000 mg/day cohorts (14 h). The 90% confidence interval of the slope estimates for C _max (22.41, 59.70), AUC_0-t (11.71, 61.14), and AUC_0-inf (10.74, 61.86) did not consistently fall within the predefined acceptable limits (79.69, 120.31) for formal dose proportionality criteria. No serious adverse events or deaths occurred in any cohort. One treatment-emergent adverse event was observed (an increase in the white blood cell count), which was not related to the study drug. A single dose of norUDCA is safe and well-tolerated, with favorable plasma pharmacokinetic profiles in healthy subjects. Based on the safety and pharmacokinetic data, the recommended dosage for further clinical trials is 1500 mg/day. Trial Registration: Clinical Trials Registry-India: CTRI/2022/11/047561.

Lung cancer and breast cancer are two types of cancer that cause and contribute to the highest mortality rate in the world. The development of anticancer agents that have high efficacy and relatively low side effects continues to be developed and is the focus of research, and one of the raw materials that can be explored is active compounds sourced from natural materials, one of which is plants. This study aims to isolate active compounds from bangun-bangun (Coleus amboinicus, Lour.) leaves, test cytotoxicity as an antilung and breast cancer agent in vitro, and conduct molecular docking studies with a network pharmacology approach on the pathways in cancer. Research methods include extraction by the maceration method and purification by column chromatography, anticancer activity testing is carried out by the microtetrazolium (MTT) test method against lung cancer (A549), breast cancer (MCF-7), and normal cells (CV-1), and molecular docking studies are carried out with a network pharmacology approach focused on proteins in cancer pathways. The results of the active isolate (I_nH-2) from n-hexane extract showed the best activity against lung cancer/A549 cells (IC₅₀ 31.74 μg/mL), and the active isolate (I_EtOAc-1) from ethyl acetate extract showed the best activity against breast cancer/MCF-7 cells (IC₅₀ 80.05 μg/mL) and showed no toxicity to normal cells (CV-1). The results of the bioinformatic study are with a network pharmacology approach on the cancer pathway of bioactive compounds from each isolate target the matrix metalloproteinase-2 (MMP-2) protein. The content of bioactive compounds from Coleus amboinicus leaves shows the potential to be used as active agents in the treatment of lung cancer and breast cancer in the future.

Background: Electrospun fiber drug delivery systems, integrated into multipurpose prevention technologies, offer a promising solution for women facing health risks from HIV/STIs and unmet contraceptive needs by providing on-demand protection in a single dosage form. This study investigates the potential of a multilayer electrospun fiber construct for pH-responsive and sustained release of the HIV microbicide tenofovir (TFV) and the CatSper channel blocker nifedipine (NFP) respectively. Method: Electrospun fibers were fabricated in a stacked architecture by blend electrospinning using polycaprolactone (PCL) as the backing layer for delivering NFP and cellulose acetate phthalate (CAP) as the top layer for delivering TFV. An analysis of surface morphology, mechanical and chemical properties, mucoadhesion, drug release profiles, encapsulation efficiency, and safety assessments was performed. Results: An encapsulation efficiency of 52.13% was achieved for TFV, with a drug loading of 7.00%, while for NFP, the encapsulation efficiency was 63.86%, with a drug loading of 0.56%. The top layer exhibited a pH-responsive release profile and Fickian diffusion in both SVF and SVF/SF environments, while the backing layer showed Fickian diffusion in SVF and a release profile closer to zero-order in SVF/SF. Conclusion: This study highlights the potential of multilayered CAP/PCL electrospun fibers for intravaginal delivery of TFV and NFP, aimed at the pre-exposure prophylaxis of HIV-1 and prevention of unplanned pregnancy.

Type II diabetes remains a significant global public health issue, affecting both individual well-being and healthcare systems worldwide. Metformin hydrochloride is widely prescribed as the first-line treatment for managing diabetes. However, the increasing reports of substandard and falsified medicines, including metformin, circulating in the markets in recent years, highlights the urgent need for reliable and portable quality assurance tools. Thin-layer chromatography (TLC) has long been extensively used as a screening method to verify the identity and quality of various medicines. In this work, we present a smartphone-assisted TLC method for quantitative analysis of metformin hydrochloride. The TLC was performed using silica gel 60 F₂₅₄ plates as the stationary phase and acetic acid-methanol-water 0.25:7:4 (v/v) as a mobile phase. We used a custom-made UV-illuminated TLC imaging box to capture images via smartphone and images were analyzed using a custom written smartphone application to calculate the R _f and the concentration of metformin in the principal TLC spots. The smartphone application, TLC Analyzer, accurately calculated the R _f values (0.604) consistent with those obtained using ImageJ software. The linearity of the method was 0.5-4 mg/mL. After optimization, the TLC Analyzer method was used to analyze metformin samples (n = 16) collected from local pharmacies. The results were compared with those from ImageJ analysis, UV-Vis spectrophotometry, and HPLC. The smartphone-based TLC Analyzer method identified 15 of the 16 samples as containing acceptable levels of metformin in accordance with pharmacopeial standards, consistent with ImageJ and spectrophotometric results. In contrast, the HPLC method indicated that all 16 samples met the pharmacopeial criteria.

Adalimumab, marketed as Humira, is a fully humanized monoclonal antibody that blocks the activity of tumor necrosis factor-alpha and is used in treating several autoimmune disorders. As one of the top-grossing pharmaceuticals, its global sales surpassed $20 billion in 2023, leading to significant biosimilar development, with 10 products available by 2025. This review analyses published preclinical studies to assess the evaluation methods employed to establish biosimilarity between Humira and four key biosimilars: ABP501 (Amjevita), FKB327 (Hulio), MSB11022 (Idacio), and SB5 (Imraldi). Our comparative analysis reveals that primary structure, glycosylation profiles, Fc receptor binding affinity, and TNF-alpha neutralization potency are critical quality attributes essential for establishing biosimilarity. Notably, while all four biosimilars demonstrated comparable functional properties to the reference product, variations in glycosylation patterns presented distinct regulatory challenges. This review is a valuable resource for biopharmaceutical scientists engaged in biosimilar development, ultimately supporting advancing more accessible and affordable treatment options while ensuring adherence to stringent efficacy, safety, and quality standards of adalimumab biosimilars.

Purpose: This cross-sectional study assessed determinants of benzodiazepine (BZP)-dispensing practices among community pharmacy dispensers in Dar es Salaam, Tanzania. Methods: A cross-sectional study involving 378 community pharmacy dispensers was conducted between March and June 2024. An adapted structured questionnaire was used to gather information on the sociodemographics, most dispensed BZPs, dispensers' knowledge, and dispensing practice of BZPs. Determinants of dispensing practice were determined by multivariable logistic regression analysis using SPSS Version 23. Results: Of 378 dispensers, 232 (61.4%) were female, 263 (69.6%) had a college education level, and 193 (51.1%) were pharmaceutical technicians. Diazepam was the most dispensed BZP (163 (43%)), followed by lorazepam (102 (27%)). More than half, 203 (53.7%), of the dispensers had inadequate knowledge, and 240 (63.5%) of dispensers had good dispensing practices. Nonpharmaceutical dispensers were less likely to have good dispensing practice (AOR = 0.16, 95% CI (0.05-0.49)) whereas having adequate knowledge of BZPs (AOR = 2.64, 95% CI (1.64-4.25)) were significantly associated with the good dispensing practice of BZPs. Conclusion: Knowledge levels and the type of pharmaceutical professionals are determinants in ensuring proper BZP-dispensing practices. These indicate the need for continuous professional development and stricter enforcement of dispensing regulations to improve pharmacy practices and prevent unauthorized BZP dispensing.

Tacca chantrieri André is a native plant from Northern Thailand with reported pharmacological effects, including antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the neuroinflammatory and cognitive-enhancing effects of Tacca chantrieri André rhizome extract (TCE) in a scopolamine-injected model, which mimics an Alzheimer's disease (AD) animal model. Animals were divided into six groups: (1) a control group, (2) a vehicle-treated group, (3) a donepezil-treated group (3 mg/kg BW) as a positive control, and (4-6) three TCE-treated groups receiving 50, 100, or 200 mg/kg BW once daily for 14 days. Starting on Day 8, animals received daily intraperitoneal injections of scopolamine (3 mg/kg BW) for 7 consecutive days to induce cognitive impairment. On day 14, behavioral tests were conducted, including the Y-maze and open field tests. On day 15, animals were euthanized, and their brains were collected for Nissl staining, immunofluorescence staining, and biochemical analyses using an ELISA kit. Our results demonstrated that TCE treatment attenuated scopolamine-induced memory deficits and neuroinflammation. Specifically, TCE administration reduced levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and decreased glial fibrillary acidic protein (GFAP) expression in the hippocampus. Additionally, TCE improved neuronal survival and enhanced serotonin levels, contributing to cognitive improvements. The qualitative analysis of TCE using LC-QTOF-MS identified various chemical constituents, including saponins, flavonoids, and phenolic compounds. These bioactive compounds contributed to the neuroprotective effects of TCE by modulating neuroinflammation and cognitive function. The neuroprotective effects of TCE suggested its potential as a therapeutic agent for memory impairment associated with AD.