Turkish journal of pharmaceutical sciences最新文献

Objectives: Benzothiazole compounds, characterized by their diverse biological and pharmacological properties, have emerged as promising molecules for suppressing cancer cell proliferation and invasion due to their antiproliferative attributes. Prior research from our laboratory revealed that 2-substituted benzothiazole compounds inhibit the proliferation of glioma and cervical cancer cells and induce apoptosis in pancreatic cancer cells. However, there is limited research on the effectiveness of benzothiazoles against hepatocellular carcinoma cells (HCC). This study sought to elucidate the anticancer potential of 2-substituted benzothiazole derivatives through their modulation of oxidative stress and inflammation mediators.

Materials and methods: Antiproliferative effects of two-step synthesized 2-substituted benzothiazole derivatives were evaluated on HepG2 cells via MTT assay. Apoptosis induction was assessed using Annexin V/PI staining; cell cycle arrest effects were determined through cell cycle analysis; cell migration was examined via wound healing assay; and mitochondrial membrane damage was quantified using JC-1 staining. Spectrophotometric measurements of total antioxidant status (TAS), total oxidant status, superoxide dismutase (SOD), total thiol, and native thiol levels were used to assess cellular redox status. Expression of nuclear factor kappa B (NF-κB), an inflammatory marker, was assessed by western blot, while inflammation-related cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase levels were measured using ELISA.

Results: This investigation unveiled benzothiazole derivatives' antiproliferative and cytotoxic properties against HepG2 cells (IC₅₀ values of 56.98 μM and 59.17 μM at 24 h, and 38.54 μM 29.63 at 48 h). The synthesized compounds exhibited the ability to suppress cell migration and induce apoptosis, mediated by mitochondrial membrane potential loss (wound‑closure rates of 84.0 and 90.4% vs. 51.7% control at 48 h, apoptosis rates of 10.70% and 45.22% vs. 1.02% control). Furthermore, these derivatives reduced SOD activity (A and B at 100 μM p<0.001), TAS levels (A and B at 100 μM, p < 0.05, p < 0.001), and dynamic disulfide content. Notably, a decrease in NF-κB protein levels, closely associated with inflammation, was observed, along with a subsequent reduction in downstream effectors COX-2 (A and B at 100 μM, p<0.001) and iNOS (A and B at 100 μM, p < 0.001).

Conclusion: The findings of this study underscore the antiproliferative effects of benzothiazole derivatives in human HCCs, coupled with their anti-inflammatory potential by diminishing NF-κB levels.

Objectives: Folk medicines used in the Gerze district of Sinop have not been previously studied in detail. This study aimed to record and compily the folk medicines used in Gerze (Sinop, Türkiye).

Materials and methods: In this ethnobotanical inventory study, scientific trips were organized to 18 villages in the Gerze district between May and August in 2009, and folk medicine information was obtained using open and semi-structured questionnaires. The obtained data were analysed by calculating use value", informant consensus factor, and relative frequency of citation.

Results: As a result, 63 plant species from 41 families were determined to be used as folk medicine. Plants from the Rosaceae and Asteraceae families are preferred in preparing folk medicines. Sempervivum brevipilum Muirhead and Serapias vomeracea (Burm.f.) Briq. were recorded for the first time as folk medicine in this research. In Gerze, folk medicines were mostly used in the respiratory tract (86 citations), and dermatological system diseases (86 citations). However, when informant consensus factor values are considered, dermatological system disorders are ranked first (0.7529) and, followed by musculoskeletal (0.7049), respiratory (0.6941), and cardiovascular system disorders (0.5882). The most cited plants were Olea europaea L. (27 citations) and Sambucus ebulus L. (23 citations). The highest use value was calculated for O. europaea subsp. europaea (0.293), and S. ebulus (0.260). At the same time, S. ebulus took first place with an relative frequency of citation value of 0.239, O. europaea subsp. europaea (0.184) fell in second place.

Conclusion: The use of 63 different plant species in folk medicine in Gerze has been recorded to eliminate a deficiency in the Turkish folk medicine inventory and be a source for future scientific studies. However, as in other regions of Türkiye, it has emerged that the folk medicine knowledge was being lost in Gerze District, and that ethnobotanical inventory studies should be carried out rapidly throughout the country.

Objectives: A novel, high-throughput liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique has been developed that uses Etravirine (ETR) as the internal standard (IS) to simultaneously quantify Doravirine (DOR), Lamivudine (LAM), and Tenofovir Disoproxil Fumarate (TDF) in human plasma. The procedure employs a precipitation extraction technique to analyze analytes from human plasma. This study aims to develop and validate a novel and reliable stability-indicating UPLC-MS/MS method for the simultaneous determination of DOR, LAM, and TDF in human plasma, using ETR as the IS.

Materials and methods: ETR, based on its stable-isotopic nature and structural and physicochemical similarity to the analytes of interest, was used as an IS. Precipitation extraction was the technique used to prepare samples. An agilent zorbax XDB C18 analytical column (2.1 × 50 mm, 3.5 μm) was used for chromatographic separation, and its isocratic mobile phase consists of acetonitrile and buffer (5 mM of ammonium formate with 0.1 % formic acid) in the ratio 80:20, v/v, at a flow rate of 0.120 mL/min.

Results: The parent-to-product ion transitions for the drugs were as follows : LAM: m/z 231.08 amu → 112.00 amu, TDF: m/z 288.33 amu → 176.17 amu, DOR: m/z 426.38 amu → 112.02 amu, and IS ETR: m/z 437.36 amu → 164.97 amu. These transitions were observed using a triple quadrupole mass spectrometer in the multiple reaction monitoring (MRM) positive ion mode. The compound's basic group content determined which positive mode to choose. For DOR, LAM and TDF, the method was validated throughout concentration ranges of 2.5-1000 ng/mL with correlation coefficients (r²) values obtained were found to be 0.99. From spiked plasma samples, the mean recovery outcomes were observed and found to be DOR, LAM, and TDF was 83.39%, 87.33%, and 85.56%. With a 3.0-minute total run time, the approach was shown to be reliable and quick.

Conclusion: A triple quadrupole mass spectrometer running in the MRM positive ion mode was used to track these transitions. The compounds' functional group content served as the basis for choosing the positive mode. The mean recovery values were obtained for three APIs from spiked plasma samples. The run times were found to be both reliable and quick. The method was proven to produce precise and specific results for the determination of selected drugs through the current study. The method is stable when exposed to various stress conditions, demonstrating minimal degradation. The current method was validated as per the ICH M10 guidelines and was found to meet the desired acceptance criteria. The developed bioanalytical method, validated in accordance with ICH M10 guidelines, demonstrated high accuracy, precision, and reproducibility for the simultaneous quantification of DOR, LAM, and TDF. Its streamlined design and reliable performance make it a valuab

Objectives: Senescent cells release a senescence-associated secretory phenotype, promoting polyploid giant cancer cells (PGCCs) to emerge, fostering tumor heterogeneity and resistance. Pentagamavunone-1 (PGV-1) emerges as a promising agent inducing senescence and prometaphase arrest, resulting in permanent cytotoxicity. This study was aimed to investigate the effect of PGV-1 in dysregulating mitosis through the modulation of PGCCs and senescence in low MYCN-expressing hepatocellular carcinoma (HCC) cells JHH4.

Materials and methods: To assess the physiological effects of PGV-1, several in vitro tests were done including the MTT assay, cell cycle assay, May-Grünwald-Giemsa staining, senescence associated-β-galactosidase (SA-β-Gal) assay, and apoptosis assay. The protein levels of the apoptosis regulatory protein were evaluated using western blot analysis. The interaction of PGV-1 toward the protein that plays a role in PGCCs formation was simulated by molecular docking and molecular dynamics (MD).

Results: The cytotoxic assay revealed that PGV-1 inhibited the proliferation of JHH4 liver cancer cells permanently. Inhibition of cell proliferation by PGV-1 was associated with the modulation of G2/M phase, particularly mitotic arrest and formation of PGCCs. The SA-β-Gal verified that PGV-1 induced senescence in cells (p<0.01), inducing PGCCs formation. Apoptotic mechanisms were validated via Annexin V staining, which showed the level of cleaved poly (ADP-ribose) polymerase (p<0.001). Molecular docking and MD simulations suggested that PGV-1 could interfere with the conformation of the chromosomal passenger complex (CPC) protein, particularly disrupting essential interactions within the inner centromere protein, Survivin, and Borealin.

Conclusion: PGV-1 induced strong cytotoxicity in HCC cells by disrupting mitosis leading to PGCC formation, senescence, and subsequent apoptotic cell death.

Objectives: Bacterial vaginosis (BV) is a common disease in women of reproductive age. Metronidazole (MET) is an antibiotic used to treat BV via the oral or vaginal route. Vaginal films are dosage forms that combine the properties of solid and gel formulations and increase patient compliance. This study aims to develop and characterize vaginal film formulations containing MET for the treatment of BV.

Materials and methods: Film formulations were prepared using the solvent casting method with poly(vinyl alcohol), hydroxypropyl methylcellulose K100M, and mixtures of these polymers. Polyethylene glycol 400 was added to the formulations as a plasticizer. The moisture content, average thickness, and weight of the film formulations were examined. Also, the mechanical properties (tensile strength and elongation at break) and ex vivo mucoadhesion properties of the films were determined with vaginal tissue. The release of MET from the films was investigated using Franz diffusion cells.

Results: The moisture content of the formulations was found to be less than 10%. It was observed that tensile strength and elongation at break values decreased when MET was loaded onto the films. Mucoadhesion values decreased with MET loading and the work of mucoadhesion values was found to be 0.070±0.053, 0.067±0.039, and 0.150±0.061 for F4, F5, and F6, respectively. The release of MET was found to be 92.7%, 65.5%, and 87.6% for F4, F5, and F6, respectively.

Conclusion: Mucoadhesive films can be used as an alternative dosage form for vaginal delivery of MET in the treatment of BV.

Objectives: This study aimed to perform pre-formulation studies, formulation development, and formulation optimization for self-nanoemulsifying drug delivery systems (SNEDDS), a lipid-based formulation approach to improve the low solubility of bosentan monohydrate (BOS).

Materials and methods: Pseudo-ternary phase diagrams were created for pre-formulation studies and formulation design for SNEDDS. The SNEDDS was optimized with BBD. The optimized BOS-loaded SNEDDS formulation was characterized by droplet size (DS), polydispersity index (PDI), dispersibility, an efficiency test of self-nanoemulsification, % transmittance, turbidity, robustness, and the effects of pH, viscosity, and thermodynamic and long-term stability studies. The in vitro dissolution studies were performed in distilled water containing 1% sodium lauryl sulfate, which is a Food and Drug Administration-recommended medium, and in biorelevant media. Ex vivo studies were conducted in biorelevant media.

Results: The optimum BOS-loaded SNEDDS had a DS of 16.76 nm and PDI of 0.200. The characterization studies satisfied SNEDDS requirements (does not deteriorate when diluted at different pHs; resistant to thermodynamic changes; self-emulsifying within 1 minute; Grade A; and transparent) for both blank and BOS-loaded SNEDDS. In long-term stability studies, it was found to be stable for six months. When in vitro dissolution was compared to the performance of the commercial product (Tracleer^®), the BOS-loaded SNEDDS showed 2.88, 7.63, 3.83, and 4.23 increases in the percentages of cumulative dissolution in fasted state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), FaSSIF-V2, and FeSSIF-V2, respectively. The ex vivo permeation study showed 12.2-, 19.1-, 20.3-, and 13.1-fold increases in drug permeation in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2 for the SNEDDS formulation, as compared to the commercial product, respectively.

Conclusion: Pre-formulation and formulation studies were carried out successfully, and lipid-based optimum BOS-loaded SNEDDS were obtained. The present study confirms the potential of optimum BOS-loaded SNEDDS, which was found to be stable over the long term, to increase the drug's solubility, in vitro dissolution, and ex vivo permeability. This formulation approach has been promising for further in vivo studies, to improve the oral bioavailability of BOS.

Objectives: The aim of this study was to determine the development of in vitro resistance and changes in biofilm forming abilities in methicillin-resistant Staphylococcus aureus (MRSA) isolates exposed to sub-minimal inhibitory concentrations (sub-MICs) of daptomycin and linezolid; and to investigate the presence of the methicillin resistance gene (mecA) and the biofilm-associated genes (icaA, icaD) by polymerase chain reaction.

Materials and methods: This study was carried out with thirty-two MRSA isolates. The susceptibility of the isolates to daptomycin and linezolid was investigated by the broth microdilution method, and MIC values were determined (1^st MIC). After serial passages, the 2^nd MIC and the 3^rd MIC values were similarly detected. Before and after serial passages, the biofilm-forming abilities of MRSA isolates were examined using the microtiter plate (MTP) method.

Results: When the daptomycin and linezolid 1^st MIC and 3^rd MIC values of the isolates were compared, there was a 2-8 fold increase in linezolid (p<0.05) and a 4-32 fold increase in daptomycin (p<0.05). According to the MTP method, 20 (62.5%) of the 32 isolates formed biofilm at various levels, while 12 (37.5%) did not form biofilm. After the second series of passages, biofilm formation was observed in 19 (59.4%) isolates with daptomycin (p>0.05) and in 16 (50%) isolates with linezolid (p>0.05). The mecA gene was found in all isolates. Also, icaA and icaD genes were detected in 31 (96.9%) of 32 MRSA isolates.

Conclusion: MRSA isolates exposed to sub-MICs of the antibiotics daptomycin and linezolid were observed to form biofilms at varying levels or to lose their ability to form biofilms. The induction, reduction or eradication of biofilm depended on the type of antibiotic and the MRSA isolate.

Objectives: Ayurvedic texts mention the use of Aegle marmelos fruit in colitis and other gastrointestinal ailments. The polyphenolic contents of the fruit, however, have poor bioavailability, limiting their therapeutic use. The study aimed to develop and optimise the A. marmelos fruit extract-phospholipid (AMEP) complex to improve the oral bioavailability of the A. marmelos extract (AME), and compare the in vivo effect of AME and AMEP in dextran sulfate sodium (DSS)-induced ulcerative colitis in rats.

Materials and methods: The research work is the first of its kind to use a hydroalcoholic extract of A. marmelos fruit in the preparation of phospholipid complexes for ameliorating UC. The complexes were prepared using the solvent evaporation method and optimised by Box-Behnken design. The work compares the in vivo activity of plain AME, its phospholipid complexes, and the standard drug (mesalamine) in the alleviation of chemical-induced colitis in rats. AMEP was optimised using response surface methodology by Box-Behnken design. AMEP was characterised using scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, zeta analysis, and particle size analysis. A DSS-induced rat model was used in vivo studies to mimic ulcerative colitis. The pathogenesis of the disease was assessed by evaluating the levels of oxidative stress markers [nitric oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD) activity], cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], disease activity index, colon length, and histopathology.

Results: The characterization confirmed the formation of AMEP, having a particle size of 673.6±4.30 nm, polydispersity index of 0.224±0.010, and zeta potential of -42.6 mV±0.51. The NO, MDA, TNF-α, and IL-6 levels were significantly reduced (p<0.0001, p<0.005, p<0.0001, p<0.01), and the SOD level was significantly increased (p<0.05) in AMEP-treated groups compared to the AME-treated groups.

Conclusion: These findings suggessts that AMEP has a powerful potential to reduce the levels of oxidative markers and inflammatory cytokines, making it a promising treatment for ulcerative colitis.

Objectives: The aim of this study was to comprehensively investigate the phytochemical composition, including essential oils, fatty acids, and phenolic constituents, and to evaluate the antioxidant and α-amylase inhibitory activities of Scabiosa pseudograminifolia Hub.-Mor. (Caprifoliaceae), an endemic species growing in Sivas province of Türkiye. The plant materials were processed to obtain essential oils, and n-hexane, methanol, and aqueous extracts for chemical and biological evaluations.

Materials and methods: Essential oils were obtained by hydrodistillation. Extracts were prepared using n-hexane, methanol, and water through maceration. The chemical compositions of the essential oil and fatty acids were analyzed using gas chromatography (GC)-mass spectrometry and GC-flame ionization detector (FID). Phenolic compounds were identified by reverse phase high performance liquid chromatography. Total phenolic and flavonoid contents, antioxidant activity [DPPH, Trolox Equivalent Antioxidant Capacity (TEAC), β-carotene bleaching, and Oxygen Radical Absorbance Capacity assays], and α-amylase inhibitory activity were all evaluated using spectrophotometric methods.

Results: Hexadecanoic acid (30.2%) and linalool (15.6%) were the main volatile compounds in the essential oil of S. pseudograminifolia. (Z)-3-Hexenal was the dominant leaf and flower volatile. The primary fatty acids were nonadecanoic and hexadecanoic acids. The aqueous extract exhibited the highest total phenolic (0.52±0.01 mg gallic acid equivalent/_gextract) and flavonoid (0.081±0.002 mg quercetin equivalent/_gextract) contents. Among the tested samples, the essential oil showed the strongest TEAC value (2.39±0.15 mM), while the aqueous extract demonstrated potent antioxidant activity in DPPH (IC₅₅: 0.16±0.04 mg/mL) and β-carotene bleaching assays (inhibitory concentration₅₅: 0.730±0.001 mg/mL). The α-amylase inhibition levels of the extracts were found to be relatively low. Chlorogenic acid was the predominant phenolic compound.

Conclusion: This study presents the first phytochemical and biological investigation of S. pseudograminifolia Hub.-Mor., an endemic species from Türkiye. Essential oil analysis revealed hexadecanoic acid and linalool as major constituents, while nonadecanoic and hexadecanoic acids were predominant among the fatty acids. The methanol extract showed strong antioxidant activity, and chlorogenic acid was identified as a key phenolic compound. These findings support the potential of this species as a valuable source of natural antioxidants.

Objectives: The multidisciplinary team approach improves adverse drug reaction (ADR) reporting and management. Our study aims to integrate a pharmacovigilance (PV) and Response Team within the general medicine department to improve ADR reporting and management.

Materials and methods: We conducted a prospective cross-sectional study for seven months in four general medicine wards. We proposed a PV and response unit team (PRUT), comprising a nursing student, and a Doctor of Pharmacy (intern). After the team received interventional educational training, we integrated them with the physician and head nurse of each general medicine inpatient ward. We then evaluated the effectiveness of the team in ADR reporting and management using a feedback survey.

Results: In this study, comorbidities (30.69%) and polypharmacy (≥5 drugs) (26.25%) were major predisposing factors. Among drug-related problems in 125 patients, inappropriate drug use (28.80%) and unclear dose timing (21.60%) were predominant. Gastrointestinal disorders were common (44.73%), with dose adjustment being the top management strategy (36.84%). Over 71% supported the PRUT for improving patient safety and reducing medication errors, noting high effectiveness in consultation (85.92%) and in reducing the ADR reporting burden (87.32%). There is a statistically significant association between the level of agreement on the effectiveness of PRUT among healthcare professionals (p<0.01). Most healthcare professionals agreed on PRUT's effectiveness without any reports of low agreement levels.

Conclusion: The PRUT effectively reported and managed ADRs. A multidisciplinary approach improves ADR reporting and management.